Effect of high-fat diet on cerebral pathological changes of cerebral small vessel disease in SHR/SP rats - Yuchi Zhang; Abdullah Md. Sheikh; Shatera Tabassum; Kenichi Iwasa; Abu Zaffar Shibly; Xiaojing Zhou; Ruochen Wang; Jubo Bhuiya; Fatema Binte Abdullah; Shozo Yano; Yoshihito Aoki; Atsushi Nagai (GeroScience, 2024)

Percutaneous biopsies of skeletal muscle and adipose tissue in individuals older than 70: methods and outcomes in the Study of Muscle, Mobility and Aging (SOMMA) - Zeke Zamora; Li-Yung Lui; Lauren M. Sparks; Jamie Justice; Mary Lyles; Landon Gentle; Heather Gregory; Reichelle X. Yeo; Erin E. Kershaw; Maja Stefanovic-Racic; Anne B. Newman; Stephen Kritchevsky; et al. (GeroScience, 2024)

Female baboon adrenal zona fasciculata and zona reticularis regulatory and functional proteins decrease across the life course - Hillary Fries Huber; Cun Li; Dongbin Xie; Kenneth G. Gerow; Thomas C. Register; Carol A. Shively; Laura A. Cox; Peter W. Nathanielsz (GeroScience, 2024)

Short-term fasting of a single amino acid extends lifespan - Tahlia L. Fulton; Mia R. Wansbrough; Christen K. Mirth; Matthew D. W. Piper (GeroScience, 2024)
Diet and health are strongly linked, though the strict changes in diet required to improve health outcomes are usually difficult to sustain. We sought to understand whether short-term bouts of amino acid–specific modifications to the diet of Drosophila melanogaster could mimic the lifespan and stress resistance benefits of dietary restriction, without the requirement for drastic reductions in food intake. We found that flies that were transiently fed diets lacking the essential amino acid isoleucine, but otherwise nutritionally complete, exhibited enhanced nicotine tolerance, indicating elevated detoxification capacity. The protection from isoleucine deprivation increased with the duration of exposure, up to a maximum at 7-day isoleucine deprivation for flies 2, 3, or 4 weeks of age, and a 5-day deprivation when flies were 5 weeks of age. Because of these beneficial effects on toxin resistance, we intermittently deprived flies of isoleucine during the first 6 weeks of adulthood and monitored the effect on lifespan. Lifespan was significantly extended when flies experienced short-term isoleucine deprivation at 3 and 5 weeks of age, regardless of whether they were also deprived at 1 week. These results indicate that short-term bouts of isoleucine deprivation can extend lifespan and highlight its cumulative and time-dependent benefits. Interestingly, we found that isoleucine-deprived flies lost their protection against nicotine within 3 days of returning to fully fed conditions. Therefore, the mechanisms underlying lifespan extension may involve transient damage clearance during the bouts of isoleucine deprivation rather than sustained enhanced detoxification capacity. These data highlight a new time-restricted, nutritionally precise method to extend life in Drosophila melanogaster and point to a more manageable dietary method to combat ageing.

A novel approach to quantifying individual's biological aging using Korea’s national health screening program toward precision public health - Jinho Yoo; Junguk Hur; Jintae Yoo; Donald Jurivich; Kyung Ju Lee (GeroScience, 2024)
Accurate prediction of biological age can inform public health measures to extend healthy lifespans and reduce chronic conditions. Multiple theoretical models and methods have been developed; however, their applicability and accuracy are still not extensive. Here, we report Differential Aging and Health Index (DAnHI), a novel measure of age deviation, developed using physical and serum biomarkers from four million individuals in Korea's National Health Screening Program. Participants were grouped into aging statuses (< 26 vs. ≥ 26, < 27 vs. ≥ 27, …, < 75 vs. ≥ 75 years) as response variables in a binary logistic regression model with thirteen biomarkers as independent variables. DAnHI for each individual was calculated as the weighted mean of their relative probabilities of being classified into each older age status, based on model ages ranging from 26 to 75. DAnHI in our large study population showed a steady increase with the increase in age and was positively associated with death after adjusting for chronological age. However, the effect size of DAnHI on the risk of death varied according to the age group and sex. The hazard ratio was highest in the 50–59-year age group and then decreased as the individuals aged. This study demonstrates that routine health check-up biomarkers can be integrated into a quantitative measure for predicting aging-related health status and death via appropriate statistical models and methodology. Our DAnHI-based results suggest that the same level of aging-related health status does not indicate the same degree of risk for death.

Extreme-aged patients (≥ 85 years) experience similar outcomes as younger geriatric patients following chronic subdural hematoma evacuation: a matched cohort study - Peyton L. Nisson; John J. Francis; Michelot Michel; Keshav Goel; Chirag G. Patil (GeroScience, 2024)
Subdural hematoma (SDH) evacuation represents one of the most frequently performed neurosurgical procedures. Several reports cite a rise in both the age and number of patient’s requiring treatment, due in part to an aging population and expanded anticoagulation use. However, limited data and conflicting conclusions exist on extreme-aged geriatric patients (≥ 85 years of age) after undergoing surgery. Patients undergoing SDH evacuation at a tertiary academic medical center between November 2013-December 2021 were retrospectively identified. The study group consisted of patients ≥ 85 years (Group 1) diagnosed with a chronic SDH surgically evacuated. A control group was created matching patients by 70–84 years of age, gender, and anticoagulation use (Group 2). Multiple metrics were evaluated between the two including length-of hospital-stay, tracheostomy/PEG placement, reoperation rate, complications, discharge location, neurological outcome at the time of discharge, and survival. A total of 130 patients were included; 65 in Group 1 and 65 in Group 2. Patient demographics, medical comorbidities, SDH characteristics, international normalized ratio, partial thromboplastin time, and use of blood thinning agents were similar between the two groups. Kaplan Meier survival analysis at one-year was 80% for Group 1 and 76% for Group 2. No significant difference was identified using the log-rank test for equality of survivor functions ( p = 0.26). All measured outcomes including GCS at time of discharge, length of stay, rate of reoperations, and neurological outcome were statistically similar between the two groups. Backwards stepwise conditional logistic regression revealed no significant association between poor outcomes at the time of discharge and age. Alternatively, anticoagulation use was found to be associated with poor outcomes (OR 3.55, 95% CI 1.08–11.60; p = 0.036). Several outcome metrics and statistical analyses were used to compare patients ≥ 85 years of age to younger geriatric patients (70–84 years) in a matched cohort study. Adjusting for age group, gender, and anticoagulation use, no significant difference was found between the two groups including neurological outcome at discharge, reoperation rate, and survival.

Surgical management of spinal pathologies in the octogenarian: a narrative review - Alexander R. Evans; Joshua Bakhsheshian; Christopher S. Graffeo; Zachary A. Smith (GeroScience, 2024)

Correction to: The CEPH aging cohort and biobank: a valuable collection of biological samples from exceptionally long‑lived French individuals and their offspring for longevity studies - Alexandre How‑Kit; Mourad Sahbatou; Lise M. Hardy; Nicolas P. Tessier; Valérie Schiavon; Hélène Le Buanec; Jean‑Marc Sebaoun; Hélène Blanché; Jean‑François Zagury; Jean‑François Deleuze (GeroScience, 2024)

Purpose in life and slow walking speed: cross-sectional and longitudinal associations - Angelina R. Sutin; Sabrina Cajuste; Yannick Stephan; Martina Luchetti; Tiia Kekäläinen; Antonio Terracciano (GeroScience, 2024)

Aging induces changes in cancer formation and microbial content in a murine model of bladder cancer - Benjamin L. Woolbright; Hao Xuan; Ishfaq Ahmed; Ganeshkumar Rajendran; Erika Abbott; Katie Dennis; Cuncong Zhong; Shahid Umar; John A. Taylor (GeroScience, 2024)

Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, “futile” fatty acid cycling, and FADH2 oxidation - Roman Abrosimov; Marius W. Baeken; Samuel Hauf; Ilka Wittig; Parvana Hajieva; Carmen E. Perrone; Bernd Moosmann (GeroScience, 2024)
Inhibition of mitochondrial complex I (NADH dehydrogenase) is the primary mechanism of the antidiabetic drug metformin and various unrelated natural toxins. Complex I inhibition can also be induced by antidiabetic PPAR agonists, and it is elicited by methionine restriction, a nutritional intervention causing resistance to diabetes and obesity. Still, a comprehensible explanation to why complex I inhibition exerts antidiabetic properties and engenders metabolic inefficiency is missing. To evaluate this issue, we have systematically reanalyzed published transcriptomic datasets from MPP-treated neurons, metformin-treated hepatocytes, and methionine-restricted rats. We found that pathways leading to NADPH formation were widely induced, together with anabolic fatty acid biosynthesis, the latter appearing highly paradoxical in a state of mitochondrial impairment. However, concomitant induction of catabolic fatty acid oxidation indicated that complex I inhibition created a “futile” cycle of fatty acid synthesis and degradation, which was anatomically distributed between adipose tissue and liver in vivo. Cofactor balance analysis unveiled that such cycling would indeed be energetically futile (-3 ATP per acetyl-CoA), though it would not be redox-futile, as it would convert NADPH into respirable FADH 2 without any net production of NADH. We conclude that inhibition of NADH dehydrogenase leads to a metabolic shift from glycolysis and the citric acid cycle (both generating NADH) towards the pentose phosphate pathway, whose product NADPH is translated 1:1 into FADH 2 by fatty acid cycling. The diabetes-resistant phenotype following hepatic and intestinal complex I inhibition is attributed to FGF21- and GDF15-dependent fat hunger signaling, which remodels adipose tissue into a glucose-metabolizing organ.

The impact of a tDCS and cognitive training intervention on task-based functional connectivity - Jessica N. Kraft; Aprinda Indahlastari; Emanuel M. Boutzoukas; Hanna K. Hausman; Cheshire Hardcastle; Alejandro Albizu; Andrew O’Shea; Nicole D. Evangelista; Emily J. Van Etten; Pradyumna K. Bharadwaj; Hyun Song; Samantha G. Smith; et al. (GeroScience, 2024)

Translatability of mouse muscle-aging for humans: the role of sex - Jelle C. B. C. de Jong; Martien P. M. Caspers; Nicole Worms; Nanda Keijzer; Robert Kleemann; Aswin L. Menke; Arie G. Nieuwenhuizen; Jaap Keijer; Lars Verschuren; Anita M. van den Hoek (GeroScience, 2024)
Muscle-aging drives sarcopenia and is a major public health issue. Mice are frequently used as a model for human muscle-aging, however, research investigating their translational value is limited. In addition, mechanisms underlying muscle-aging may have sex-specific features in humans, but it is not yet assessed whether these are recapitulated in mice. Here, we studied the effects of aging on a functional, histological and transcriptional level at multiple timepoints in male and female mice (4, 17, 21 and 25 months), with particular emphasis on sex-differences. The effects of natural aging on the transcriptome of quadriceps muscle were compared to humans on pathway level. Significant loss of muscle mass occurred late, at 25 months, in both male (-17%, quadriceps) and female mice (-10%, quadriceps) compared to young control mice. Concomitantly, we found in female, but not male mice, a slower movement speed in the aged groups compared to the young mice (P < 0.001). Consistently, weighted gene co-expression network analysis revealed a stronger association between the aging-related reduction of movement and aging-related changes in muscle transcriptome of female compared to male mice (P < 0.001). In male, but not female mice, major distinctive aging-related changes occurred in the last age group (25 months), which highlights the necessity for careful selection of age using mice as a muscle-aging model. Furthermore, contrasting to humans, more aging-related changes were found in the muscle transcriptome of male mice compared to female mice (4090 vs. 2285 differentially expressed genes at 25 months, respectively). Subsequently, male mice recapitulated more muscle-aging related pathways characteristic for both male and female humans. In conclusion, our data show that sex has a critical effect on the mouse muscle-aging trajectory, although these do not necessarily reflect sex differences observed in the human muscle-aging trajectory.

The plasma metabolome is associated with preservation of physiological function following lifelong aerobic exercise in mice - Kevin O. Murray; Grace S. Maurer; Rachel A. Gioscia-Ryan; Melanie C. Zigler; Katelyn R. Ludwig; Angelo D’Alessandro; Julie A. Reisz; Matthew J. Rossman; Douglas R. Seals; Zachary S. Clayton (GeroScience, 2024)

Cardiorespiratory fitness is associated with cognitive performance in 80 + -year-olds: Detangling processing levels - Stephanie Fröhlich; Dieter F. Kutz; Katrin Müller; Claudia Voelcker-Rehage (GeroScience, 2024)
Cardiorespiratory fitness is known to protect against cognitive decline in older adults. Specifically, it has been shown that physical activity and fitness are beneficial for executive functions that are crucial for independent living up to old age. In this study, 115 individuals aged 80 years and older underwent a cardiorespiratory fitness assessment using the two-minute step test and had their electroencephalogram recorded during a colored flanker task in order to measure executive function performance. Cardiorespiratory fitness was related to quicker responses during the flanker task. A mediation analysis was carried out to determine whether these positive effects were mediated through event-related potentials (N1, N2, or P3) or motor-related cortical potentials (MRCP). Cardiorespiratory fitness was related to better visual discriminative processing as indicated by larger occipital N1 amplitudes. In addition, fitness was associated with larger MRCP amplitudes, which are a correlate of the response generation process. Fitness was not found to have a significant effect on fronto-central N2 or parietal P3, which are thought to capture cognitive control processes such as conflict detection and response inhibition. Moreover, all effects reported were present in all three flanker trial conditions (congruent, neutral, and incongruent). Thus, these results indicate that the quicker response times in fitter people were related to visual processing and motor response generation rather than cognitive control.

