Biological aging of different blood cell types - Saara Marttila; Sonja Rajić; Joanna Ciantar; Jonathan K. L. Mak; Ilkka S. Junttila; Laura Kummola; Sara Hägg; Emma Raitoharju; Laura Kananen (GeroScience, 2024)
Biological age (BA) captures detrimental age-related changes. The best-known and most-used BA indicators include DNA methylation–based epigenetic clocks and telomere length (TL). The most common biological sample material for epidemiological aging studies, whole blood, is composed of different cell types. We aimed to compare differences in BAs between blood cell types and assessed the BA indicators’ cell type-specific associations with chronological age (CA). An analysis of DNA methylation–based BA indicators, including TL, methylation level at cg16867657 in ELOVL2 , as well as the Hannum, Horvath, DNAmPhenoAge, and DunedinPACE epigenetic clocks, was performed on 428 biological samples of 12 blood cell types. BA values were different in the majority of the pairwise comparisons between cell types, as well as in comparison to whole blood ( p < 0.05). DNAmPhenoAge showed the largest cell type differences, up to 44.5 years and DNA methylation-based TL showed the lowest differences. T cells generally had the "youngest" BA values, with differences across subsets, whereas monocytes had the "oldest" values. All BA indicators, except DunedinPACE, strongly correlated with CA within a cell type. Some differences such as DNAmPhenoAge-difference between naïve CD4 + T cells and monocytes were constant regardless of the blood donor's CA (range 20–80 years), while for DunedinPACE they were not. In conclusion, DNA methylation–based indicators of BA exhibit cell type–specific characteristics. Our results have implications for understanding the molecular mechanisms underlying epigenetic clocks and underscore the importance of considering cell composition when utilizing them as indicators for the success of aging interventions.

Cross-platform proteomics signatures of extreme old age - Eric R. Reed; Kevin B. Chandler; Prisma Lopez; Catherine E. Costello; Stacy L. Andersen; Thomas T. Perls; Mengze Li; Harold Bae; Mette Soerensen; Stefano Monti; Paola Sebastiani (GeroScience, 2024)

Association of sarcopenia with regional brain atrophy and white matter lesions in a general older population: the Hisayama Study - Takahiro Tajimi; Naoki Hirabayashi; Yoshihiko Furuta; Taro Nakazawa; Takanori Honda; Jun Hata; Tomoyuki Ohara; Mao Shibata; Takanari Kitazono; Yasuharu Nakashima; Toshiharu Ninomiya (GeroScience, 2024)

Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy - Steve Horvath; Ezequiel Lacunza; Martina Canatelli Mallat; Enrique L. Portiansky; Maria D. Gallardo; Robert T. Brooke; Priscila Chiavellini; Diana C. Pasquini; Mauricio Girard; Marianne Lehmann; Qi Yan; Ake T. Lu; et al. (GeroScience, 2024)
Several studies have indicated that interrupted epigenetic reprogramming using Yamanaka transcription factors (OSKM) can rejuvenate cells from old laboratory animals and humans. However, the potential of OSKM-induced rejuvenation in brain tissue has been less explored. Here, we aimed to restore cognitive performance in 25.3-month-old female Sprague–Dawley rats using OSKM gene therapy for 39 days. Their progress was then compared with the cognitive performance of untreated 3.5-month-old rats as well as old control rats treated with a placebo adenovector. The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation. In summary, the administration of Yamanaka genes via viral vectors rejuvenates the functional capabilities and the epigenetic landscape of the rat hippocampus.

Association between adult education, brain volume and dementia risk: longitudinal cohort study of UK Biobank participants - Jiayin Jin; Andrew Sommerlad; Naaheed Mukadam (GeroScience, 2024)
Less childhood education is a potentially modifiable risk factor for developing incident dementia but it is not known if education in later life is protective. We sought to add to previous work by testing the association between adult education and brain volume as well as exploring the impact of continuing adult education versus intermittent participation. We used data from participants of the UK Biobank cohort, with no prevalent dementia who were asked about adult education participation at baseline and at follow-up. Dementia status was ascertained from self-report or electronic health records. Cox proportional hazards models were built to estimate hazard ratios (HRs) between participation in adult education and dementia risk. In 499,337 participants aged between 40 and 69 at baseline with 13.2 years mean follow-up, in analyses adjusted for age, sex, education, deprivation, ethnicity, hypertension, diabetes, ethnicity, obesity, smoking, alcohol use, physical inactivity and social isolation, we replicated previous findings of a protective effect of adult education on dementia risk (HR 0.82, 95% CI 0.74–0.90, P < 0.001), and showed a trend towards protection against dementia if adult education was continued rather than intermittent. Additionally, adult education did not impact on total brain volume (coefficient − 657.4, 95% CI − 2795.1 to 1480.3, P = 0.547) but it was associated with increased hippocampal volume (coefficient 33.9, 95% CI 8.9 to 59.0, P = 0.008) indicating a potential mechanism for protection against dementia. We have added evidence indicating that continuing adult education participation may be beneficial, although numbers for this analysis were very small. Analysis of brain volume indicated that adult education may have a protective effect by preserving hippocampal size or slowing volume loss, in line with the cognitive reserve hypothesis.

Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant - Annika Traa; Aura A. Tamez González; Jeremy M. Van Raamsdonk (GeroScience, 2024)
The dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cell’s ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast, Drosophila and C. elegans . Disruption of the mitochondrial fission gene drp-1 drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with RNA interference clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels, food consumption or mitochondrial membrane potential. Disruption of mitophagy through RNA interference targeting pink-1 decreased the lifespan of daf-2;drp-1 worms suggesting that increased mitophagy contributes to their extended lifespan. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.

Body composition and aging: cross-sectional results from the INSPIRE study in people 20 to 93 years old - Marguerite Briand; Jeremy Raffin; Emmanuel Gonzalez-Bautista; Patrick Ritz; Gabor Abellan Van Kan; Fabien Pillard; Marie Faruch-Bilfeld; Sophie Guyonnet; Cédric Dray; Bruno Vellas; Philipe de Souto Barreto; Yves Rolland (GeroScience, 2024)
Aging is characterized by several major changes, including altered body composition, which is associated with numerous negative clinical consequences such as sarcopenia, osteoporosis, and frailty. The study is to evaluate body composition parameters depending on age and sex in a population ranging from the young adult to the very old, and to identify break points in the association between body composition and age. In this cross-sectional study, we included the enrolment population of the French INSPIRE-T prospective cohort, accounting for 915 subjects (62% female). Age ranged from 20 to 93 years, median age (years) was 63 (IQR 27). Body composition (lean mass, fat mass, and bone mineral content) was assessed with dual-X-ray absorptiometry (DXA). Different break points in the relationship between age and body composition variables in males and females were identified using a segmented regression analysis adjusted on physical activity, nutritional status, educational level, and comorbidities. Lean mass decreased from the age of 55 years for males (CI 95% 44–66) and 31 years for females (CI 95% 23–39). For fat mass, we observed a trend towards an increase with age for males. For females, we observed an increase with age up to age 75 (CI 95% 62–86), followed by a decreasing trend. In this study, we described the relationship between body composition and age as a function of sex, establishing a foundation for further studies on predictive biomarkers of age-related body composition alteration.

Longitudinal relationships between depressive symptoms, functional impairment, and physical activity in later late life - Lisa Y. Xiong; Madeline Wood Alexander; Hugo Cogo-Moreira; Che-Yuan Wu; Michael Eid; Nathan Herrmann; Damien Gallagher; Jodi D. Edwards; Krista L. Lanctôt; Susan Marzolini; David A. Bennett; Jennifer S. Rabin; et al. (GeroScience, 2024)

Relationship between frailty and executive function by age and sex in the Canadian Longitudinal Study on Aging - Molly K. Courish; Myles W. O’Brien; Selena P. Maxwell; Said Mekari; Derek S. Kimmerly; Olga Theou (GeroScience, 2024)

Revisiting the “Timed Up and Go” test: a 12-s cut-off can predict Hospitalization Associated Functional Decline in older adults - Orly Gatenio-Hefling; Roy Tzemah-Shahar; Kfir Asraf; Omer Dilian; Efrat Gil; Maayan Agmon (GeroScience, 2024)
Early detection of functional decline, a major risk among hospitalized older adults, can facilitate interventions that could significantly reduce it. We aimed to examine the contribution of the Timed Up and Go (TUG) test in predicting Hospitalization Associated Functional Decline (HAFD) among older adults, able to independently ambulate before admission. We used a cross-sectional study design; a total of 310 older adults (age ≥ 65) hospitalized in internal medicine wards between December 2018 and August 2020 were included; exclusion criteria were inability to ambulate, a diagnosis restricting mobility, hospitalization for end-of-life care, or impaired cognition. The Modified Barthel Index was used to assess HAFD; it was administered at admission to evaluate patients’ independence in activities of daily living 2 weeks prior hospitalization, and at discharge. The TUG test was performed on admission and to predict significant functional decline (defined by a reduction of three points or more in the Modified Barthel Index), while accounting for demographics, length of hospitalization, comorbidity burden (Charlson’s comorbidity index), and cognitive function (ALFI-MMSE). Participants were divided into three groups according to their TUG score—under or over a cut-off score of 12 s, or inability to complete the test. Adjusting for age, comorbidity, cognitive ability, and duration of hospitalization, the group that performed the test in less than 12 s showed no statistically significant change in the Modified Barthel Index, therefore no significant HAFD. The other groups showed a statistically significant decline in function. Risk for significant HAFD is currently underestimated in clinical settings, limited to subjective assessment, and underused in the context of implementing early interventions to prevent HAFD. The TUG may support screening for those at risk of hospitalizing-associated functional decline and could help identify patients suitable for preventative interventions.

White matter microstructural integrity as a key to effective propagation of gamma entrainment in humans - Yeseung Park; Euisuk Yoon; Jieun Park; Jun Sung Kim; Ji Won Han; Jong Bin Bae; Sang-Su Kim; Do-Won Kim; Se Joon Woo; Jaehyeok Park; Wheesung Lee; Seunghyup Yoo; et al. (GeroScience, 2024)
Gamma entrainment through sensory stimulation has the potential to reduce the pathology of Alzheimer’s disease in mouse models. However, clinical trials in Alzheimer’s disease (AD) patients have yielded inconsistent results, necessitating further investigation. This single-center pre-post intervention study aims to explore the influence of white matter microstructural integrity on gamma rhythm propagation from the visual cortex to AD-affected regions in 31 cognitively normal volunteers aged ≥ 65. Gamma rhythm propagation induced by optimal FLS was measured. Diffusion tensor imaging was employed to assess the integrity of white matter tracts of interest. After excluding 5 participants with a deficit in steady-state visually evoked potentials, 26 participants were included in the final analysis. In the linear regression analyses, gamma entrainment was identified as a significant predictor of gamma propagation ( p < 0.001). Furthermore, the study identified white matter microstructural integrity as a significant predictor of gamma propagation by flickering light stimulation ( p < 0.05), which was specific to tracts that connect occipital and temporal or frontal regions. These findings indicate that, despite robust entrainment of gamma rhythms in the visual cortex, their propagation to other regions may be impaired if the microstructural integrity of the white matter tracts connecting the visual cortex to other areas is compromised. Consequently, our findings have expanded our understanding of the prerequisites for effective gamma entrainment and suggest that future clinical trials utilizing visual stimulation for gamma entrainment should consider white matter tract microstructural integrity for candidate selection and outcome analysis.

Correction to: Lifespan effects in male UM‑HET3 mice treated with sodium thiosulfate, 16‑hydroxyestriol, and late‑start canagliflozin - Richard A. Miller; David E. Harrison; Gino A. Cortopassi; Ishmael Dehghan; Elizabeth Fernandez; Michael Garratt; John G. Geisler; Brett C. Ginsburg; Melissa L. Han; Nisi Jiang; Catherine C. Kaczorowski; Navasuja Kumar; et al. (GeroScience, 2024)

Exploring the complexity of EEG patterns in Parkinson’s disease - Lorenzo Nucci; Francesca Miraglia; Chiara Pappalettera; Paolo Maria Rossini; Fabrizio Vecchio (GeroScience, 2024)

Maternal α-casein deficiency extends the lifespan of offspring and programmes their body composition - Andreas F. Kolb; Claus Mayer; Alina Zitskaja; Linda Petrie; Khulod Hasaballah; Claire Warren; Ailsa Carlisle; Simon Lillico; Bruce Whitelaw (GeroScience, 2024)
Early nutrition has significant effects on physiological outcomes during adult life. We have analysed the effect of maternal α-casein (CSN1S1) deficiency on the physiological fate of dams and their offspring. α-casein deficiency reduces maternal milk protein concentration by more than 50% and attenuates the growth of pups to 27% ( p < 0.001) of controls at the point of weaning. This is associated with a permanent reduction in adult body weight (− 31% at 25 weeks). Offspring nursed by α-casein deficient dams showed a significantly increased lifespan (+ 20%, χ 2 : 10.6; p = 0.001). Liver transcriptome analysis of offspring nursed by α-casein deficient dams at weaning revealed gene expression patterns similar to those found in dwarf mice (reduced expression of somatotropic axis signalling genes, increased expression of xenobiotic metabolism genes). In adult mice, the expression of somatotropic axis genes returned to control levels. This demonstrates that, in contrast to dwarf mice, attenuation of the GH-IGF signalling axis in offspring nursed by α-casein deficient dams is transient, while the changes in body size and lifespan are permanent. Offspring nursed by α-casein deficient dams showed permanent changes in body composition. Absolute and relative adipose tissue weights ( p < 0.05), the percentage of body fat ( p < 0.001) as well as adipocyte size in epididymal white adipose tissue are all reduced. Serum leptin levels were 25% of those found in control mice ( p < 0.001). Liver lipid content and lipid composition were significantly altered in response to postnatal nutrition. This demonstrates the nutrition in early life programmes adult lipid metabolism, body composition and lifespan.

Boosting working memory in the elderly: driving prefrontal theta–gamma coupling via repeated neuromodulation - Lukas Diedrich; Hannah I. Kolhoff; Clara Bergmann; Mathias Bähr; Andrea Antal (GeroScience, 2024)
The escalating global burden of age-related neurodegenerative diseases and associated healthcare costs necessitates innovative interventions to stabilize or enhance cognitive functions. Deficits in working memory (WM) are linked to alterations in prefrontal theta–gamma cross-frequency coupling. Low-intensity transcranial alternating current stimulation (tACS) has emerged as a non-invasive, low-cost approach capable of modulating ongoing oscillations in targeted brain areas through entrainment. This study investigates the impact of multi-session peak-coupled theta–gamma cross-frequency tACS administered to the dorsolateral prefrontal cortex (DLPFC) on WM performance in older adults. In a randomized, sham-controlled, triple-blinded design, 77 participants underwent 16 stimulation sessions over six weeks while performing n -back tasks. Signal detection measures revealed increased 2-back sensitivity and robust modulations of response bias, indicating improved WM and decision-making adaptations, respectively. No effects were observed in the 1-back condition, emphasizing dependencies on cognitive load. Repeated tACS reinforces behavioral changes, indicated by increasing effect sizes. This study supports prior research correlating prefrontal theta–gamma coupling with WM processes and provides unique insights into the neurocognitive benefits of repeated tACS intervention. The well-tolerated and highly effective multi-session tACS intervention among the elderly underscores its therapeutic potential in vulnerable populations.

The mouse Social Frailty Index (mSFI): a novel behavioral assessment for impaired social functioning in aging mice - Charles W. Collinge; Maria Razzoli; Rachel Mansk; Seth McGonigle; Dudley W. Lamming; Christina A. Pacak; Ingrid van der Pluijm; Laura Niedernhofer; Alessandro Bartolomucci (GeroScience, 2024)
Various approaches exist to quantify the aging process and estimate biological age on an individual level. Frailty indices based on an age-related accumulation of physical deficits have been developed for human use and translated into mouse models. However, declines observed in aging are not limited to physical functioning but also involve social capabilities. The concept of “social frailty” has been recently introduced into human literature, but no index of social frailty exists for laboratory mice yet. To fill this gap, we developed a mouse Social Frailty Index (mSFI) consisting of seven distinct assays designed to quantify social functioning which is relatively simple to execute and is minimally invasive. Application of the mSFI in group-housed male C57BL/6 mice demonstrated a progressively elevated levels of social frailty through the lifespan. Conversely, group-housed females C57BL/6 mice manifested social frailty only at a very old age. Female mice also showed significantly lower mSFI score from 10 months of age onward when compared to males. We also applied the mSFI in male C57BL/6 mice under chronic subordination stress and in chronic isolation, both of which induced larger increases in social frailty compared to age-matched group-housed males. Lastly, we show that the mSFI is enhanced in mouse models that show accelerated biological aging such as progeroid Ercc1 −/Δ and Xpg − / − mice of both sexes compared to age matched littermate wild types. In summary, the mSFI represents a novel index to quantify trajectories of biological aging in mice and may help elucidate links between impaired social behavior and the aging process.

Association between dietary (poly)phenol intake and the ATHLOS Healthy Ageing Scale in the Polish arm of the HAPIEE study - Urszula Stepaniak; Giuseppe Grosso; Maciej Polak; Barbara Gradowicz-Prajsnar; Magdalena Kozela; Martin Bobak; Albert Sanchez-Niubo; Denes Stefler; Josep Maria Haro; Andrzej Pająk (GeroScience, 2024)
Inverse association between (poly)phenol intake and age-related disorders has been demonstrated; however, little is known whether they affect comprehensively assessed healthy aging. The aim of this study was to evaluate the associations between the intake of (poly)phenol (including selected classes and subclasses) and healthy aging scores related to biopsychosocial aspects of health and functioning. A cross-sectional study was performed using data on 9774 randomly selected citizens of Krakow (Poland) who were 45–69 years of age. Dietary (poly)phenol intake was evaluated using a food frequency questionnaire and matching food consumption data with the Phenol-Explorer database. The healthy aging scores were estimated from the ATHLOS Healthy Ageing Scale (HAS) developed by the Ageing Trajectories of Health-Longitudinal Opportunities and Synergies (ATHLOS) consortium. Beta coefficients were calculated using multivariable linear regression models. In multivariable adjusted models, there were significant positive associations between the ATHLOS HAS score and intake of total (poly)phenols ( b per increase of 100 mg/day = 0.081; 95% CI, 0.050; 0.112) and among main classes of (poly)phenols with phenolic acids ( b = 0.139; 95% CI, 0.098; 0.180). Intake of remaining classes of (poly)phenols (flavonoids, lignans, stilbenes, and others) was not related to the ATHLOS HAS score. Among individual classes studied, hydroxycinnamic acids, flavonols, flavones, and dihydrochalcones were associated with better healthy aging. The findings suggest the beneficial effect of total dietary (poly)phenol and some classes and subclasses of (poly)phenol intake in terms of healthy aging in Poland. These findings should be confirmed in other settings and with prospective data.

Phosphodiesterase 9A inhibition improves aging-related increase in pulmonary vascular resistance in mice - Vadym Buncha; Katie Anne Fopiano; Liwei Lang; Daria V. Ilatovskaya; Alexander Verin; Zsolt Bagi (GeroScience, 2024)

Association between inflammatory markers, body composition and frailty in home-dwelling elderly: an 8-year follow-up study - Pia Bålsrud; Stine M. Ulven; Inger Ottestad; Kjetil Retterstøl; Ursula Schwab; Kirsten B. Holven (GeroScience, 2024)
Frailty has been linked to inflammation and changes in body composition, but the findings are inconsistent. To explore this, we used the Frailty Index (FI) definition to (1) investigate the association between levels of inflammatory markers (baseline) and change in FI score after 8 years of follow-up and (2) investigate the longitudinal associations between inflammatory markers, body composition, and frailty. Home-dwelling elderly (≥ 70 years) were invited to participate in the study and re-invited to a follow-up visit 8 years later. This study includes a total of 133 participants. The inflammatory markers included were high-sensitive C-reactive protein (hs-CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and glycoprotein acetyls (Gp-acetyls). We used the body composition markers fat mass, fat-free mass, and waist circumference. The FI score consisted of 38 variables. Additional clinical assessments such as blood pressure and body mass index (BMI), as well as information about daily medications, were collected at both visits. Linear regression model and Spearman’s rank correlation were used to investigate associations. We showed that the FI score increased after 8 years, and participants with higher hs-CRP levels at baseline had the largest change in the FI score. Changes in fat mass were significantly correlated with changes in hs-CRP and IL-6, and changes in waist circumference were significantly correlated with changes in TNF-α. The use of drugs increased during the 8 years of follow-up, which may have attenuated the associations between inflammation and frailty. However, elevated concentrations of hs-CRP in the elderly may be associated with an increased risk of frailty in subsequent years.

High rate of potentially inappropriate medication use in older people: a case–control study - András Érszegi; Dezső Csupor; Gabriella Bodó; Zsófia Engi; Muh. Akbar Bahar; Mária Matuz; Ria Benkő; Zoltán Pető; Réka Viola (GeroScience, 2024)
Annually, 172 million fall events cause temporary or permanent impairment in older adults, and this number is increasing. Contributing factors that increase the risk for falls include age, polypharmacy, and malnutrition. This study evaluated medications mainly included in the EU(7)-PIM (potentially inappropriate medication) list. From March 21, 2022, to July 6, 2022, 945 patients who experienced a fall and visited the Department of Emergency Medicine at the Albert Szent-Györgyi Health Centre of the University of Szeged in Hungary. Data from 886 patients were collected (study group). The control group included 1364 patient data collected from three general practice in Hungary. The use of ≥ 2 EU(7)-PIM drugs was found to be associated with increased risk for falls (adjusted odds ratio [AOR], 1.38; 95% confidence interval [CI] 1.01–1.88). Piracetam (AOR, 1.81; 95% CI, 1.28–2.57) and trimetazidine (AOR, 1.62; 95% CI, 1.17–2.24) were associated with increased risk for falls. Doxazosin was associated with a low risk for falls (AOR, 0.59; 95% CI, 0.41–0.86). Tiapride (AOR, 3.54; 95% CI, 1.75–7.17), gliclazide (AOR, 1.57; 95% CI, 1.02–2.43), and vinpocetine (AOR, 1.95; 95% CI, 1.29–2.95) are not included in the EU(7)-PIM list; however, they are associated with increased risk for falls. Long-acting benzodiazepines (AOR, 1.79; 95% CI, 1.20–2.68), antidepressants (AOR, 1.89; 95% 95% CI, 1.37–2.61), serotonin–norepinephrine reuptake inhibitor (AOR, 2.82; 95% CI, 1.41–5.67; p < 0.01), and selective serotonin reuptake inhibitor (AOR, 1.88; 95% CI, 1.24–2.85) were also associated with increased risk for falls. However, Z-drugs were associated with a low risk for falls (AOR, 0.57; 95% CI, 0.36–0.92). With the help of this tool, trimetazidine and piracetam are filtered as EU(7)-PIM drugs associated with increased risk for falls.

Phylloquinone improves endothelial function, inhibits cellular senescence, and vascular inflammation - Anna Kieronska-Rudek; Agnieszka Kij; Anna Bar; Anna Kurpinska; Tasnim Mohaissen; Marek Grosicki; Marta Stojak; Magdalena Sternak; Elżbieta Buczek; Bartosz Proniewski; Kamil Kuś; Joanna Suraj-Prazmowska; et al. (GeroScience, 2024)
Phylloquinon (PK) and menaquinones (MK) are both naturally occurring compounds belonging to vitamin K group. Present study aimed to comprehensively analyze the influence of PK in several models of vascular dysfunction to determine whether PK has vasoprotective properties, similar to those previously described for MK. Effects of PK and MK on endothelial dysfunction were studied in ApoE/LDLR −/− mice in vivo, in the isolated aorta incubated with TNF, and in vascular cells as regard inflammation and cell senescence (including replicative and stress-induced models of senescence). Moreover, the vascular conversion of exogenous vitamins to endogenous MK-4 was analyzed. PK, as well as MK, given for 8 weeks in diet (10 mg/kg) resulted in comparable improvement in endothelial function in the ApoE/LDLR −/− mice. Similarly, PK and MK prevented TNF-induced impairment of endothelium-dependent vasorelaxation in the isolated aorta. In in vitro studies in endothelial and vascular smooth muscle cells, we identified that both PK and MK displayed anti-senescence effects via decreasing DNA damage while in endothelial cells anti-inflammatory activity was ascribed to the modulation of NFκB activation. The activity of PK and MK was comparable in terms of their effect on senescence and inflammation. Presence of endogenous synthesis of MK-4 from PK in aorta and endothelial and smooth muscle cells suggests a possible involvement of MK in vascular effects of PK. In conclusion, PK and MK display comparable vasoprotective effects, which may be ascribed, at least in part, to the inhibition of cell senescence and inflammation. The vasoprotective effect of PK in the vessel wall can be related to the direct effects of PK, as well as to the action of MK formed from PK in the vascular wall.