The influence of APOE status on rate of cognitive decline - Cassandra Morrison; Michael D. Oliver; Virginia Berry; Farooq Kamal; Mahsa Dadar (GeroScience, 2024)
Background Apolipoprotein (APOE) ɛ4 positivity and subjective cognitive decline (SCD) both increase risk of Alzheimer’s disease (AD) development. However, few studies have examined the relationship between SCD and APOE status, especially using longitudinal data. The current study examined whether APOE is associated with the rate of cognitive change in SCD and mild cognitive impairment (MCI). Methods A sample of 3494 older adults (1990 normal controls, NC, 775 SCD, and 729 MCI) with a mean follow-up of 9.09 years were included from the Rush Alzheimer’s Disease Center Research Sharing Hub. Linear mixed effects models examined the relationship between APOE status and cognitive change in older adults with SCD normal controls, and people with MCI. Results The presence of at least one ɛ2 allele in SCD and MCI results in cognitive change rates similar to a NC with the ɛ3ɛ3 genotype. Older adult SCD-ɛ4 individuals exhibited increased rate of cognitive decline compared to all groups, including NC-ɛ4 and MCI-ɛ4. Conclusion People with SCD with at least one ɛ4 allele experience increased rates of cognitive decline compared to cognitively healthy older adults and people with MCI. These findings have important implications for treatments and interventions and can improve future research and clinical trials by targeting people in the preclinical AD phase (i.e., SCD) who also possess at least one APOE ɛ4 allele.

The role of physical activity in the association between disability and mortality among US older adults: a nationwide prospective cohort study - Rocio Izquierdo-Gomez; David Martínez-Gómez; Nora Shields; María del Rosario Ortola-Vidal; Fernando Rodríguez-Artalejo; Verónica Cabanas-Sánchez (GeroScience, 2024)
To examine whether physical activity can mitigate the mortality risk associated with disability in activities of daily living and instrumental activities in daily living among older adults. This analysis comprised 177,360 US participants (104,556 women), aged ≥ 60 years, with valid data from the 1997 through 2018 waves of the US National Health Interview Survey. Participants reported the frequency and duration of leisure-time PA, and their disabilities in activities of daily living and instrumental activities in daily living. Mortality data were obtained from the National Death Index. Over a mean (SD) follow-up of 8.02 (5.43) years, 66,694 deaths occurred from all-cause, 22,673 from cardiovascular disease, and 13,845 from cancer. Among people with disability in activities in daily living, those reaching physical activity recommendations had 25%, 24% and 33% lower risk of all-cause mortality, cardiovascular diseases, and cancer death, respectively, compared with those who do not meet physical activity recommendations. Values were 23%, 22% and 24% for those with disability in instrumental activities in daily living. Risk reductions associated with reaching the recommended physical activity ranged 16% to 29% for people without disability. Combining disability type and compliance with physical activity, individuals with disability in activities of daily living or instrumental activities in daily living who meet the recommended physical activity had moderately higher mortality than those without disability who did not achieve the recommended physical activity. Compliance with physical activity recommendations can partially mitigate excess mortality resulting from disability in activities in daily living or instrumental activities in daily living in older adults.

Association of biological aging with frailty and post-transplant outcomes among adults with cirrhosis - Sara C. LaHue; Matias Fuentealba; Stephanie Roa Diaz; Srilakshmi Seetharaman; Thelma Garcia; David Furman; Jennifer C. Lai; John C. Newman (GeroScience, 2024)

Common synaptic inputs and persistent inward currents of vastus lateralis motor units are reduced in older male adults - Yuxiao Guo; Eleanor J. Jones; Jakob Škarabot; Thomas B. Inns; Bethan E. Phillips; Philip J. Atherton; Mathew Piasecki (GeroScience, 2024)
Although muscle atrophy may partially account for age-related strength decline, it is further influenced by alterations of neural input to muscle. Persistent inward currents (PIC) and the level of common synaptic inputs to motoneurons influence neuromuscular function. However, these have not yet been described in the aged human quadriceps. High-density surface electromyography (HDsEMG) signals were collected from the vastus lateralis of 15 young (mean ± SD, 23 ± 5 y) and 15 older (67 ± 9 y) men during submaximal sustained and 20-s ramped contractions. HDsEMG signals were decomposed to identify individual motor unit discharges, from which PIC amplitude and intramuscular coherence were estimated. Older participants produced significantly lower knee extensor torque ( p < 0.001) and poorer force tracking ability ( p < 0.001) than young. Older participants also had lower PIC amplitude ( p = 0.001) and coherence estimates in the alpha frequency band ( p < 0.001) during ramp contractions when compared to young. Persistent inward currents and common synaptic inputs are lower in the vastus lateralis of older males when compared to young. These data highlight altered neural input to the clinically and functionally important quadriceps, further underpinning age-related loss of function which may occur independently of the loss of muscle mass.

Association of postoperative delirium with serum and cerebrospinal fluid proteomic profiles: a prospective cohort study in older hip fracture patients - Lucía Lozano-Vicario; Ángel Javier Muñoz-Vázquez; Robinson Ramírez-Vélez; Arkaitz Galbete-Jiménez; Joaquín Fernández-Irigoyen; Enrique Santamaría; Bernardo Abel Cedeno-Veloz; Fabricio Zambom-Ferraresi; Barbara C. Van Munster; José Ramón Ortiz-Gómez; Ángel Manuel Hidalgo-Ovejero; Román Romero-Ortuno; et al. (GeroScience, 2024)

Senolytic treatment does not mitigate oxidative stress-induced muscle atrophy but improves muscle force generation in CuZn superoxide dismutase knockout mice - Agnieszka K. Borowik; Marcus M. Lawrence; Frederick F. Peelor; Katarzyna M. Piekarz; Abby Crosswhite; Arlan Richardson; Benjamin F. Miller; Holly Van Remmen; Jacob L. Brown (GeroScience, 2024)

Metformin treatment of juvenile mice alters aging-related developmental and metabolic phenotypes in sex-dependent and sex-independent manners - Yun Zhu; Morgan Engmann; David Medina; Xiuqi Han; Pratyusa Das; Andrzej Bartke; Buffy S. Ellsworth; Rong Yuan (GeroScience, 2024)

Frontal–temporal regional differences in brain energy metabolism and mitochondrial function using 31P MRS in older adults - Francesca V. Lopez; Andrew O’Shea; Zhiguang Huo; Steven T. DeKosky; Theodore P. Trouard; Gene E. Alexander; Adam J. Woods; Dawn Bowers (GeroScience, 2024)

Brain control of dual-task walking can be improved in aging and neurological disease - Roee Holtzer; Jaeun Choi; Robert W. Motl; Frederick W. Foley; Mark E. Wagshul; Manuel E. Hernandez; Meltem Izzetoglu (GeroScience, 2024)

Eliminating senescent cells by white adipose tissue–targeted senotherapy alleviates age-related hepatic steatosis through decreasing lipolysis - Qi Tang; Xiaotao Xing; Haisen Huang; Jian Yang; Maojiao Li; Xun Xu; Xin Gao; Cheng Liang; Weidong Tian; Li Liao (GeroScience, 2024)

Impact of knockout of dual-specificity protein phosphatase 5 on structural and mechanical properties of rat middle cerebral arteries: implications for vascular aging - Chengyun Tang; Huawei Zhang; Jane J. Border; Yedan Liu; Xing Fang; Joshua R. Jefferson; Andrew Gregory; Claire Johnson; Tae Jin Lee; Shan Bai; Ashok Sharma; Seung Min Shin; et al. (GeroScience, 2024)

Early neurological changes in aging cervical spine: insights from PROMIS mobility assessment - Sanaa Hameed; Fauziyya Muhammad; Grace Haynes; Lonnie Smith; Ali F. Khan; Zachary A. Smith (GeroScience, 2024)

Anticipating the future of the COVID-19 pandemic: insights into the emergence of SARS-CoV-2 variant JN.1 and its projected impact on older adults - Jorge Quarleri; M. Victoria Delpino; Veronica Galvan (GeroScience, 2024)

Cell-free ascites from ovarian cancer patients induces Warburg metabolism and cell proliferation through TGFβ-ERK signaling - Dóra Szeőcs; Beáta Vida; Gábor Petővári; Szilárd Póliska; Eszter Janka; Adrienn Sipos; Karen Uray; Anna Sebestyén; Zoárd Krasznai; Péter Bai (GeroScience, 2024)
Ascites plays a key role in supporting the metastatic potential of ovarian cancer cells. Shear stress and carry-over of cancer cells by ascites flow support carcinogenesis and metastasis formation. In addition, soluble factors may participate in the procarcinogenic effects of ascites in ovarian cancer. This study aimed to determine the biological effects of cell-free ascites on carcinogenesis in ovarian cancer cells. Cell-free ascites from ovarian cancer patients (ASC) non-selectively induced cell proliferation in multiple models of ovarian cancer and untransformed primary human dermal fibroblasts. Furthermore, ASC induced a Warburg-type rearrangement of cellular metabolism in A2780 ovarian cancer cells characterized by increases in cellular oxygen consumption and glycolytic flux; increases in glycolytic flux were dominant. ASC induced mitochondrial uncoupling and fundamentally reduced fatty acid oxidation. Ascites-elicited effects were uniform among ascites specimens. ASC-elicited transcriptomic changes in A2780 ovarian cancer cells included induction of the TGFβ-ERK/MEK pathway, which plays a key role in inducing cell proliferation and oncometabolism. ASC-induced gene expression changes, as well as the overexpression of members of the TGFβ signaling system, were associated with poor survival in ovarian cancer patients. We provided evidence that the activation of the autocrine/paracrine of TGFβ signaling system may be present in bladder urothelial carcinoma and stomach adenocarcinoma. Database analysis suggests that the TGFβ system may feed forward bladder urothelial carcinoma and stomach adenocarcinoma. Soluble components of ASC support the progression of ovarian cancer. These results suggest that reducing ascites production may play an essential role in the treatment of ovarian cancer by inhibiting the progression and reducing the severity of the disease.

Fisetin modulates the gut microbiota alongside biomarkers of senescence and inflammation in a DSS-induced murine model of colitis - Sarah A. Ashiqueali; Diptaraj Chaudhari; Xiang Zhu; Sarah Noureddine; Sarah Siddiqi; Driele N. Garcia; Aleksandra Gostynska; Maciej Stawny; Blazej Rubis; Bianka M. Zanini; Mishfak A. M. Mansoor; Augusto Schneider; et al. (GeroScience, 2024)

The interplay of aging, adipose tissue, and COVID-19: a potent alliance with implications for health - Jorge Quarleri; M. Victoria Delpino (GeroScience, 2024)

Factors influencing gait performance in older adults in a dual-task paradigm - Karina Elizabeth Andrade Lara; José Carlos Cabrera Linares; Juan Antonio Párraga Montilla; Pedro Ángel Latorre Román (GeroScience, 2024)

Neutrophil, lymphocyte count, and neutrophil to lymphocyte ratio predict multimorbidity and mortality—results from the Baltimore Longitudinal Study on Aging follow-up study - Raffaello Pellegrino; Roberto Paganelli; Angelo Di Iorio; Stefania Bandinelli; Antimo Moretti; Giovanni Iolascon; Eleonora Sparvieri; Domiziano Tarantino; Toshiko Tanaka; Luigi Ferrucci (GeroScience, 2024)

Irradiation-induced hair graying in mice: an experimental model to evaluate the effectiveness of interventions targeting oxidative stress, DNA damage prevention, and cellular senescence - Anna Ungvari; Tamas Kiss; Rafal Gulej; Stefano Tarantini; Boglarka Csik; Andriy Yabluchanskiy; Peter Mukli; Anna Csiszar; Melissa L. Harris; Zoltan Ungvari (GeroScience, 2024)
Hair graying, also known as canities or achromotrichia, is a natural phenomenon associated with aging and is influenced by external factors such as stress, environmental toxicants, and radiation exposure. Understanding the mechanisms underlying hair graying is an ideal approach for developing interventions to prevent or reverse age-related changes in regenerative tissues. Hair graying induced by ionizing radiation (γ-rays or X-rays) has emerged as a valuable experimental model to investigate the molecular pathways involved in this process. In this review, we examine the existing evidence on radiation-induced hair graying, with a particular focus on the potential role of radiation-induced cellular senescence. We explore the current understanding of hair graying in aging, delve into the underlying mechanisms, and highlight the unique advantages of using ionizing-irradiation–induced hair graying as a research model. By elucidating the molecular pathways involved, we aim to deepen our understanding of hair graying and potentially identify novel therapeutic targets to address this age-related phenotypic change.

Prognostic accuracy of 70 individual frailty biomarkers in predicting mortality in the Canadian Longitudinal Study on Aging - Joanna M. Blodgett; Mario Ulisses Pérez-Zepeda; Judith Godin; Dustin Scott Kehler; Melissa K. Andrew; Susan Kirkland; Kenneth Rockwood; Olga Theou (GeroScience, 2024)
The frailty index (FI) uses a deficit accumulation approach to derive a single, comprehensive, and replicable indicator of age-related health status. Yet, many researchers continue to seek a single “frailty biomarker” to facilitate clinical screening. We investigated the prognostic accuracy of 70 individual biomarkers in predicting mortality, comparing each with a composite FI. A total of 29,341 individuals from the comprehensive cohort of the Canadian Longitudinal Study on Aging were included (mean, 59.4 ± 9.9 years; 50.3% female). Twenty-three blood-based biomarkers and 47 test-based biomarkers (e.g., physical, cardiac, cardiology) were examined. Two composite FIs were derived: FI-Blood and FI-Examination. Mortality status was ascertained using provincial vital statistics linkages and contact with next of kin. Areas under the curve were calculated to compare prognostic accuracy across models (i.e., age, sex, biomarker, FI) in predicting mortality. Compared to an age-sex only model, the addition of individual biomarkers demonstrated improved model fit for 24/70 biomarkers (11 blood, 13 test-based). Inclusion of FI-Blood or FI-Examination improved mortality prediction when compared to any of the 70 biomarker-age-sex models. Individual addition of seven biomarkers (walking speed, chair rise, time up and go, pulse, red blood cell distribution width, C-reactive protein, white blood cells) demonstrated an improved fit when added to the age-sex-FI model. FI scores had better mortality risk prediction than any biomarker. Although seven biomarkers demonstrated improved prognostic accuracy when considered alongside an FI score, all biomarkers had worse prognostic accuracy on their own. Rather than a single biomarker test, implementation of routine FI assessment in clinical settings may provide a more accurate and reliable screening tool to identify those at increased risk of adverse outcomes.