Correction to: Molecular cross‑talk between long COVID‑19 and Alzheimer’s disease - Magdalena Pszczołowska; Kamil Walczak; Weronika Miśków; Katarzyna Antosz; Joanna Batko; Julia Karska; Jerzy Leszek (GeroScience, 2024)

Klotho enhances diastolic function in aged hearts through Sirt1-mediated pathways - Nastaran Daneshgar; Renny Lan; Michael Regnier; Samuel G. Mackintosh; Ravinandan Venkatasubramanian; Dao-Fu Dai (GeroScience, 2024)

Integrated renal and sympathetic mechanisms underlying the development of sex- and age-dependent hypertension and the salt sensitivity of blood pressure - Alissa A. Frame; Kayla M. Nist; Kiyoung Kim; Franco Puleo; Jesse D. Moreira; Hailey Swaldi; James McKenna; Richard D. Wainford (GeroScience, 2024)
Aging is a non-modifiable understudied risk factor for hypertension. We hypothesized that sympathetically mediated activation of renal sodium reabsorption drives age-dependent hypertension and the salt sensitivity of blood pressure (BP). Using 3-, 8-, and 16-month-old male and female Sprague–Dawley rats as a model of normal aging, we assessed BP, indices of sympathetic tone, and the physiological responses to acute and chronic sodium challenge including sodium chloride cotransporter (NCC) regulation. The effects of renal nerve ablation and NCC antagonism were assessed in hypertensive male rats. We observed sex-dependent impaired renal sodium handling (24 h sodium balance (meq), male 3-month 0.36 ± 0.1 vs. 16-month 0.84 ± 0.2; sodium load excreted during 5% bodyweight isotonic saline volume expansion (%) male 3-month 77 ± 5 vs. 16-month 22 ± 8), hypertension (MAP (mmHg) male 3-month 123 ± 4 vs. 16-month 148 ± 6), and the salt sensitivity of BP in aged male, but not female, rats. Attenuated sympathoinhibitory afferent renal nerve (ARN) responses contributed to increased sympathetic tone and hypertension in male rats. Increased sympathetic tone contributes to renal sodium retention, in part through increased NCC activity via a dysfunctional with-no-lysine kinase-(WNK) STE20/SPS1-related proline/alanine-rich kinase signaling pathway, to drive hypertension and the salt sensitivity of BP in aged male rats. NCC antagonism and renal nerve ablation, which reduced WNK dysfunction and decreased NCC activity, attenuated age-dependent hypertension in male Sprague–Dawley rats. The contribution of an impaired sympathoinhibitory ARN reflex to sex- and age-dependent hypertension in an NCC-dependent manner, via an impaired WNK1/WNK4 dynamic, suggests this pathway as a mechanism-based target for the treatment of age-dependent hypertension.

Proteomic analysis of lung responses to SARS-CoV-2 infection in aged non-human primates: clinical and research relevance - Andreu Garcia-Vilanova; Anna Allué-Guardia; Nadine M. Chacon; Anwari Akhter; Dhiraj Kumar Singh; Deepak Kaushal; Blanca I. Restrepo; Larry S. Schlesinger; Joanne Turner; Susan T. Weintraub; Jordi B. Torrelles (GeroScience, 2024)

Association of physical function with connectivity in the sensorimotor and dorsal attention networks: why examining specific components of physical function matters - Madeline C. Boyd; Jonathan H. Burdette; Michael E. Miller; Robert G. Lyday; Christina E. Hugenschmidt; W. Jack Rejeski; Sean L. Simpson; Laura D. Baker; Chal E. Tomlinson; Stephen B. Kritchevsky; Paul J. Laurienti (GeroScience, 2024)
Declining physical function with aging is associated with structural and functional brain network organization. Gaining a greater understanding of network associations may be useful for targeting interventions that are designed to slow or prevent such decline. Our previous work demonstrated that the Short Physical Performance Battery (eSPPB) score and body mass index (BMI) exhibited a statistical interaction in their associations with connectivity in the sensorimotor cortex (SMN) and the dorsal attention network (DAN). The current study examined if components of the eSPPB have unique associations with these brain networks. Functional magnetic resonance imaging was performed on 192 participants in the BNET study, a longitudinal and observational trial of community-dwelling adults aged 70 or older. Functional brain networks were generated for resting state and during a motor imagery task. Regression analyses were performed between eSPPB component scores (gait speed, complex gait speed, static balance, and lower extremity strength) and BMI with SMN and DAN connectivity. Gait speed, complex gait speed, and lower extremity strength significantly interacted with BMI in their association with SMN at rest. Gait speed and complex gait speed were interacted with BMI in the DAN at rest while complex gait speed, static balance, and lower extremity strength interacted with BMI in the DAN during motor imagery. Results demonstrate that different components of physical function, such as balance or gait speed and BMI, are associated with unique aspects of brain network organization. Gaining a greater mechanistic understanding of the associations between low physical function, body mass, and brain physiology may lead to the development of treatments that not only target specific physical function limitations but also specific brain networks.

Lifelong longitudinal assessment of the contribution of multi-fractal fluctuations to heart rate and heart rate variability in aging mice: role of the sinoatrial node and autonomic nervous system - Motahareh Moghtadaei; Syevda Tagirova; Ismayil Ahmet; Jack Moen; Edward G. Lakatta; Robert A. Rose (GeroScience, 2024)

A systematic review of diet and medication use among centenarians and near-centenarians worldwide - Zhaoli Dai; Sue Yi Lee; Srishti Sharma; Shahid Ullah; Edwin C. K. Tan; Henry Brodaty; Aletta E. Schutte; Perminder S. Sachdev (GeroScience, 2024)
Centenarians represent a phenomenon of successful aging. This systematic review aimed to understand lifestyles and health practices, focusing on diet and medication use for healthy longevity in community-based adults 95 years or over. Medline, CINAHL, Scopus, and gray literature were searched from 1 January 2000 to 10 December 2022. Study quality was assessed using the Modified Newcastle-Ottawa Scale (mNOS). Pooled prevalence [%; 95% confidence interval] for categorical variables and pooled mean for continuous variables were estimated for demographics, weight status, lifestyle factors, medications, and health conditions. Of 3392 records screened, 34 studies were included in the review, and 71% (24/34) met the 6/8 criteria in mNOS. Centenarians/near-centenarians’ ages ranged from 95 to 118 years, with 75% (71–78%) female and 78% (68–88%) living in rural areas. They had an overall healthy lifestyle: current smoking (7%; 5–9%), drinking (23%; 17–30%), normal weight (52%; 42–61%), overweight (14%; 8–20%), physical activity (23%; 20–26%), and sleep satisfaction (68%; 65–72%). Diet averaged 59.6% carbohydrate, 18.5% protein, and 29.3% fat; over 60% consumed a diverse diet, and < 20% preferred salty food, contributing to lower mortality risks and functional decline. About half used antihypertensives (49%; 14–84%) or other cardiovascular drugs (48%; 24–71%), with an average of 4.6 medications. Common health issues included impaired basic activities of daily living (54%; 33–74%), hypertension (43%; 21–65%), and dementia (41%; 23–59%). The findings of this systemic review underscore the pivotal role of dietary practice and weight management in healthcare strategies to promote healthy ageing. It also recognises rural living styles and sleep hygiene as potential factors contributing to healthy longevity.

The performance of metabolomics-based prediction scores for mortality in older patients with solid tumors - Yara van Holstein; Simon P. Mooijaart; Mathijs van Oevelen; Floor J. van Deudekom; Dina Vojinovic; Daniele Bizzarri; Erik B. van den Akker; Raymond Noordam; Joris Deelen; Diana van Heemst; Nienke A. de Glas; Cynthia Holterhues; et al. (GeroScience, 2024)
Prognostic information is needed to balance benefits and risks of cancer treatment in older patients. Metabolomics-based scores were previously developed to predict 5- and 10-year mortality (MetaboHealth) and biological age (MetaboAge). This study aims to investigate the association of MetaboHealth and MetaboAge with 1-year mortality in older patients with solid tumors, and to study their predictive value for mortality in addition to established clinical predictors. This prospective cohort study included patients aged ≥ 70 years with a solid malignant tumor, who underwent blood sampling and a geriatric assessment before treatment initiation. The outcome was all-cause 1-year mortality. Of the 192 patients, the median age was 77 years. With each SD increase of MetaboHealth, patients had a 2.32 times increased risk of mortality (HR 2.32, 95% CI 1.59–3.39). With each year increase in MetaboAge, there was a 4% increased risk of mortality (HR 1.04, 1.01–1.07). MetaboHealth and MetaboAge showed an AUC of 0.66 (0.56–0.75) and 0.60 (0.51–0.68) for mortality prediction accuracy, respectively. The AUC of a predictive model containing age, primary tumor site, distant metastasis, comorbidity, and malnutrition was 0.76 (0.68–0.83). Addition of MetaboHealth increased AUC to 0.80 (0.74–0.87) ( p = 0.09) and AUC did not change with MetaboAge (0.76 (0.69–0.83) ( p = 0.89)). Higher MetaboHealth and MetaboAge scores were associated with 1-year mortality. The addition of MetaboHealth to established clinical predictors only marginally improved mortality prediction in this cohort with various types of tumors. MetaboHealth may potentially improve identification of older patients vulnerable for adverse events, but numbers were too small for definitive conclusions. The TENT study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22–10-2019.

Coffee consumption and cardiometabolic health: a comprehensive review of the evidence - Zoltan Ungvari; Setor K. Kunutsor (GeroScience, 2024)
This review provides a comprehensive synthesis of longitudinal observational and interventional studies on the cardiometabolic effects of coffee consumption. It explores biological mechanisms, and clinical and policy implications, and highlights gaps in the evidence while suggesting future research directions. It also reviews evidence on the causal relationships between coffee consumption and cardiometabolic outcomes from Mendelian randomization (MR) studies. Findings indicate that while coffee may cause short-term increases in blood pressure, it does not contribute to long-term hypertension risk. There is limited evidence indicating that coffee intake might reduce the risk of metabolic syndrome and non-alcoholic fatty liver disease. Furthermore, coffee consumption is consistently linked with reduced risks of type 2 diabetes (T2D) and chronic kidney disease (CKD), showing dose-response relationships. The relationship between coffee and cardiovascular disease is complex, showing potential stroke prevention benefits but ambiguous effects on coronary heart disease. Moderate coffee consumption, typically ranging from 1 to 5 cups per day, is linked to a reduced risk of heart failure, while its impact on atrial fibrillation remains inconclusive. Furthermore, coffee consumption is associated with a lower risk of all-cause mortality, following a U-shaped pattern, with the largest risk reduction observed at moderate consumption levels. Except for T2D and CKD, MR studies do not robustly support a causal link between coffee consumption and adverse cardiometabolic outcomes. The potential beneficial effects of coffee on cardiometabolic health are consistent across age, sex, geographical regions, and coffee subtypes and are multi-dimensional, involving antioxidative, anti-inflammatory, lipid-modulating, insulin-sensitizing, and thermogenic effects. Based on its beneficial effects on cardiometabolic health and fundamental biological processes involved in aging, moderate coffee consumption has the potential to contribute to extending the healthspan and increasing longevity. The findings underscore the need for future research to understand the underlying mechanisms and refine health recommendations regarding coffee consumption.

Genetic and environmental determinants of bone quality: a cross-sectional analysis of the Hungarian Twin Registry - Szilvia Mészáros; Márton Piroska; Tamás Leel-Őssy; Ádám Domonkos Tárnoki; Dávid László Tárnoki; Zsófia Jokkel; Helga Szabó; Éva Hosszú; Emőke Csupor; Réka Kollár; Árpád Kézdi; Ádám G. Tabák; et al. (GeroScience, 2024)
There is abundant evidence that bone mineral content is highly heritable, while the heritability of bone quality (i.e. trabecular bone score [TBS] and quantitative ultrasound index [QUI]) is rarely investigated. We aimed to disentangle the role of genetic, shared and unique environmental factors on TBS and QUI among Hungarian twins. Our study includes 82 twin (48 monozygotic, 33 same-sex dizygotic) pairs from the Hungarian Twin Registry. TBS was determined by DXA, QUI by calcaneal bone ultrasound. To estimate the genetic and environmental effects, we utilized ACE-variance decomposition. For the unadjusted model of TBS, an AE model provided the best fit with > 80% additive genetic heritability. Adjustment for age, sex, BMI and smoking status improved model fit with 48.0% of total variance explained by independent variables. Furthermore, there was a strong dominant genetic effect (73.7%). In contrast, unadjusted and adjusted models for QUI showed an AE structure. Adjustments improved model fit and 25.7% of the total variance was explained by independent variables. Altogether 70–90% of the variance in QUI was related to additive genetic influences. We found a strong genetic heritability of bone quality in unadjusted models. Half of the variance of TBS was explained by age, sex and BMI. Furthermore, the adjusted model suggested that the genetic component of TBS could be dominant or an epistasis could be present. In contrast, independent variables explained only a quarter of the variance of QUI and the additive heritability explained more than half of all the variance.

Aging is associated with sex-specific alteration in the expression of genes encoding for neuroestradiol synthesis and signaling proteins in the mouse trigeminal somatosensory input - Álvaro Bautista-Abad; Nuria García-Magro; Daniel Pinto-Benito; Julio Eduardo Cáceres-Pajuelo; Carlos Vicente Alises; Danny Ganchala; Natalia Lagunas; Pilar Negredo; Luis Miguel García-Segura; Maria-Angeles Arevalo; Daniela Grassi (GeroScience, 2024)
Pain perception is influenced by sex and aging, with previous studies indicating the involvement of aromatase, the estradiol synthase enzyme, in regulating pain perception. Previous research has established the presence of aromatase in dorsal root ganglia sensory neurons and its role in modulating pain perception. The present study aims to explore the implications of aging and sex on the expression of aromatase and estrogen receptors in the trigeminal ganglion. The study examined mRNA levels of aromatase, ERs, and the androgen receptor (AR) in the trigeminal ganglion of 3-month-old and 27-month-old male and female mice, as well as 3-month-old mice from the four-core genotype (FCG) transgenic model. The latter facilitates the assessment of gonadal hormone and sex chromosome implications for sex-specific traits. Aromatase localization in the ganglion was further assessed through immunohistochemistry. Aromatase immunoreactivity was observed for the first time in sensory neurons within the trigeminal ganglion. Trigeminal ganglion gene expressions were detected for aromatase, ERs, and AR in both sexes. Aromatase, ERβ, and GPER gene expressions were higher in young males versus young females. Analyses of the FCG model indicated that sex differences depended solely on gonadal sex. The aging process induced an enhancement in the expression of aromatase, ERs, and AR genes across both sexes, culminating in a reversal of the previously observed gender-based differences. the potential impact of estrogen synthesis and signaling in the trigeminal ganglion on age and sex differences warrants consideration, particularly in relation to trigeminal sensory functions and pain perception. Graphical abstract Age and gonadal sex influence ERs, AR, and ARO levels in the trigeminal ganglion. Although somatosensory perception shows a decline in the elderly, the incidence of trigeminal neuralgia intensifies in aged adults and is predominantly prevalent in women relative to men. The increased expression of aromatase and estrogen receptors in aged female animals suggests that the modulatory influence that neuroestradiol exerts over the trigeminal somatosensory input, inclusive of pain, undergoes changes in elderly male and female individuals in a sex-specific manner.

Exploring the role of microRNAs as diagnostic and prognostic biomarkers in canine mammary tumors - Tiago Ferreira; Rui M. Gil da Costa; Francisca Dias; Adelina Gama; Vítor M. Gaspar; João F. Mano; Paula A. Oliveira; Rui Medeiros (GeroScience, 2024)
Canine mammary tumors (CMTs) represent a significant health concern in dogs, with a high incidence among intact female dogs. CMTs are a promising comparative model for human breast cancer, due to sharing several pathophysiological features. Additionally, CMTs have a strong genetic correlation with their human counterpart, including the expression of microRNAs (miRNAs). MiRNAs are a class of non-coding RNAs that play important roles in post-translational regulation of gene expression, being implicated in carcinogenesis, tumor progression, and metastasis. Moreover, miRNAs hold promise as diagnostic, prognostic, and metastatic biomarkers. Understanding the molecular mechanisms underlying CMTs is crucial for improving diagnosis, prognosis, and monitoring of treatments. Herein, we provide a comprehensive overview of the current knowledge on miRNAs in CMTs, highlighting their roles in carcinogenesis and their potential as biomarkers. Additionally, we highlight the current limitations and critically discuss the overarching challenges in this field, emphasizing the need for future research to translate miRNA findings into veterinary clinical practice.

Extended lifespan in female Drosophila melanogaster through late-life calorie restriction - Michael Li; Jacob Macro; Billy J. Huggins; Kali Meadows; Dushyant Mishra; Dominique Martin; Kavitha Kannan; Blanka Rogina (GeroScience, 2024)
Calorie restriction has many beneficial effects on healthspan and lifespan in a variety of species. However, how late in life application of caloric restriction can extend fly life is not clear. Here we show that late-life calorie restriction increases lifespan in female Drosophila melanogaster aged on a high-calorie diet. This shift results in rapid decrease in mortality rate and extends fly lifespan. In contrast, shifting female flies from a low- to a high-calorie diet leads to a rapid increase in mortality and shorter lifespan. These changes are mediated by immediate metabolic and physiological adaptations. One of such adaptation is rapid adjustment in egg production, with flies directing excess energy towards egg production when shifted to a high diet, or away from reproduction in females shifted to low-caloric diet. However, lifelong female fecundity reveals no associated fitness cost due to CR when flies are shifted to a high-calorie diet. In view of high conservation of the beneficial effects of CR on physiology and lifespan in a wide variety of organisms, including humans, our findings could provide valuable insight into CR applications that could provide health benefits later in life.

Impact of periodontal disease on cognitive disorders, dementia, and depression: a systematic review and meta-analysis - Vittorio Dibello; Carlo Custodero; Raffaele Cavalcanti; Domenico Lafornara; Antonio Dibello; Madia Lozupone; Antonio Daniele; Alberto Pilotto; Francesco Panza; Vincenzo Solfrizzi (GeroScience, 2024)

Associations between epigenetic aging and diabetes mellitus in a Swedish longitudinal study - Daniel Wikström Shemer; Shayan Mostafaei; Bowen Tang; Nancy L Pedersen; Ida K Karlsson; Tove Fall; Sara Hägg (GeroScience, 2024)
Diabetes mellitus type 2 (T2D) is associated with accelerated biological aging and the increased risk of onset of other age-related diseases. Epigenetic changes in DNA methylation levels have been found to serve as reliable biomarkers for biological aging. This study explores the relationship between various epigenetic biomarkers of aging and diabetes risk using longitudinal data. Data from the Swedish Adoption/Twin Study of Aging (SATSA) was collected from 1984 to 2014 and included 536 individuals with at least one epigenetic measurement. The following epigenetic biomarkers of aging were employed: DNAm PAI-1, DNAmTL, DunedinPACE, PCHorvath1, PCHorvath2, PCHannum, PCPhenoAge, and PCGrimAge. Firstly, longitudinal analysis of biomarker trajectories was done. Secondly, linear correlations between the biomarkers and time to diabetes were studied within individuals developing diabetes. Thirdly, Cox proportional hazards (PH) models were used to assess the associations between these biomarkers and time of diabetes diagnosis, with adjustments for chronological age, sex, education, smoking, blood glucose, and BMI. The longitudinal trajectories of the biomarkers revealed differences between individuals with and without diabetes. Smoothened average curves for DunedinPACE and DNAm PAI-1 were higher for individuals with diabetes around the age 60–70, compared to controls. Likewise, DunedinPACE and DNAm PAI-1 were higher closer to diabetes onset. However, no significant associations were found between the epigenetic biomarkers of aging and risk of diabetes in Cox PH models. Our findings suggest the potential value of developing epigenetic biomarkers specifically tailored to T2D, should we wish to model and explore the potential for predicting the disease.

Longitudinal fragility phenotyping contributes to the prediction of lifespan and age-associated morbidity in C57BL/6 and Diversity Outbred mice - Alison Luciano; Laura Robinson; Gaven Garland; Bonnie Lyons; Ron Korstanje; Andrea Di Francesco; Gary A. Churchill (GeroScience, 2024)
Aging studies in mammalian models often depend on natural lifespan data as a primary outcome. Tools for lifespan prediction could accelerate these studies and reduce the need for veterinary intervention. Here, we leveraged large-scale longitudinal frailty and lifespan data on two genetically distinct mouse cohorts to evaluate noninvasive strategies to predict life expectancy in mice. We applied a modified frailty assessment, the Fragility Index, derived from existing frailty indices with additional deficits selected by veterinarians. We developed an ensemble machine learning classifier to predict imminent mortality (95% proportion of life lived [95PLL]). Our algorithm represented improvement over previous predictive criteria but fell short of the level of reliability that would be needed to make advanced prediction of lifespan and thus accelerate lifespan studies. Highly sensitive and specific frailty-based predictive endpoint criteria for aged mice remain elusive. While frailty-based prediction falls short as a surrogate for lifespan, it did demonstrate significant predictive power and as such must contain information that could be used to inform the conclusion of aging experiments. We propose a frailty-based measure of healthspan as an alternative target for aging research and demonstrate that lifespan and healthspan criteria reveal distinct aspects of aging in mice.

Testing the amount of nicotinamide mononucleotide and urolithin A as compared to the label claim - E Sandalova; H Li; L Guan; SD Raj; TG Lim; E Tian; BK Kennedy; AB Maier (GeroScience, 2024)
Healthy Longevity Medicine aims to optimize health by targeting aging processes across the lifespan. Addressing accelerated aging involves adaptation of lifestyle and the use of geroprotective drugs and supplements, including nutritional supplements and bioactive compounds. The Food and Drug Administration, under the Dietary Supplement Health and Education Act, categorizes bioactive compounds and medicinal products as dietary supplements. While numerous companies sell ingredients that can be deemed geroprotectors, there's limited oversight in their quality control. Governmental safety authorities only verify the presence of prohibited compounds, not the accuracy of ingredients listed on labels. Here, Nicotinamide mononucleotide and Urolithin A supplements, easily accessible online or in pharmacies, were tested for their active ingredient content. Results showed a significant deviation from the labeled amounts, ranging from + 28.6% to -100%. This indicates a considerable disparity in the quality of geroprotective supplements. To address this variability, collaboration between and within societies representing healthcare professionals, industry and regulatory bodies is imperative to ensure the quality of geroprotective supplements.

Empagliflozin rescues lifespan and liver senescence in naturally aged mice - Jiangchuan Long; Ziyu Ren; Yaqian Duan; Wei Tao; Xi Li; Shengbing Li; Ke Li; Qixuan Huang; Jie Chen; Mengliu Yang; Yang Li; Xie Luo; et al. (GeroScience, 2024)

Guideline for designing microbiome studies in neoplastic diseases - Edit Mikó; Adrienn Sipos; Emese Tóth; Andrea Lehoczki; Monika Fekete; Éva Sebő; Gábor Kardos; Péter Bai (GeroScience, 2024)
Oncobiosis has emerged as a key contributor to the development, and modulator of the treatment efficacy of cancer. Hereby, we review the modalities through which the oncobiome can support the progression of tumors, and the emerging therapeutic opportunities they present. The review highlights the inherent challenges and limitations faced in sampling and accurately characterizing oncobiome. Additionally, the review underscores the critical need for the standardization of microbial analysis techniques and the consistent reporting of microbiome data. We provide a suggested metadata set that should accompany microbiome datasets from oncological settings so that studies remain comparable and decipherable.

Neurological diagnostic tests for patients with and without delirium: a prospective observational study - Noémie Waefler; Imen Abid; Victor Montaut; Jacques Donzé; Hervé Zender; Gregor John (GeroScience, 2024)
Since most of the precipitating factors of delirium are not due to neurological disorders, neurological diagnostic tests (NDTs) may be of limited value. We hypothesized that delirium has a high burden of NDTs with a low diagnostic yield. All patients admitted to the internal medicine wards of a single secondary teaching hospital between November 2019 and January 2020 were eligible. Within the first 48 h of their admission, they had a formal evaluation by a neuropsychologist to screen for presence of delirium. NDTs (brain MRI, brain CT, electroencephalography (EEG), and lumbar puncture) performed during the hospital stay were compared between patients with and without delirium using a logistic regression model stratified by a propensity score. The proportions of diagnostic yield (acute anomalies that changed the treatment management) provided by each type of examination were compared. Of 217 patients included, 19/32 patients (61%) with delirium had one or more NDTs, compared to 48/185 (26%) without delirium (adjusted OR 2.7; 95%CI 1.1–6.7; p = 0.027). The proportions of NDT results affecting management for patients with and without delirium were 13 and 20% for brain CT scans ( p = 0.71), 29 and 38% for brain MRI ( p = 0.99), and 20 and 10% for EEGs ( p = 0.99), respectively. The higher proportion of NDTs performed on patients with delirium was associated with a low diagnostic yield, although not statistically different from those performed among inpatients without delirium. There is a need for restrictive, evidence-based guidelines to help with the work-up for patients with delirium.

Longitudinal detection of gait alterations associated with hypertension-induced cerebral microhemorrhages in mice: predictive role of stride length and stride time asymmetry and increased gait entropy - Zoltan Ungvari; Mihaly Muranyi; Rafal Gulej; Sharon Negri; Adam Nyul-Toth; Boglarka Csik; Roland Patai; Shannon Conley; Madison Milan; Jonathan Bagwell; Daniel O’Connor; Amber Tarantini; et al. (GeroScience, 2024)
Cerebral microhemorrhages (CMHs) are of paramount importance as they not only signify underlying vascular pathology but also have profound implications for cognitive function and neurological health, serving as a critical indicator for the early detection and management of vascular cognitive impairment (VCI). This study aimed to investigate the effects of hypertension-induced CMHs on gait dynamics in a mouse model, focusing on the utility of advanced gait metrics as sensitive indicators of subclinical neurological alterations associated with CMHs. To induce CMHs, we employed a hypertensive mouse model, using a combination of Angiotensin II and L-NAME to elevate blood pressure, further supplemented with phenylephrine to mimic transient blood pressure fluctuations. Gait dynamics were analyzed using the CatWalk system, with emphasis on symmetry indices for Stride Length (SL), Stride Time (ST), and paw print area, as well as measures of gait entropy and regularity. The study spanned a 30-day experimental period, capturing day-to-day variations in gait parameters to assess the impact of CMHs. Temporary surges in gait asymmetry, detected as deviations from median gait metrics, suggested the occurrence of subclinical neurological signs associated with approximately 50% of all histologically verified CMHs. Our findings also demonstrated that increases in gait entropy correlated with periods of increased gait asymmetry, providing insights into the complexity of gait dynamics in response to CMHs. Significant correlations were found between SL and ST symmetry indices and between these indices and the paw print area symmetry index post-hypertension induction, indicating the interdependence of spatial and temporal aspects of gait affected by CMHs. Collectively, advanced gait metrics revealed sensitive, dynamic alterations in gait regulation associated with CMHs, resembling the temporal characteristics of transient ischemic attacks (TIAs). This underscores their potential as non-invasive indicators of subclinical neurological impacts. This study supports the use of detailed gait analysis as a valuable tool for detecting subtle neurological changes, with implications for the early diagnosis and monitoring of cerebral small vessel disease (CSVD) in clinical settings.