Baseline and usual triglyceride-glucose index and the risk of chronic kidney disease: a prospective cohort study - Setor K. Kunutsor; Samuel Seidu; Sudhir Kurl; Jari A. Laukkanen (GeroScience, 2024)
Triglyceride-glucose (TyG) index is an emerging marker of adverse cardiometabolic conditions such as cardiovascular disease and type 2 diabetes. The long-term relevance of TyG index to chronic kidney disease (CKD) is uncertain. We aimed to assess the association of TyG index with CKD risk and its utility in risk prediction in a prospective study. The TyG index was calculated using fasting triglycerides and fasting plasma glucose (FPG) levels measured in 2362 men aged 42–61 years with normal kidney function using the formula: Ln (fasting triglycerides [mg/dL] × FPG [mg/dL]/2). Multivariable adjusted hazard ratios (HRs) (95% confidence intervals, CIs) were estimated for CKD. Correction for within-person variability was made using data from repeat measurements of triglycerides and FPG taken 11 years after baseline. Over a median follow-up duration of 17.5 years, 223 CKD cases were recorded. The age-adjusted regression dilution ratio for the TyG index was 0.54 (95% CI, 0.48–0.60). The risk of CKD increased continuously with increasing TyG index across the range 9.3 to 11.6 ( p value for nonlinearity<.001). In analysis adjusted for established risk factors, a unit higher TyG index was associated with an increased risk of CKD (HR 1.59, 95% CI 1.24–2.05). Comparing extreme tertiles of the TyG index, the corresponding adjusted HR (95% CI) for CKD was 1.61 (1.15–2.27). Addition of the TyG index to a CKD risk prediction model containing established risk factors improved risk discrimination and reclassification ( p value for difference in −2 log likelihood<.001; NRI=47.66%, p =.014; IDI=0.0164, p <.001). Higher TyG index is associated with an increased risk of CKD and improves the prediction and classification of CKD beyond established risk factors. Using single baseline estimations of the TyG index to investigate its association with CKD risk could considerably under-estimate the true association.

Titan mice as a model to test interventions that attenuate frailty and increase longevity - Benedikt Gille; Annika Müller-Eigner; Shari Gottschalk; Erika Wytrwat; Martina Langhammer; Shahaf Peleg (GeroScience, 2024)

Modulation of movement-related oscillatory signatures by cognitive interference in healthy aging - Yasra Arif; Jake J. Son; Hannah J. Okelberry; Hallie J. Johnson; Madelyn P. Willett; Alex I. Wiesman; Tony W. Wilson (GeroScience, 2024)

Longitudinal changes in the functional connectivity of individuals at risk of Alzheimer’s disease - Alejandra García-Colomo; Alberto Nebreda; Martín Carrasco-Gómez; Jaisalmer de Frutos-Lucas; Federico Ramirez-Toraño; Carlos Spuch; María Comis-Tuche; Ricardo Bruña; Soraya Alfonsín; Fernando Maestú (GeroScience, 2024)

Cell Tree Rings: the structure of somatic evolution as a human aging timer - Attila Csordas; Botond Sipos; Terezia Kurucova; Andrea Volfova; Frantisek Zamola; Boris Tichy; Damien G Hicks (GeroScience, 2024)
Biological age is typically estimated using biomarkers whose states have been observed to correlate with chronological age. A persistent limitation of such aging clocks is that it is difficult to establish how the biomarker states are related to the mechanisms of aging. Somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. Cell lineage trees inferred from these mutations reflect the somatic evolutionary process, and thus, it has been conjectured, the aging status of the body. Such a timer has been impractical thus far, however, because detection of somatic variants in single cells presents a significant technological challenge. Here, we show that somatic mutations detected using single-cell RNA sequencing (scRNA-seq) from thousands of cells can be used to construct a cell lineage tree whose structure correlates with chronological age. De novo single-nucleotide variants (SNVs) are detected in human peripheral blood mononuclear cells using a modified protocol. A default model based on penalized multiple regression of chronological age on 31 metrics characterizing the phylogenetic tree gives a Pearson correlation of 0.81 and a median absolute error of ~4 years between predicted and chronological ages. Testing of the model on a public scRNA-seq dataset yields a Pearson correlation of 0.85. In addition, cell tree age predictions are found to be better predictors of certain clinical biomarkers than chronological age alone, for instance glucose, albumin levels, and leukocyte count. The geometry of the cell lineage tree records the structure of somatic evolution in the individual and represents a new modality of aging timer. In addition to providing a numerical estimate of “cell tree age,” it unveils a temporal history of the aging process, revealing how clonal structure evolves over life span. Cell Tree Rings complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.

Intracellular iron accumulation facilitates mycobacterial infection in old mouse macrophages - Stephen K. Kotey; Xuejuan Tan; Owen Fleming; Ramakrishnama Raju Kasiraju; Audrey L. Dagnell; Kyle N. Van Pelt; Janet Rogers; Steven D. Hartson; Nidheesh Thadathil; Ramasamy Selvarani; Rojina Ranjit; Sreemathi Logan; et al. (GeroScience, 2023)
Aging has a significant impact on the immune system, leading to a gradual decline in immune function and changes in the body’s ability to respond to bacterial infections. Non-tuberculous mycobacteria (NTM), also known as atypical mycobacteria or environmental mycobacteria, are commonly found in soil, water, and various environmental sources. While many NTM species are considered opportunistic pathogens, some can cause significant infections, particularly in individuals with compromised immune systems, such as older individuals. When mycobacteria enter the body, macrophages are among the first immune cells to encounter them and attempt to engulf mycobacteria through a process called phagocytosis. Some NTM species, including Mycobacterium avium ( M. avium ) can survive and replicate within macrophages. However, little is known about the interaction between NTM and macrophages in older individuals. In this study, we investigated the response of bone marrow–derived macrophage (BMMs) isolated from young (5 months) and old (25 months) mice to M. avium serotype 4, one of the main NTM species in patients with pulmonary NTM diseases. Our results demonstrated that BMMs from old mice have an increased level of intracellular iron and are more susceptible to M. avium serotype 4 infection compared to BMMs from young mice. The whole-cell proteomic analysis indicated a dysregulated expression of iron homeostasis–associated proteins in old BMMs regardless of mycobacterial infection. Deferoxamine, an iron chelator, significantly rescued mycobacterial killing and phagolysosome maturation in BMMs from old mice. Therefore, our data for the first time indicate that an intracellular iron accumulation improves NTM survival within macrophages from old mice and suggest a potential application of iron-chelating drugs as a host-directed therapy for pulmonary NTM infection in older individuals.

Tobacco exposure, but not aging, shifts the frequency of peripheral blood B cell subpopulations - Thalyta Nery Carvalho Pinto; Cibele Cristine Berto Marques da Silva; Regina Maria Carvalho Pinto; Alberto José da Silva Duarte; Gil Benard; Juliana Ruiz Fernandes (GeroScience, 2023)

Hyperbaric oxygen alleviates selective domains of cognitive and motor deficits in female 5xFAD mice - Paapa Mensah-Kane; Delaney L. Davis; Helen S. Shi; Oanh T. Trinh; Philip H. Vann; Ladislav Dory; Nathalie Sumien (GeroScience, 2023)

Association of skeletal muscle oxidative capacity with muscle function, sarcopenia-related exercise performance, and intramuscular adipose tissue in older adults - Akito Yoshiko; Kana Shiozawa; Shiori Niwa; Hideyuki Takahashi; Teruhiko Koike; Kohei Watanabe; Keisho Katayama; Hiroshi Akima (GeroScience, 2023)

PEDF protects retinal pigment epithelium from ferroptosis and ameliorates dry AMD-like pathology in a murine model - Wei Xiang; Longhui Li; Qin Zhao; Yongcheng Zeng; Jinhui Shi; Zitong Chen; Guoquan Gao; Kunbei Lai (GeroScience, 2023)

Correction to: Therapeutic efficacies of mitochondria‑targeted esculetin and metformin in the improvement of age‑associated atherosclerosis via regulating AMPK activation - Sriravali Pulipaka; Gajalakshmi Singuru; Shashikanta Sahoo; Altab Shaikh; Rajamannar Thennati; Srigiridhar Kotamraju (GeroScience, 2023)

The CEPH aging cohort and biobank: a valuable collection of biological samples from exceptionally long-lived French individuals and their offspring for longevity studies - Alexandre How-Kit; Mourad Sahbatou; Lise M. Hardy; Nicolas P. Tessier; Valérie Schiavon; Hélène Le Buanec; Jean-Marc Sebaoun; Hélène Blanché; Jean-François Zagury; Jean-François Deleuze (GeroScience, 2023)
The increasing aging of the human population is currently and for the coming decades a major public health issue in many countries, requiring the implementation of global public health policies promoting healthy and successful aging. Individuals are not equal in the face of aging and some can present exceptional healthspan and/or lifespan, which are notably influenced by both genetic and environmental factors. Research and studies on human aging, healthy aging and longevity should rely in particular on cohorts of long-lived individuals, also including biological samples allowing studies on the biology of aging and longevity. In this manuscript, we provide for the first time a complete description of the CEPH (Centre d’Etude du Polymophisme Humain) Aging cohort, an exceptional cohort recruited during the 90s to 2000s, including more than 1700 French long-lived individuals (≥ 90 years old) born between 1875 and 1916 as well as for some of them their siblings and offspring. Among the participants, 1265 were centenarians, including 255 semi-supercentenarians ([105–110] years old) and 25 supercentenarians (≥ 110 years old). The available anthropometric, epidemiologic and clinical data for the cohort participants are described and especially the collection of blood-derived biological samples associated with the cohort which includes DNA, cryopreserved cells and cell lines, plasma, and serum. This biological collection from the first cohort of centenarians in the world is an inestimable resource for ongoing and future molecular, cellular, and functional studies aimed at deciphering the mechanisms of human (successful) aging and longevity.

Comparative study of machine learning methods for modeling associations between risk factors and future dementia cases - Vaka Valsdóttir; María K. Jónsdóttir; Brynja Björk Magnúsdóttir; Milan Chang; Yi-Han Hu; Vilmundur Gudnason; Lenore J. Launer; Hlynur Stefánsson (GeroScience, 2023)

The prevalence of frailty and its effect on the outcome in cardiac resynchronization therapy patients - Luca Katalin Kuthi; Walter Richard Schwertner; Boglárka Veres; Eperke Dóra Merkel; Richard Masszi; Anett Behon; Attila Kovács; István Osztheimer; Endre Zima; Levente Molnár; László Gellér; Annamária Kosztin; et al. (GeroScience, 2023)
Frailty is a complex clinical syndrome associated with aging and comorbidities, which correlates with unfavorable outcomes. However, in heart failure patients, frailty is very common, data is scarce about those, who are eligible for Cardiac Resynchronization Therapy (CRT) implantation. We investigated the incidence of frailty and the association of Frailty Index (FI) with the outcome. Thirty baseline clinical parameters were used by the Rockwood cumulative deficit method to determine patients' FI in our single-center cohort. Based on previous studies, patients with FI ≤ 0.210 were considered as non-frail, those with FI 0.10–0.210 were classified in Frail-1, with FI > 0.10 in Frail-2 groups, respectively. Echocardiographic response after 12 months and all-cause mortality were investigated by frailty groups. Among 1004 included patients, 75 (7%) were considered Non-frail, 271 (27%) grouped in Frail-1, and 658 (66%) in Frail-2 with a median FI of 0.36 (0.28–0.43). Patients in Frail-2 group were older, with more comorbidities compared with non-frail patients or those in Group Frail-1. During the median follow-up time of 4.8 years, 29 (39%) patients died in the Non-frail, 140 (52%) in Frail-1, and 471 (72%) in the Frail-2 groups (log-rank p < 0.001). Group Frail-2 showed an unfavorable outcome compared to the non-frail (HR 2.49, 95%CI 1.92–3.22; p < 0.001) and the Frail-1 group (1.83, 95%CI 1.55–2.16; p < 0.001). In our HFrEF patients eligible for CRT implantation, patients were exceedingly vulnerable with a high prevalence of frailty. The calculated frailty index was associated with outcome and proved to be prevalent in individual risk stratification.

Rejuvenation of cerebromicrovascular function in aged mice through heterochronic parabiosis: insights into neurovascular coupling and the impact of young blood factors - Rafal Gulej; Ádám Nyúl-Tóth; Boglarka Csik; Benjamin Petersen; Janet Faakye; Sharon Negri; Siva Sai Chandragiri; Peter Mukli; Andriy Yabluchanskiy; Shannon Conley; Derek M. Huffman; Anna Csiszar; et al. (GeroScience, 2023)

Fingerprints of decreased cognitive performance on fractal connectivity dynamics in healthy aging - Zalan Kaposzta; Akos Czoch; Peter Mukli; Orestis Stylianou; Deland Hu Liu; Andras Eke; Frigyes Samuel Racz (GeroScience, 2023)
Analysis of brain functional connectivity (FC) could provide insight in how and why cognitive functions decline even in healthy aging (HA). Despite FC being established as fluctuating over time even in the resting state (RS), dynamic functional connectivity (DFC) studies involving healthy elderly individuals and assessing how these patterns relate to cognitive performance are yet scarce. In our recent study we showed that fractal temporal scaling of functional connections in RS is not only reduced in HA, but also predicts increased response latency and reduced task solving accuracy. However, in that work we did not address changes in the dynamics of fractal connectivity (FrC) strength itself and its plausible relationship with mental capabilities. Therefore, here we analyzed RS electroencephalography recordings of the same subject cohort as previously, consisting of 24 young and 19 healthy elderly individuals, who also completed 7 different cognitive tasks after data collection. Dynamic fractal connectivity (dFrC) analysis was carried out via sliding-window detrended cross-correlation analysis (DCCA). A machine learning method based on recursive feature elimination was employed to select the subset of connections most discriminative between the two age groups, identifying 56 connections that allowed for classifying participants with an accuracy surpassing 92%. Mean of DCCA was found generally increased, while temporal variability of FrC decreased in the elderly when compared to the young group. Finally, dFrC indices expressed an elaborate pattern of associations—assessed via Spearman correlation—with cognitive performance scores in both groups, linking fractal connectivity strength and variance to increased response latency and reduced accuracy in the elderly population. Our results provide further support for the relevance of FrC dynamics in understanding age-related cognitive decline and might help to identify potential targets for future intervention strategies.

Recapitulation of anti-aging phenotypes by global overexpression of PTEN in mice - Mary Hager; Peter Chang; Michael Lee; Calvin M. Burns; S. Joseph Endicott; Richard A. Miller; Xinna Li (GeroScience, 2023)
The PTEN gene negatively regulates the oncogenic PI3K-AKT pathway by encoding a lipid and protein phosphatase that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphate (PIP 3 ) resulting in the inhibition of PI3K and downstream inhibition of AKT. Overexpression of PTEN in mice leads to a longer lifespan compared to control littermates, although the mechanism is unknown. Here, we provide evidence that young adult PTENOE mice exhibit many characteristics shared by other slow-aging mouse models, including those with mutations that affect GH/IGF1 pathways, calorie-restricted mice, and mice treated with anti-aging drugs. PTENOE white adipose tissue (WAT) has increased UCP1, a protein linked to increased thermogenesis. WAT of PTENOE mice also shows a change in polarization of fat-associated macrophages, with elevated levels of arginase 1 (Arg1, characteristic of M2 macrophages) and decreased production of inducible nitric oxide synthase (iNOS, characteristic of M1 macrophages). Muscle and hippocampus showed increased expression of the myokine FNDC5, and higher levels of its cleavage product irisin in plasma, which has been linked to increased conversion of WAT to more thermogenic beige/brown adipose tissue. PTENOE mice also have an increase, in plasma and liver, of GPLD1, which is known to improve cognition in mice. Hippocampus of the PTENOE mice has elevation of both BDNF and DCX, indices of brain resilience and neurogenesis. These changes in fat, macrophages, liver, muscle, hippocampus, and plasma may be considered “aging rate indicators” in that they seem to be consistently changed across many of the long-lived mouse models and may help to extend lifespan by delaying many forms of late-life illness. Our new findings show that PTENOE mice can be added to the group of long-lived mice that share this multi-tissue suite of biochemical characteristics.

The effect of aperiodic components in distinguishing Alzheimer’s disease from frontotemporal dementia - Zhuyong Wang; Anyang Liu; Jianshen Yu; Pengfei Wang; Yuewei Bi; Sha Xue; Jiajun Zhang; Hongbo Guo; Wangming Zhang (GeroScience, 2023)

PCSK9: an emerging player in cardiometabolic aging and its potential as a therapeutic target and biomarker - Anna Csiszar; Stefano Tarantini; Andriy Yabluchanskiy; Zoltan Ungvari (GeroScience, 2023)
Proprotein convertase subtilisin/kexin type 9 (PCSK9), renowned for its pivotal role in low-density lipoprotein (LDL) regulation, has emerged as a compelling regulator of cardiometabolic aging. Beyond its well-established involvement in cholesterol metabolism, PCSK9’s multifaceted influence on the aging processes of the cardiovascular and metabolic systems is garnering increasing attention. This review delves into the evolving landscape of PCSK9 in the context of cardiometabolic aging, offering fresh insights into its potential implications. Drawing inspiration from pioneering research conducted by the Pacher laboratory (Arif et al., Geroscience, 2023, PMID: 37726433), we delve into the intricate interplay of PCSK9 within the aging heart and liver, shedding light on its newfound significance. Recent studies underscore PCSK9’s pivotal role in liver aging, suggesting intriguing connections between hepatic aging, lipid metabolism, and cardiovascular health. Additionally, we explore the therapeutic potential of PCSK9 as both a target and a biomarker, within the context of age-related cardiovascular disease.

A systematic review and meta-analysis of the effects of physical exercise on white matter integrity and cognitive function in older adults - Weikun Zhang; Chenglin Zhou; Antao Chen (GeroScience, 2023)

Sex differences in the progression to Alzheimer’s disease: a combination of functional and structural markers - Alberto Fernández; Pablo Cuesta; Alberto Marcos; Mercedes Montenegro-Peña; Miguel Yus; Inmaculada Concepción Rodríguez-Rojo; Ricardo Bruña; Fernando Maestú; María Eugenia López (GeroScience, 2023)

Analysis of epigenetic clocks links yoga, sleep, education, reduced meat intake, coffee, and a SOCS2 gene variant to slower epigenetic aging - Rezvan Noroozi; Joanna Rudnicka; Aleksandra Pisarek; Bożena Wysocka; Aleksander Masny; Michał Boroń; Kamila Migacz-Gruszka; Paulina Pruszkowska-Przybylska; Magdalena Kobus; Dagmara Lisman; Grażyna Zielińska; Aleksandra Iljin; et al. (GeroScience, 2023)

Interplay of body mass index and metabolic syndrome: association with physiological age from midlife to late-life - Peggy Ler; Alexander Ploner; Deborah Finkel; Chandra A. Reynolds; Yiqiang Zhan; Juulia Jylhävä; Anna K. Dahl Aslan; Ida K. Karlsson (GeroScience, 2023)
Obesity and metabolic syndrome (MetS) share common pathophysiological characteristics with aging. To better understand their interplay, we examined how body mass index (BMI) and MetS jointly associate with physiological age, and if the associations changed from midlife to late-life. We used longitudinal data from 1,825 Swedish twins. Physiological age was measured as frailty index (FI) and functional aging index (FAI) and modeled independently in linear mixed-effects models adjusted for chronological age, sex, education, and smoking. We assessed curvilinear associations of BMI and chronological age with physiological age, and interactions between BMI, MetS, and chronological age. We found a significant three-way interaction between BMI, MetS, and chronological age on FI (p-interaction = 0·006), not FAI. Consequently, we stratified FI analyses by age: < 65, 65–85, and ≥ 85 years, and modeled FAI across ages. Except for FI at ages ≥ 85, BMI had U-shaped associations with FI and FAI, where BMI around 26-28 kg/m 2 was associated with the lowest physiological age. MetS was associated with higher FI and FAI, except for FI at ages < 65, and modified the BMI-FI association at ages 65–85 (p-interaction = 0·02), whereby the association between higher BMI levels and FI was stronger in individuals with MetS. Age modified the MetS-FI association in ages ≥ 85, such that it was stronger at higher ages (p-interaction = 0·01). Low BMI, high BMI, and metabolic syndrome were associated with higher physiological age, contributing to overall health status among older individuals and potentially accelerating aging.

A machine learning approach for quantifying age-related histological changes in the mouse kidney - Susan Sheehan; Seamus Mawe; Mandy Chen; Jenna Klug; Warren Ladiges; Ron Korstanje; J. Matthew Mahoney (GeroScience, 2023)
The ability to quantify aging-related changes in histological samples is important, as it allows for evaluation of interventions intended to effect health span. We used a machine learning architecture that can be trained to detect and quantify these changes in the mouse kidney. Using additional held out data, we show validation of our model, correlation with scores given by pathologists using the Geropathology Research Network aging grading scheme, and its application in providing reproducible and quantifiable age scores for histological samples. Aging quantification also provides the insights into possible changes in image appearance that are independent of specific geropathology-specified lesions. Furthermore, we provide trained classifiers for H&E-stained slides, as well as tutorials on how to use these and how to create additional classifiers for other histological stains and tissues using our architecture. This architecture and combined resources allow for the high throughput quantification of mouse aging studies in general and specifically applicable to kidney tissues.

Early cerebral amyloid-β accumulation and hypermetabolism are associated with subtle cognitive deficits before accelerated cerebral atrophy - Aftab Bakhtiari; Krisztina Benedek; Ian Law; Birgitte Fagerlund; Erik Lykke Mortensen; Merete Osler; Martin Lauritzen; Henrik B. W. Larsson; Mark B. Vestergaard (GeroScience, 2023)
Aims Alzheimer’s disease (AD) is characterized by the accumulation of amyloid beta (A β ) in the brain. The deposition of A β is believed to initiate a detrimental cascade, including cerebral hypometabolism, accelerated brain atrophy, and cognitive problems—ultimately resulting in AD. However, the timing and causality of the cascade resulting in AD are not yet fully established. Therefore, we examined whether early A β accumulation affects cerebral glucose metabolism, atrophy rate, and age-related cognitive decline before the onset of neurodegenerative disease. Methods Participants from the Metropolit 1953 Danish Male Birth Cohort underwent brain positron emission tomography (PET) imaging using the radiotracers [ 11 C]Pittsburgh Compound-B (PiB) ( N = 70) and [ 18 F]Fluorodeoxyglucose (FDG) ( N = 76) to assess cerebral A β accumulation and glucose metabolism, respectively. The atrophy rate was calculated from anatomical magnetic resonance imaging (MRI) scans conducted presently and 10 years ago. Cognitive decline was examined from neurophysiological tests conducted presently and ten or 5 years ago. Results Higher A β accumulation in AD-critical brain regions correlated with greater visual memory decline ( p = 0.023). A β accumulation did not correlate with brain atrophy rates. Increased cerebral glucose metabolism in AD-susceptible regions correlated with worse verbal memory performance ( p = 0.040). Conclusions A β accumulation in known AD-related areas was associated with subtle cognitive deficits. The association was observed before hypometabolism or accelerated brain atrophy, suggesting that A β accumulation is involved early in age-related cognitive dysfunction. The association between hypermetabolism and worse memory performance may be due to early compensatory mechanisms adapting for malfunctioning neurons by increasing metabolism.

Investigating the association between a history of depression and biomarkers of Alzheimer’s disease, cerebrovascular disease, and neurodegeneration in patients with dementia - Patrick Salwierz; Simrika Thapa; Foad Taghdiri; Anna Vasilevskaya; Chloe Anastassiadis; David F. Tang-Wai; Angela C. Golas; M. Carmela Tartaglia (GeroScience, 2023)

Prediction of 1-year change in knee extension strength by neuromuscular properties in older adults - Tetsuya Hirono; Ryosuke Takeda; Taichi Nishikawa; Kohei Watanabe (GeroScience, 2023)

Correction to: Role of Toll-like receptor 2 and 4 signaling pathways on the inflammatory response to resistance training in elderly subjects - Paula Rodriguez-Miguelez; Rodrigo Fernandez-Gonzalo; Mar Almar; Yubisay Mejías; Ana Rivas; José A. de Paz; María J. Cuevas; Javier González-Gallego (GeroScience, 2023)

The Semmelweis Study: a longitudinal occupational cohort study within the framework of the Semmelweis Caring University Model Program for supporting healthy aging - Zoltan Ungvari; Adam G. Tabák; Roza Adany; György Purebl; Csilla Kaposvári; Vince Fazekas-Pongor; Tamás Csípő; Zsófia Szarvas; Krisztián Horváth; Peter Mukli; Piroska Balog; Robert Bodizs; et al. (GeroScience, 2023)
The Semmelweis Study is a prospective occupational cohort study that seeks to enroll all employees of Semmelweis University (Budapest, Hungary) aged 25 years and older, with a population of 8866 people, 70.5% of whom are women. The study builds on the successful experiences of the Whitehall II study and aims to investigate the complex relationships between lifestyle, environmental, and occupational risk factors, and the development and progression of chronic age-associated diseases. An important goal of the Semmelweis Study is to identify groups of people who are aging unsuccessfully and therefore have an increased risk of developing age-associated diseases. To achieve this, the study takes a multidisciplinary approach, collecting economic, social, psychological, cognitive, health, and biological data. The Semmelweis Study comprises a baseline data collection with open healthcare data linkage, followed by repeated data collection waves every 5 years. Data are collected through computer-assisted self-completed questionnaires, followed by a physical health examination, physiological measurements, and the assessment of biomarkers. This article provides a comprehensive overview of the Semmelweis Study, including its origin, context, objectives, design, relevance, and expected contributions.

Correction to: Functional mobility and physical fitness are improved through a multicomponent training program in institutionalized older adults - Sergio López‑López; Vanesa Abuín‑Porras; Luis A. Berlanga; Michelle Matos‑Duarte; Luis Perea‑Unceta; Carlos Romero‑Morales; Helios Pareja‑Galeano (GeroScience, 2023)

Preventing spontaneous cerebral microhemorrhages in aging mice: a novel approach targeting cellular senescence with ABT263/navitoclax - Janet Faakye; Ádám Nyúl-Tóth; Mihaly Muranyi; Rafal Gulej; Boglarka Csik; Santny Shanmugarama; Stefano Tarantini; Sharon Negri; Calin Prodan; Peter Mukli; Andriy Yabluchanskiy; Shannon Conley; et al. (GeroScience, 2023)

Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used - David E. Harrison; Randy Strong; Peter Reifsnyder; Nadia Rosenthal; Ron Korstanje; Elizabeth Fernandez; Kevin Flurkey; Brett C. Ginsburg; Meredith D. Murrell; Martin A. Javors; Marisa Lopez-Cruzan; James F. Nelson; et al. (GeroScience, 2023)
In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% ( p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% ( p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE ( n ) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang–Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.