Cross-frequency modulation of postural fluctuations and scalp EEG in older adults: error amplification feedback for rapid balance adjustments - Yi-Ching Chen; Yi-Ying Tsai; Wei-Min Huang; Chen-Guang Zhao; Ing-Shiou Hwang (GeroScience, 2024)

Rotating magnetic field improved cognitive and memory impairments in a sporadic ad model of mice by regulating microglial polarization - Mengqing Li; Qinyao Yu; Umer Anayyat; Hua Yang; Yunpeng Wei; Xiaomei Wang (GeroScience, 2024)

The association of structural versus load-dependent large artery stiffness mechanisms with cerebrovascular damage and cortical atrophy in humans - Matthew K. Armstrong; Shivangi Jain; Virginia Nuckols; Ryan Pewowaruk; Xinyu Zhang; Lyndsey DuBose; Matthew Sodoma; Bryan Madero; Michelle W. Voss; Gary L. Pierce (GeroScience, 2024)

Improved resilience and proteostasis mediate longevity upon DAF-2 degradation in old age - Adrian Molière; Ji Young Cecilia Park; Anita Goyala; Elena M. Vayndorf; Bruce Zhang; Kuei Ching Hsiung; Yoonji Jung; Sujeong Kwon; Cyril Statzer; David Meyer; Richard Nguyen; Joseph Chadwick; et al. (GeroScience, 2024)
Little is known about the possibility of reversing age-related biological changes when they have already occurred. To explore this, we have characterized the effects of reducing insulin/IGF-1 signaling (IIS) during old age. Reduction of IIS throughout life slows age-related decline in diverse species, most strikingly in the nematode Caenorhabditis elegans . Here we show that even at advanced ages, auxin-induced degradation of DAF-2 in single tissues, including neurons and the intestine, is still able to markedly increase C. elegans lifespan. We describe how reversibility varies among senescent changes. While senescent pathologies that develop in mid-life were not reversed, there was a rejuvenation of the proteostasis network, manifesting as a restoration of the capacity to eliminate otherwise intractable protein aggregates that accumulate with age. Moreover, resistance to several stressors was restored. These results support several new conclusions. (1) Loss of resilience is not solely a consequence of pathologies that develop in earlier life. (2) Restoration of proteostasis and resilience by inhibiting IIS is a plausible cause of the increase in lifespan. And (3), most interestingly, some aspects of the age-related transition from resilience to frailty can be reversed to a certain extent. This raises the possibility that the effect of IIS and related pathways on resilience and frailty during aging in higher animals might possess some degree of reversibility.

Short lifespan is one’s fate, long lifespan is one’s achievement: lessons from Daphnia - Thomas C. Beam; Mchale Bright; Amelia C. Pearson; Ishaan Dua; Meridith Smith; Ashit K. Dutta; Shymal C. Bhadra; Saad Salman; Caleb N. Strickler; Cora E. Anderson; Leonid Peshkin; Lev Y. Yampolsky (GeroScience, 2024)

Correction to: Using non‑invasive behavioral and physiological data to measure biological age in wild baboons - Chelsea J. Weibel; Mauna R. Dasari; David A. Jansen; Laurence R. Gesquiere; Raphael S. Mututua; J. Kinyua Warutere; Long’ida I. Siodi; Susan C. Alberts; Jenny Tung; Elizabeth A. Archie (GeroScience, 2024)

Differentiation in theta and gamma activation in weight-shifting learning between people with parkinson’s disease of different anxiety severities - Yu-Ting Hung; Ruey-Meei Wu; Cheng-Ya Huang (GeroScience, 2024)

Home-based monitoring of cerebral oxygenation in response to postural changes using near-infrared spectroscopy - Marjolein Klop; Jurgen A. H. R. Claassen; Marianne J. Floor-Westerdijk; Richard J. A. van Wezel; Andrea B. Maier; Carel G. M. Meskers (GeroScience, 2024)
Orthostatic hypotension (OH) is prevalent in older adults and can cause falls and hospitalization. Diagnostic intermittent blood pressure (BP) measurements are only a proxy for cerebral perfusion and do not reflect daily-life BP fluctuations. Near-infrared spectroscopy (NIRS)-measured cerebral oxygenation potentially overcomes these drawbacks. This study aimed to determine feasibility, face validity, and reliability of NIRS in the home environment. Ten participants with OH (2 female, mean age 77, SD 3.7) and 11 without OH (5 female, mean age 78, SD 6.7) wore a NIRS sensor at home on two different days for 10–11 h per day. Preceded by a laboratory-situated test, cerebral oxygenation was measured during three standardized supine-stand tests per day and during unsupervised daily life activities. Data availability, quality, and user experience were assessed (feasibility), as well as differences in posture-related oxygenation responses between participants with and without OH and between symptomatic (dizziness, light-headedness, blurred vision) and asymptomatic postural changes (face validity). Reliability was assessed through repetitive supine-stand tests. Up to 80% of the standardized home-based supine-stand tests could be analyzed. Oxygenation recovery values were lower for participants with OH ( p = 0 .03–0.15); in those with OH, oxygenation showed a deeper maximum drop for symptomatic than asymptomatic postural changes ( p = 0.04). Intra-class correlation coefficients varied from 0.07 to 0.40, with no consistent differences over measurements. This proof-of-concept study shows feasibility and face validity of at-home oxygenation monitoring using NIRS, confirming its potential value for diagnosis and monitoring in OH and OH-related symptoms. Further data are needed for conclusions about reliability.

Rho-kinase inhibition reduces systolic blood pressure and forearm vascular resistance in healthy older adults: a double-blind, randomized, placebo-controlled pilot study - Nate P. Bachman; Nathaniel B. Ketelhut; Michael Blomquist; Janée D. Terwoord (GeroScience, 2024)

The neurovascular unit and its correlation with cognitive performance in patients with cerebral small vessel disease: a canonical correlation analysis approach - Maud van Dinther; Paulien H. M. Voorter; Eleana Zhang; Sander M. J. van Kuijk; Jacobus F. A. Jansen; Robert J. van Oostenbrugge; Walter H. Backes; Julie Staals (GeroScience, 2024)
Growing evidence indicates an important role of neurovascular unit (NVU) dysfunction in the pathophysiology of cerebral small vessel disease (cSVD). Individually measurable functions of the NVU have been correlated with cognitive function, but a combined analysis is lacking. We aimed to perform a unified analysis of NVU function and its relation with cognitive performance. The relationship between NVU function in the white matter and cognitive performance (both latent variables composed of multiple measurable variables) was investigated in 73 patients with cSVD (mean age 70 ± 10 years, 41% women) using canonical correlation analysis. MRI-based NVU function measures included (1) the intravoxel incoherent motion derived perfusion volume fraction ( f) and microvascular diffusivity ( D* ), reflecting cerebral microvascular flow; (2) the IVIM derived intermediate volume fraction ( f int ), indicative of the perivascular clearance system; and (3) the dynamic contrast-enhanced MRI derived blood–brain barrier (BBB) leakage rate ( K i ) and leakage volume fraction ( V L ), reflecting BBB integrity. Cognitive performance was composed of 13 cognitive test scores. Canonical correlation analysis revealed a strong correlation between the latent variables NVU function and cognitive performance ( r 0.73; p = 0.02). For the NVU, the dominating variables were D *, f int , and K i . Cognitive performance was driven by multiple cognitive tests comprising different cognitive domains. The functionality of the NVU is correlated with cognitive performance in cSVD. Instead of focusing on individual pathophysiological mechanisms, future studies should target NVU dysfunction as a whole to acquire a coherent understanding of the complex disease mechanisms that occur in the NVU in cSVD. Trial registration: NTR3786 (Dutch Trial Register).

Correction to: Genome integrity as a potential index of longevity in Ashkenazi Centenarian’s families - Mariana Andrawus; Gil Ben David; Ivana Terziyska; Lital Sharvit; Aviv Bergman; Nir Barzilai; Srilakshmi M. Raj; Diddahally R. Govindaraju; Gil Atzmon (GeroScience, 2024)

The longevity-associated BPIFB4 gene guarantees vascular homeostasis and immune protection through platelets - Elena Ciaglia; Francesco Montella; Albino Carrizzo; Valentina Lopardo; Roberta Maria Esposito; Cristina Basile; Antonio Damato; Massimiliano De Lucia; Anna Maciag; Gaia Spinetti; Maria Serena Milella; Davide Maselli; et al. (GeroScience, 2024)
Beyond their activity in hemostasis and thrombosis, recent advances attribute platelets a pro-youthful role capable to attenuate immune senescence and age-related neuroinflammation. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models has proved strategic to cope with frailty conditions, aging-related events, e.g., cardiovascular ones, and immune dysfunction mainly through a favorable conditioning of the immune system. However, whether platelets participate in LAV-BPIFB4 therapeutic action is currently unknown. Herein, we discovered that platelets were instrumental in boosting the favorable health outcomes of the systemic AAV-LAV-BPIFB4 gene transfer in vivo , as the α-CD42b platelet depletion completely abolished the vascular protective action of LAV-BPIFB4 and suppressed its pro-resolutive CD206 + anti-/CD86 + pro-inflammatory Ly6C + monocyte skewing to LPS stimulation. Of note, this is associated with a huge drop in the protective levels of BPIFB4 in the plasma of AAV-LAV-BPIFB4-injected C57BL/6 mice, indicating that plasma circulating platelets may be a reservoir of the BPIFB4 protein. Indeed, we noticed that BPIFB4 was released by human platelets, a process that is amplified in LAV-allele carrier donors. Accordingly, lentivirus-mediated overexpression of human LAV-BPIFB4 isoform, but not WT-BPIFB4 isoform was able in leading differentiated megakaryocytes to release more platelet-like-particles enriched for BPIFB4. In addition, in vitro , the M2 macrophage polarization increased when releasate from platelets, and even more from LAV pre-stimulated once, was added in monocyte cell culture. Our data suggest that platelet release of BPIFB4 and of yet-to-be-determined unidentified factors mediates the therapeutic efficacy of LAV-BPIFB4 treatment.

Epigenetic age acceleration is a distinctive trait of epithelioid sarcoma with potential therapeutic implications - Simon Haefliger; Olga Chervova; Christopher Davies; Chet Loh; Roberto Tirabosco; Fernanda Amary; Nischalan Pillay; Steve Horvath; Stephan Beck; Adrienne M. Flanagan; Iben Lyskjær (GeroScience, 2024)
Recently, DNA methylation clocks have been proven to be precise age predictors, and the application of these clocks in cancer tissue has revealed a global age acceleration in a majority of cancer subtypes when compared to normal tissue from the same individual. The polycomb repressor complex 2 plays a pivotal role in the aging process, and its targets have been shown to be enriched in CpG sites that gain methylation with age. This complex is further regulated by the chromatin remodeling complex SWItch/Sucrose Non-Fermentable and its core subunit, notably the tumor suppressor gene SMARCB1 , which under physiological conditions inhibits the activity of the polycomb repressor complex 2. Hence, the loss of function of core members of the SWItch/sucrose non-fermentable complex, such as the tumor suppressor gene SMARCB1 , results in increased activity of polycomb repressor complex 2 and interferes with the aging process. SMARCB1 -deficient neoplasms represent a family of rare tumors, including amongst others malignant rhabdoid tumors, atypical teratoid and rhabdoid tumors, and epithelioid sarcomas. As aging pathways have recently been proposed as therapeutic targets for various cancer types, these tumors represent candidates for testing such treatments. Here, by deriving epigenetic age scores from more than 1000 tumor samples, we identified epigenetic age acceleration as a hallmark feature of epithelioid sarcoma. This observation highlights the potential of targeting aging pathways as an innovative treatment approach for patients with epithelioid sarcoma.

The C. elegans Myc-family of transcription factors coordinate a dynamic adaptive response to dietary restriction - Adam B. Cornwell; Yun Zhang; Manjunatha Thondamal; David W. Johnson; Juilee Thakar; Andrew V. Samuelson (GeroScience, 2024)

Cerebrovascular dysregulation and postoperative cognitive alterations after carotid endarterectomy - Ágnes Dóra Sándor; Zsófia Czinege; András Szabó; Eszter Losoncz; Krisztina Tóth; Zsuzsanna Mihály; Péter Sótonyi; Béla Merkely; Andrea Székely (GeroScience, 2024)
There are controversial data about the effect of carotid endarterectomy regarding postoperative cognitive function. Our aim was to analyze the effect of cerebral tissue saturation monitored by near-infrared spectroscopy (NIRS) on cognitive function. Perioperative data of 103 asymptomatic patients undergoing elective carotid surgery under general anesthesia were analyzed. Preoperatively and 3 months after the operation, MMSE (Mini Mental State Examination) and MoCA (Montreal Cognitive Assessment) tests were conducted. For cerebral monitoring, NIRS was used, and the lowest rSO 2 value and the degree of desaturation were calculated. Cognitive changes were defined as one standard deviation change from the preoperative test scores, defined as postoperative neurocognitive decline (PNCD) and cognitive improvement (POCI). PNCD was found in 37 patients (35.92%), and POCI was found in 18 patients (17.47%). Female gender, patients with diabetes, and the degree of desaturation were independently associated with PNCD. The degree of desaturation during the cross-clamp period negatively correlated with the change in the MoCA scores ( R = − 0.707, p = 0.001). The 15.5% desaturation ratio had 86.5% sensitivity and 78.8% specificity for discrimination. For POCI, a desaturation of less than 12.65% had 72.2% sensitivity and 67.1% specificity. POCI was associated with lower preoperative MOCA scores and a lower degree of desaturation. We found a significant relation between the change of postoperative cognitive function proven by the MoCA test and cerebral tissue saturation during the clamping period in patients undergoing carotid endarterectomy.

Improving mentalizing deficits in older age with region-specific transcranial direct current stimulation - Alexander Lischke; Rike Pahnke; Anna Mäder; Andrew K. Martin; Marcus Meinzer (GeroScience, 2024)
Older adults have difficulties to detect the intentions, thoughts, and feelings of others, indicating an age-associated decline of socio-cognitive abilities that are known as “mentalizing”. These deficits in mental state recognition are driven by neurofunctional alterations in brain regions that are implicated in mentalizing, such as the right temporo-parietal junction (rTPJ) and the dorso-medial prefrontal cortex (dmPFC). We tested whether focal transcranial current stimulation (tDCS) of the rTPJ and dmPFC has the potential to eliminate mentalizing deficits in older adults. Mentalizing deficits were assessed with a novel mindreading task that required the recognition of mental states in child faces. Older adults ( n = 60) performed worse than younger adults ( n = 30) on the mindreading task, indicating age-dependent deficits in mental state recognition. These mentalizing deficits were ameliorated in older adults who received sham-controlled andodal tDCS over the rTPJ ( n = 30) but remained unchanged in older adults who received sham-controlled andodal tDCS over the dmPFC ( n = 30). We, thus, showed for the first time that anodal tDCS over the rTPJ has the potential to remediate age-dependent mentalizing deficits in a region-specific way. This provides a rationale for exploring stimulation-based interventions targeting mentalizing deficits in older age.

Glycan clock of ageing—analytical precision and time-dependent inter- and i-individual variability - Borna Rapčan; Manshu Song; Azra Frkatović-Hodžić; Tea Pribić; Jakov Vuk; Anđelo Beletić; Maja Hanić; Julija Jurić; Petra Tominac; Josip Milas; Vedrana Ivić; Sven Viland; et al. (GeroScience, 2024)
Ageing is a complex biological process with variations among individuals, leading to the development of ageing clocks to estimate biological age. Glycans, particularly in immunoglobulin G (IgG), have emerged as potential biomarkers of ageing, with changes in glycosylation patterns correlating with chronological age. For precision analysis, three different plasma pools were analysed over 26 days in tetraplicates, 312 samples in total. In short-term variability analysis, two cohorts were analysed: AstraZeneca MFO cohort of 26 healthy individuals (median age 20) and a cohort of 70 premenopausal Chinese women (median age 22.5) cohort monitored over 3 months. Long-term variability analysis involved two adult men aged 47 and 57, monitored for 5 and 10 years, respectively. Samples were collected every 3 months and 3 weeks, respectively. IgG N -glycan analysis followed a standardized approach by isolating IgG, its subsequent denaturation and deglycosylation followed by glycan cleanup and labelling. Capillary gel electrophoresis with laser-induced fluorescence (CGE-LIF) and ultra-performance liquid chromatography analyses were employed for glycan profiling. Statistical analysis involved normalization, batch correction, and linear mixed models to assess time effects on derived glycan traits. The intermediate precision results consistently exhibited very low coefficient of variation values across all three test samples. This consistent pattern underscores the high level of precision inherent in the CGE method for analysing the glycan clock of ageing. The AstraZeneca MFO cohort did not show any statistically significant trends, whereas the menstrual cycle cohort exhibited statistically significant trends in digalactosylated (G2), agalactosylated (G0) and fucosylation (F). These trends were attributed to the effects of the menstrual cycle. Long-term stability analysis identified enduring age-related trends in both subjects, showing a positive time effect in G0 and bisected N -acetylglucosamine, as well as a negative time effect in G2 and sialylation, aligning with earlier findings. Time effects measured for monogalactosylation, and F remained substantially lower than ones observed for other traits. The study found that IgG N -glycome analysis using CGE-LIF exhibited remarkably high intermediate precision. Moreover, the study highlights the short- and long-term stability of IgG glycome composition, coupled with a notable capacity to adapt and respond to physiological changes and environmental influences such as hormonal changes, disease, and interventions. The discoveries from this study propel personalized medicine forward by deepening our understanding of how IgG glycome relates to age-related health concerns. This study underscores the reliability of glycans as a biomarker for tracking age-related changes and individual health paths.

Post-acute sequelae of SARS-CoV-2 infection (Long COVID) in older adults - Samantha J. Russell; Karen Parker; Andrea Lehoczki; David Lieberman; Indu S. Partha; Serena J. Scott; Linda R. Phillips; Mindy J. Fain; Janko Ž. Nikolich (GeroScience, 2024)

Characterizing phenotypic data of Peromyscus leucopus compared to C57BL/6J Mus musculus and diversity outbred (DO) Mus musculus - Lauren A. Wimer; Asia Davis-Castillo; Sofiya Galkina; Serban Ciotlos; Cavan Patterson; Leandro Prado; Maria Castro Munoz; Nicolas Martin; Sharon Epstein; Nicholas Schaum; Simon Melov (GeroScience, 2024)
Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse ( Peromyscus leucopus ) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus . While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.

Decoding the best automated segmentation tools for vascular white matter hyperintensities in the aging brain: a clinician’s guide to precision and purpose - Lucia Torres-Simon; Alberto del Cerro-León; Miguel Yus; Ricardo Bruña; Lidia Gil-Martinez; Alberto Marcos Dolado; Fernando Maestú; Juan Arrazola-Garcia; Pablo Cuesta (GeroScience, 2024)

A Fully-Automated Senescence Test (FAST) for the high-throughput quantification of senescence-associated markers - Francesco Neri; Selma N. Takajjart; Chad A. Lerner; Pierre-Yves Desprez; Birgit Schilling; Judith Campisi; Akos A. Gerencser (GeroScience, 2024)
Cellular senescence is a major driver of aging and age-related diseases. Quantification of senescent cells remains challenging due to the lack of senescence-specific markers and generalist, unbiased methodology. Here, we describe the Fully-Automated Senescence Test (FAST), an image-based method for the high-throughput, single-cell assessment of senescence in cultured cells. FAST quantifies three of the most widely adopted senescence-associated markers for each cell imaged: senescence-associated β-galactosidase activity (SA-β-Gal) using X-Gal, proliferation arrest via lack of 5-ethynyl-2’-deoxyuridine (EdU) incorporation, and enlarged morphology via increased nuclear area. The presented workflow entails microplate image acquisition, image processing, data analysis, and graphing. Standardization was achieved by (i) quantifying colorimetric SA-β-Gal via optical density; (ii) implementing staining background controls; and (iii) automating image acquisition, image processing, and data analysis. In addition to the automated threshold-based scoring, a multivariate machine learning approach is provided. We show that FAST accurately quantifies senescence burden and is agnostic to cell type and microscope setup. Moreover, it effectively mitigates false-positive senescence marker staining, a common issue arising from culturing conditions. Using FAST, we compared X-Gal with fluorescent C 12 FDG live-cell SA-β-Gal staining on the single-cell level. We observed only a modest correlation between the two, indicating that those stains are not trivially interchangeable. Finally, we provide proof of concept that our method is suitable for screening compounds that modify senescence burden. This method will be broadly useful to the aging field by enabling rapid, unbiased, and user-friendly quantification of senescence burden in culture, as well as facilitating large-scale experiments that were previously impractical.

Intrinsic aerobic capacity modulates Alzheimer’s disease pathological hallmarks, brain mitochondrial function and proteome during aging - Benjamin A. Kugler; Colton R. Lysaker; Edziu Franczak; Brittany M. Hauger; Vivien Csikos; Julia A. Stopperan; Julie A. Allen; John A. Stanford; Lauren G. Koch; Steven L. Britton; John P. Thyfault; Heather M. Wilkins (GeroScience, 2024)
Low aerobic capacity is strongly associated with all-cause mortality and risk for Alzheimer’s disease (AD). Individuals with early dementia and AD have lower aerobic capacity compared to age-matched controls. The mechanism by which aerobic capacity influences AD risk is unknown but is likely mediated by sexual dimorphism and tissue-level differences in mitochondrial energetics. Here, we used rats selectively bred for large differences in intrinsic aerobic exercise capacity. Brain tissue from 18-month and 24-month-old female and male low-capacity runner (LCR) and high-capacity runner (HCR) rats were analyzed for markers of mitochondrial function and AD-associated pathologies. LCR rats, irrespective of sex, exhibited a greater increase in brain amyloid beta (Aβ 42 ) and tau hyperphosphorylation (pTau thr181 /total tau) with aging. In female LCR rats, brain mitochondrial respiration at states 3, 4, and FCCP-induced uncoupling, when stimulated with pyruvate/malate, was reduced at 18 and 24 months, leading to lower ATP-linked mitochondrial respiration compared to mitochondria from HCR rats. Male LCR rats also showed reduced complex II-stimulated mitochondrial respiration (succinate + rotenone) at 24 months compared to HCR rats. Differences in mitochondrial respiration were associated with tau hyperphosphorylation and Aβ42 alterations in both HCR and LCR strains. Proteomic analysis unveiled a distinct difference in the mitochondrial proteome, wherein female LCR rats displayed diminished mitochondrial translation and oxidative phosphorylation (OXPHOS) proteins at 18 months compared to female HCR rats. Conversely, male LCR rats exhibited increased OXPHOS protein abundance but reduced tricarboxylic acid (TCA) cycle proteins compared to male HCR rats. These findings underscore a robust association between intrinsic aerobic exercise capacity, brain mitochondrial function, and AD pathologies during aging.

Most genetic roots of fungal and animal aging are hundreds of millions of years old according to phylostratigraphy analyses of aging networks - Hugo Bonnefous; Jérôme Teulière; François-Joseph Lapointe; Philippe Lopez; Eric Bapteste (GeroScience, 2024)

Vascular dysfunction occurs prior to the onset of amyloid pathology and Aβ plaque deposits colocalize with endothelial cells in the hippocampus of female APPswe/PSEN1dE9 mice - Emily W. Waigi; Laena Pernomian; Alexia M. Crockett; Tiago J. Costa; Paul Townsend; R. Clinton Webb; Joseph A. McQuail; Cameron G. McCarthy; Fiona Hollis; Camilla F. Wenceslau (GeroScience, 2024)
Increasing evidence shows that cardiovascular diseases (CVDs) are associated with an increased risk of cognitive impairment and Alzheimer’s diseases (AD). It is unknown whether systemic vascular dysfunction occurs prior to the development of AD, if this occurs in a sex-dependent manner, and whether endothelial cells play a role in the deposition of amyloid beta (Aβ) peptides. We hypothesized that vascular dysfunction occurs prior to the onset of amyloid pathology, thus escalating its progression. Furthermore, endothelial cells from female mice will present with an exacerbated formation of Aβ peptides due to an exacerbated pressure pulsatility. To test this hypothesis, we used a double transgenic mouse model of early-onset AD (APPswe/PSEN1dE9). We evaluated hippocampus-dependent recognition memory and the cardiovascular function by echocardiography and direct measurements of blood pressure through carotid artery catheterization. Vascular function was evaluated in resistance arteries, morphometric parameters in the aortas, and immunofluorescence in the hippocampus and aortas. We observed that endothelial dysfunction occurred prior to the onset of amyloid pathology irrespective of sex. However, during the onset of amyloid pathology, only female APP/PS1 mice had vascular stiffness in the aorta. There was elevated Aβ deposition which colocalized with endothelial cells in the hippocampus from female APP/PS1 mice. Overall, these data showed that vascular abnormalities may be an early marker, and potential mediator of AD, but exacerbated aortic stiffness and pressure pulsatility after the onset of amyloid pathology may be associated with a greater burden of Aβ formation in hippocampal endothelial cells from female but not male APP/PS1 mice. Graphical Abstract

Photobiomodulation in the aging brain: a systematic review from animal models to humans - Lucía Rodríguez-Fernández; Candela Zorzo; Jorge L. Arias (GeroScience, 2024)
Aging is a multifactorial biological process that may be associated with cognitive decline. Photobiomodulation (PBM) is a non-pharmacological therapy that shows promising results in the treatment or prevention of age-related cognitive impairments. The aim of this review is to compile the preclinical and clinical evidence of the effect of PBM during aging in healthy and pathological conditions, including behavioral analysis and neuropsychological assessment, as well as brain-related modifications. 37 studies were identified by searching in PubMed, Scopus, and PsycInfo databases. Most studies use wavelengths of 800, 810, or 1064 nm but intensity and days of application were highly variable. In animal studies, it has been shown improvements in spatial memory, episodic-like memory, social memory, while different results have been found in recognition memory. Locomotor activity improved in Parkinson disease models. In healthy aged humans, it has been outlined improvements in working memory, cognitive inhibition, and lexical/semantic access, while general cognition was mainly enhanced on Alzheimer disease or mild cognitive impairment. Anxiety assessment is scarce and shows mixed results. As for brain activity, results outline promising effects of PBM in reversing metabolic alterations and enhancing mitochondrial function, as evidenced by restored CCO activity and ATP levels. Additionally, PBM demonstrated neuroprotective, anti-inflammatory, immunomodulatory and hemodynamic effects. The findings suggest that PBM holds promise as a non-invasive intervention for enhancing cognitive function, and in the modulation of brain functional reorganization. It is necessary to develop standardized protocols for the correct, beneficial, and homogeneous use of PBM.