Age- and sex-related differences in trunk kinematics during walking in able-bodied adults - Tamaya Van Criekinge; Ann Hallemans; Patricia Van de Walle; Lizeth H. Sloot (GeroScience, 2023)

Survival and longevity of European rulers: geographical influences and exploring potential factors, including the Mediterranean diet — a historical analysis from 1354 to the twentieth century - Bálint Madarász; Vince Fazekas-Pongor; Zsófia Szarvas; Mónika Fekete; János Tamás Varga; Stefano Tarantini; Anna Csiszar; Vincenzo Lionetti; Adam G. Tabák; Zoltan Ungvari; Judit Forrai (GeroScience, 2023)
Significant regional variability in lifespan in Europe is influenced by environmental factors and lifestyle behaviors, including diet. This study investigates the impact of geographical region on the lifespan of European rulers spanning from the fourteenth century to the present day. By analyzing historical records and literature, we aim to identify region-specific dietary patterns and lifestyle factors that may have contributed to longer lifespans among rulers. The hypothesis to be tested is that rulers from Southern European countries, where the traditional Mediterranean diet is consumed by the local people, may exhibit longer lifespans compared to rulers from other regions, due to the well-documented health benefits associated with this dietary pattern. We extracted comprehensive information for each ruler, encompassing their sex, birth and death dates, age, age of enthronement, duration of rulership, country, and cause of death (natural vs. non-natural). To determine their nationality, we coded rulers based on their hypothetical present-day residence (2023). Utilizing the EuroVoc Geographical classification, we categorized the countries into four regions: Northern, Western, Southern, Central and Eastern Europe. While Cox regression models did not find significant differences in survival rates among regions, further analysis stratified by time periods revealed intriguing trends. Contrary to our initial predictions, the Northern region displayed better survival rates compared to the Southern region between 1354 and 1499, whereas survival rates were similar across regions from 1500 to 1749. However, after 1750, all regions, except the Southern region, exhibited significantly improved survival rates, suggesting advancements in healthcare and lifestyle factors. These findings underscore the dynamic influence of both region and time period on health and longevity. Interestingly, despite the prevalence of the Mediterranean diet in the Southern region of Europe, rulers from this region did not demonstrate longer lifespans compared to their counterparts in other regions. This suggests that additional lifestyle factors may have played a more prominent role in their longevity. In conclusion, our study sheds light on the intricate relationship between region, time period, and lifespan among European rulers. Although the Mediterranean diet is often associated with health benefits, our findings indicate that it alone may not account for differences in ruler longevity across regions. Further research is warranted to explore the impact of other lifestyle factors on the health and lifespan of European rulers throughout history.

Low circulating levels of miR-17 and miR-126-3p are associated with increased mortality risk in geriatric hospitalized patients affected by cardiovascular multimorbidity - Francesca Marchegiani; Rina Recchioni; Mirko Di Rosa; Francesco Piacenza; Fiorella Marcheselli; Anna Rita Bonfigli; Roberta Galeazzi; Giulia Matacchione; Maurizio Cardelli; Antonio Domenico Procopio; Andrea Corsonello; Antonio Cherubini; et al. (GeroScience, 2023)
MultiMorbidity (MM), defined as the co-occurrence of two or more chronic conditions, is associated with poorer health outcomes, such as recurrent hospital readmission and mortality. As a group of conditions, cardiovascular disease (CVD) exemplifies several challenges of MM, and the identification of prognostic minimally invasive biomarkers to stratify mortality risk in patients affected by cardiovascular MM is a huge challenge. Circulating miRNAs associated to inflammaging and endothelial dysfunction, such as miR-17, miR-21-5p, and miR-126-3p, are expected to have prognostic relevance. We analyzed a composite profile of circulating biomarkers, including miR-17, miR-21-5p, and miR-126-3p, and routine laboratory biomarkers in a sample of 246 hospitalized geriatric patients selected for cardiovascular MM from the Report-AGE INRCA database and BioGER INRCA biobank, to evaluate the association with all-cause mortality during 31 days and 12 and 24 months follow-up. Circulating levels of miR-17, miR-126-3p, and some blood parameters, including neutrophil to lymphocyte ratio (NLR) and eGFR, were significantly associated with mortality in these patients. Overall, our results suggest that in a cohort of geriatric hospitalized patients affected by cardiovascular MM, lower circulating miR-17 and miR-126-3p levels could contribute to identify patients at higher risk of short- and medium-term mortality.

Age-related decrease in inter-subject similarity of cortical morphology and task and resting-state functional connectivity - Junhong Yu (GeroScience, 2023)

Cerebrospinal fluid neutral lipids predict progression from mild cognitive impairment to Alzheimer’s disease - Farida Dakterzada; Mariona Jové; Raquel Huerto; Anna Carnes; Joaquim Sol; Reinald Pamplona; Gerard Piñol-Ripoll (GeroScience, 2023)
Genetic, metabolic, and clinical evidence links lipid dysregulation to an increased risk of Alzheimer’s disease (AD). However, the role of lipids in the pathophysiological processes of AD and its clinical progression is unclear. We investigated the association between cerebrospinal fluid (CSF) lipidome and the pathological hallmarks of AD, progression from mild cognitive impairment (MCI) to AD, and the rate of cognitive decline in MCI patients. The CSF lipidome was analyzed by liquid chromatography coupled to mass spectrometry in an LC-ESI-QTOF-MS/MS platform for 209 participants: 91 AD, 92 MCI, and 26 control participants. The MCI patients were followed up for a median of 58 (± 12.5) months to evaluate their clinical progression to AD. Forty-eight (52.2%) MCI patients progressed to AD during follow-up. We found that higher CSF levels of hexacosanoic acid and ceramide Cer(d38:4) were associated with an increased risk of amyloid beta 42 (Aβ42) positivity in CSF, while levels of phosphatidylethanolamine PE(40:0) were associated with a reduced risk. Higher CSF levels of sphingomyelin SM(30:1) were positively associated with pathological levels of phosphorylated tau in CSF. Cholesteryl ester CE(11D3:1) and an unknown lipid were recognized as the most associated lipid species with MCI to AD progression. Furthermore, TG(O-52:2) was identified as the lipid most strongly associated with the rate of progression. Our results indicate the involvement of membrane and intracellular neutral lipids in the pathophysiological processes of AD and the progression from MCI to AD dementia. Therefore, CSF neutral lipids can be used as potential prognostic markers for AD.

The impact of social determinants of health on early outcomes after adult Chiari surgery - Sherwin Tavakol; Kristin Zieles; Mikayla Peters; Michael Omini; Sixia Chen; Andrew Jea (GeroScience, 2023)

Sarcopenia: no consensus, no diagnostic criteria, and no approved indication—How did we get here? - William J. Evans; Jack Guralnik; Peggy Cawthon; James Appleby; Francesco Landi; Lindsay Clarke; Bruno Vellas; Luigi Ferrucci; Ronenn Roubenoff (GeroScience, 2023)
In addition to the role of skeletal muscle in movement and locomotion, muscle plays a critical role in a broad array of metabolic processes that can contribute to improved health or risk of disease. The age-associated loss of muscle has been termed sarcopenia. The muscle is the primary site of insulin-stimulated glucose disposal and the largest component of basal metabolic rate, directly and indirectly affects bone density, produces myokines with pleiotropic effect on muscle and other tissues including the brain, and stores essential amino acids essential for the maintenance of protein synthesis during periods of reduced food intake and stress. As such, not surprisingly deterioration of skeletal muscle health, typically operationalized as decline of muscle mass and muscle strength is both a powerful risk factor and main consequence of chronic diseases, disability, and loss of independence, and it is one of the strongest risk factors for mortality. However, skeletal muscle remains one of the most plastic of all tissues, with rapid changes in rates of protein synthesis and degradation in response to physical activity and inactivity, inflammation, and nutritional and hormonal status. This has made the development of pharmacological therapies to increase muscle mass (or prevent loss), an important goal for decades. However, while remarkable advances in the understanding of molecular and cellular regulation of muscle protein metabolism have occurred recently, there are no approved drugs for the treatment of sarcopenia, the loss of skeletal muscle affecting millions of older people. The goal of this paper is to describe the possible reasons for the lack of new and effective pharmacotherapies to treat one of the most important risk factors for age-associated disease and loss of independence.

Increased brain cytokine level associated impairment of vigilance and memory in aged rats can be alleviated by alpha7 nicotinic acetylcholine receptor agonist treatment - Zsolt Kristóf Bali; Lili Veronika Nagy; Nóra Bruszt; Kornélia Bodó; Péter Engelmann; Zsófia Hernádi; Kitti Göntér; Sai Ambika Tadepalli; István Hernádi (GeroScience, 2023)
Age-related neurocognitive disorders are common problems in developed societies. Aging not only affects memory processes, but may also disturb attention, vigilance, and other executive functions. In the present study, we aimed to investigate age-related cognitive deficits in rats and associated molecular alterations in the brain. We also aimed to test the effects of the alpha7 nicotinic acetylcholine receptor (nAChR) agonist PHA-543613 on memory as well as on the sustained attention and vigilance of aged rats. Short- and long-term spatial memories of the rats were tested using the Morris water maze (MWM) task. To measure attention and vigilance, we designed a rat version of the psychomotor vigilance task (PVT) that is frequently used in human clinical examinations. At the end of the behavioral experiments, mRNA and protein expression of alpha7 nAChRs, cytokines, and brain-derived neurotrophic factor (BDNF) were quantitatively measured in the hippocampus, frontal cortex, striatum, and cerebellum. Aged rats showed marked cognitive deficits in both the MWM and the PVT. The deficit was accompanied by increased IL-1beta and TNFalpha mRNA expression and decreased BDNF protein expression in the hippocampus. PHA-543613 significantly improved the reaction time of aged rats in the PVT, especially for unexpectedly appearing stimuli, while only slightly (non-significantly) alleviating spatial memory deficits in the MWM. These results indicate that targeting alpha7 nAChRs may be an effective strategy for the amelioration of attention and vigilance deficits in age-related neurocognitive disorders.

A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment - Miranda E. Orr; Eithan Kotkowski; Paulino Ramirez; Darcy Bair-Kelps; Qianqian Liu; Charles Brenner; Mark S. Schmidt; Peter T. Fox; Anis Larbi; Crystal Tan; Glenn Wong; Jonathan Gelfond; et al. (GeroScience, 2023)

Soluble TNFR1 has greater reproducibility than IL-6 for the assessment of chronic inflammation in older adults: the case for a new inflammatory marker in aging - Thomas Laskow; Jacqueline Langdon; Sam Sepehri; Marcela Davalos-Bichara; Ravi Varadhan; Jeremy Walston (GeroScience, 2023)

The 24-h profile of the DNA repair enzyme 8-oxoguanine glycosylase 1 (OGG1) is associated with age, TNF-α, and waist circumference in healthy adults - Per Arkenberg; Manuela Dittmar (GeroScience, 2023)
It is unknown how the DNA repair enzyme OGG1 relates to healthy aging in humans, in particular to inflammaging, that is associated with increased levels of TNF-α. This study aimed (1) to investigate how 24-h profiles for OGG1 change during healthy aging and (2) to analyze the relationship of OGG1 with TNF-α, central body fat, cortisol and oxidative DNA/RNA damage. In a cross-sectional study in 20 healthy older and 20 young women, salivary levels of OGG1, TNF-α, cortisol and oxidative DNA/RNA damage were quantified by ELISAs every 4 h for a 24-h period. Trunk circumferences were taken as measures of central body fat. Older women, compared to young women, exhibited significantly lower protein levels of OGG1 throughout the whole 24-h period, a 2.5 times lower 24-h mean level for OGG1 ( P < 0.00001) and loss of 24-h variation of OGG1. Both age groups demonstrated significant 24-h variation for TNF-alpha, cortisol and oxidative damage. The 24-h mean level for TNF-α was more than twice as high in older compared to young women ( P = 0.011). Regression analysis detected that age, TNF-α and waist circumference were negative significant predictors of OGG1, explaining 56% of variance of OGG1 ( P < 0.00001), while levels of cortisol and oxidative damage were no predictors of OGG1. Results indicate a strong decrease of protein levels of OGG1 and a loss of 24-h variation during natural cellular aging. The negative relationship, found between OGG1 and TNF-α and between OGG1 and waist circumference, suggests involvement of proinflammatory processes in DNA repair.

Immune proteins C1q and CD47 may contribute to aberrant microglia-mediated synapse loss in the aging monkey brain that is associated with cognitive impairment - Sarah A. DeVries; Bryce Conner; Christina Dimovasili; Tara L. Moore; Maria Medalla; Farzad Mortazavi; Douglas L. Rosene (GeroScience, 2023)

Role of the kisspeptin-KISS1R axis in the pathogenesis of chronic kidney disease and uremic cardiomyopathy - Hoa Dinh; Zsuzsanna Z. A. Kovács; Merse Kis; Klaudia Kupecz; Anita Sejben; Gergő Szűcs; Fanni Márványkövi; Andrea Siska; Marah Freiwan; Szonja Polett Pósa; Zsolt Galla; Katalin Eszter Ibos; et al. (GeroScience, 2023)
The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300–350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction’s echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory ( Il6, Tnf ), fibrosis ( Col1 ), and apoptosis markers ( Bax/Bcl2 ) relative to the CKD group. In summary, KP-13’s influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.

Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging - Theresa Mau; Haley N. Barnes; Terri L. Blackwell; Philip A. Kramer; Scott R. Bauer; David J. Marcinek; Sofhia V. Ramos; Daniel E. Forman; Frederico G. S. Toledo; Russell T. Hepple; Stephen B. Kritchevsky; Steven R. Cummings; et al. (GeroScience, 2023)

Heterogeneity of increased biological age in type 2 diabetes correlates with differential tissue DNA methylation, biological variables, and pharmacological treatments - Briana N. Cortez; Hui Pan; Samuel Hinthorn; Han Sun; Nicola Neretti; Anna L. Gloyn; Cristina Aguayo-Mazzucato (GeroScience, 2023)

Machine learning-based morphological quantification of replicative senescence in human fibroblasts - Emma M. Welter; Sofia Benavides; Trevor K. Archer; Oksana Kosyk; Anthony S. Zannas (GeroScience, 2023)

Metabolomic characterization of vigor to frailty among community-dwelling older Black and White men and women - Megan M. Marron; Shanshan Yao; Ravi V. Shah; Venkatesh L. Murthy; Anne B. Newman (GeroScience, 2023)

Therapeutic efficacies of mitochondria-targeted esculetin and metformin in the improvement of age-associated atherosclerosis via regulating AMPK activation - Sriravali Pulipaka; Gajalakshmi Singuru; Shashikanta Sahoo; Altab Shaikh; Rajamannar Thennati; Srigiridhar Kotamraju (GeroScience, 2023)

Identified senescence endotypes in aged cartilage are reflected in the blood metabolome - Ilja Boone; Margo Tuerlings; Rodrigo Coutinho de Almeida; Johannes Lehmann; Yolande Ramos; Rob Nelissen; Eline Slagboom; Peter de Keizer; Ingrid Meulenbelt (GeroScience, 2023)
Heterogeneous accumulation of senescent cells expressing the senescence-associated secretory phenotype (SASP) affects tissue homeostasis which leads to diseases, such as osteoarthritis (OA). In this study, we set out to characterize heterogeneity of cellular senescence within aged articular cartilage and explored the presence of corresponding metabolic profiles in blood that could function as representative biomarkers. Hereto, we set out to perform cluster analyses, using a gene-set of 131 senescence genes ( N = 57) in a previously established RNA sequencing dataset of aged articular cartilage and a generated metabolic dataset in overlapping blood samples. Using unsupervised hierarchical clustering and pathway analysis, we identified two robust cellular senescent endotypes. Endotype-1 was enriched for cell proliferating pathways, expressing forkhead box protein O4 ( FOXO4) , RB transcriptional corepressor like 2 ( RBL2) , and cyclin-dependent kinase inhibitor 1B ( CDKN1B) ; the FOXO mediated cell cycle was identified as possible target for endotype-1 patients. Endotype-2 showed enriched inflammation-associated pathways, expressed by interleukin 6 ( IL6) , matrix metallopeptidase (MMP)1/3 , and vascular endothelial growth factor (VEGF) C and SASP pathways were identified as possible targets for endotype-2 patients. Notably, plasma-based metabolic profiles in overlapping blood samples ( N = 21) showed two corresponding metabolic clusters in blood. These non-invasive metabolic profiles could function as biomarkers for patient-tailored targeting of senescence in OA.

Whole brain irradiation–induced endothelial dysfunction in the mouse brain - Tamas Kiss; Anna Ungvari; Rafal Gulej; Ádám Nyúl-Tóth; Stefano Tarantini; Zoltan Benyo; Boglarka Csik; Andriy Yabluchanskiy; Peter Mukli; Anna Csiszar; Zoltan Ungvari (GeroScience, 2023)
Whole brain irradiation (WBI), also known as whole brain radiation therapy (WBRT), is a well-established treatment for multiple brain metastases and as a preventive measure to reduce the risk of recurrence after surgical removal of a cerebral metastasis. However, WBI has been found to lead to a gradual decline in neurocognitive function in approximately 50% of patients who survive the treatment, significantly impacting their overall quality of life. Recent preclinical investigations have shed light on the underlying mechanisms of this adverse effect, revealing a complex cerebrovascular injury that involves the induction of cellular senescence in various components of the neurovascular unit, including endothelial cells. The emergence of cellular senescence following WBI has been implicated in the disruption of the blood-brain barrier and impairment of neurovascular coupling responses following irradiation. Building upon these findings, the present study aims to test the hypothesis that WBI-induced endothelial injury promotes endothelial dysfunction, which mimics the aging phenotype. To investigate this hypothesis, we employed a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks) on young mice. Both the WBI-treated and control mice were fitted with a cranial window, enabling the assessment of microvascular endothelial function. In order to evaluate the endothelium-dependent, NO-mediated cerebral blood flow (CBF) responses, we topically administered acetylcholine and ATP, and measured the resulting changes using laser Doppler flowmetry. We found that the increases in regional CBF induced by acetylcholine and ATP were significantly diminished in mice subjected to WBI. These findings provide additional preclinical evidence supporting the notion that WBI induces dysfunction in cerebrovascular endothelial cells, which in turn likely contributes to the detrimental long-term effects of the treatment. This endothelial dysfunction resembles an accelerated aging phenotype in the cerebrovascular system and is likely causally linked to the development of cognitive impairment. By integrating these findings with our previous results, we have deepened our understanding of the lasting consequences of WBI. Moreover, our study underscores the critical role of cerebromicrovascular health in safeguarding cognitive function over the long term. This enhanced understanding highlights the importance of prioritizing cerebromicrovascular health in the context of preserving cognitive abilities.

Reduction in metabolic noise reveals rejuvenation following transient severe caloric restriction - Guy Levkovich; Inna Bendikov-Bar; Sergey Malitsky; Maxim Itkin; Mark Rusal; Dmitri Lokshtanov; Dmitry Shinder; Dror Sagi (GeroScience, 2023)
Among land vertebrates, the laying hen stands out due to its great reproductive efficiency: producing an egg daily all year long. This production rate makes the laying hen a special model animal to study the general process of reproduction and aging. One unique aspect of hens is their ability to undergo reproductive plasticity and to rejuvenate their reproductive tract during molting, a standard industrial feed restriction protocol for transiently pausing reproduction, followed by improved laying efficiency almost to peak production. Here we use longitudinal metabolomics, immunology, and physiological assays to show that molting promotes reproduction, compresses morbidity, and restores youthfulness when applied to old hens. We identified circulating metabolic biomarkers that quantitatively predict the reproduction and age of individuals. Lastly, we introduce metabolic noise, a robust, unitless, and quantifiable measure for heterogeneity of the complete metabolome as a general marker that can indicate the rate of aging of a population. Indeed, metabolic noise increased with age in control hens, whereas molted hens exhibited reduced noise following molting, indicating systemic rejuvenation. Our results suggest that metabolic noise can be used as a quick and universal proxy for assessing successful aging treatments, accelerating the timeline for drug development.

Murine cartilage microbial DNA deposition occurs rapidly following the introduction of a gut microbiome and changes with obesity, aging, and knee osteoarthritis - Vladislav Izda; Leoni Schlupp; Emmaline Prinz; Gabby Dyson; Montana Barrett; Christopher M. Dunn; Emily Nguyen; Cassandra Sturdy; Matlock A. Jeffries (GeroScience, 2023)
Cartilage microbial DNA patterns have been recently characterized in osteoarthritis (OA). The objectives of this study were to evaluate the gut origins of cartilage microbial DNA, to characterize cartilage microbial changes with age, obesity, and OA in mice, and correlate these to gut microbiome changes. We used 16S rRNA sequencing performed longitudinally on articular knee cartilage from germ-free (GF) mice following oral microbiome inoculation and cartilage and cecal samples from young and old wild-type mice with/without high-fat diet-induced obesity (HFD) and with/without OA induced by destabilization of the medial meniscus (DMM) to evaluate gut and cartilage microbiota. Microbial diversity was assessed, groups compared, and functional metagenomic profiles reconstructed. Findings were confirmed in an independent cohort by clade-specific qPCR. We found that cartilage microbial patterns developed at 48 h and later timepoints following oral microbiome inoculation of GF mice. Alpha diversity was increased in SPF mouse cartilage samples with age ( P = 0.013), HFD ( P = 5.6E-4), and OA ( P = 0.029) but decreased in cecal samples with age ( P = 0.014) and HFD ( P = 1.5E-9). Numerous clades were altered with aging, HFD, and OA, including increases in Verrucomicrobia in both cartilage and cecal samples. Functional analysis suggested changes in dihydroorotase, glutamate-5-semialdehyde dehydrogenase, glutamate-5-kinase, and phosphoribosylamine-glycine ligase, in both cecum and cartilage, with aging, HFD, and OA. In conclusion, cartilage microbial DNA patterns develop rapidly after the introduction of a gut microbiome and change in concert with the gut microbiome during aging, HFD, and OA in mice. DMM-induced OA causes shifts in both cartilage and cecal microbiome patterns independent of other factors.

Aerobic exercise training effects on hippocampal volume in healthy older individuals: a meta-analysis of randomized controlled trials - Guilherme Moraes Balbim; Nárlon Cássio Boa Sorte Silva; Lisanne ten Brinke; Ryan S. Falck; Tibor Hortobágyi; Urs Granacher; Kirk I. Erickson; Rebeca Hernández-Gamboa; Teresa Liu-Ambrose (GeroScience, 2023)

Lateralized brunt of sleep deprivation on white matter injury in a rat model of Alzheimer’s disease - Xin Mao; Ding Han; Wensheng Guo; Wanning Zhang; Hongqi Wang; Guitao Zhang; Ning Zhang; Liangyun Jin; Binbin Nie; Hui Li; Yizhi Song; Yan Wu; et al. (GeroScience, 2023)

Comparative biology and non-traditional approaches for basic aging research for facilitating translational studies - Mary Ann Ottinger; Donna Holmes (GeroScience, 2023)

Rapid measurement of ageing by automated monitoring of movement of C. elegans populations - Giulia Zavagno; Adelaide Raimundo; Andy Kirby; Christopher Saunter; David Weinkove (GeroScience, 2023)
Finding new interventions that slow ageing and maintain human health is a huge challenge of our time. The nematode Caenorhabditis elegans offers a rapid in vivo method to determine whether a compound extends its 2 to 3-week lifespan. Measuring lifespan is the standard method to monitor ageing, but a compound that extends lifespan will not necessarily maintain health. Here, we describe the automated monitoring of C. elegans movement from early to mid-adulthood as a faster healthspan-based method to measure ageing. Using the WormGazer™ technology, multiple Petri dishes each containing several C. elegans worms are imaged simultaneously and non-invasively by an array of cameras that can be scaled easily. This approach demonstrates that most functional decline in C. elegans occurs during the first week of adulthood. We find 7 days of imaging is sufficient to measure the dose-dependent efficacy of sulfamethoxazole to slow ageing, compared to 40 days required for a parallel lifespan experiment. Understanding any negative consequences of interventions that slow ageing is important. We show that the long-lived mutant age-1(hx546) stays active for longer than the wild type but it moves slower in early adulthood. Thus, continuous analysis of movement can rapidly identify interventions that slow ageing while simultaneously revealing any negative effects on health.

Socioeconomic status, lifestyle and risk of incident dementia: a prospective cohort study of 276730 participants - Ya-Nan Ou; Yan-Bo Zhang; Yu-Zhu Li; Shu-Yi Huang; Wei Zhang; Yue-Ting Deng; Bang-Sheng Wu; Lan Tan; Qiang Dong; An Pan; Ren-Jie Chen; Jian-Feng Feng; et al. (GeroScience, 2023)

Correction to: Old plasma dilution reduces human biological age: a clinical study - Daehwan Kim; Dobri D. Kiprov; Connor Luellen; Michael Lieb; Chao Liu; Etsuko Watanabe; Xiaoyue Mei; Kaitlin Cassaleto; Joel Kramer; Michael J. Conboy; Irina M. Conboy (GeroScience, 2023)

A network-based approach to explore comorbidity patterns among community-dwelling older adults living alone - Chiyoung Lee; Yeon-Hwan Park; Belong Cho; Hye Ah Lee (GeroScience, 2023)

Correction to: Blood biomarker profiles and exceptional longevity: comparison of centenarians and non‑centenarians in a 35‑year follow‑up of the Swedish AMORIS cohort - Shunsuke Murata; Marcus Ebeling; Anna C. Meyer; Katharina Schmidt‑Mende; Niklas Hammar; Karin Modig (GeroScience, 2023)

ATAC-clock: An aging clock based on chromatin accessibility - Francesco Morandini; Cheyenne Rechsteiner; Kevin Perez; Viviane Praz; Guillermo Lopez Garcia; Laura C. Hinte; Ferdinand von Meyenn; Alejandro Ocampo (GeroScience, 2023)
The establishment of aging clocks highlighted the strong link between changes in DNA methylation and aging. Yet, it is not known if other epigenetic features could be used to predict age accurately. Furthermore, previous studies have observed a lack of effect of age-related changes in DNA methylation on gene expression, putting the interpretability of DNA methylation-based aging clocks into question. In this study, we explore the use of chromatin accessibility to construct aging clocks. We collected blood from 159 human donors and generated chromatin accessibility, transcriptomic, and cell composition data. We investigated how chromatin accessibility changes during aging and constructed a novel aging clock with a median absolute error of 5.27 years. The changes in chromatin accessibility used by the clock were strongly related to transcriptomic alterations, aiding clock interpretation. We additionally show that our chromatin accessibility clock performs significantly better than a transcriptomic clock trained on matched samples. In conclusion, we demonstrate that the clock relies on cell-intrinsic chromatin accessibility alterations rather than changes in cell composition. Further, we present a new approach to construct epigenetic aging clocks based on chromatin accessibility, which bear a direct link to age-related transcriptional alterations, but which allow for more accurate age predictions than transcriptomic clocks.

Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes - Stephen A. Banse; Christine A. Sedore; Erik Johnson; Anna L. Coleman-Hulbert; Brian Onken; David Hall; E. Grace Jackson; Phu Huynh; Anna C. Foulger; Suzhen Guo; Theo Garrett; Jian Xue; et al. (GeroScience, 2023)
The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies—for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

Correction to: Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno‑/GrimAge and DNA‑methylation based PAI1 - Cynthia D. J. Kusters; Kimberly C. Paul; Ake T. Lu; Luigi Ferrucci; Beate R. Ritz; Alexandra M. Binder; Steve Horvath (GeroScience, 2023)

Intermittent working memory training during adulthood protects against age-related long-term spatial reference memory decline in rats - Alexandra Barbelivien; Laura Durieux; Eliabel Seys; Monique Majchrzak (GeroScience, 2023)

Fibrinogen in mice cerebral microvessels induces blood–brain barrier dysregulation with aging via a dynamin-related protein 1–dependent pathway - Partha K. Chandra; Manesh Kumar Panner Selvam; Jorge A. Castorena-Gonzalez; Ibolya Rutkai; Suresh C. Sikka; Ricardo Mostany; David W. Busija (GeroScience, 2023)
We previously reported evidence that oxidative stress during aging leads to adverse protein profile changes of brain cortical microvessels (MVs: end arterioles, capillaries, and venules) that affect mRNA/protein stability, basement membrane integrity, and ATP synthesis capacity in mice. As an extension of our previous study, we also found that proteins which comprise the blood–brain barrier (BBB) and regulate mitochondrial quality control were also significantly decreased in the mice’s cortical MVs with aging. Interestingly, the neuroinflammatory protein fibrinogen (Fgn) was increased in mice brain MVs, which corresponds with clinical reports indicating that the plasma Fgn concentration increased progressively with aging. In this study, protein–protein interaction network analysis indicated that high expression of Fgn is linked with downregulated expression of both BBB- and mitochondrial fission/fusion–related proteins in mice cortical MVs with aging. To investigate the mechanism of Fgn action, we observed that 2 mg/mL or higher concentration of human plasma Fgn changed cell morphology, induced cytotoxicity, and increased BBB permeability in primary human brain microvascular endothelial cells (HBMECs). The BBB tight junction proteins were significantly decreased with increasing concentration of human plasma Fgn in primary HBMECs. Similarly, the expression of phosphorylated dynamin-related protein 1 (pDRP1) and other mitochondrial fission/fusion–related proteins were also significantly reduced in Fgn-treated HBMECs. Interestingly, DRP1 knockdown by shRNA(h) resulted in the reduction of both BBB- and mitochondrial fission/fusion–related proteins in HBMECs. Our results suggest that elevated Fgn downregulates DRP1, leading to mitochondrial-dependent endothelial and BBB dysfunction in the brain microvasculature.