Mid-life plasma proteins associated with late-life prefrailty and frailty: a proteomic analysis - Fangyu Liu; Jennifer A. Schrack; Jeremy Walston; Rasika A. Mathias; B. Gwen Windham; Morgan E. Grams; Josef Coresh; Keenan A. Walker (GeroScience, 2024)

Benefits of calorie restriction in mice are mediated via energy imbalance, not absolute energy or protein intake - Daniel L. Smith; Sharon E. Mitchell; Maria S. Johnson; Victoria K. Gibbs; Stephanie Dickinson; Beate Henschel; Rui Li; Kathryn A. Kaiser; Daniella E. Chusyd; Andrew W. Brown; David B. Allison; John R. Speakman; et al. (GeroScience, 2024)
Caloric restriction (CR) results in reduced energy and protein intake, raising questions about protein restriction’s contribution to CR longevity benefits. We kept ad libitum ( AL )–fed male C57BL/6J mice at 27°C (AL27) and pair-fed (PF) mice at 22°C (22(PF27)). The 22(PF27) group was fed to match AL27 while restricted for calories due to cold-induced metabolism. The 22(PF27) mice had significantly lower body weight, lean mass, fat mass, leptin, IGF-1, and TNF-α levels than AL27 mice ( p <0.001 for all). Manipulations over ~11 weeks resulted in significant differences in body temperature, physical activity, and expression of key genes linked to hunger in the hypothalamus. Survival was significantly greater in 22(PF27) compared to AL27 overall ( p <0.001). CR in the context of equivalent energy and protein intake resulted in hormonal, metabolic, and physiological benefits and extended longevity. Hence, energy imbalance, rather than low energy or protein intake per se, mediates the benefits of CR.

Evaluation of off-label rapamycin use on oral health - Johnny Hudson; Tammi Kaeberlein; Akashdeep Mahal; Nelson Wong; Mina Ghorbanifarajzadeh; Frank Radella; Anar Isman; Andy Nyquist; Sajad Zalzala; George Haddad; Matt Kaeberlein; Jonathan Y. An (GeroScience, 2024)

Whole exome sequencing analyses reveal novel genes in telomere length and their biomedical implications - Wei-Shi Liu; Bang-Sheng Wu; Liu Yang; Shi-Dong Chen; Ya-Ru Zhang; Yue-Ting Deng; Xin-Rui Wu; Xiao-Yu He; Jing Yang; Jian-Feng Feng; Wei Cheng; Yu-Ming Xu; et al. (GeroScience, 2024)

Association of vitamin D and bisphenol A levels with cardiovascular risk in an elderly Italian population: results from the InCHIANTI study - Maria Luisa Brandi; Francesca Marini; Simone Parri; Stefania Bandinelli; Teresa Iantomasi; Francesca Giusti; Eleonora Talluri; Giovanna Sini; Fabrizio Nannipieri; Santina Battaglia; Giovanni Tripepi; Colin Gerard Egan; et al. (GeroScience, 2024)
Few studies have evaluated the association between circulating levels of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH) 2 D), and the endocrine disruptor bisphenol A (BPA), with risk of cardiovascular (CV) disease in elderly individuals. This was a cross-sectional study in a subgroup of elderly people from the InCHIANTI Biobank in Italy. We examined the association between circulating serum vitamin D metabolites, 1,25(OH) 2 D, 25(OH)D, and the endocrine disrupting agent BPA, with an arbitrary CV risk score and the European Society of Cardiology-based 10-year CV risk (SCORE2/SCORE2-OP) using univariate and multiple regression. In 299 individuals, blood samples were tested for serum values of 25(OH)D, 1,25(OH) 2 D and urinary BPA levels. One hundred eighty individuals (60.2%) were deficient (< 20 ng/ml) in 25(OH)D. Levels of 25(OH)D and 1,25(OH) 2 D were negatively correlated with CV risk score ( p < 0.0001 for both) as well as SCORE2/SCORE2-OP ( p < 0.0001 for both) while BPA levels were positively correlated with both CV risk scores ( p < 0.0001 for both). In a logistic regression model, male gender (odds ratio; OR: 2.1, 95% CI:1.1–3.8, p = 0.022), obesity (OR:2.8, 95% CI:1.2–6.5, p = 0.016) and BPA levels ≥ 110 ng/dl (OR:20.9, 95% CI:9.4–46.8, p < 0.0001) were associated with deficient levels of 25(OH)D. 1,25(OH)2D levels < 41 ng/dl and 25(OH)D levels < 20 ng/ml were associated with CV risk score ≥ 3 (OR: 4.16, 95% CI: 2.32–7.4, p < 0.0001 and OR: 1.86, 95% CI: 1.02–3.39, p = 0.044) respectively and 1,25(OH)2D levels < 41 ng/dl were associated with SCORE2/SCORE2-OP of ≥ 20% (OR:2.98, 95% CI: 1.7–5.2, p = 0.0001). In this cross-sectional analysis, BPA exposure was associated with significantly reduced levels of vitamin D that in turn were significantly associated with increased CV risk.

An ethical assessment of professional opinions on concerns, chances, and limitations of the implementation of an artificial intelligence-based technology into the geriatric patient treatment and continuity of care - Nina Parchmann; David Hansen; Marcin Orzechowski; Florian Steger (GeroScience, 2024)
With the introduction of an artificial intelligence-based dashboard into the clinic, the project SURGE-Ahead responds to the importance of improving perioperative geriatric patient treatment and continuity of care. The use of artificial intelligence to process and analyze data automatically, aims at an evidence-based evaluation of the patient’s health condition and recommending treatment options. However, its development and introduction raise ethical questions. To ascertain professional perspectives on the clinical use of the dashboard, we have conducted 19 semi-structured qualitative interviews with head physicians, computer scientists, jurists, and ethicists. The application of a qualitative content analysis and thematic analysis enabled the detection of main ethical concerns, chances, and limitations. These ethical considerations were categorized: changes of the patient-physician relationship and the current social reality are expected, causing de-skilling and an active participation of the artificial intelligence. The interviewees anticipated a redistribution of human resources, time, knowledge, and experiences as well as expenses and financing. Concerns of privacy, accuracy, transparency, and explainability were stated, and an insufficient data basis, an intensifying of existing inequalities and systematic discrimination considering a fair access emphasized. Concluding, the patient-physician relationship, social reality, redistribution of resources, fair access, as well as data-related aspects of the artificial intelligence-based system could conflict with the ethical principles of autonomy, non-maleficence, beneficence, and social justice. To respond to these ethical concerns, a responsible use of the dashboard and a critical verification of therapy suggestions is mandatory, and the application limited by questions at the end of life and taking life-changing decisions.

Growth hormone-receptor disruption in mice reduces osteoarthritis and chondrocyte hypertrophy - Huanhuan Liu; Trent Davis; Silvana Duran-Ortiz; Tom Martino; Austin Erdely; Shane Profio; Benjamin Osipov; Gabriela G. Loots; Darlene E. Berryman; Patrick M. O’Connor; John J. Kopchick; Shouan Zhu (GeroScience, 2024)
Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline ( GHR -/- ) or adult inducible ( iGHR -/- ) GHR deficiency. Knee joints from male and female GHR -/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR -/- and WT mice at 22 months of age were scanned by micro-CT (μCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR -/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR -/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR -/- mice were only moderately protected from developing aging-associated OA. iGHR -/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR -/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR -/- in either individual or combined sex analyses. Both GHR -/- and iGHR -/- mice had fewer COLX + hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR -/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR -/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR -/- mice.

Unraveling the link between cardiorespiratory fitness and cancer: a state-of-the-art review - Setor K. Kunutsor; Leonard A. Kaminsky; Andrea Lehoczki; Jari A. Laukkanen (GeroScience, 2024)
Cardiorespiratory fitness (CRF) not only reflects an individual’s capacity to perform physical activities but also encapsulates broader effects on the basic biology of aging. This review aims to summarize the evidence on the influence of CRF on overall and site-specific cancer risks. It delves into the biological mechanisms through which CRF may exert its effects, explores the clinical implications of these findings, identifies gaps in the current evidence base, and suggests directions for future research. The synthesis of findings reveals that higher CRF levels (general threshold of > 7 METs) are consistently associated with a reduced risk of a range of cancers, including head and neck, lung, breast, gastrointestinal, particularly pancreatic and colorectal, bladder, overall cancer incidence and mortality, and potentially stomach and liver, bile duct, and gall bladder cancers. These inverse associations between CRF and cancer risk do not generally differ across age groups, sex, race, or adiposity, suggesting a universal protective effect of CRF. Nonetheless, evidence linking CRF with skin, mouth and pharynx, kidney, and endometrial cancers is limited and inconclusive. Conversely, higher CRF levels may be potentially linked to an increased risk of prostate cancer and hematological malignancies, such as leukemia and myeloma, although the evidence is still not conclusive. CRF appears to play a significant role in reducing the risk of several cancers through various biological mechanisms, including inflammation reduction, immune system enhancement, hormonal regulation, and metabolic improvements. Overall, enhancing CRF through regular physical activity offers a vital, accessible strategy for reducing cancer risk and extending the health span. Future research should aim to fill the existing evidence gaps regarding specific cancers and elucidate the detailed dose–response relationships between CRF levels and cancer risk. Studies are also needed to elucidate the causal relationships and mechanistic pathways linking CRF to cancer outcomes.

Age-related decline in thickness and surface area in the cortical surface and hippocampus: lifespan trajectories and decade-by-decade analyses - Junhong Yu (GeroScience, 2024)

Linking peripheral atherosclerosis to blood–brain barrier disruption: elucidating its role as a manifestation of cerebral small vessel disease in vascular cognitive impairment - Ádám Nyúl-Tóth; Roland Patai; Anna Csiszar; Anna Ungvari; Rafal Gulej; Peter Mukli; Andriy Yabluchanskiy; Zoltan Benyo; Peter Sotonyi; Calin I. Prodan; Eric M. Liotta; Peter Toth; et al. (GeroScience, 2024)
Aging plays a pivotal role in the pathogenesis of cerebral small vessel disease (CSVD), contributing to the onset and progression of vascular cognitive impairment and dementia (VCID). In older adults, CSVD often leads to significant pathological outcomes, including blood–brain barrier (BBB) disruption, which in turn triggers neuroinflammation and white matter damage. This damage is frequently observed as white matter hyperintensities (WMHs) in neuroimaging studies. There is mounting evidence that older adults with atherosclerotic vascular diseases, such as peripheral artery disease, ischemic heart disease, and carotid artery stenosis, face a heightened risk of developing CSVD and VCID. This review explores the complex relationship between peripheral atherosclerosis, the pathogenesis of CSVD, and BBB disruption. It explores the continuum of vascular aging, emphasizing the shared pathomechanisms that underlie atherosclerosis in large arteries and BBB disruption in the cerebral microcirculation, exacerbating both CSVD and VCID. By reviewing current evidence, this paper discusses the impact of endothelial dysfunction, cellular senescence, inflammation, and oxidative stress on vascular and neurovascular health. This review aims to enhance understanding of these complex interactions and advocate for integrated approaches to manage vascular health, thereby mitigating the risk and progression of CSVD and VCID.

Shared plasma metabolomic profiles of cognitive and mobility decline predict future dementia - Qu Tian; Shanshan Yao; Megan M. Marron; Erin E. Greig; Supriya Shore; Luigi Ferrucci; Ravi Shah; Venkatesh L. Murthy; Anne B. Newman (GeroScience, 2024)
Experiencing decline in both cognition and mobility is associated with a substantially higher dementia risk than cognitive decline only. Metabolites associated with both cognitive and mobility declines may be early predictors of dementia and reveal specific pathways to dementia. We analyzed data from 2450 participants initially free of dementia who had 613 metabolites measured in plasma in 1998–1999 (mean age = 75.2 ± 2.9 years old, 37.8% Black, 50% women) from the Health, Aging and Body Composition study. Dementia diagnosis was determined by race-specific decline in 3MS scores, medication use, and hospital records through 2014. Cognition and mobility were repeatedly measured using 3MS and a 20-m walking test up to 10 years, respectively. We examined metabolite associations with changes in 3MS ( n = 2046) and gait speed ( n = 2019) using multivariable linear regression adjusted for age, sex, race, and baseline performance and examined metabolite associations with dementia risk using Cox regression. During a mean follow-up of 9.3 years, 534 (21.8%) participants developed dementia. On average, 3MS declined 0.47/year and gait declined 0.04 m/sec/year. After covariate adjustment, 75 metabolites were associated with cognitive decline, and 111 metabolites were associated with gait decline (FDR-adjusted p < 0.05). Twenty-six metabolites were associated with both cognitive and gait declines. Eighteen of 26 metabolites were associated with dementia risk ( p < 0.05), notably amino acids, glycerophospholipids (lysoPCs, PCs, PEs), and sphingolipids. Results remained similar after adjusting for cardiovascular disease or apolipoprotein E ɛ4 carrier status. During aging, metabolomic profiles of cognitive decline and mobility decline show distinct and shared signatures. Shared metabolomic profiles suggest that inflammation and deficits in mitochondria and the urea cycle in addition to the central nervous system may play key roles in both cognitive and mobility declines and predict dementia. Future studies are warranted to investigate longitudinal metabolite changes and metabolomic markers with dementia pathologies.

Identifying modifiable factors and their joint effect on brain health: an exposome-wide association study - Liang-Yu Huang; Yi-Jun Ge; Yan Fu; Yong-Li Zhao; Ya-Nan Ou; Yi Zhang; Ling-Zhi Ma; Shi-Dong Chen; Ze-Xin Guo; Jian-Feng Feng; Wei Cheng; Lan Tan; et al. (GeroScience, 2024)

The companion dog as a model for inflammaging: a cross-sectional pilot study - Sarah M. Schmid; Jessica M. Hoffman; Jena Prescott; Holley Ernst; Daniel E. L. Promislow; Joshua M. Akey; Brooke Benton; Elhanan Borenstein; Marta G. Castelhano; Amanda E. Coleman; Kate E. Creevy; Kyle Crowder; et al. (GeroScience, 2024)

Semantic processing in older adults is associated with distributed neural activation which varies by association and abstractness of words - Amanda Garcia; Ronald A. Cohen; Kailey G. Langer; Alexandria G. O’Neal; Eric C. Porges; Adam J. Woods; John B. Williamson (GeroScience, 2024)

Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and incident dementia: The UK Biobank study - Hind A. Beydoun; May A. Beydoun; Nicole Noren Hooten; Jordan Weiss; Zhiguang Li; Michael F. Georgescu; Christian A. Maino Vieytes; Osorio Meirelles; Lenore J. Launer; Michele K. Evans; Alan B. Zonderman (GeroScience, 2024)

Lifespan regulation by targeting heme signaling in yeast - Praveen K. Patnaik; Nour Nady; Hanna Barlit; Ali Gülhan; Vyacheslav M. Labunskyy (GeroScience, 2024)
Heme is an essential prosthetic group that serves as a co-factor and a signaling molecule. Heme levels decline with age, and its deficiency is associated with multiple hallmarks of aging, including anemia, mitochondrial dysfunction, and oxidative stress. Dysregulation of heme homeostasis has been also implicated in aging in model organisms suggesting that heme may play an evolutionarily conserved role in controlling lifespan. However, the underlying mechanisms and whether heme homeostasis can be targeted to promote healthy aging remain unclear. Here, we used Saccharomyces cerevisiae as a model to investigate the role of heme in aging. For this, we have engineered a heme auxotrophic yeast strain expressing a plasma membrane-bound heme permease from Caenorhabditis elegans (ceHRG-4). This system can be used to control intracellular heme levels independently of the biosynthetic enzymes by manipulating heme concentration in the media. We observed that heme supplementation leads to a significant extension of yeast replicative lifespan. Our findings revealed that the effect of heme on lifespan is independent of the Hap4 transcription factor. Surprisingly, heme-supplemented cells had impaired growth on YPG medium, which requires mitochondrial respiration to be used, suggesting that these cells are respiratory deficient. Together, our results demonstrate that heme homeostasis is fundamentally important for aging biology, and manipulating heme levels can be used as a promising therapeutic target for promoting longevity.

Relationship between skeletal mitochondrial function and digital markers of free-living physical activity in older adults - Amal A. Wanigatunga; Fangyu Liu; Ryan J. Dougherty; Karen Bandeen Roche; Jacek K. Urbanek; Marta Zampino; Eleanor M. Simonsick; Qu Tian; Jennifer A. Schrack; Luigi Ferrucci (GeroScience, 2024)

Hypothalamic sex-specific metabolic shift by canagliflozin during aging - Hashan S. M. Jayarathne; Ryan Sullivan; Lukas Stilgenbauer; Lucas K. Debarba; Artur Kuchumov; Lisa Koshko; Sydney Scofield; Wanqing Liu; Brett C. Ginsburg; Richard A. Miller; Marianna Sadagurski (GeroScience, 2024)
The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, and metabolic homeostasis. Recent studies have shown that a SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice and improve central metabolic control via increases in hypothalamic insulin responsiveness in aged males, as well as reduced age-associated hypothalamic inflammation. We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. Starting the treatment from 7 months of age, we show that 4 weeks of Cana treatment significantly reduced body weight and fat mass in male but not female mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that Cana treatment increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed increased sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups. Overall, our data provide critical evidence for sex-specific mechanisms that are affected by Cana during aging suggesting key targets of hypothalamic Cana-induced neuroprotection for metabolic control.

Self-rated health, epigenetic ageing, and long-term mortality in older Australians - Danmeng Lily Li; Allison M. Hodge; Melissa C. Southey; Graham G. Giles; Roger L. Milne; Pierre-Antoine Dugué (GeroScience, 2024)
Self-rated health (SRH) is a subjective indicator of overall health based on a single questionnaire item. Previous evidence found that it is a strong predictor of mortality, although the underlying mechanism is poorly understood. Epigenetic age is an objective, emerging biomarker of health, estimated using DNA methylation data at hundreds of sites across the genome. This study aimed to assess the overlap and interaction between SRH and epigenetic ageing in predicting mortality risk. We used DNA methylation data from 1059 participants in the Melbourne Collaborative Cohort Study (mean age: 69 years) to calculate three age-adjusted measures of epigenetic ageing: GrimAge , PhenoAge , and DunedinPACE . SRH was assessed using a five-category questionnaire item (“excellent, very good, good, fair, poor”). Cox models were used to assess the associations of SRH, epigenetic ageing, and their interaction, with all-cause mortality over up to 17 years of follow-up ( N deaths = 345). The association of SRH with mortality per category increase was HR = 1.29; 95%CI: 1.14–1.46. The association was slightly attenuated after adjusting for all three epigenetic ageing measures (HR = 1.25, 95%CI: 1.10–1.41). A strong gradient was observed in the association of GrimAge ( P interaction = 0.006) and DunedinPACE ( P interaction = 0.002) with mortality across worsening SRH strata. For example, the association between DunedinPACE and mortality in participants with “excellent” SRH was HR = 1.02, 95%CI: 0.73–1.43 and for “fair/poor” HR = 1.72, 95%CI: 1.35–2.20. SRH and epigenetic ageing were synergistic risk factors of mortality in our study. These findings suggest that consideration of subjective and objective factors may improve general health assessment, which has implications for the ongoing development of molecular markers of ageing.

Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats - Anna Szilágyi; Barbara Takács; Réka Szekeres; Vera Tarjányi; Dávid Nagy; Dániel Priksz; Mariann Bombicz; Rita Kiss; Adrienn Mónika Szabó; Andrea Lehoczki; Rudolf Gesztelyi; Béla Juhász; et al. (GeroScience, 2024)
Aging is accompanied by an increased prevalence of degenerative conditions, including those affecting ocular health, which significantly impact quality of life and increase the burden on healthcare systems. Among these, retinal aging is of particular concern due to its direct link to vision impairment, a leading cause of disability in the elderly. Vision loss in the aging population is associated with heightened risks of cognitive decline, social isolation, and morbidity. This study addresses the critical gap in our understanding of modifiable lifestyle factors, such as physical exercise, that may mitigate retinal aging and its related pathologies. We investigated the effects of different exercise regimens—voluntary (recreational-type) and forced (high-intensity)—on the retinal health of aging Wistar rats (18-month-old), serving as a model for studying the translational potential of exercise interventions in humans. Male Wistar rats were divided into four groups: a young control (3-month-old) for baseline comparison, an aged sedentary control, an aged group engaging in voluntary exercise via a running wheel in their cage, and an aged group subjected to forced exercise on a treadmill for six sessions of 20 min each per week. After a 6-month experimental period, we assessed retinal function via electroretinography (ERG), measured retinal thickness histologically, and analyzed protein expression changes relevant to oxidative stress, inflammation, and anti-aging mechanisms. Our findings reveal that voluntary exercise positively impacts retinal function and morphology, reducing oxidative stress and inflammation markers while enhancing anti-aging protein expression. In contrast, forced exercise showed diminished benefits. These insights underscore the importance of exercise intensity and preference in preserving retinal health during aging. The study highlights the potential of recreational physical activity as a non-invasive strategy to counteract retinal aging, advocating for further research into exercise regimens as preventative therapies for age-related ocular degenerations.

Facilitation of working memory capacity by transcranial direct current stimulation: a secondary analysis from the augmenting cognitive training in older adults (ACT) study - Serkan Aksu; Aprinda Indahlastari; Andrew O’Shea; Michael Marsiske; Ronald Cohen; Gene E. Alexander; Steven T. DeKosky; Georg A. Hishaw; Yunfeng Dai; Samuel S. Wu; Adam J. Woods (GeroScience, 2024)

Avidity maturation of humoral response following primary and booster doses of BNT162b2 mRNA vaccine among nursing home residents and healthcare workers - Oladayo A. Oyebanji; Nicholas Sundheimer; Vaishnavi Ragavapuram; Brigid M. Wilson; Yasin Abul; Stefan Gravenstein; Jürgen Bosch; Christopher L. King; David H. Canaday (GeroScience, 2024)
Infections, despite vaccination, can be clinically consequential for frail nursing home residents (NHR). Poor vaccine-induced antibody quality may add risk for such subsequent infections and more severe disease. We assessed antibody binding avidity, as a surrogate for antibody quality, among NHR and healthcare workers (HCW). We longitudinally sampled 112 NHR and 52 HCWs who received the BNT162b2 mRNA vaccine after each dose up to the Wuhan-BA.4/5-based Omicron bivalent boosters. We quantified anti-spike, anti-receptor binding domain (RBD), and avidity levels to the ancestral Wuhan, Delta, and Omicron BA.1 & 4/5 strains. The primary vaccination series produced substantial anti-spike and RBD levels which were low in avidity against all strains tested. Antibody avidity progressively increased in the 6–8 months that followed. Avidity significantly increased after the 1st booster but not for subsequent boosters. This study underscores the importance of booster vaccination among NHR and HCWs. The 1st booster dose increases avidity, increasing vaccine-induced functional antibody. The higher cross-reactivity of higher avidity antibodies to other SARS-CoV-2 strains should translate to better protection from ever-evolving strains. Higher avidities may help explain how the vaccine’s protective effects persist despite waning antibody titers after each vaccine dose.

Ingestion of β-nicotinamide mononucleotide increased blood NAD levels, maintained walking speed, and improved sleep quality in older adults in a double-blind randomized, placebo-controlled study - Masashi Morifuji; Seiichiro Higashi; Shukuko Ebihara; Masashi Nagata (GeroScience, 2024)

Fmo induction as a tool to screen for pro-longevity drugs - Shijiao Huang; Rebecca L. Cox; Angela Tuckowski; Safa Beydoun; Ajay Bhat; Marshall B. Howington; Marjana Sarker; Hillary Miller; Ethan Ruwe; Emily Wang; Xinna Li; Emily A. Gardea; et al. (GeroScience, 2024)

Systemic metabolic benefits of 17α-estradiol are not exclusively mediated by ERα in glutamatergic or GABAergic neurons - Celine Camon; Mel Prescott; Christine Neyt; Caroline Decourt; Michael B. Stout; Rebecca E. Campbell; Michael Garratt (GeroScience, 2024)
17α-Estradiol (17αE2), a less-feminising enantiomer of 17β-estradiol, has been shown to prolong lifespan and improve metabolic health in a sex-specific manner in male, but not in female mice. Recent studies have demonstrated the pivotal role of estrogen receptor α (ERα) in mediating the effects of 17αE2 on metabolic health. However, the specific tissues and/or neuronal signalling pathways that 17αE2 acts through remain to be elucidated. ERα expression in glutamatergic and GABAergic neurons (principal excitatory and inhibitory neurons respectively) in the hypothalamus is essential for estradiol signalling. Therefore, we hypothesised that knocking out ERα from one of these neuronal populations would attenuate the established beneficial metabolic effects of 17αE2 in male mice exposed to a high fat diet. To test this hypothesis we used two established brain specific ERα KO models, targeting either glutamatergic or GABAergic neurons (Vglut2/Vgat-ERαKO). We show that both of these ERα KO models exhibit a strong reduction in ERα expression in the arcuate nucleus of the hypothalamus, a control centre for metabolic regulation. Deletion of ERα from GABAergic neurons significantly diminished the effect of 17αE2 on body weight relative to controls, although these animals still show metabolic benefits with 17αE2 treatment. The response to 17αE2 was unaffected by ERα deletion in glutamatergic neurons. Our results support a benefit of 17αE2 treatment in protection against metabolic dysfunction, but these effects do not depend on exclusive ERα expression in glutamatergic and GABAergic neurons and persist when ERα expression is strongly reduced in the arcuate nucleus of the hypothalamus.

Carotid-femoral pulse wave velocity score, an estimator of cognitive performance in the elderly: results from the Toledo Study for Healthy Aging - Fabio A. Quiñónez Bareiro; José A. Carnicero; Ana Alfaro Acha; Cristina Rosado Artalejo; María C. Grau Jimenez; Leocadio Rodriguez Mañas; Francisco J. García García (GeroScience, 2024)

EEG entropy insights in the context of physiological aging and Alzheimer’s and Parkinson’s diseases: a comprehensive review - Alessia Cacciotti; Chiara Pappalettera; Francesca Miraglia; Paolo Maria Rossini; Fabrizio Vecchio (GeroScience, 2024)

Five years later, with double the demographic data, naked mole-rat mortality rates continue to defy Gompertzian laws by not increasing with age - J. Graham Ruby; Megan Smith; Rochelle Buffenstein (GeroScience, 2024)
The naked mole-rat ( Heterocephalus glaber ) is a mouse-sized rodent species, notable for its eusociality and long lifespan. Previously, we reported that demographic aging, i.e., the exponential increase of mortality hazard that accompanies advancing age in mammals and other organisms, does not occur in naked mole-rats (Ruby et al., 2018), a finding that has potential implications for human healthy aging. The demographic data supporting that conclusion had taken over three decades to accumulate, starting with the original rearing of H. glaber in captivity. This finding was controversial since many of the animals in that study were relatively young. In the 5 years following that study, we have doubled our quantity of demographic data. Here, we re-evaluated our prior conclusions in light of these new data and found them to be not only supported but indeed strengthened. We additionally provided insight into the social dynamics of captive H. glaber with data and analyses of body weight and colony size versus mortality. Finally, we provide a phylogenetically proximal comparator in the form of lifespan data from our Damaraland mole-rat ( Fukomys damarensis ) colony and demographic meta-analysis of those data along with published data from Ansell’s mole-rat ( Fukomys anselli ). We found Fukomys mortality hazard to increase gradually with age, an observation with inferences on the evolution of exceptional lifespan among mole-rats and the ecological factors that may have accompanied that evolution.

Optimizing cardiopulmonary rehabilitation duration for long COVID patients: an exercise physiology monitoring approach - Zsofia Szarvas; Monika Fekete; Gergo Jozsef Szollosi; Katica Kup; Rita Horvath; Maya Shimizu; Fuko Tsuhiya; Ha Eun Choi; Huang-Tzu Wu; Vince Fazekas-Pongor; Kinga Nedda Pete; Renata Cserjesi; et al. (GeroScience, 2024)
The presence of prolonged symptoms after COVID infection worsens the workability and quality of life. 200 adults with long COVID syndrome were enrolled after medical, physical, and mental screening, and were divided into two groups based on their performance. The intervention group ( n = 100) received supervised rehabilitation at Department of Pulmonology, Semmelweis University with the registration number 160/2021 between 01/APR/2021–31/DEC/2022, while an age-matched control group ( n = 100) received a single check-up. To evaluate the long-term effects of the rehabilitation, the intervention group was involved in a 2- and 3-month follow-up, carrying out cardiopulmonary exercise test. Our study contributes understanding long COVID rehabilitation, emphasizing the potential benefits of structured cardiopulmonary rehabilitation in enhancing patient outcomes and well-being. Significant difference was found between intervention group and control group at baseline visit in pulmonary parameters, as forced vital capacity, forced expiratory volume, forced expiratory volume, transfer factor for carbon monoxide, transfer coefficient for carbon monoxide, and oxygen saturation (all p < 0.05). Our follow-up study proved that a 2-week long, patient-centered pulmonary rehabilitation program has a positive long-term effect on people with symptomatic long COVID syndrome. Our data showed significant improvement between two and three months in maximal oxygen consumption ( p < 0.05). Multidisciplinary, individualized approach may be a key element of a successful cardiopulmonary rehabilitation in long COVID conditions, which improves workload, quality of life, respiratory function, and status of patients with long COVID syndrome.

Hepatic WDR23 proteostasis mediates insulin homeostasis by regulating insulin-degrading enzyme capacity - Chatrawee Duangjan; Thalida Em Arpawong; Brett N. Spatola; Sean P. Curran (GeroScience, 2024)
Maintaining insulin homeostasis is critical for cellular and organismal metabolism. In the liver, insulin is degraded by the activity of the insulin-degrading enzyme (IDE). Here, we establish a hepatic regulatory axis for IDE through WDR23-proteostasis. Wdr23KO mice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lacking WDR23 also increase IDE expression and display dysregulated phosphorylation of insulin signaling cascade proteins, IRS-1, AKT2, MAPK, FoxO, and mTOR, similar to cells treated with insulin, which can be mitigated by chemical inhibition of IDE. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults, supporting the use of WDR23 as a new molecular determinant of metabolic health in humans.

Everolimus alleviates CD4+ T cell inflammation by regulating autophagy and cellular redox homeostasis - Jack Donato Rockhold; Heather Marszalkowski; Marco Sannella; Kaleigh Gibney; Lyanne Murphy; Emelia Zukowski; Gabriella H. Kalantar; Sara SantaCruz-Calvo; Samantha N. Hart; Madison K. Kuhn; Jingting Yu; Olivia Stefanik; et al. (GeroScience, 2024)

Quantification of age-related changes in the structure and mechanical function of skin with multiscale imaging - Alan E. Woessner; Nathan J. Witt; Jake D. Jones; Edward A. Sander; Kyle P. Quinn (GeroScience, 2024)
The mechanical properties of skin change during aging but the relationships between structure and mechanical function remain poorly understood. Previous work has shown that young skin exhibits a substantial decrease in tissue volume, a large macro-scale Poisson’s ratio, and an increase in micro-scale collagen fiber alignment during mechanical stretch. In this study, label-free multiphoton microscopy was used to quantify how the microstructure and fiber kinematics of aged mouse skin affect its mechanical function. In an unloaded state, aged skin was found to have less collagen alignment and more non-enzymatic collagen fiber crosslinks. Skin samples were then loaded in uniaxial tension and aged skin exhibited a lower mechanical stiffness compared to young skin. Aged tissue also demonstrated less volume reduction and a lower macro-scale Poisson’s ratio at 10% uniaxial strain, but not at 20% strain. The magnitude of 3D fiber realignment in the direction of loading was not different between age groups, and the amount of realignment in young and aged skin was less than expected based on theoretical fiber kinematics affine to the local deformation. These findings provide key insights on how the collagen fiber microstructure changes with age, and how those changes affect the mechanical function of skin, findings which may help guide wound healing or anti-aging treatments.

Quantification of healthspan in aging mice: introducing FAMY and GRAIL - Dudley W. Lamming (GeroScience, 2024)

A cocktail of rapamycin, acarbose, and phenylbutyrate prevents age-related cognitive decline in mice by targeting multiple aging pathways - Zhou Jiang; Qianpei He; Jackson Wezeman; Martin Darvas; Warren Ladiges (GeroScience, 2024)
Aging is a primary risk factor for cognitive impairment and exacerbates multiple biological processes in the brain, including but not limited to nutrient sensing, insulin signaling, and histone deacetylation activity. Therefore, a pharmaceutical intervention of aging that targets distinct but overlapping pathways provides a basis for testing combinations of drugs as a cocktail. Our previous study showed that middle-aged mice treated with a cocktail of rapamycin, acarbose, and phenylbutyrate for 3 months had increased resilience to age-related cognitive decline. This finding provided the rationale to investigate the transcriptomic and molecular changes within the brains of mice that received this cocktail treatment or control treatment. Transcriptomic profiles were generated through ribonucleic acid (RNA) sequencing, and pathway analysis was performed by gene set enrichment analysis to evaluate the overall RNA message effect of the drug cocktail. Molecular endpoints representing aging pathways were measured using immunohistochemistry to further validate the attenuation of brain aging in the hippocampus of mice that received the cocktail treatment, each individual drug or control. Results showed that biological processes that enhance aging were suppressed, with an increased trend of autophagy in the brains of mice given the drug cocktail. The molecular endpoint assessments indicated that treatment with the drug cocktail was overall more effective than any of the individual drugs for relieving cognitive impairment by targeting multiple aging pathways.

Clinical biomarker-based biological age predicts deaths in Brazilian adults: the ELSA-Brasil study - Amanda Viana Machado; Juliana Freitas de Mello e Silva; Enrico Antônio Colosimo; Belinda L. Needham; Chams Bicalho Maluf; Luana Giatti; Lidyane V. Camelo; Sandhi Maria Barreto (GeroScience, 2024)

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin - Richard A. Miller; David E. Harrison; Gino A. Cortopassi; Ishmael Dehghan; Elizabeth Fernandez; Michael Garratt; John G. Geisler; Brett C. Ginsburg; Melissa L. Han; Catherine C. Kaczorowski; Navasuja Kumar; Scott F. Leiser; et al. (GeroScience, 2024)

Amyloid β accelerates age-related proteome-wide protein insolubility - Edward Anderton; Manish Chamoli; Dipa Bhaumik; Christina D. King; Xueshu Xie; Anna Foulger; Julie K. Andersen; Birgit Schilling; Gordon J. Lithgow (GeroScience, 2024)
Loss of proteostasis is a highly conserved feature of aging across model organisms and results in the accumulation of insoluble protein aggregates. Protein insolubility is also a unifying feature of major age-related neurodegenerative diseases, including Alzheimer's Disease (AD), in which hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven generalized protein insolubility as a contributing factor. However, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro and lifespan in vivo. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. Specifically, we uncovered that Aβ expression drives proteome-wide protein insolubility in C. elegans , even in young animals, and this insoluble proteome is highly similar to the insoluble proteome driven by normal aging, this vulnerable sub-proteome we term the core insoluble proteome (CIP). We show that the CIP is enriched with proteins that modify Aβ toxicity in vivo, suggesting the possibility of a vicious feedforward cycle in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the geroprotective, gut-derived metabolite, Urolithin A, relieves Aβ toxicity, supporting its use in clinical trials for dementia and age-related diseases.

Neuroanatomical substrates of depression in dementia with Lewy bodies and Alzheimer’s disease - Manon Querry; Anne Botzung; Benjamin Cretin; Catherine Demuynck; Candice Muller; Alix Ravier; Benoît Schorr; Mary Mondino; Léa Sanna; Paulo Loureiro de Sousa; Nathalie Philippi; Frédéric Blanc (GeroScience, 2024)

Multi-night acoustic stimulation is associated with better sleep, amyloid dynamics, and memory in older adults with cognitive impairment - Céline J. Zeller; Marina Wunderlin; Korian Wicki; Charlotte E. Teunissen; Christoph Nissen; Marc A. Züst; Stefan Klöppel (GeroScience, 2024)
Sleep is a potential early, modifiable risk factor for cognitive decline and dementia. Impaired slow wave sleep (SWS) is pronounced in individuals with cognitive impairment (CI). Cognitive decline and impairments of SWS are bi-directionally linked in a vicious cycle. SWS can be enhanced non-invasively using phase-locked acoustic stimulation (PLAS), potentially breaking this vicious cycle. Eighteen healthy older adults (HC, age mean±sd , 68.3 ± 5.1) and 16 older adults (age mean±sd , 71.9 ± 3.9) with CI (Montreal Cognitive Assessment ≤ 25) underwent one baseline (sham-PLAS) night and three consecutive stimulation nights (real-PLAS). EEG responses and blood-plasma amyloid beta Aβ42/Aβ40 ratio were measured pre- and post-intervention, as was episodic memory. The latter was again evaluated 1 week and 3 months after the intervention. In both groups, PLAS induced a significant electrophysiological response in both voltage- and time–frequency analyses, and memory performance improved in association with the magnitude of this response. In the CI group, both electrophysiological and associated memory effects were delayed compared to the healthy group. After 3 intervention nights, electrophysiological response to PLAS was no longer different between CI and HC groups. Only in the CI sample, stronger electrophysiological responses were significantly associated with improving post-intervention Aβ42/Aβ40 ratios. PLAS seems to improve SWS electrophysiology, memory, and amyloid dynamics in older adults with CI. However, effects on memory require more time to unfold compared to healthy older adults. This indicates that PLAS may become a potential tool to ameliorate cognitive decline, but longer interventions are necessary to compensate for declining brain integrity. This study was pre-registered (clinicaltrials.gov: NCT04277104).

Reliable detection of stochastic epigenetic mutations and associations with cardiovascular aging - Yaroslav Markov; Morgan Levine; Albert T. Higgins-Chen (GeroScience, 2024)

Single episode of moderate to severe traumatic brain injury leads to chronic neurological deficits and Alzheimer’s-like pathological dementia - Kumar Vaibhav; Mayuri Gulhane; Pankaj Ahluwalia; Manish Kumar; Meenakshi Ahluwalia; Ashiq M. Rafiq; Vibha Amble; Manuela G. Zabala; Jacob B. Miller; Liam Goldman; Ashis K. Mondal; Ferenc Deak; et al. (GeroScience, 2024)

The influence of immobility on muscle loss in older people with frailty and fragility fractures - Eleanor K. Lunt; Adam L. Gordon; Paul L. Greenhaff; John F. R. Gladman (GeroScience, 2024)
This longitudinal study aimed to assess muscle morphological and functional changes in older patients admitted with fragility fractures managed by immobilisation of the affected limb for at least 6 weeks. Patients aged ≥ 70 hospitalised with non-weight bearing limb fractures, and functionally limited to transfers only, were recruited. Handgrip (HGS) and knee extensor strength (KES), Vastus Lateralis muscle thickness (VLMT) and cross-sectional area at ultrasound (VLCSA) were measured in the non-injured limb at hospital admission, 1, 3 and 6 weeks later. Barthel Index, mobility aid use and residential status were recorded at baseline and 16 weeks. Longitudinal changes in muscle measurements were analysed using one-way repeated measures ANOVA. In a sub-study, female patients’ baseline measurements were compared to 11 healthy, female, non-frail, non-hospitalised control volunteers (HC) with comparable BMI, aged ≥ 70, using independent t tests. Fifty patients (44 female) participated. Neither muscle strength nor muscle size changed over a 6-week immobilisation. Dependency increased significantly from pre-fracture to 16 weeks. At baseline, the patient subgroup was weaker (HGS 9.2 ± 4.7 kg vs. 19.9 ± 5.8 kg, p < 0.001; KES 4.5 ± 1.5 kg vs. 7.8 ± 1.3 kg, p < 0.001) and had lower muscle size (VLMT 1.38 ± 0.47 cm vs. 1.75 ± 0.30 cm, p = 0.02; VLCSA 8.92 ± 4.37 cm 2 vs. 13.35 ± 3.97 cm 2 , p = 0.005) than HC. The associations with lower muscle strength measures but not muscle size remained statistically significant after adjustment for age. Patients with non-weight bearing fractures were weaker than HC even after accounting for age differences. Although functional dependency increased after fracture, this was not related to muscle mass or strength loss, which remained unchanged.

Abnormal EEG microstates in Alzheimer’s disease: predictors of β-amyloid deposition degree and disease classification - Yibing Yan; Manman Gao; Zhi Geng; Yue Wu; Guixian Xiao; Lu Wang; Xuerui Pang; Chaoyi Yang; Shanshan Zhou; Hongru Li; Panpan Hu; Xingqi Wu; et al. (GeroScience, 2024)
Electroencephalography (EEG) microstates are used to study cognitive processes and brain disease-related changes. However, dysfunctional patterns of microstate dynamics in Alzheimer's disease (AD) remain uncertain. To investigate microstate changes in AD using EEG and assess their association with cognitive function and pathological changes in cerebrospinal fluid (CSF). We enrolled 56 patients with AD and 38 age- and sex-matched healthy controls (HC). All participants underwent various neuropsychological assessments and resting-state EEG recordings. Patients with AD also underwent CSF examinations to assess biomarkers related to the disease. Stepwise regression was used to analyze the relationship between changes in microstate patterns and CSF biomarkers. Receiver operating characteristics analysis was used to assess the potential of these microstate patterns as diagnostic predictors for AD. Compared with HC, patients with AD exhibited longer durations of microstates C and D, along with a decreased occurrence of microstate B. These microstate pattern changes were associated with Stroop Color Word Test and Activities of Daily Living scale scores (all P < 0.05). Mean duration, occurrences of microstate B, and mean occurrence were correlated with CSF Aβ 1–42 levels, while duration of microstate C was correlated with CSF Aβ 1–40 levels in AD (all P < 0.05). EEG microstates are used to predict AD classification with moderate accuracy. Changes in EEG microstate patterns in patients with AD correlate with cognition and disease severity, relate to Aβ deposition, and may be useful predictors for disease classification.

Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain - Rafal Gulej; Ádám Nyúl-Tóth; Boglarka Csik; Roland Patai; Benjamin Petersen; Sharon Negri; Siva Sai Chandragiri; Santny Shanmugarama; Peter Mukli; Andriy Yabluchanskiy; Shannon Conley; Derek Huffman; et al. (GeroScience, 2024)

Genome integrity as a potential index of longevity in Ashkenazi Centenarian’s families - Mariana Andrawus; Gil Ben David; Ivana Terziyska; Lital Sharvit; Aviv Bergman; Nir Barzilai; Srilakshmi M. Raj; Diddahally R. Govindaraju; Gil Atzmon (GeroScience, 2024)
The aging process, or senescence, is characterized by age-specific decline in physical and physiological function, and increased frailty and genomic changes, including mutation accumulation. However, the mechanisms through which changes in genomic architecture influence human longevity have remained obscure. Copy number variants (CNVs), an abundant class of genomic variants, offer unique opportunities for understanding age-related genomic changes. Here we report the spectrum of CNVs in a cohort of 670 Ashkenazi Jewish centenarians, their progeny, and unrelated controls. The average ages of these groups were 97.4 ± 2.8, 69.2 ± 9.2, and 66.5 ± 7.0 respectively. For the first time, we compared different size classes of CNVs, from 1 kB to 100 MB in size. Using a high-resolution custom Affymetrix array, targeting 44,639 genomic regions, we identified a total of 12,166, 22,188, and 10,285 CNVs in centenarians, their progeny, and control groups, respectively. Interestingly, the offspring group showed the highest number of unique CNVs, followed by control and centenarians. While both gains and losses were found in all three groups, centenarians showed a significantly higher average number of both total gains and losses relative to their controls ( p < 0.0327, 0.0182, respectively). Moreover, centenarians showed a lower total length of genomic material lost, suggesting that they may maintain superior genomic integrity over time. We also observe a significance fold increase of CNVs among the offspring, implying greater genomic integrity and a putative mechanism for longevity preservation. Genomic regions that experienced loss or gains appear to be distributed across many sites in the genome and contain genes involved in DNA transcription, cellular transport, developmental pathways, and metabolic functions. Our findings suggest that the exceptional longevity observed in centenarians may be attributed to the prolonged maintenance of functionally important genes. These genes are intrinsic to specific genomic regions as well as to the overall integrity of the genomic architecture. Additionally, a strong association between longer CNVs and differential gene expression observed in this study supports the notion that genomic integrity could positively influence longevity.

Intensive antihypertensive treatment does not lower cerebral blood flow or cause orthostatic hypotension in frail older adults - Ralf W. J. Weijs; Bente M. de Roos; Dick H. J. Thijssen; Jurgen A. H. R. Claassen (GeroScience, 2024)
This study aimed to examine the effects of intensive antihypertensive treatment (AHT), i.e., systolic blood pressure target ≤ 140 mmHg, on cerebral blood flow, cerebral autoregulation, and orthostatic hypotension, in a representative population of frail older adults. Fourteen frail hypertensive patients (six females; age 80.3 ± 5.2 years; Clinical Frailty Scale 4–7; unattended SBP ≥ 150 mmHg) underwent measurements before and after a median 7-week AHT targeting SBP ≤ 140 mmHg. Transcranial Doppler measurements of middle cerebral artery velocity (MCAv), reflecting changes in cerebral blood flow (CBF), were combined with finger plethysmography recordings of continuous BP. Transfer function analysis assessed cerebral autoregulation (CA). ANCOVA analysed AHT-induced changes in CBF and CA and evaluated non-inferiority of the relative change in CBF (margin: -10%; covariates: pre-AHT values and AHT-induced relative mean BP change). McNemar-tests analysed whether the prevalence of OH and initial OH, assessed by sit/supine-to-stand challenges, increased with AHT. Unattended mean arterial pressure decreased by 15 mmHg following AHT. Ten (71%) participants had good quality TCD assessments. Non-inferiority was confirmed for the relative change in MCAv (95%CI: -2.7, 30.4). CA remained normal following AHT ( P > 0.05), and the prevalence of OH and initial OH did not increase ( P ≥ 0.655). We found that AHT in frail, older patients does not reduce CBF, impair autoregulation, or increase (initial) OH prevalence. These observations may open doors for more intensive AHT targets upon individualized evaluation and monitoring of hypertensive frail patients. Clinical Trial Registration: This study is registered at ClinicalTrials.gov (NCT05529147; September 1, 2022) and EudraCT (2022-001283-10; June 28, 2022).

Association between physical fitness and executive functions in cognitively healthy female older adults: a cross-sectional study - Shirko Ahmadi; Isadora Quirion; Pierre Faivre; Pierre Philippe Wilson Registe; Myles W. O’Brien; Nick W. Bray; Olivier Dupuy; Martin Sénéchal; Mathieu Bélanger; Said Mekari (GeroScience, 2024)

Sex-specific relationships of inflammatory biomarkers with blood pressure in older adults - Joanna Sulicka-Grodzicka; Barbara Wizner; Tomasz Zdrojewski; Małgorzata Mossakowska; Monika Puzianowska-Kuźnicka; Jerzy Chudek; Andrzej Więcek; Mariusz Korkosz; Elisabetta Caiazzo; Pasquale Maffia; Mateusz Siedlinski; Franz H. Messerli; et al. (GeroScience, 2024)
Emerging evidence indicates an association between blood pressure and inflammation, yet this relationship remains unclear in older adults, despite the elevated prevalence of hypertension. We investigated the association between blood pressure, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and white blood cell (WBC) count in a cohort of 3571 older adults aged 65 and above, and 587 middle-aged participants (55–59 years old). In women aged 65 and above, the relationship between inflammatory markers and blood pressure was consistent, with hs-CRP and WBC emerging as predictors of high blood pressure. For hs-CRP, the adjusted odds ratio (OR) was 1.5 (95% CI, 1.07 to 2.10, P = 0.02), and for WBC, the adjusted OR was 1.41 (95% CI, 1.02 to 1.94, P = 0.04), comparing the highest to the lowest quartiles. In men, only the WBC count was significantly associated with an increased OR for high BP (adjusted OR 1.49, 95% CI, 1.09 to 2.02, P = 0.01) across quartiles. Across the entire study population, in a fully adjusted model, all inflammatory markers were modestly associated with blood pressure levels, while the effect of being over 65 years was the most significant predictor of high blood pressure (OR 1.84, 95% CI, 1.50 to 2.25, P < 0.001). The link between key inflammation markers and blood pressure in older adults varies by sex and biomarker type and may differ from the relationship observed in younger individuals. These relationships are likely to be affected by factors linked to age.

Age-related shifts in mental health determinants from a deprived area in the European Union: informing the national healthy aging program of Hungary - Nora Kovacs; Eva Biro; Peter Piko; Zoltan Ungvari; Roza Adany (GeroScience, 2024)
Mental disorders are among the leading causes of disability worldwide, disproportionately affecting older people. This study aims to assess the mental health of elderly individuals living in a deprived region of Hungary, and to identify and estimate the weight of different determinants of mental health across different age groups. A cross-sectional study was conducted with randomly selected samples of individuals (n = 860) aged 18 years and older in Northeast Hungary. The World Health Organization Well-Being Index (WHO-5), the single-item Life Satisfaction Scale, and the 12-item General Health Questionnaire (GHQ-12) were used to measure mental health of the participants. Multiple linear regression analysis was performed to measure the association between sociodemographic and health-related variables and mental health. Overall, the mean WHO-5 score was 69.2 ± 18.1 and it showed a significant decrease by age ( p < 0.001), with the lowest score observed in aged 75 years and above ( p < 0.001). The mean life satisfaction score was 7.5 ± 1.9 and it showed a significant decreasing trend over the life course ( p < 0.001). The highest level of psychological distress as assessed by GHQ-12 was observed in the group aged 75 years or older (11.5 ± 6.0, p < 0.001). Multiple linear regression indicated that self-reported financial status, social support, sense of control over their health, activity limitation and pain intensity were the most important determinants of mental health among older adults. Interventions to improve the mental health of older adults should focus on the positive impact of social support, the reduction of financial insecurity and the use of effective pain relief medications.

Hemodynamic gain index and risk of chronic kidney disease: A prospective cohort study of middle-aged and older men - Setor K. Kunutsor; Jari A. Laukkanen (GeroScience, 2024)
The hemodynamic gain index (HGI), a novel non-invasive hemodynamic marker, represents a promising advancement in cardiovascular risk assessment. Cardiovascular disease and chronic kidney disease (CKD) are closely intertwined and share bidirectional relationships. We aimed to assess the association of HGI with CKD risk in a prospective study. Hemodynamic gain index was calculated using heart rate and systolic blood pressure (SBP) responses measured in 1765 men aged 42–61 years with normal kidney function during exercise testing using the formula: [(Heart rate max x SBP max )—(Heart rate rest x SBP rest )]/(Heart rate rest x SBP rest ). Multivariable adjusted hazard ratios (HRs) (95% confidence intervals, CIs) were estimated for CKD. Over a median follow-up duration of 25.9 years, 175 CKD cases occurred. In analysis adjusted for established risk factors, a unit (bpm/mmHg) higher HGI was associated with a decreased risk of CKD (HR 0.78, 95% CI 0.65–0.95). Comparing extreme tertiles of HGI, the corresponding adjusted HR (95% CI) for CKD was 0.53 (0.33–0.85). Addition of HGI to a CKD risk prediction model containing established risk factors improved risk discrimination and reclassification ( p -value for difference in -2 log likelihood = .011; net-reclassification-improvement = 59.37%, p = .018; integrated-discrimination-improvement = 0.0064, p = .008). Higher HGI is associated with a lower CKD risk and improves the prediction and classification of CKD beyond common established risk factors.