Comparative analysis of animal lifespan - Nicole C. Riddle; Peggy R. Biga; Anne M. Bronikowski; James R. Walters; Gerald S. Wilkinson; Jingyue Ellie Duan; Anthony Gamble; Erica Larschan; Richard P. Meisel; Ritambhara Singh; Ashley Webb (GeroScience, 2023)
Comparative studies of aging are a promising approach to identifying general properties of and processes leading to aging. While to date, many comparative studies of aging in animals have focused on relatively narrow species groups, methodological innovations now allow for studies that include evolutionary distant species. However, comparative studies of aging across a wide range of species that have distinct life histories introduce additional challenges in experimental design. Here, we discuss these challenges, highlight the most pressing problems that need to be solved, and provide suggestions based on current approaches to successfully carry out comparative aging studies across the animal kingdom.

Divergence in aerobic capacity and energy expenditure influence metabolic tissue mitochondrial protein synthesis rates in aged rats - Edziu Franczak; Adrianna Maurer; Vivien Csikos Drummond; Benjamin A. Kugler; Emily Wells; Madi Wenger; Frederick F. Peelor; Abby Crosswhite; Colin S. McCoin; Lauren G. Koch; Steven L. Britton; Benjamin F. Miller; et al. (GeroScience, 2023)

Frailty is associated with worse executive function and higher cerebral blood velocity in cognitively healthy older adults: a cross-sectional study - Myles W. O’Brien; Nick W. Bray; Isadora Quirion; Shirko Ahmadi; Pierre Faivre; Martin Sénéchal; Olivier Dupuy; Mathieu Bélanger; Said Mekari (GeroScience, 2023)

Degenerative cervical myelopathy: establishing severity thresholds for neuromotor dysfunction in the aging spine using the NIH Toolbox Assessment Scale - Fauziyya Muhammad; Sanaa Hameed; Grace Haynes; Esmaeil Mohammadi; Ali F. Khan; Hakeem Shakir; Zachary A. Smith (GeroScience, 2023)

Reversal of biological age in multiple rat organs by young porcine plasma fraction - Steve Horvath; Kavita Singh; Ken Raj; Shraddha I. Khairnar; Akshay Sanghavi; Agnivesh Shrivastava; Joseph A. Zoller; Caesar Z. Li; Claudia B. Herenu; Martina Canatelli-Mallat; Marianne Lehmann; Siniša Habazin; et al. (GeroScience, 2023)
Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young adult pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n = 613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain, liver, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n = 1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers, behavioral responses encompassing cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro- to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.

Label-free quantitative proteomics in serum reveals candidate biomarkers associated with low bone mineral density in Mexican postmenopausal women - Diana I. Aparicio-Bautista; Adriana Becerra-Cervera; Berenice Rivera-Paredez; Israel Aguilar-Ordoñez; Emmanuel Ríos-Castro; Juan P. Reyes-Grajeda; Jorge Salmerón; Alberto Hidalgo-Bravo; Rafael Velázquez-Cruz (GeroScience, 2023)

Inhibition of p53-MDM2 binding reduces senescent cell abundance and improves the adaptive responses of skeletal muscle from aged mice - Georgia L. Nolt; Alexander R. Keeble; Yuan Wen; Aubrey C. Strong; Nicholas T. Thomas; Taylor R. Valentino; Camille R. Brightwell; Kevin A. Murach; Sini Patrizia; Harald Weinstabl; Andreas Gollner; John J. McCarthy; et al. (GeroScience, 2023)
Skeletal muscle adaptation to external stimuli, such as regeneration following injury and hypertrophy in response to resistance exercise, are blunted with advanced age. The accumulation of senescent cells, along with defects in myogenic progenitor cell (MPC) proliferation, have been strongly linked as contributing factors to age-associated impairment in muscle adaptation. p53 plays an integral role in all these processes, as upregulation of p53 causes apoptosis in senescent cells and prevents mitotic catastrophe in MPCs from old mice. The goal of this study was to determine if a novel pharmaceutical agent (BI01), which functions by upregulating p53 through inhibition of binding to MDM2, the primary p53 regulatory protein, improves muscle regeneration and hypertrophy in old mice. BI01 effectively reduced the number of senescent cells in vitro but had no effect on MPC survival or proliferation at a comparable dose. Following repeated oral gavage with 2 mg/kg of BI01 (OS) or vehicle (OV), old mice (24 months) underwent unilateral BaCl 2 injury in the tibialis anterior (TA) muscle, with PBS injections serving as controls. After 7 days, satellite cell number was higher in the TA of OS compared to OV mice, as was the expression of genes involved in ATP production. By 35 days, old mice treated with BI01 displayed reduced senescent cell burden, enhanced regeneration (higher muscle mass and fiber cross-sectional area) and restoration of muscle function relative to OV mice. To examine the impact of 2 mg/kg BI01 on muscle hypertrophy, the plantaris muscle was subjected to 28 days of mechanical overload (MOV) in OS and OV mice. In response to MOV, OS mice had larger plantaris muscles and muscle fibers than OV mice, particularly type 2b + x fibers, associated with reduced senescent cells. Together our data show that BI01 is an effective senolytic agent that may also augment muscle metabolism to enhance muscle regeneration and hypertrophy in old mice.

Intrinsic functional brain connectivity changes following aerobic exercise, computerized cognitive training, and their combination in physically inactive healthy late-middle-aged adults: the Projecte Moviment - Stavros I. Dimitriadis; Alba Castells-Sánchez; Francesca Roig-Coll; Rosalía Dacosta-Aguayo; Noemí Lamonja-Vicente; Pere Torán-Monserrat; Alberto García-Molina; Gemma Monte-Rubio; Chelsea Stillman; Alexandre Perera-Lluna; Maria Mataró (GeroScience, 2023)
Lifestyle interventions have positive neuroprotective effects in aging. However, there are still open questions about how changes in resting-state functional connectivity (rsFC) contribute to cognitive improvements. The Projecte Moviment is a 12-week randomized controlled trial of a multimodal data acquisition protocol that investigated the effects of aerobic exercise (AE), computerized cognitive training (CCT), and their combination (COMB). An initial list of 109 participants was recruited from which a total of 82 participants (62% female; age = 58.38 ± 5.47) finished the intervention with a level of adherence > 80%. Only in the COMB group, we revealed an extended network of 33 connections that involved an increased and decreased rsFC within and between the aDMN/pDMN and a reduced rsFC between the bilateral supplementary motor areas and the right thalamus. No global and especially local rsFC changes due to any intervention mediated the cognitive benefits detected in the AE and COMB groups. Projecte Moviment provides evidence of the clinical relevance of lifestyle interventions and the potential benefits when combining them.

Neuropathological and sociodemographic factors associated with the cortical amyloid load in aging and Alzheimer’s disease - Sayonara P. da Silva; Carla C. M. de Castro; Lívia N. Rabelo; Rovena C. Engelberth; Bernardino Fernández-Calvo; Felipe P. Fiuza (GeroScience, 2023)

How cognitive performance changes according to the ankle-brachial index score in an elderly cohort? Results from the Toledo Study of Healthy Ageing - 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, 2023)

The impact of cardiovascular diagnostics and treatments on fall risk in older adults: a scoping review and evidence map - Anouschka C. Pronk; Liping Wang; Eveline P. van Poelgeest; Mariska M. G. Leeflang; Joost G. Daams; Alfons G. Hoekstra; Nathalie van der Velde (GeroScience, 2023)
Background We aimed to summarize the published evidence on the fall risk reducing potential of cardiovascular diagnostics and treatments in older adults. Methods Design: scoping review and evidence map. Data sources: Medline and Embase. Eligibility criteria: all available published evidence; Key search concepts: “older adults,” “cardiovascular evaluation,” “cardiovascular intervention,” and “falls.” Studies reporting on fall risk reducing effect of the diagnostic/treatment were included in the evidence map. Studies that investigated cardiovascular diagnostics or treatments within the context of falls, but without reporting a fall-related outcome, were included in the scoping review for qualitative synthesis. Results Two articles on cardiovascular diagnostics and eight articles on cardiovascular treatments were included in the evidence map. Six out of ten studies concerned pacemaker intervention of which one meta-analyses that included randomized controlled trials with contradictory results. A combined cardiovascular assessment/evaluation (one study) and pharmacotherapy in orthostatic hypotension (one study) showed fall reducing potential. The scoping review contained 40 articles on cardiovascular diagnostics and one on cardiovascular treatments. It provides an extensive overview of several diagnostics (e.g., orthostatic blood pressure measurements, heart rhythm assessment) useful in fall prevention. Also, diagnostics were identified, that could potentially provide added value in fall prevention (e.g., blood pressure variability and head turning). Conclusion Although the majority of studies showed a reduction in falls after the intervention, the total amount of evidence regarding the effect of cardiovascular diagnostics/treatments on falls is small. Our findings can be used to optimize fall prevention strategies and develop an evidence-based fall prevention care pathway. Adhering to the World guidelines on fall prevention recommendations, it is crucial to undertake a standardized assessment of cardiovascular risk factors, followed by supplementary testing and corresponding interventions, as effective components of fall prevention strategies. In addition, accompanying diagnostics such as blood pressure variability and head turning can be of added value.

Castration reduces mortality and increases resilience in male mice: what is next? - Nisi Jiang; Catherine J. Cheng; Randy Strong; James F. Nelson (GeroScience, 2023)

Effect of calorie restriction on redox status during chemically induced estropause in female mice - Bianca M. Ávila; Bianka M. Zanini; Karina P. Luduvico; Jéssica D. Hense; Driele N. Garcia; Juliane Prosczek; Francielle M. Stefanello; Jeffrey B. Mason; Michal M. Masternak; Augusto Schneider (GeroScience, 2023)

Epicardial fat and insulin resistance in healthy older adults: a cross-sectional analysis - Aliki Kalmpourtzidou; Ilaria Di Napoli; Alessandra Vincenti; Rachele De Giuseppe; Pietro Mariano Casali; Chiara Elena Tomasinelli; Fulvio Ferrara; Francesco Tursi; Hellas Cena (GeroScience, 2023)
Insulin resistance (IR) and cardiovascular diseases (CVD) are relevant concerns in the elderly population; as the world’s population ages, IR and CVD are two universal public health problems. While a link between IR a CVD has been established, the mediating mechanisms are uncertain and rigorous investigations are needed to fully elucidate them. The study aimed at assessing the relationship between epicardial fat (EF), an indicator of cardiovascular risk, and IR in Italian free-living elderly ( n = 89). Baseline data from a previous cohort was used. Anthropometric measurements, EF, and IR-related variables, including the HOMA-IR index and other biochemical parameters were obtained. The correlation between EF and IR was explored. Further analysis was conducted to identify significant differences regarding IR variables among EF quartiles. EF correlated positively with glucose levels in females, males and the total population. The pairwise comparison among EF quartiles showed significant differences in glucose levels, HOMA-IR index, triglycerides, and total cholesterol levels. To our knowledge, this is the only study assessing the relationship between EF and IR in healthy elderly, while most of the studies have investigated EF and IR in diseased populations. Further research with a longitudinal approach should be conducted to design concrete conclusions about this relationship.

A variant in the 5′UTR of ERBB4 is associated with lifespan in Golden Retrievers - Robert B. Rebhun; Daniel York; Flora M. D. De Graaf; Paula Yoon; Kevin L. Batcher; Madison E. Luker; Stephanie Ryan; Jamie Peyton; Michael S. Kent; Joshua A. Stern; Danika L. Bannasch (GeroScience, 2023)
Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer’s disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4 , the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5′UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together ( n = 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p = 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p = 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs ( p = 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 ( p = 0.026 and p = 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4 in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer.

Aging is associated with impaired triggering of TRPV3-mediated cutaneous vasodilation: a crucial process for local heat exposure - Lisa S. Martin; Audrey Josset-Lamaugarny; Thomas El Jammal; Sylvie Ducreux; Fabien P. Chevalier; Bérengère Fromy (GeroScience, 2023)

Frailty prevalence in 42 European countries by age and gender: development of the SHARE Frailty Atlas for Europe - János G. Pitter; Antal Zemplényi; Balázs Babarczy; Bertalan Németh; Zoltán Kaló; Zoltán Vokó (GeroScience, 2023)
Comparative frailty prevalence data across European countries is sparse due to heterogeneous measurement methods. The Survey of Health, Ageing and Retirement (SHARE) initiative conducted interviews with probability sampling of non-institutionalized elderly people in several European countries. Previous frailty analyses of SHARE datasets were limited to initial SHARE countries and did not provide age- and gender-stratified frailty prevalence. Our aim was to provide age- and gender-stratified frailty prevalence estimates in all European countries, with predictions where necessary. From 29 SHARE participating countries, 311,915 individual surveys were analyzed. Frailty prevalence was estimated by country and gender in 5-year age bands using the SHARE Frailty Instrument and a frailty index. Association of frailty prevalence with age, gender, and GDP per capita (country-specific economic indicator for predictions) was investigated in multivariate mixed logistic regression models with or without multiple imputation. Female gender and increasing age were significantly associated with higher frailty prevalence. Higher GDP per capita, with or without purchasing power parity adjustment, was significantly associated with lower frailty prevalence in the 65–79 age groups in all analyses. Observed and predicted data on frailty rates by country are provided in the interactive SHARE Frailty Atlas for Europe. Our study provides age- and gender-stratified frailty prevalence estimates for all European countries, revealing remarkable between-country heterogeneity. Higher frailty prevalence is strongly associated with lower GDP per capita, underlining the importance of investigating transferability of evidence across countries at different developmental levels and calling for improved policies to reduce inequity in risk of developing frailty across European countries.