Evaluating osteoporosis and bone quality in the aging spine: modern considerations for surgical management in the geriatric population - Miles Hudson; Jenna Meyer; Alexander Evans; Chandan Krishna; Zachary A. Smith; Joshua Bakhsheshian (GeroScience, 2024)

Cannabinoids and healthy ageing: the potential for extending healthspan and lifespan in preclinical models with an emphasis on Caenorhabditis elegans - Zhizhen Wang; Jonathon C. Arnold (GeroScience, 2024)
There is a significant global upsurge in the number and proportion of older persons in the population. With this comes an increasing prevalence of age-related conditions which pose a major challenge to healthcare systems. The development of anti-ageing treatments may help meet this challenge by targeting the ageing process which is a common denominator to many health problems. Cannabis-like compounds (cannabinoids) are reported to improve quality of life and general well-being in human trials, and there is increasing preclinical research highlighting that they have anti-ageing activity. Moreover, preclinical evidence suggests that endogenous cannabinoids regulate ageing processes. Here, we review the anti-ageing effects of the cannabinoids in various model systems, including the most extensively studied nematode model, Caenorhabditis elegans . These studies highlight that the cannabinoids lengthen healthspan and lifespan, with emerging evidence that they may also hinder the development of cellular senescence. The non-psychoactive cannabinoid cannabidiol (CBD) shows particular promise, with mechanistic studies demonstrating it may work through autophagy induction and activation of antioxidative systems. Furthermore, CBD improves healthspan parameters such as diminishing age-related behavioural dysfunction in models of both healthy and accelerated ageing. Translation into mammalian systems provides an important next step. Moreover, looking beyond CBD, future studies could probe the multitude of other cannabis constituents for their anti-ageing activity.

Trends in prevalence, mortality, and risk factors of dementia among the oldest-old adults in the United States: the role of the obesity epidemic - Xueshan Cao; Minmin Wang; Mengge Zhou; Yuanqi Mi; Vince Fazekas-Pongor; David Major; Andrea Lehoczki; Yang Guo (GeroScience, 2024)

Using non-invasive behavioral and physiological data to measure biological age in wild baboons - Chelsea J. Weibel; Mauna R. Dasari; David A. Jansen; Laurence R. Gesquiere; Raphael S. Mututua; J. Kinyua Warutere; Long’ida I. Siodi; Susan C. Alberts; Jenny Tung; Elizabeth A. Archie (GeroScience, 2024)
Biological aging is near-ubiquitous in the animal kingdom, but its timing and pace vary between individuals and over lifespans. Prospective, individual-based studies of wild animals—especially non-human primates—help identify the social and environmental drivers of this variation by indicating the conditions and exposure windows that affect aging processes. However, measuring individual biological age in wild primates is challenging because several of the most promising methods require invasive sampling. Here, we leverage observational data on behavior and physiology, collected non-invasively from 319 wild female baboons across 2402 female-years of study, to develop a composite predictor of age: the non-invasive physiology and behavior (NPB) clock. We found that age predictions from the NPB clock explained 51% of the variation in females’ known ages. Further, deviations from the clock’s age predictions predicted female survival: females predicted to be older than their known ages had higher adult mortality. Finally, females who experienced harsh early-life conditions were predicted to be about 6 months older than those who grew up in more benign conditions. While the relationship between early adversity and NPB age is noisy, this estimate translates to a predicted 2–3 year reduction in mean adult lifespan in our model. A constraint of our clock is that it is tailored to data collection approaches implemented in our study population. However, many of the clock’s components have analogs in other populations, suggesting that non-invasive data can provide broadly applicable insight into heterogeneity in biological age in natural populations.

Newer treatment paradigm improves outcomes in the most common neurosurgical disease of the elderly: a literature review of middle meningeal artery embolization for chronic subdural hematoma - Luca H. Debs; Samantha E. Walker; Scott Y. Rahimi (GeroScience, 2024)
Chronic subdural hematoma (cSDH) is one of the most prevalent neurosurgical diseases, especially in the elderly. Yet, its incidence is predicted to increase further, paralleling the growth of the geriatric population. While surgical evacuation is technically straightforward, it is associated with significant morbidity and mortality. In fact, 30% of patients are expected to have hematoma recurrence and to need repeat surgical evacuation, and 20% of patients are expected to lose independence and require long-term care. A pathophysiology more complex than originally presumed explains the disappointing results observed for decades. At its core, the formation of microcapillaries and anastomotic channels with the middle meningeal artery (MMA) perpetuates a constant cycle resulting in persistence of hematoma. The rationale behind MMA embolization is simple: to stop cSDH at its source. Over the last few years, this “newer” option has been heavily studied. It has shown tremendous potential in decreasing hematoma recurrence and improving neurological outcomes. Whether combined with surgical evacuation or performed as the only treatment, the scientific evidence to its benefits is unequivocal. Here, we aimed to review cSDH in the elderly and discuss its more recent treatment options with an emphasis on MMA embolization.

Autopsy findings in cancer patients infected with SARS-CoV-2 show a milder presentation of COVID-19 compared to non-cancer patients - Éva Kocsmár; Ildikó Kocsmár; Flóra Elamin; Laura Pápai; Ákos Jakab; Tibor Várkonyi; Tibor Glasz; Gergely Rácz; Adrián Pesti; Krisztina Danics; András Kiss; Gergely Röst; et al. (GeroScience, 2024)
COVID-19, caused by SARS-CoV-2, manifests with differing severity across distinct patient subgroups, with outcomes influenced by underlying comorbidities such as cancer, which may cause functional and compositional alterations of the immune system during tumor progression. We aimed to investigate the association of SARS-CoV-2 infection and its complications with cancer in a large autopsy series and the role of COVID-19 in the fatal sequence leading to death. A total of 2641 adult autopsies were investigated, 539 of these were positive for SARS-CoV-2. Among the total number of patients analyzed, 829 had active cancer. Overall, the cohort included 100 patients who simultaneously had cancer and SARS-CoV-2 infection. The course of COVID-19 was less severe in cancer patients, including a significantly lower incidence of viral and bacterial pneumonia, occurring more frequently as a contributory disease or coexisting morbidity, or as SARS-CoV-2 positivity without viral disease. SARS-CoV-2 positivity was more frequent among non-metastatic than metastatic cancer cases, and in specific tumor types including hematologic malignancies. COVID-19 was more frequently found to be directly involved in the fatal sequence in patients undergoing active anticancer therapy, but less frequently in perioperative status, suggesting that the underlying malignancy and consequent surgery are more important factors leading to death perioperatively than viral disease. The course of COVID-19 in cancer patients was milder and balanced during the pandemic. This may be due to relative immunosuppressed status, and the fact that even early/mild viral infections can easily upset their condition, leading to death from their underlying cancer or its complications.

Echocardiographic characterization of age- and sex-associated differences in cardiac function and morphometry in nonhuman primates - Maria Cristina Florio; Laura Fusini; Gloria Tamborini; Christopher Morrell; Alise McDonald; Michelle Walcott; Kenneth Ridley; Kelli L. Vaughan; Julie A. Mattison; Mauro Pepi; Edward G. Lakatta; Maurizio C. Capogrossi (GeroScience, 2024)

Increases in regional brain volume across two native South American male populations - Nikhil N. Chaudhari; Phoebe E. Imms; Nahian F. Chowdhury; Margaret Gatz; Benjamin C. Trumble; Wendy J. Mack; E. Meng Law; M. Linda Sutherland; James D. Sutherland; Christopher J. Rowan; L. Samuel Wann; Adel H. Allam; et al. (GeroScience, 2024)
Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between industrialized and non-industrialized populations can help to suggest lifestyle correlates of brain health. The Tsimane, indigenous to the Bolivian Amazon, derive their subsistence from foraging and horticulture and are physically active. The Moseten, a mixed-ethnicity farming population, are physically active but less than the Tsimane. Within both populations ( N = 1024; age range = 46–83), we calculated regional brain volumes from computed tomography and compared their cross-sectional trends with age to those of UK Biobank (UKBB) participants ( N = 19,973; same age range). Surprisingly among Tsimane and Moseten (T/M) males, some parietal and occipital structures mediating visuospatial abilities exhibit small but significant increases in regional volume with age. UKBB males exhibit a steeper negative trend of regional volume with age in frontal and temporal structures compared to T/M males. However, T/M females exhibit significantly steeper rates of brain volume decrease with age compared to UKBB females, particularly for some cerebro-cortical structures (e.g., left subparietal cortex). Across the three populations, observed trends exhibit no interhemispheric asymmetry. In conclusion, the age-related rate of regional brain volume change may differ by lifestyle and sex. The lack of brain volume reduction with age is not known to exist in other human population, highlighting the putative role of lifestyle in constraining regional brain atrophy and promoting elements of non-industrialized lifestyle like higher physical activity.

Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches - Tihamer Molnar; Andrea Lehoczki; Monika Fekete; Reka Varnai; Laszlo Zavori; Szabina Erdo-Bonyar; Diana Simon; Tímea Berki; Peter Csecsei; Erzsebet Ezer (GeroScience, 2024)
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.

Multimodal brain age prediction using machine learning: combining structural MRI and 5-HT2AR PET-derived features - Ruben P. Dörfel; Joan M. Arenas-Gomez; Claus Svarer; Melanie Ganz; Gitte M. Knudsen; Jonas E. Svensson; Pontus Plavén-Sigray (GeroScience, 2024)
To better assess the pathology of neurodegenerative disorders and the efficacy of neuroprotective interventions, it is necessary to develop biomarkers that can accurately capture age-related biological changes in the human brain. Brain serotonin 2A receptors (5-HT2AR) show a particularly profound age-related decline and are also reduced in neurodegenerative disorders, such as Alzheimer’s disease. This study investigates whether the decline in 5-HT2AR binding, measured in vivo using positron emission tomography (PET), can be used as a biomarker for brain aging. Specifically, we aim to (1) predict brain age using 5-HT2AR binding outcomes, (2) compare 5-HT2AR-based predictions of brain age to predictions based on gray matter (GM) volume, as determined with structural magnetic resonance imaging (MRI), and (3) investigate whether combining 5-HT2AR and GM volume data improves prediction. We used PET and MR images from 209 healthy individuals aged between 18 and 85 years (mean = 38, std = 18) and estimated 5-HT2AR binding and GM volume for 14 cortical and subcortical regions. Different machine learning algorithms were applied to predict chronological age based on 5-HT2AR binding, GM volume, and the combined measures. The mean absolute error (MAE) and a cross-validation approach were used for evaluation and model comparison. We find that both the cerebral 5-HT2AR binding (mean MAE = 6.63 years, std = 0.74 years) and GM volume (mean MAE = 6.95 years, std = 0.83 years) predict chronological age accurately. Combining the two measures improves the prediction further (mean MAE = 5.54 years, std = 0.68). In conclusion, 5-HT2AR binding measured using PET might be useful for improving the quantification of a biomarker for brain aging.

Prognostic significance of a signature based on senescence-related genes in colorectal cancer - Zoltan Ungvari; Anna Ungvari; Giampaolo Bianchini; Balázs Győrffy (GeroScience, 2024)
Colorectal cancer, recognized as a quintessential age-related disease, underscores the intricate interplay between aging mechanisms and disease pathogenesis. Cellular senescence, a DNA damage-induced cellular stress response, is characterized by cell cycle arrest, the expression of an inflammatory senescence-associated secretory phenotype, and alterations in extracellular matrix metabolism. It is widely recognized as a fundamental and evolutionarily conserved mechanism of aging. Guided by geroscience principles, which assert that the pathogenesis of age-related diseases involves cellular mechanisms of aging, this study delves into the role of senescence-related genes in colon cancer progression. Leveraging a gene set reflective of senescence-associated pathways, we employed uni- and multivariate Cox proportional hazards survival analysis combined with the determination of the false discovery rate to analyze correlations between gene expression and survival. The integrated database of 1130 colon cancer specimens with available relapse-free survival time and relapse event data from ten independent cohorts provided a robust platform for survival analyses. We identified senescence-related genes associated with differential expression levels linked to shorter survival. Our findings unveil a prognostic signature utilizing cellular senescence-related genes (hazard ratio: 2.73, 95% CI 2.12–3.52, p = 6.4E − 16), offering valuable insights into survival prediction in colon cancer. Multivariate analysis underscored the independence of the senescence-related signature from available epidemiological and pathological variables. This study highlights the potential of senescence-related genes as prognostic biomarkers. Overall, our results underscore the pivotal role of cellular senescence, a fundamental mechanism of aging, in colon cancer progression.

Sex-specific cardiovascular remodeling leads to a divergent sex-dependent development of heart failure in aged hypertensive rats - Árpád Kovács; Saltanat Zhazykbayeva; Melissa Herwig; Gábor Á. Fülöp; Tamás Csípő; Nikolett Oláh; Roua Hassoun; Heidi Budde; Hersh Osman; Mustafa Kaçmaz; Kornelia Jaquet; Dániel Priksz; et al. (GeroScience, 2024)
Introduction The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. Methods We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca 2+ -dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). Results TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca 2+ -sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. Conclusion Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.

Age-associated B cell infiltration in salivary glands represents a hallmark of Sjögren’s-like disease in aging mice - Harini Bagavant; Justyna Durslewicz; Marcelina Pyclik; Magdalena Makuch; Joanna A. Papinska; Umesh S. Deshmukh (GeroScience, 2024)

How does a fly die? Insights into ageing from the pathophysiology of Drosophila mortality - Eliano dos Santos; Helena M. Cochemé (GeroScience, 2024)
The fruit fly Drosophila melanogaster is a common animal model in ageing research. Large populations of flies are used to study the impact of genetic, nutritional and pharmacological interventions on survival. However, the processes through which flies die and their relative prevalence in Drosophila populations are still comparatively unknown. Understanding the causes of death in an animal model is essential to dissect the lifespan-extending interventions that are organism- or disease-specific from those broadly applicable to ageing. Here, we review the pathophysiological processes that can lead to fly death and discuss their relation to ageing.

Repetitive element transcript accumulation is associated with inflammaging in humans - Meghan E. Smith; Devin Wahl; Alyssa N. Cavalier; Gabriella T. McWilliams; Matthew J. Rossman; Gregory R. Giordano; Angela D. Bryan; Douglas R. Seals; Thomas J. LaRocca (GeroScience, 2024)

Atherosclerotic burden and cerebral small vessel disease: exploring the link through microvascular aging and cerebral microhemorrhages - Anna Csiszar; Anna Ungvari; Roland Patai; Rafal Gulej; Andriy Yabluchanskiy; Zoltan Benyo; Illes Kovacs; Peter Sotonyi; Angelia C. Kirkpartrick; Calin I. Prodan; Eric M. Liotta; Xin A. Zhang; et al. (GeroScience, 2024)
Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health.

NASH triggers cardiometabolic HFpEF in aging mice - Dániel Kucsera; Mihály Ruppert; Nabil V. Sayour; Viktória E. Tóth; Tamás Kovács; Zsombor I. Hegedűs; Zsófia Onódi; Alexandra Fábián; Attila Kovács; Tamás Radovits; Béla Merkely; Pál Pacher; et al. (GeroScience, 2024)
Both heart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) develop due to metabolic dysregulation, has similar risk factors (e.g., insulin resistance, systemic inflammation) and are unresolved clinical challenges. Therefore, the potential link between the two disease is important to study. We aimed to evaluate whether NASH is an independent factor of cardiac dysfunction and to investigate the age dependent effects of NASH on cardiac function. C57Bl/6 J middle aged (10 months old) and aged mice (24 months old) were fed either control or choline deficient (CDAA) diet for 8 weeks. Before termination, echocardiography was performed. Upon termination, organ samples were isolated for histological and molecular analysis. CDAA diet led to the development of NASH in both age groups, without inducing weight gain, allowing to study the direct effect of NASH on cardiac function. Mice with NASH developed hepatomegaly, fibrosis, and inflammation. Aged animals had increased heart weight. Conventional echocardiography revealed normal systolic function in all cohorts, while increased left ventricular volumes in aged mice. Two-dimensional speckle tracking echocardiography showed subtle systolic and diastolic deterioration in aged mice with NASH. Histologic analyses of cardiac samples showed increased cross-sectional area, pronounced fibrosis and Col1a1 gene expression, and elevated intracardiac CD68 + macrophage count with increased Il1b expression. Conventional echocardiography failed to reveal subtle change in myocardial function; however, 2D speckle tracking echocardiography was able to identify diastolic deterioration. NASH had greater impact on aged animals resulting in cardiac hypertrophy, fibrosis, and inflammation.

The Gehan test identifies life-extending compounds overlooked by the log-rank test in the NIA Interventions Testing Program: Metformin, Enalapril, caffeic acid phenethyl ester, green tea extract, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride - Nisi Jiang; Jonathan Gelfond; Qianqian Liu; Randy Strong; James F. Nelson (GeroScience, 2024)
The National Institute on Aging Interventions Testing Program (ITP) has so far identified 12 compounds that extend the lifespan of genetically heterogeneous mice using the log-rank test. However, the log-rank test is relatively insensitive to any compound that does not uniformly reduce mortality across the lifespan. This test may thus miss compounds that only reduce mortality before midlife, for example, a plausible outcome if a compound only mitigates risk factors before midlife or if its efficacy is reduced at later ages. We therefore reanalyzed all data collected by the ITP from 2004–2022 using the Gehan test, which is more sensitive to mortality differences earlier in the life course and does not assume a uniformly reduced mortality hazard across the lifespan. The Gehan test identified 5 additional compounds, metformin, enalapril, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), caffeic acid phenethyl ester (CAPE), and green tea extract (GTE), which significantly increased survival but were previously missed by the log-rank test. Three (metformin, enalapril, and 17-DMAG) were only effective in males and two (CAPE and GTE) were only effective in females. In addition, 1,3-butanediol, which by log-rank analysis increased survival in females but not males, increased survival in males by the Gehan test. These results suggest that statistical tests sensitive to non-uniformity of drug efficacy across the lifespan should be included in the standard statistical testing protocol to minimize overlooking geroprotective interventions.

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons - Daniel A. Adekunbi; Hillary F. Huber; Cun Li; Peter W. Nathanielsz; Laura A. Cox; Adam B. Salmon (GeroScience, 2024)

Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer’s disease - Jordan N. Williamson; Shirley A. James; Sean P. Mullen; Bradley P. Sutton; Tracey Wszalek; Beni Mulyana; Peter Mukli; Andriy Yabluchanskiy; Michael Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; et al. (GeroScience, 2024)

Spousal bereavement and its effects on later life physical and cognitive capability: the Tromsø study - Bjørn Heine Strand; Asta K. Håberg; Harpa Sif Eyjólfsdóttir; Almar Kok; Vegard Skirbekk; Oliver Huxhold; Gøril Kvamme Løset; Carin Lennartsson; Henrik Schirmer; Katharina Herlofson; Marijke Veenstra (GeroScience, 2024)
Spousal bereavement is associated with health declines and increased mortality risk, but its specific impact on physical and cognitive capabilities is less studied. A historical cohort study design was applied including married Tromsø study participants ( N =5739) aged 50–70 years with baseline self-reported overall health and health-related factors and measured capability (grip strength, finger tapping, digit symbol coding, and short-term recall) at follow-up. Participants had data from Tromsø4 (1994–1995) and Tromsø5 (2001), or Tromsø6 (2007–2008) and Tromsø7 (2015–2016). Propensity score matching, adjusted for baseline confounders (and baseline capability in a subset), was used to investigate whether spousal bereavement was associated with poorer subsequent capability. Spousal bereavement occurred for 6.2% on average 3.7 years (SD 2.0) before the capability assessment. There were no significant bereavement effects on subsequent grip strength, immediate recall, or finger-tapping speed. Without adjustment for baseline digit symbol coding test performance, there was a negative significant effect on the digit symbol coding test (ATT −1.33; 95% confidence interval −2.57, −0.10), but when baseline digit symbol coding test performance was taken into account in a smaller subsample, using the same set of matching confounders, there was no longer any association (in the subsample ATT changed from −1.29 (95% CI −3.38, 0.80) to −0.04 (95% CI −1.83, 1.75). The results in our study suggest that spousal bereavement does not have long-term effects on the intrinsic capacity components physical or cognition capability to a notable degree.

The association between blood biological age at rehabilitation admission and physical activity during rehabilitation in geriatric inpatients: RESORT - Jessica K. Lu; Lihuan Guan; Weilan Wang; Anna G. M. Rojer; Fedor Galkin; Jorming Goh; Andrea B. Maier (GeroScience, 2024)
Geriatric rehabilitation inpatients have high levels of sedentary behaviour (SB) and low levels of physical activity (PA). Biological age predicted by blood biomarkers is indicative of adverse outcomes. The objective was to determine the association between blood biological age at rehabilitation admission and levels of SB and PA during rehabilitation in geriatric inpatients. Inpatients admitted to geriatric rehabilitation wards at the Royal Melbourne Hospital (Melbourne, Australia) from October 22, 2019, to March 29, 2020, in the REStORing health of acute unwell adulTs (RESORT) observational cohort were included. Blood biological age was predicted using SenoClock-BloodAge, a hematological ageing clock. Patients wore an inertial sensor to measure SB and PA. Logistic regression analyses were conducted. A total of 111 patients (57.7% female) with mean age 83.3 ± 7.5 years were included in the analysis. The mean blood biological age was 82.7 ± 8.4 years. Patients with 1-year higher blood biological age had higher odds of having high SB measured as non-upright time greater than 23 h/day (odds ratio (OR): 1.050, 95% confidence interval (CI): 1.000–1.102). Individuals having 1-year higher age deviation trended towards lower odds of having high levels of PA measured as stepping time greater than 7.4 min/day (OR: 0.916, CI: 0.836–1.005) and as greater than 19.5 sit-to-stand transitions/day (OR: 0.915, CI: 0.836–1.002). In conclusion, higher biological age was associated with higher levels of SB and trended towards lower PA. Incorporating blood biological age could facilitate resource allocation and the development of more tailored rehabilitation plans.

Reduced insulin/IGF-1 signalling upregulates two anti-viral immune pathways, decreases viral load and increases survival under viral infection in C. elegans - Elizabeth M. L. Duxbury; Hanne Carlsson; Annabel Kimberley; Yvonne Ridge; Katie Johnson; Alexei A. Maklakov (GeroScience, 2024)
Reduced insulin/IGF-1 signalling (rIIS) improves survival across diverse taxa and there is a growing interest in its role in regulating immune function. Whilst rIIS can improve anti-bacterial resistance, the consequences for anti-viral immunity are yet to be systematically examined. Here, we show that rIIS in adult Caenorhabditis elegans increases the expression of key genes in two different anti-viral immunity pathways, whilst reducing viral load in old age, increasing survival and reducing rate-of-senescence under infection by naturally occurring positive-sense single-stranded RNA Orsay virus. We found that both drh-1 in the anti-viral RNA interference (RNAi) pathway and cde-1 in the terminal uridylation-based degradation of viral RNA pathway were upregulated in early adulthood under rIIS and increased anti-viral resistance was not associated with reproductive costs. Remarkably, rIIS increased anti-viral gene expression only in infected worms, potentially to curb the costs of constitutively upregulated immunity. RNA viruses are found across taxa from plants to mammals and we demonstrate a novel role for rIIS in regulating resistance to viral infection. We therefore highlight this evolutionarily conserved signalling pathway as a promising therapeutic target to improve anti-viral immunity.

Yoga-based lifestyle intervention for healthy ageing in older adults: a two-armed, waitlist randomized controlled trial with multiple primary outcomes - Atmakur Snigdha; Vijaya Majumdar; N. K. Manjunath; Amrutha Jose (GeroScience, 2024)

Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging - Naibedya Dutta; Joe A. Gerke; Sofia F. Odron; Joseph D. Morris; Adam Hruby; Juri Kim; Toni Castro Torres; Sarah J. Shemtov; Jacqueline G. Clarke; Michelle C. Chang; Hooriya Shaghasi; Marissa N. Ray; et al. (GeroScience, 2024)
Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8- O -acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells when compared to both MTZ and Rote, which has promising potential for anticancer therapeutic development. Furthermore, in vivo experiments with these small molecules utilizing a C. elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPR MT ) pathway, that extends lifespan of worms when applied in their adult stage. We also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilizes the transcription factors ATFS-1 and HSF1, which are involved in the UPR MT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging. Graphical Abstract

The behavioural effect of short-term cognitive and physical intervention therapies in old dogs - Zsófia Bognár; Dóra Szabó; Borbála Turcsán; Enikő Kubinyi (GeroScience, 2024)
Efforts to counteract age-related decline have resulted in the emergence of various interventions. However, everyday benefits are rarely reported in elderly people. Dogs provide an excellent model for studying aging and interventions due to their similarities to humans. Our aim was to investigate whether a combined physical and cognitive intervention (most effective in humans) could enhance the performance of pet dogs and lead to far transfer effects (improvement in not just the trained specific task). We examined the impact of three-month-long intervention therapies (cognitive, physical, combined) on the cognitive performance and behaviour of old, healthy dogs (N = 72; aged 7.68–14.54 years) using a 12-subtest behavioural test battery. We did not find the combined intervention group outperforming either the cognitive-only or physical-only therapy groups. Physical interventions, either alone or in combination, improved dogs' behavioural flexibility and social behaviour. Cognitive interventions, either alone or in combination, increased neophilia. Furthermore, all intervention therapies made dogs more engaged with their environment. Moreover, less old, around eight years old dogs, exhibited improved social behaviour, problem solving ability, and increased neophilia by their second test occasion. Additionally, dogs' performance was influenced by their health, training, daily play with the owner, and activity/excitability traits. In sum, both cognitive and physical intervention therapies can have an impact on the behaviour of old, healthy pet dogs. However, these therapies may be more effective when longer or applied at a younger age, as the healthy older dogs were less likely to show improvement.

DPP-4 inhibitors sitagliptin and PF-00734,200 mitigate dopaminergic neurodegeneration, neuroinflammation and behavioral impairment in the rat 6-OHDA model of Parkinson’s disease - Seong-Jin Yu; Yun Wang; Hui Shen; Eun-Kyung Bae; Yazhou Li; Kumar Sambamurti; Michael A. Tones; Margaret M. Zaleska; Barry J. Hoffer; Nigel H. Greig (GeroScience, 2024)
Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70–80% plasma and 20–30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD.

Genome-wide analysis of hepatic DNA methylation reveals impact of epigenetic aging on xenobiotic metabolism and transport genes in an aged mouse model - Sara Abudahab; Mohamad M. Kronfol; Mikhail G. Dozmorov; Thomas Campbell; Fay M. Jahr; Jasmine Nguyen; Ola AlAzzeh; Dalia Y. Al Saeedy; Ashley Victor; Sera Lee; Shravani Malay; Dana M. Lapato; et al. (GeroScience, 2024)
Hepatic xenobiotic metabolism and transport decline with age, while intact xenobiotic metabolism is associated with longevity. However, few studies have examined the genome-wide impact of epigenetic aging on these processes. We used reduced representation bisulfite sequencing (RRBS) to map DNA methylation changes in liver DNA from mice ages 4 and 24 months. We identified several thousand age-associated differentially methylated sites (a-DMS), many of which overlapped genes encoding Phase I and Phase II drug metabolizing enzymes, in addition to ABC and SLC classes of transporters. Notable genes harboring a-DMS were Cyp1a2 , Cyp2d9 , and Abcc2 that encode orthologs of the human drug metabolizing enzymes CYP1A2 and CYP2D6, and the multidrug resistance protein 2 (MRP2) transporter. Cyp2d9 hypermethylation with age was significantly associated with reduced gene expression, while Abcc2 expression was unchanged with age. Cyp1a2 lost methylation with age while, counterintuitively, its expression also reduced with age. We hypothesized that age-related dysregulation of the hepatic transcriptional machinery caused down-regulation of genes despite age-related hypomethylation. Bioinformatic analysis of hypomethylated a-DMS in our sample found them to be highly enriched for hepatic nuclear factor 4 alpha (HNF4α) binding sites. HNF4α promotes Cyp1a2 expression and is downregulated with age, which could explain the reduction in Cyp1a2 expression. Overall, our study supports the broad impact of epigenetic aging on xenobiotic metabolism and transport. Future work should evaluate the interplay between hepatic nuclear receptor function and epigenetic aging. These results may have implications for studies of longevity and healthy aging.

Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine β-synthase, H2S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy - Theodora Panagaki; Lucia Janickova; Dunja Petrovic; Karim Zuhra; Tamás Ditrói; Eszter P. Jurányi; Olivier Bremer; Kelly Ascenção; Thilo M. Philipp; Péter Nagy; Milos R. Filipovic; Csaba Szabo (GeroScience, 2024)
Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer’s disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine β-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (H 2 S) pathway in the pathogenesis of neurobehavioral dysfunction in DS. The data demonstrate that CBS is higher in the brain of the DS mice than in the brain of wild-type mice, with primary localization in astrocytes. DS mice exhibited impaired recognition memory and spatial learning, loss of synaptosomal function, endoplasmic reticulum stress, and autophagy. Treatment of mice with aminooxyacetate, a prototypical CBS inhibitor, improved neurobehavioral function, reduced the degree of reactive gliosis in the DS brain, increased the ability of the synaptosomes to generate ATP, and reduced endoplasmic reticulum stress. H 2 S levels in the brain of DS mice were higher than in wild-type mice, but, unexpectedly, protein persulfidation was decreased. Many of the above alterations were more pronounced in the female DS mice. There was a significant dysregulation of metabolism in the brain of DS mice, which affected amino acid, carbohydrate, lipid, endocannabinoid, and nucleotide metabolites; some of these alterations were reversed by treatment of the mice with the CBS inhibitor. Thus, the CBS/H 2 S pathway contributes to the pathogenesis of neurological dysfunction in DS in the current animal model.

Combined aerobic and strength exercise training on biological ageing in Singaporean breast cancer patients: protocol for the Breast Cancer Exercise Intervention (BREXINT) Pilot Study - Patrick Henry Sebastian Sitjar; Si Ying Tan; Mabel Wong; Jingmei Li; Rufaihah Binte Abdul Jalil; Huizhen Aw; Elaine Hsuen Lim; Jorming Goh (GeroScience, 2024)

The duration of lithium use and biological ageing: telomere length, frailty, metabolomic age and all-cause mortality - Julian Mutz; Win Lee Edwin Wong; Timothy R. Powell; Allan H. Young; Gavin S. Dawe; Cathryn M. Lewis (GeroScience, 2024)
Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality. The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use and duration of the first prescription period) and telomere length, frailty, metabolomic age (MileAge) delta, pulse rate and all-cause mortality. Five hundred ninety-one individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions ( β = − 0.022, 95% CI − 0.081 to 0.037, p = 0.47), the total duration of use ( β = − 0.005, 95% CI − 0.023 to 0.013, p = 0.57) or the duration of the first prescription period ( β = − 0.018, 95% CI − 0.051 to 0.015, p = 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or MileAge delta. However, a higher prescription count and a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict all-cause mortality. We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by the duration of use.

Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders - Yazhou Li; Kelli L. Vaughan; Yun Wang; Seong-Jin Yu; Eun-Kyung Bae; Ian A. Tamargo; Katherine O. Kopp; David Tweedie; Cheng-Chuan Chiang; Keith T. Schmidt; Debomoy K. Lahiri; Michael A. Tones; et al. (GeroScience, 2024)
The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson’s disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.

A combination nutritional supplement reduces DNA methylation age only in older adults with a raised epigenetic age - Kirsty C. McGee; Jack Sullivan; Jon Hazeldine; Lisa J. Schmunk; Daniel E. Martin-Herranz; Thomas Jackson; Janet M. Lord (GeroScience, 2024)
An increase in systemic inflammation (inflammaging) is one of the hallmarks of aging. Epigenetic (DNA methylation) clocks can quantify the degree of biological aging and this can be reversed by lifestyle and pharmacological intervention. We aimed to investigate whether a multi-component nutritional supplement could reduce systemic inflammation and epigenetic age in healthy older adults. We recruited 80 healthy older participants (mean age ± SD: 71.85 ± 6.23; males = 31, females = 49). Blood and saliva were obtained pre and post a 12-week course of a multi-component supplement, containing: Vitamin B3, Vitamin C, Vitamin D, Omega 3 fish oils, Resveratrol, Olive fruit phenols and Astaxanthin. Plasma GDF-15 and C-reactive protein (CRP) concentrations were quantified as markers of biological aging and inflammation respectively. DNA methylation was assessed in whole blood and saliva and used to derive epigenetic age using various clock algorithms. No difference between the epigenetic and chronological ages of participants was observed pre- and post-treatment by the blood-based Horvath or Hannum clocks, or the saliva-based InflammAge clock. However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195). Our data suggest a possible benefit of combined nutritional supplementation in individuals with an accelerated epigenetic age and inflammaging.

A loss of primary cilia by a reduction in mTOR signaling correlates with age-related deteriorations in condylar cartilage - Megumi Kitami; Masaru Kaku; Lay Thant; Takeyasu Maeda (GeroScience, 2024)

Relationship of psychotropic medication use with physical function among postmenopausal women - Hind A. Beydoun; May A. Beydoun; Edward Kwon; Brook T. Alemu; Alan B. Zonderman; Robert Brunner (GeroScience, 2024)
To examine cross-sectional and longitudinal relationships of psychotropic medications with physical function after menopause. Analyses involved 4557 Women’s Health Initiative Long Life Study (WHI-LLS) participants (mean age at WHI enrollment (1993–1998): 62.8 years). Antidepressant, anxiolytic, and sedative/hypnotic medications were evaluated at WHI enrollment and 3-year follow-up visits. Performance-based physical function [Short Physical Performance Battery (SPPB)] was assessed at the 2012–2013 WHI-LLS visit. Self-reported physical function [RAND-36] was examined at WHI enrollment and the last available follow-up visit—an average of 22 [±2.8] (range: 12–27) years post-enrollment. Multivariable regression models controlled for socio-demographic, lifestyle, and health characteristics. Anxiolytics were not related to physical function. At WHI enrollment, antidepressant use was cross-sectionally related to worse self-reported physical function defined as a continuous ( β = −6.27, 95% confidence interval [CI]: −8.48, −4.07) or as a categorical (< 78 vs. ≥ 78) (odds ratio [OR] = 2.10, 95% CI: 1.48, 2.98) outcome. Antidepressant use at WHI enrollment was also associated with worse performance-based physical function (SPPB) [< 10 vs. ≥ 10] (OR = 1.53, 95% CI: 1.05, 2.21) at the 2012–2013 WHI-LLS visit. Compared to non-users, those using sedative/hypnotics at WHI enrollment but not at the 3-year follow-up visit reported a faster decline in physical function between WHI enrollment and follow-up visits. Among postmenopausal women, antidepressant use was cross-sectionally related to worse self-reported physical function, and with worse performance-based physical function after > 20 years of follow-up. Complex relationships found for hypnotic/sedatives were unexpected and necessitate further investigation.

Impact of visceral adipose tissue on longevity and metabolic health: a comparative study of gene expression in perirenal and epididymal fat of Ames dwarf mice - Agnieszka Zaczek; Andrzej Lewiński; Małgorzata Karbownik-Lewińska; Andrea Lehoczki; Adam Gesing (GeroScience, 2024)

Age-related decline in cognitive flexibility and inadequate preparation: evidence from task-state network analysis - Haishuo Xia; Ting Li; Yongqing Hou; Zijin Liu; Antao Chen (GeroScience, 2024)

Longitudinal aortic strain, ventriculo-arterial coupling and fatty acid oxidation: novel insights into human cardiovascular aging - Hongzhou Zhang; Shuang Leng; Fei Gao; Jean-Paul Kovalik; Ru-San Tan; Hai Ning Wee; Kee Voon Chua; Jianhong Ching; Xiaodan Zhao; John Allen; Qinghua Wu; Tim Leiner; et al. (GeroScience, 2024)

Anti-cytomegalovirus antibody levels stratify human immune profiles across the lifespan - Makiko Watanabe; Lisa Davidson; Patricia Smith; Peter F. Castellucio; Mladen Jergovic; Jennifer L. Uhrlaub; Megan J. Smithey; Lori E. Fantry; Brett Dechambre; Rachel C. Wilson; Kenneth C. Knox; Jie Ren; et al. (GeroScience, 2024)

Age-related effects on a hierarchical structure of canine cognition - Zsófia Bognár; Borbála Turcsán; Tamás Faragó; Dóra Szabó; Ivaylo Borislavov Iotchev; Enikő Kubinyi (GeroScience, 2024)
The current study investigates whether there are statistically independent age-related influences on the canine cognitive structure and how individual factors moderate cognitive aging on both cross-sectional and longitudinal samples. A battery of seven tasks was administered to 129 pet dogs, on which exploratory and confirmatory factor analyses were employed to unveil the correlational structure underlying individual differences in cognitive performance. The best-fitting model featured a hierarchical structure with two first-order cognitive domains (individual problem solving, learning) and a second-order common factor. These higher order factors exhibited consistency over a period of at least 2.5 years. External validation linked the common factor positively to discrimination and reversal learning performance, exploration, neophilia, activity/excitability, and training level while negatively to cognitive dysfunction symptoms, suggesting that it is a good candidate for a general cognitive factor ( canine g ). Structural equation models identified three distinct age-related influences, operating on associative learning, on memory, and on canine g . Health status moderated the negative age- canine g relationship, with a stronger association observed in dogs with poorer health status, and no relationship for dogs in good health. On a longitudinal sample ( N = 99), we showed that the direction and magnitude of change in canine g over up to 3 years is affected by various interactions between the dogs’ age, communication score, baseline performance, and time elapsed since the baseline measurement. These findings underscore the presence of a general cognitive factor in dogs and reveal intriguing parallels between human and canine aging, affirming the translational value of dogs in cognition and aging research.

Establishing healthy longevity clinics in publicly funded hospitals - Sara L. R. Bonnes; Tzipora Strauss; Allyson K. Palmer; Ryan T. Hurt; Louis Island; Abigail Goshen; Laureen Y. T. Wang; James L. Kirkland; Evelyne Bischof; Andrea B. Maier (GeroScience, 2024)
Healthy longevity medicine integrates geroscience and other disciplines into clinical settings, aiming to optimize health throughout one’s lifespan. Multiple factors have led to increased consumer engagement, with private clinics currently meeting the demand for guidance to improve healthy longevity. The establishment of healthy longevity clinics in publicly funded hospitals is a significant development, making longevity-focused healthcare more accessible. These clinics rely on multidisciplinary teams of physicians and allied health professionals. Diagnostics involve comprehensive evaluations of medical history, physical examinations, and various clinical tests to detect early signs of age-related functional decline. Interventions in healthy longevity medicine encompass lifestyle modifications, supplements, repurposed drugs, and social and environmental interventions. Collaboration with research institutions and industry partners is crucial for advancing healthy longevity medicine and creating standardized protocols. In this article, we review the process of creating healthy longevity clinics in public hospitals to ensure the best possible care for individuals pursuing healthy longevity.

Neuroprotective treatment with the nitrone compound OKN-007 mitigates age-related muscle weakness in aging mice - Hongyang Xu; Katarzyna M. Piekarz; Jacob L. Brown; Shylesh Bhaskaran; Nataliya Smith; Rheal A. Towner; Holly Van Remmen (GeroScience, 2024)

Detecting aortic valve stenosis based on the non-invasive blood pressure waveform—a proof of concept study - Eline Kho; Jimmy Schenk; Alexander P. J. Vlaar; Marije M. Vis; Marije Wijnberge; Lotte B. Stam; Martijn van Mourik; Harald T. Jorstad; Henning Hermanns; Berend E. Westerhof; Denise P. Veelo; Bjorn J. P. van der Ster (GeroScience, 2024)
The incidence of aortic valve stenosis (AoS) increases with age, and once diagnosed, symptomatic severe AoS has a yearly mortality rate of 25%. AoS is diagnosed with transthoracic echocardiography (TTE), however, this gold standard is time consuming and operator and acoustic window dependent. As AoS affects the arterial blood pressure waveform, AoS-specific waveform features might serve as a diagnostic tool. Aim of the present study was to develop a novel, non-invasive, AoS detection model based on blood pressures waveforms. This cross-sectional study included patients with AoS undergoing elective transcatheter or surgical aortic valve replacement. AoS was determined using TTE, and patients with no or mild AoS were labelled as patients without AoS, while patients with moderate or severe AoS were labelled as patients with AoS. Non-invasive blood pressure measurements were performed in awake patients. Ten minutes of consecutive data was collected. Several blood pressure-based features were derived, and the median, interquartile range, variance, and the 1st and 9th decile of the change of these features were calculated. The primary outcome was the development of a machine-learning model for AoS detection, investigating multiple classifiers and training on the area under the receiver-operating curve (AUROC). In total, 101 patients with AoS and 48 patients without AoS were included. Patients with AoS showed an increase in left ventricular ejection time (0.02 s, p = 0.001), a delayed maximum upstroke in the systolic phase (0.015 s, p < 0.001), and a delayed maximal systolic pressure (0.03 s, p < 0.001) compared to patients without AoS. With the logistic regression model, a sensitivity of 0.81, specificity of 0.67, and AUROC of 0.79 were found. The majority of the population without AoS was male (85%), whereas in the population with AoS this was evenly distributed (54% males). Age was significantly (5 years, p < 0.001) higher in the population with AoS. In the present study, we developed a novel model able to distinguish no to mild AoS from moderate to severe AoS, based on blood pressure features with high accuracy. Clinical registration number: The study entailing patients with TAVR treatment was registered at ClinicalTrials.gov (NCT03088787, https://clinicaltrials.gov/ct2/show/NCT03088787 ). The study with elective cardiac surgery patients was registered with the Netherland Trial Register (NL7810, https://trialsearch.who.int/Trial2.aspx?TrialID=NL7810 ).

Modulation of neural gene networks by estradiol in old rhesus macaque females - Rita Cervera-Juanes; Kip D. Zimmerman; Larry Wilhelm; Dongqin Zhu; Jessica Bodie; Steven G. Kohama; Henryk F. Urbanski (GeroScience, 2024)
The postmenopausal decrease in circulating estradiol (E2) levels has been shown to contribute to several adverse physiological and psychiatric effects. To elucidate the molecular effects of E2 on the brain, we examined differential gene expression and DNA methylation (DNAm) patterns in the nonhuman primate brain following ovariectomy (Ov) and subsequent subcutaneous bioidentical E2 chronic treatment. We identified several dysregulated molecular networks, including MAPK signaling and dopaminergic synapse response, that are associated with ovariectomy and shared across two different brain areas, the occipital cortex (OC) and prefrontal cortex (PFC). The finding that hypomethylation ( p = 1.6 × 10 −51 ) and upregulation ( p = 3.8 × 10 −3 ) of UBE2M across both brain regions provide strong evidence for molecular differences in the brain induced by E2 depletion. Additionally, differential expression ( p = 1.9 × 10 −4 ; interaction p = 3.5 × 10 −2 ) of LTBR in the PFC provides further support for the role E2 plays in the brain, by demonstrating that the regulation of some genes that are altered by ovariectomy may also be modulated by Ov followed by hormone replacement therapy (HRT). These results present real opportunities to understand the specific biological mechanisms that are altered with depleted E2. Given E2’s potential role in cognitive decline and neuroinflammation, our findings could lead to the discovery of novel therapeutics to slow cognitive decline. Together, this work represents a major step toward understanding molecular changes in the brain that are caused by ovariectomy and how E2 treatment may revert or protect against the negative neuro-related consequences caused by a depletion in estrogen as women approach menopause.

Proteomic analysis of P. gingivalis-Lipopolysaccharide induced neuroinflammation in SH-SY5Y and HMC3 cells - Ambika Verma; Gohar Azhar; Pankaj Patyal; Wei Zhang; Xiaomin Zhang; Jeanne Y. Wei (GeroScience, 2024)

RelA-mediated signaling connects adaptation to chronic cardiomyocyte stress with myocardial and systemic inflammation in the ADCY8 model of accelerated aging - Vikas Kumar; Kevin Christian Bermea; Dhaneshwar Kumar; Amit Singh; Anjali Verma; Mary Kaileh; Ranjan Sen; Edward G. Lakatta; Luigi Adamo (GeroScience, 2024)

Di-(2-ethylhexyl) phthalate exposure induces premature testicular senescence by disrupting mitochondrial respiratory chain through STAT5B-mitoSTAT3 in Leydig cell - Haiming Cao; Qigen Xie; Peng Luo; Jiaqi Chen; Kai Xia; Lin Ma; Demeng Chen; Chunhua Deng; Zi Wan (GeroScience, 2024)

Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice - Bianka Machado Zanini; Bianca Machado de Avila; Driele Neske Garcia; Jéssica Damé Hense; Gabriel Barreto Veiga; Mariana Machado Barreto; Sarah Ashiqueali; Jeffrey B. Mason; Hariom Yadav; Michal Masternak; Augusto Schneider (GeroScience, 2024)

Age-related changes in human brain functional connectivity using graph theory and machine learning techniques in resting-state fMRI data - Sepideh Baghernezhad; Mohammad Reza Daliri (GeroScience, 2024)

Fitness age outperforms body mass index in differentiating aging patterns and health risk profiles of healthy adults aged 51–80 years - Manca A.; Ventura L.; Martinez G.; Morrone M.; Boi A.; Fiorito G.; Mercante B.; Cano A.; Catte M. G.; Cruciani S.; Pozzati C.; Uccula A.; et al. (GeroScience, 2024)
Physical fitness has been extensively shown to strongly associate with general health status and major health risks. Here we tested the ability of a novel estimate of fitness age (FitAge) to differentiate aging trajectories. This study aimed at (1) testing the ability of FitAge to differentiate aging patterns among decelerated, normal, and accelerated agers in selected health domains, (2) estimating the risk for developing major health issues depending on the aging trajectory, and (3) comparing FitAge to body mass index (BMI) categorization in differentiating healthy from unhealthy aging patterns. A total of 176 volunteers participated in this cross-sectional study. Participants underwent clinical screening and a comprehensive assessment of body composition, nutritional and health-related status, cognitive functioning, and haematochemical analyses with routine tests, oxidative stress, and inflammation markers. Scores for major health risks were also computed. FitAge outperformed BMI in estimating major health risk scores and was able to differentiate decelerated from normal and accelerated agers for health risk profile and several physiological domains. Body composition, immune system activation, and inflammation markers emerged as those variables flagging the largest differences between decelerated and accelerated aging patterns. The novel estimate of biological aging can accurately differentiate both in women and men decelerated from accelerated agers in almost all the domains scrutinized. Overall, decelerated aging is linked to positively oriented features which associate with reduced risk of developing major health issues. The present findings have potential relevance and practical implications to identify individuals at higher risk of accelerated aging according to their FitAge estimated via simple and cost-effective motor tests.

The impact of exercise on blood-based biomarkers of Alzheimer’s disease in cognitively unimpaired older adults - Kelsey R. Sewell; Stephanie R. Rainey-Smith; Steve Pedrini; Jeremiah J. Peiffer; Hamid R. Sohrabi; Kevin Taddei; Shaun J. Markovic; Ralph N. Martins; Belinda M. Brown (GeroScience, 2024)
Physical activity is a promising preventative strategy for Alzheimer’s disease: it is associated with lower dementia risk, better cognition, greater brain volume and lower brain beta-amyloid. Blood-based biomarkers have emerged as a low-cost, non-invasive strategy for detecting preclinical Alzheimer’s disease, however, there is limited literature examining the effect of exercise (a structured form of physical activity) on blood-based biomarkers. The current study investigated the influence of a 6-month exercise intervention on levels of plasma beta-amyloid (Aβ42 , Aβ40, Aβ42/40), phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) chain in cognitively unimpaired older adults, and as a secondary aim, whether blood-based biomarkers related to cognition. Ninety-nine community-dwelling older adults (69.1 ± 5.2) were allocated to an inactive control, or to moderate or high intensity exercise groups where they cycled twice weekly for six months. At baseline and six months (post-intervention), fasted blood was collected and analysed using single molecule array (SIMOA) assays, and cognition was assessed. Results demonstrated no change in levels of any plasma biomarker from pre- to post-intervention. At baseline, higher NfL was associated with poorer cognition ( β = -0.33, SE = 0.13, adjusted p = .042). Exploratory analyses indicated higher cardiorespiratory fitness was associated with higher NfL and GFAP levels in apolipoprotein E ( APOE ) ε4 non-carriers compared to ε4 carriers (NfL, β = -0.43, SE = 0.19, p = .029; GFAP, β = -0.41, SE = 0.20, p = .044), though this association was mediated by body mass index (BMI). These results highlight the importance of considering BMI in analysis of blood-based biomarkers, especially when investigating differences between APOE ε4 carriers and non-carriers. Our results also indicate that longer follow-up periods may be required to observe exercise-induced change in blood-based biomarkers.

Dialysis disequilibrium syndrome in neurosurgery: literature review and illustrative case example - Alexander R. Evans; Xiaochun Zhao; Griffin L. Ernst; Jorge Ortiz-Garcia; Ian F. Dunn; John Burke (GeroScience, 2024)

Somatic mutations in aging and disease - Peijun Ren; Jie Zhang; Jan Vijg (GeroScience, 2024)

Resistance exercise effects on hippocampus subfield volumes and biomarkers of neuroplasticity and neuroinflammation in older adults with low and high risk of mild cognitive impairment: a randomized controlled trial - Wouter A. J. Vints; Julija Šeikinaitė; Evrim Gökçe; Simona Kušleikienė; Milda Šarkinaite; Kristina Valatkeviciene; Vida J. Česnaitienė; Jeanine Verbunt; Oron Levin; Nerijus Masiulis (GeroScience, 2024)
Physical exercise is suggested to promote hippocampal neuroplasticity by increasing circulating neurotrophic and anti-inflammatory factors. Our aim was to explore the interplay between the effect of progressive resistance exercise on blood biomarker levels, hippocampal neurometabolite levels and hippocampal volume in older adults with a low compared to a high risk of mild cognitive impairment (MCI). Seventy apparently healthy male/female older adults (aged 60–85 years old) were randomly allocated to a 12 week lower limb progressive resistance or no intervention, stratified for low (< 26/30) or high (≥ 26/30) Montreal Cognitive Assessment (MoCA) score, indicating MCI risk. Outcome measures were blood levels of insulin-like growth factor-1 (IGF-1), interleukin-6 (IL-6) or kynurenine (KYN); hippocampal total and subfield volumes of the cornu ammonis 1 (CA1) and 4 (CA4), subiculum, presubiculum, and dentate gyrus measured with magnetic resonance imaging (MRI); and hippocampus neurometabolites including total N-acetylaspartate (NAA), myo-inositol (mIns), and total creatine (Cr) measured with proton magnetic resonance spectroscopy ( 1 H-MRS). We evaluated the intervention effect, cognitive status effect, their interaction and the bivariate relationship between exercise-induced changes between the outcome measures. Higher kynurenine levels (p = 0.015) and lower subiculum volumes (p = 0.043) were found in older adults with high MCI risk compared to older adults with low MCI risk. Exercise-induced CA1 volume changes were negatively correlated with hippocampal tNAA/mIns level changes (r = -0.605, p = 0.006). This study provides valuable insight in the multifactorial processes related to resistance training in older adults with low or high MCI risk.

DNA methylation-based estimators of telomere length show low correspondence with paternal age at conception and other measures of external validity of telomere length - Dan T. A. Eisenberg; Calen P. Ryan; Nanette R. Lee; Delia B. Carba; Julie L. MacIsaac; Kristy Dever; Parmida Atashzay; Michael S. Kobor; Christopher Kuzawa (GeroScience, 2024)

The common marmoset as a translational model of age-related osteoarthritis - Dennis M. Minton; Aditya R. Ailiani; Michael D. K. Focht; Mariana E. Kersh; Angela J. Marolf; Kelly S. Santangelo; Adam B. Salmon; Adam R. Konopka (GeroScience, 2024)

Endothelial specific prolyl hydroxylase domain-containing protein 2 deficiency attenuates aging-related obesity and exercise intolerance - Lihong Pan; Xiaochen He; Rui Xu; Umesh Bhattarai; Ziru Niu; Jussara do Carmo; Yuxiang Sun; Heng Zeng; John S. Clemmer; Jian-Xiong Chen; Yingjie Chen (GeroScience, 2024)
Obesity and exercise intolerance greatly reduce the life quality of older people. Prolyl hydroxylase domain-containing protein 2 (PHD2) is an important enzyme in modulating hypoxia-inducible factor-alpha (HIF) protein. Using vascular endothelial cell-specific PHD2 gene knockout (PHD2 ECKO) mice, we investigated the role of endothelial PHD2 in aging-related obesity and exercise capacity. Briefly, PHD2 ECKO mice were obtained by crossing PHD2-floxed mice with VE-Cadherin (Cdh5)-Cre transgenic mice. The effect of PHD2 ECKO on obesity and exercise capacity in PHD2 ECKO mice and control PHD2 f/f mice were determined in young mice (6 to 7 months) and aged mice (16–18 months). We found that aged PHD2 ECKO mice, but not young mice, exhibited a lean phenotype, characterized by lower fat mass, and its ratio to lean weight, body weight, or tibial length, while their food uptake was not reduced compared with controls. Moreover, as compared with aged control mice, aged PHD2 ECKO mice exhibited increased oxygen consumption at rest and during exercise, and the maximum rate of oxygen consumption (VO 2 max) during exercise. Furthermore, as compared with corresponding control mice, both young and aged PHD2 ECKO mice demonstrated improved glucose tolerance and lower insulin resistance. Together, these data demonstrate that inhibition of vascular endothelial PHD2 signaling significantly attenuates aging-related obesity, exercise intolerance, and glucose intolerance.

Mitochondrial disorders leading to Alzheimer’s disease—perspectives of diagnosis and treatment - Magdalena Pszczołowska; Kamil Walczak; Weronika Miśków; Magdalena Mroziak; Justyna Chojdak-Łukasiewicz; Jerzy Leszek (GeroScience, 2024)
Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia globally. The pathogenesis of AD remains still unclear. The three main features of AD are extracellular deposits of amyloid beta (Aβ) plaque, accumulation of abnormal formation hyper-phosphorylated tau protein, and neuronal loss. Mitochondrial impairment plays an important role in the pathogenesis of AD. There are problems with decreased activity of multiple complexes, disturbed mitochondrial fusion, and fission or formation of reactive oxygen species (ROS). Moreover, mitochondrial transport is impaired in AD. Mouse models in many research show disruptions in anterograde and retrograde transport. Both mitochondrial transportation and network impairment have a huge impact on synapse loss and, as a result, cognitive impairment. One of the very serious problems in AD is also disruption of insulin signaling which impairs mitochondrial Aβ removal. Discovering precise mechanisms leading to AD enables us to find new treatment possibilities. Recent studies indicate the positive influence of metformin or antioxidants such as MitoQ, SS-31, SkQ, MitoApo, MitoTEMPO, and MitoVitE on mitochondrial functioning and hence prevent cognitive decline. Impairments in mitochondrial fission may be treated with mitochondrial division inhibitor-1 or ceramide. Graphical Abstract (Graphic content via Canva Pro)

Learning ratio performance on a brief visual learning and memory test moderates cognitive training gains in Double Decision task in healthy older adults - Cheshire Hardcastle; Jessica N. Kraft; Hanna K. Hausman; Andrew O’Shea; Alejandro Albizu; Nicole D. Evangelista; Emanuel M. Boutzoukas; Emily J. Van Etten; Pradyumna K. Bharadwaj; Hyun Song; Samantha G. Smith; Eric Porges; et al. (GeroScience, 2024)

The relationship between 11 different polygenic longevity scores, parental lifespan, and disease diagnosis in the UK Biobank - Janith Don; Andrew J. Schork; Gwênlyn Glusman; Noa Rappaport; Steve R. Cummings; David Duggan; Anish Raju; Kajsa-Lotta Georgii Hellberg; Sophia Gunn; Stefano Monti; Thomas Perls; Jodi Lapidus; et al. (GeroScience, 2024)
Large-scale genome-wide association studies (GWAS) strongly suggest that most traits and diseases have a polygenic component. This observation has motivated the development of disease-specific “polygenic scores (PGS)” that are weighted sums of the effects of disease-associated variants identified from GWAS that correlate with an individual’s likelihood of expressing a specific phenotype. Although most GWAS have been pursued on disease traits, leading to the creation of refined “Polygenic Risk Scores” (PRS) that quantify risk to diseases, many GWAS have also been pursued on extreme human longevity, general fitness, health span, and other health-positive traits. These GWAS have discovered many genetic variants seemingly protective from disease and are often different from disease-associated variants (i.e., they are not just alternative alleles at disease-associated loci) and suggest that many health-positive traits also have a polygenic basis. This observation has led to an interest in “polygenic longevity scores (PLS)” that quantify the “risk” or genetic predisposition of an individual towards health. We derived 11 different PLS from 4 different available GWAS on lifespan and then investigated the properties of these PLS using data from the UK Biobank (UKB). Tests of association between the PLS and population structure, parental lifespan, and several cancerous and non-cancerous diseases, including death from COVID-19, were performed. Based on the results of our analyses, we argue that PLS are made up of variants not only robustly associated with parental lifespan, but that also contribute to the genetic architecture of disease susceptibility, morbidity, and mortality.

The structural–functional-connectivity coupling of the aging brain - Hui Zhang; Peng Cao; Henry K. F. Mak; Edward S. Hui (GeroScience, 2024)
Aging primarily affects memory and executive functions, a relationship that may be underpinned by the fact that almost all adults over 60 years old develop small vessel disease (SVD). The fact that a wide range of neuropathologies could only explain up to 43% of the variation in age-related cognitive impairment suggests that other factors, such as cognitive reserve, may play a role in the brain’s resilience against aging-related cognitive decline. This study aims to examine the relationship between structural–functional-connectivity coupling (SFC), and aging, cognitive abilities and reserve, and SVD-related neuropathologies using a cohort of n = 176 healthy elders from the Harvard Aging Brain Study. The SFC is a recently proposed biomarker that reflects the extent to which anatomical brain connections can predict coordinated neural activity. After controlling for the effect of age, sex, and years of education, global SFC, as well as the intra-network SFC of the dorsolateral somatomotor and dorsal attention networks, and the inter-network SFC between dorsolateral somatomotor and frontoparietal networks decreased with age. The global SFC decreased with total cognitive score. There were significant interaction effects between years of education versus white matter hyperintensities and between years of education versus cerebral microbleeds on inter-network SFC. Enlarged perivascular space in basal ganglia was associated with higher inter-network SFC. Our results suggest that cognitive ability is associated with brain coupling at the global level and cognitive reserve with brain coupling at the inter-functional-brain-cluster level with interaction effect from white matter hyperintensities and cerebral microbleed in a cohort of healthy elderlies.

Ergothioneine promotes longevity and healthy aging in male mice - Makoto Katsube; Takahiro Ishimoto; Yutaro Fukushima; Asuka Kagami; Tsuyoshi Shuto; Yukio Kato (GeroScience, 2024)
Healthy aging has emerged as a crucial issue with the increase in the geriatric population worldwide. Food-derived sulfur-containing amino acid ergothioneine (ERGO) is a potential dietary supplement, which exhibits various beneficial effects in experimental animals although the preventive effects of ERGO on aging and/or age-related impairments such as frailty and cognitive impairment are unclear. We investigated the effects of daily oral supplementation of ERGO dissolved in drinking water on lifespan, frailty, and cognitive impairment in male mice from 7 weeks of age to the end of their lives. Ingestion of 4 ~ 5 mg/kg/day of ERGO remarkably extended the lifespan of male mice. The longevity effect of ERGO was further supported by increase in life and non-frailty spans of Caenorhabditis elegans in the presence of ERGO. Compared with the control group, the ERGO group showed significantly lower age-related declines in weight, fat mass, and average and maximum movement velocities at 88 weeks of age. This was compatible with dramatical suppression by ERGO of the age-related increments in plasma biomarkers (BMs) such as the chemokine ligand 9, creatinine, symmetric dimethylarginine, urea, asymmetric dimethylarginine, quinolinic acid, and kynurenine. The oral intake of ERGO also rescued age-related impairments in learning and memory ability, which might be associated with suppression of the age-related decline in hippocampal neurogenesis and TDP43 protein aggregation and promotion of microglial shift to the M2 phenotype by ERGO ingestion. Ingestion of ERGO may promote longevity and healthy aging in male mice, possibly through multiple biological mechanisms.

CheekAge: a next-generation buccal epigenetic aging clock associated with lifestyle and health - Maxim N. Shokhirev; Nicole S. Torosin; Daniel J. Kramer; Adiv A. Johnson; Trinna L. Cuellar (GeroScience, 2024)
Epigenetic aging clocks are computational models that predict age using DNA methylation information. Initially, first-generation clocks were developed to make predictions using CpGs that change with age. Over time, next-generation clocks were created using CpGs that relate to both age and health. Since existing next-generation clocks were constructed in blood, we sought to develop a next-generation clock optimized for prediction in cheek swabs, which are non-invasive and easy to collect. To do this, we collected MethylationEPIC data as well as lifestyle and health information from 8045 diverse adults. Using a novel simulated annealing approach that allowed us to incorporate lifestyle and health factors into training as well as a combination of CpG filtering, CpG clustering, and clock ensembling, we constructed CheekAge, an epigenetic aging clock that has a strong correlation with age, displays high test–retest reproducibility across replicates, and significantly associates with a plethora of lifestyle and health factors, such as BMI, smoking status, and alcohol intake. We validated CheekAge in an internal dataset and multiple publicly available datasets, including samples from patients with progeria or meningioma. In addition to exploring the underlying biology of the data and clock, we provide a free online tool that allows users to mine our methylomic data and predict epigenetic age.

Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort - Ramon Casanova; Keenan A. Walker; Jamie N. Justice; Andrea Anderson; Michael R. Duggan; Jenifer Cordon; Ryan T. Barnard; Lingyi Lu; Fang-Chi Hsu; Sanaz Sedaghat; Anna Prizment; Stephen B. Kritchevsky; et al. (GeroScience, 2024)
Machine learning models are increasingly being used to estimate “brain age” from neuroimaging data. The gap between chronological age and the estimated brain age gap (BAG) is potentially a measure of accelerated and resilient brain aging. Brain age calculated in this fashion has been shown to be associated with mortality, measures of physical function, health, and disease. Here, we estimate the BAG using a voxel-based elastic net regression approach, and then, we investigate its associations with mortality, cognitive status, and measures of health and disease in participants from Atherosclerosis Risk in Communities (ARIC) study who had a brain MRI at visit 5 of the study. Finally, we used the SOMAscan assay containing 4877 proteins to examine the proteomic associations with the MRI-defined BAG. Among N = 1849 participants (age, 76.4 (SD 5.6)), we found that increased values of BAG were strongly associated with increased mortality and increased severity of the cognitive status. Strong associations with mortality persisted when the analyses were performed in cognitively normal participants. In addition, it was strongly associated with BMI, diabetes, measures of physical function, hypertension, prevalent heart disease, and stroke. Finally, we found 33 proteins associated with BAG after a correction for multiple comparisons. The top proteins with positive associations to brain age were growth/differentiation factor 15 (GDF-15), Sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SEVP 1), matrilysin (MMP7), ADAMTS-like protein 2 (ADAMTS), and heat shock 70 kDa protein 1B (HSPA1B) while EGF-receptor (EGFR), mast/stem-cell-growth-factor-receptor (KIT), coagulation-factor-VII, and cGMP-dependent-protein-kinase-1 (PRKG1) were negatively associated to brain age. Several of these proteins were previously associated with dementia in ARIC. These results suggest that circulating proteins implicated in biological aging, cellular senescence, angiogenesis, and coagulation are associated with a neuroimaging measure of brain aging.

Association of birthweight and risk of incident dementia: a prospective cohort study - Xiaxuan Huang; Shiqi Yuan; Yitong Ling; Shanyuan Tan; Hongtao Cheng; Anding Xu; Jun Lyu (GeroScience, 2024)

Performance of digital technologies in assessing fall risks among older adults with cognitive impairment: a systematic review - Vanessa Koh; Lai Wei Xuan; Tan Kai Zhe; Navrag Singh; David B. Matchar; Angelique Chan (GeroScience, 2024)

Functional deterioration of vascular mitochondrial and glycolytic capacity in the aortic rings of aged mice - Agnieszka Karaś; Anna Bar; Kanchana Pandian; Agnieszka Jasztal; Zuzanna Kuryłowicz; Barbara Kutryb-Zając; Elżbieta Buczek; Stefano Rocchetti; Tasnim Mohaissen; Agata Jędrzejewska; Amy C. Harms; Patrycja Kaczara; et al. (GeroScience, 2024)
Vascular ageing is associated with increased arterial stiffness and cardiovascular mortality that might be linked to altered vascular energy metabolism. The aim of this study was to establish a Seahorse XFe96 Analyzer-based methodology for the reliable, functional assessment of mitochondrial respiration and glycolysis in single murine aortic rings and to validate this functional assay by characterising alterations in vascular energy metabolism in aged mice. Healthy young and old C57BL/6 mice were used for the analyses. An optimised setup consisting of the Seahorse XFe96 Analyzer and Seahorse Spheroid Microplates was applied for the mitochondrial stress test and the glycolysis stress test on the isolated murine aortic rings, supplemented with analysis of NAD content in the aorta. To confirm the age-dependent stiffness of the vasculature, pulse wave velocity was measured in vivo. In addition, the activity of vascular nitric oxide synthase and vascular wall morphology were analysed ex vivo. The vascular ageing phenotype in old mice was confirmed by increased aortic stiffness, vascular wall remodelling, and nitric oxide synthase activity impairment. The rings of the aorta taken from old mice showed changes in vascular energy metabolism, including impaired spare respiratory capacity, maximal respiration, glycolysis, and glycolytic capacity, as well as a fall in the NAD pool. In conclusion, optimised Seahorse XFe96-based analysis to study energy metabolism in single aortic rings of murine aorta revealed a robust impairment of functional vascular respiratory and glycolytic capacity in old mice linked to NAD deficiency that coincided with age-related aortic wall remodelling and stiffness.

Longevity and anti-aging effects of curcumin supplementation - Mehran Izadi; Nariman Sadri; Amirhossein Abdi; Mohammad Mahdi Raeis Zadeh; Dorsa jalaei; Mohammad Mahdi Ghazimoradi; Sara Shouri; Safa Tahmasebi (GeroScience, 2024)

Metabolic dysfunction and the development of physical frailty: an aging war of attrition - William A. Fountain; Taylor S. Bopp; Michael Bene; Jeremy D. Walston (GeroScience, 2024)

Correction to: The influence of APOE status on rate of cognitive decline - Cassandra Morrison; Michael D. Oliver; Virginia Berry; Farooq Kamal; Mahsa Dadar (GeroScience, 2024)

Exclusion of older patients from randomized clinical trials in Parkinson’s disease - Danuta Kłosowska; Urszula Fiszer; Jarosław Dulski; Andrzej Górski; Jan Borysowski (GeroScience, 2024)

Molecular cross-talk between long COVID-19 and Alzheimer’s disease - Magdalena Pszczołowska; Kamil Walczak; Weronika Misków; Katarzyna Antosz; Joanna Batko; Julia Karska; Jerzy Leszek (GeroScience, 2024)
The long COVID (coronavirus disease), a multisystemic condition following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, is one of the widespread problems. Some of its symptoms affect the nervous system and resemble symptoms of Alzheimer’s disease (AD)—a neurodegenerative condition caused by the accumulation of amyloid beta and hyperphosphorylation of tau proteins. Multiple studies have found dependence between these two conditions. Patients with Alzheimer’s disease have a greater risk of SARS-CoV-2 infection due to increased levels of angiotensin-converting enzyme 2 (ACE2), and the infection itself promotes amyloid beta generation which enhances the risk of AD. Also, the molecular pathways are alike—misregulations in folate-mediated one-carbon metabolism, a deficit of Cq10, and disease-associated microglia. Medical imaging in both of these diseases shows a decrease in the volume of gray matter, global brain size reduction, and hypometabolism in the parahippocampal gyrus, thalamus, and cingulate cortex. In some studies, a similar approach to applied medication can be seen, including the use of amino adamantanes and phenolic compounds of rosemary. The significance of these connections and their possible application in medical practice still needs further study but there is a possibility that they will help to better understand long COVID.

Vascular smooth muscle cell-specific Igf1r deficiency exacerbates the development of hypertension-induced cerebral microhemorrhages and gait defects - Lauren R. Miller; Marisa A. Bickel; Michaela L. Vance; Hannah Vaden; Domonkos Nagykaldi; Adam Nyul-Toth; Elizabeth C. Bullen; Tripti Gautam; Stefano Tarantini; Andriy Yabluchanskiy; Tamas Kiss; Zoltan Ungvari; et al. (GeroScience, 2024)

Predictive ability of both the healthy aging index and the frailty index for all-cause mortality - Felipe Diaz-Toro; Gabriela Nazar; Alejandra-Ximena Araya; Fanny Petermann-Rocha (GeroScience, 2024)
Aim We aimed to develop and assess a modified healthy aging index (HAI) among Chileans aged 60 years and older and compare its predictive ability for all-cause mortality risk with the frailty index (FI). Methods This prospective study analyzed data from the Chilean National Health Survey (CNHS) conducted in 2009–2010. We included 847 adults with complete data to construct the HAI and FI. The HAI comprised five indicators (lung function, systolic blood pressure, fasting glucose, cognitive status, and glomerular filtration rate), while the FI assessed frailty using a 36-item scale. HAI scores were calculated by summing the indicator scores, ranging from 0 to 10, with higher scores indicating poorer health. Receiver operating curves (ROC) and area under the curve (AUC) were used to assess predictive validity. Associations with all-cause mortality were assessed using Cox proportional hazard models adjusted by confounders. Results The mean HAI score was 4.06, while the FI score was 0.24. The AUC for mortality was higher for the HAI than the FI (0.640, 95% confidence interval (CI) 0.601 to 0.679 vs. 0.586, 95% CI 0.545 to 0.627). After adjusting for confounders, the FI showed a higher mortality risk compared to the HAI (2.63, 95% CI 1.76 to 3.51 vs. 1.16, 95% CI 1.08 to 1.26). Conclusion The FI and HAI were valid predictors for all-cause mortality in the Chilean population. Integrating these indices into research and clinical practice can significantly enhance our capacity to identify at-risk individuals.

Age associated susceptibility to SARS-CoV-2 infection in the K18-hACE2 transgenic mouse model - Varun Dwivedi; Vinay Shivanna; Shalini Gautam; Jennifer Delgado; Amberlee Hicks; Marco Argonza; Reagan Meredith; Joanne Turner; Luis Martinez-Sobrido; Jordi B. Torrelles; Viraj Kulkarni (GeroScience, 2024)

Epigenetic clock in the aorta and age-related endothelial dysfunction in mice - Ewelina Pośpiech; Anna Bar; Aleksandra Pisarek-Pacek; Agnieszka Karaś; Wojciech Branicki; Stefan Chlopicki (GeroScience, 2024)
While epigenetic age (EA) of mouse blood can be determined using DNA methylation analysis at three CpG sites in the Prima1 , Hsf4 and Kcns1 genes it is not known whether this approach is useful for predicting vascular biological age. In this study we validated the 3-CpG estimator for age prediction in mouse blood, developed a new predictive model for EA in mouse aorta, and assessed whether epigenetic age acceleration (EAA) measured with blood and aorta samples correlates with age-dependent endothelial dysfunction. Endothelial function was characterized in vivo by MRI in 8–96-week-old C57BL/6 mice. Arterial stiffness was measured by USG-doppler. EA-related changes within 41 CpG sites in Prima1 , Kcns1 and Hsf4 loci, were analyzed in the aorta and blood using bisulfite amplicon high-throughput sequencing. Progressive age-dependent endothelial dysfunction and changes in arterial stiffness were observed in 36-96-week-old C57BL/6 mice. Methylation levels of the investigated loci correlated with chronological age in blood and the aorta. The new model for EA estimation in aorta included three cytosines located in the Kcns1 and Hsf4 , explained R 2 = 87.8% of the variation in age, and predicted age with an mean absolute error of 9.6 weeks in the independent test set. EAA in the aorta was associated with endothelial dysfunction in the abdominal aorta and femoral artery what was consistent with the EAA direction estimated in blood samples. The rate of vascular biological ageing in mice, reflected by the age-dependent systemic endothelial dysfunction, could be estimated using DNA methylation measurements at three loci in aorta and blood samples.

Intermittent fasting promotes rejuvenation of immunosenescent phenotypes in aged adipose tissue - Kafi N. Ealey; Jacques Togo; Ju Hee Lee; Yash Patel; Jae-Ryong Kim; So-Young Park; Hoon-Ki Sung (GeroScience, 2024)

Correction to: Ultra‑processed food consumption and nutritional frailty in older age - Roberta Zupo; Rossella Donghia; Fabio Castellana; Ilaria Bortone; Sara De Nucci; Annamaria Sila; Rossella Tatoli; Luisa Lampignano; Giancarlo Sborgia; Francesco Panza; Madia Lozupone; Giuseppe Colacicco; et al. (GeroScience, 2024)

Secondary infections and long-term outcomes among hospitalized elderly and non-elderly patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and treated with baricitinib: a comparative study from the national centre of Hungary - Zsófia Gáspár; Bálint Gergely Szabó; Hajnalka Andrikovics; Andrea Ceglédi; Martin RAJMON; Anita Ábrahám; Zsuzsanna Várnai; Noémi Kiss-Dala; János Szlávik; János Sinkó; István Vályi-Nagy; Botond Lakatos (GeroScience, 2024)
Baricitinib is considered a first-line treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adult patients with an associated cytokine storm syndrome (CSS). Our objective was to compare rates of secondary infections and long-term outcomes of elderly and non-elderly patients who received baricitinib for COVID-19. We conducted a single-centre observational study between November 2020 and September 2023, focusing on hospitalized adult SARS-CoV-2 patients with CSS, categorized as elderly (≥ 65 years) and non-elderly (< 65 years). Enrolment, severity stratification, and diagnosis of infectious complications followed predefined criteria. Outcomes of all-cause mortality and rates of non-severe and severe secondary infections were assessed at 1-year post-treatment initiation. Kaplan–Meier analysis was performed for survival analysis. In total, 490 patients were enrolled (median age 65 ± 23 (21–100) years (years, median ± IQR, min–max); 49.18% elderly; 59.59% male). Elderly patients were admitted to the hospital significantly earlier (7 ± 5 days vs. 8 ± 4 days; p = 0.02), experienced a higher occurrence of severe COVID-19 (121/241, 50.21% vs. 98/249, 39.36%; p = 0.02), and required the use of non-invasive ventilation at baseline (167/225, 74.22% vs. 153/236, 64.83%; p = 0.03). At 1 year, all-cause mortality was significantly higher in the elderly subgroup (111/241, 46.06% vs. 29/249, 11.65%; p < 0.01). At 90 days and 1 year, rates of any severe secondary infection were also more prevalent among the elderly (56/241, 23.24% vs. 37/249 14.86%; p = 0.02 and 58/241, 24.07% vs. 39/249, 15.66%; p = 0.02). In conclusion, elderly SARS-CoV-2-infected patients experience a more severe clinical course, higher secondary infection rates, and increased risk for long-term mortality, regardless of immunomodulatory therapy.

Senolytic treatment fails to improve ovarian reserve or fertility in female mice - Driele N. Garcia; Jessica D. Hense; Bianka M. Zanini; Jose V. V. Isola; Juliane B. Prosczek; Sarah Ashiqueali; Thais L. Oliveira; Jeffrey B. Mason; Ines C. Schadock; Carlos C. Barros; Michael B. Stout; Michal M. Masternak; et al. (GeroScience, 2024)

GrimAge is elevated in older adults with mild COVID-19 an exploratory analysis - Paola García-delaTorre; Nadia Alejandra Rivero-Segura; Sergio Sánchez-García; Kristhian Becerril-Rojas; Francisco Ernesto Sandoval-Rodriguez; Diana Castro-Morales; Miguel Cruz-Lopez; Miguel Vazquez-Moreno; Ruth Rincón-Heredia; Perla Ramirez-Garcia; Juan Carlos Gomez-Verjan (GeroScience, 2024)

Exploring the potential of combining transcranial magnetic stimulation and electroencephalography to investigate mild cognitive impairment and Alzheimer’s disease: a systematic review - J. D. Hall; Jacob M. Green; Yu-Chin A. Chen; Yilin Liu; Hangbin Zhang; Mark H. Sundman; Ying-hui Chou (GeroScience, 2024)

Fear extinction is impaired in aged rats - Payton K. Robinson; Erisa Met Hoxha; Destine Williams; Kimberly P. Kinzig; Sydney Trask (GeroScience, 2024)