HRV-guided training vs traditional HIIT training in cardiac rehabilitation: a randomized controlled trial - María Carrasco-Poyatos; Rut López-Osca; Ignacio Martínez-González-Moro; Antonio Granero-Gallegos (GeroScience, 2023)

Immune cell composition varies by age, sex and exposure to social adversity in free-ranging Rhesus Macaques - Mitchell R. Sanchez Rosado; Nicole Marzan-Rivera; Marina M. Watowich; Andrea D. Negron-Del Valle; Petraleigh Pantoja; Melissa A. Pavez-Fox; Erin R. Siracusa; Eve B. Cooper; Josue E. Negron-Del Valle; Daniel Phillips; Angelina Ruiz-Lambides; Melween I. Martinez; et al. (GeroScience, 2023)

The effect of glycine administration on the characteristics of physiological systems in human adults: A systematic review - Janjira Soh; Shivaanishaa Raventhiran; Jasinda H. Lee; Zi Xiang Lim; Jorming Goh; Brian K. Kennedy; Andrea B. Maier (GeroScience, 2023)
Functional decline of physiological systems during ageing leads to age-related diseases. Dietary glycine increases healthy lifespan in model organisms and might decrease inflammation in humans, suggesting its geroprotective potential. This review summarises the evidence of glycine administration on the characteristics of eleven physiological systems in adult humans. Databases were searched using key search terms: ‘glycine’, ‘adult’, ‘supplementation’/ ‘administration’/ ‘ingestion’/ ‘treatment’. Glycine was administered to healthy and diseased populations (18 and 34 studies) for up to 14 days and 4 months, respectively. The nervous system demonstrated the most positive effects, including improved psychiatric symptoms from longer-term glycine administration in psychiatric populations. While longer-term glycine administration improved sleep in healthy populations, these studies had small sample sizes with a high risk of bias. Larger and long-term studies with more robust study designs in healthy populations to examine the effects of glycine administration on preventing, delaying or reversing the ageing process are warranted.

The association of leukocyte telomere length with exceptional longevity among older women - Nhat Quang N. Thai; Andrea Z. LaCroix; Bernhard Haring; Jean Wactawski-Wende; JoAnn E. Manson; Alexander Ivan B. Posis; Aladdin H. Shadyab (GeroScience, 2023)

Systemic inflammatory and gut microbiota responses to fracture in young and middle-aged mice - Joseph L. Roberts; Brandon Chiedo; Hicham Drissi (GeroScience, 2023)

Autonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies - Sergio Giunta; Shijin Xia; Giuseppe Pelliccioni; Fabiola Olivieri (GeroScience, 2023)
Inflammaging refers to the age-related low grade, sterile, chronic, systemic, and long-lasting subclinical, proinflammatory status, currently recognized as the main risk factor for development and progression of the most common age-related diseases (ARDs). Extensive investigations were focused on a plethora of proinflammatory stimuli that can fuel inflammaging, underestimating and partly neglecting important endogenous anti-inflammaging mechanisms that could play a crucial role in such age-related proinflammatory state. Studies on autonomic nervous system (ANS) functions during aging highlighted an imbalance toward an overactive sympathetic nervous system (SNS) tone, promoting proinflammatory conditions, and a diminished parasympathetic nervous system (PNS) activity, playing anti-inflammatory effects mediated by the so called cholinergic anti-inflammatory pathway (CAP). At the molecular level, CAP is characterized by signals communicated via the vagus nerve (with the possible involvement of the splenic nerves) through acetylcholine release to downregulate the inflammatory actions of macrophages, key players of inflammaging. Notably, decreased vagal function and increased burden of activated/senescent macrophages (macrophaging) probably precede the development of several age-related risk factors and diseases, while increased vagal function and reduced macrophaging could be associated with relevant reduction of risk profiles. Hypothalamic–pituitary–adrenal axis (HPA axis) is another pathway related to ANS promoting some anti-inflammatory response mainly through increased cortisol levels. In this perspective review, we highlighted that CAP and HPA, representing broadly “anti-inflammaging” mechanisms, have a reduced efficacy and lose effectiveness in aged people, a phenomenon that could contribute to fuel inflammaging. In this framework, strategies aimed to re-balance PNS/SNS activities could be explored to modulate systemic inflammaging especially at an early subclinical stage, thus increasing the chances to reach the extreme limit of human lifespan in healthy status.

OVCH1 Antisense RNA 1 is differentially expressed between non-frail and frail old adults - Imad Abugessaisa; Ri-Ichiroh Manabe; Tsugumi Kawashima; Michihira Tagami; Chitose Takahashi; Yasushi Okazaki; Stefania Bandinelli; Takeya Kasukawa; Luigi Ferrucci (GeroScience, 2023)
While some old adults stay healthy and non-frail up to late in life, others experience multimorbidity and frailty often accompanied by a pro-inflammatory state. The underlying molecular mechanisms for those differences are still obscure. Here, we used gene expression analysis to understand the molecular underpinning between non-frail and frail individuals in old age. Twenty-four adults (50% non-frail and 50% frail) from InCHIANTI study were included. Total RNA extracted from whole blood was analyzed by Cap Analysis of Gene Expression (CAGE). CAGE identified transcription start site (TSS) and active enhancer regions. We identified a set of differentially expressed (DE) TSS and enhancer between non-frail and frail and male and female participants. Several DE TSSs were annotated as lncRNA (XIST and TTTY14) and antisense RNAs (ZFX-AS1 and OVCH1 Antisense RNA 1). The promoter region chr6:366,786,54-366,787,97;+ was DE and overlapping the longevity CDKN1A gene. GWAS-LD enrichment analysis identifies overlapping LD-blocks with the DE regions with reported traits in GWAS catalog (isovolumetric relaxation time and urinary tract infection frequency). Furthermore, we used weighted gene co-expression network analysis (WGCNA) to identify changes of gene expression associated with clinical traits and identify key gene modules. We performed functional enrichment analysis of the gene modules with significant trait/module correlation. One gene module is showing a very distinct pattern in hub genes. Glycogen Phosphorylase L (PYGL) was the top ranked hub gene between non-frail and frail. We predicted transcription factor binding sites (TFBS) and motif activity. TF involved in age-related pathways (e.g., FOXO3 and MYC) shows different expression patterns between non-frail and frail participants. Expanding the study of OVCH1 Antisense RNA 1 and PYGL may help understand the mechanisms leading to loss of homeostasis that ultimately causes frailty.

Practice makes imperfect: stronger implicit interference with practice in individuals at high risk of developing Alzheimer’s disease - Shao-Min Hung; Sara W. Adams; Cathleen Molloy; Daw-An Wu; Shinsuke Shimojo; Xianghong Arakaki (GeroScience, 2023)
Early screening to determine patient risk of developing Alzheimer’s will allow better interventions and planning but necessitates accessible methods such as behavioral biomarkers. Previously, we showed that cognitively healthy older individuals whose cerebrospinal fluid amyloid/tau ratio indicates high risk of cognitive decline experienced implicit interference during a high-effort task, signaling early changes in attention. To further investigate attention’s effect on implicit interference, we analyzed two experiments completed sequentially by the same high- and low-risk individuals. We hypothesized that if attention modulates interference, practice would affect the influence of implicit distractors. Indeed, while both groups experienced a strong practice effect, the association between practice and interference effects diverged between groups: stronger practice effects correlated with more implicit interference in high-risk participants, but less interference in low-risk individuals. Furthermore, low-risk individuals showed a positive correlation between implicit interference and EEG low-range alpha event-related desynchronization when switching from high- to low-load tasks. This suggests that lower attention on the task was correlated with stronger interference, a typical phenomenon in the younger population. These results demonstrate how attention impacts implicit interference and highlight early differences in perception between high- and low-risk individuals.

Connecting memory and functional brain networks in older adults: a resting-state fMRI study - Jori L. Waner; Hanna K. Hausman; Jessica N. Kraft; Cheshire Hardcastle; Nicole D. Evangelista; Andrew O’Shea; Alejandro Albizu; Emanuel M. Boutzoukas; Emily J. Van Etten; Pradyumna K. Bharadwaj; Hyun Song; Samantha G. Smith; et al. (GeroScience, 2023)

Age-specific difference in the temporal relationships between updated cardiovascular health construct and arterial stiffness in middle-aged and older adults - Jiaojiao Huang; Xiaoli Xu; Yingxia Zhou; Zhuojun Xin; Qiuyu Cao; Ruixin He; Tianzhichao Hou; Yi Ding; Jieli Lu; Tiange Wang; Zhiyun Zhao; Yu Xu; et al. (GeroScience, 2023)

Intricate relationship between obstructive sleep apnea and dementia in older adults - Erica Ercolano; Leonardo Bencivenga; Maria Emiliana Palaia; Giovanni Carbone; Francesco Scognamiglio; Giuseppe Rengo; Grazia Daniela Femminella (GeroScience, 2023)
Numerous evidence reports direct correlation between cognitive impairment, Alzheimer’s disease and sleep disorders, in particular obstructive sleep apnea. Both obstructive sleep apnea and Alzheimer’s disease are highly prevalent conditions whose incidence increases with age. Several studies demonstrate how sleep-disordered breathing may lead to poor cognition, even though the underlying mechanisms of this association remain partially unclear. According to the most recent studies, obstructive sleep apnea may be considered a modifiable risk factor for cognitive dysfunction. In the present review, the authors aim to integrate recent research examining obstructive sleep apnea and Alzheimer’s disease biomarkers, also focusing on the mechanisms that support this correlation, including but not limited to the role of hypoxia and cardiovascular risk. Moreover, the potential favourable effect of obstructive sleep apnea therapy on cognitive function is discussed, to evaluate the benefits deriving from appropriate treatment of sleep-disordered breathing on cognition.

Skeletal muscle myostatin mRNA expression is upregulated in aged human adults with excess adiposity but is not associated with insulin resistance and ageing - Andrew Wilhelmsen; Francis B. Stephens; Andrew J. Bennett; Leonidas G. Karagounis; Simon W. Jones; Kostas Tsintzas (GeroScience, 2023)
Myostatin negatively regulates skeletal muscle growth and appears upregulated in human obesity and associated with insulin resistance. However, observations are confounded by ageing, and the mechanisms responsible are unknown. The aim of this study was to delineate between the effects of excess adiposity, insulin resistance and ageing on myostatin mRNA expression in human skeletal muscle and to investigate causative factors using in vitro models. An in vivo cross-sectional analysis of human skeletal muscle was undertaken to isolate effects of excess adiposity and ageing per se on myostatin expression. In vitro studies employed human primary myotubes to investigate the potential involvement of cross-talk between subcutaneous adipose tissue (SAT) and skeletal muscle, and lipid-induced insulin resistance. Skeletal muscle myostatin mRNA expression was greater in aged adults with excess adiposity than age-matched adults with normal adiposity (2.0-fold higher; P < 0.05) and occurred concurrently with altered expression of genes involved in the maintenance of muscle mass but did not differ between younger and aged adults with normal adiposity. Neither chronic exposure to obese SAT secretome nor acute elevation of fatty acid availability (which induced insulin resistance) replicated the obesity-mediated upregulation of myostatin mRNA expression in vitro. In conclusion, skeletal muscle myostatin mRNA expression is uniquely upregulated in aged adults with excess adiposity and insulin resistance but not by ageing alone. This does not appear to be mediated by the SAT secretome or by lipid-induced insulin resistance. Thus, factors intrinsic to skeletal muscle may be responsible for the obesity-mediated upregulation of myostatin, and future work to establish causality is required.

Beyond the aging spine – a systematic review of functional changes in the human brain in cervical spondylotic myelopathy - Ali Fahim Khan; Fauziyya Muhammad; Esmaeil Mohammadi; Christen O’Neal; Grace Haynes; Sanaa Hameed; Brynden Walker; Michael L. Rohan; Andriy Yabluchanskiy; Zachary Adam Smith (GeroScience, 2023)

Blazing a trail for the clinical use of rapamycin as a geroprotecTOR - Adam R. Konopka; Dudley W. Lamming; Brittany A. Grasso; Rebecca C. Marrah; Sara Decker; Neetika Garg; Yeonhee Park; Sin Yin Lim; Judith A. Simcox; Cara L. Green; Isaac Grunow; Amanjot K. Yadev; et al. (GeroScience, 2023)

Comparative analysis of health status and health service utilization patterns among rural and urban elderly populations in Hungary: a study on the challenges of unhealthy aging - Nora Kovacs; Peter Piko; Attila Juhasz; Csilla Nagy; Beatrix Oroszi; Zoltan Ungvari; Roza Adany (GeroScience, 2023)
The demographic transition poses a significant challenge for health systems, especially in Central and Eastern European (CEE) countries, where the healthcare needs of aging populations are on the rise. This study aimed to describe and compare the health status and utilization of health services among the elderly residing in urban and rural areas of the most deprived region in Hungary. A comprehensive health survey was conducted in 2022, involving a randomly selected sample of 443 older adults (≥ 65 years) in Northeast Hungary. Multivariable logistic regression models adjusting for age, sex, education, financial status, chronic diseases, and activity limitations were used to investigate the association between type of residence and health service use. Among the study participants, 62.3% were female, 38.3% attained primary education, 12.5% reported a bad or very bad financial situation and 52.6% lived in urban areas. Overall, 24% of the elderly rated their health as very good or good (27.8% in urban and 19.7% in rural areas), while 57.8% (52.6% and 63.5% in urban and rural areas) reported limitations in daily activities. Compared to urban residents, rural residents reported lower rates of dentist visits ( p = 0.006), specialist visits ( p = 0.028), faecal occult blood testing ( p < 0.001), colorectal cancer screening with colonoscopy ( p = 0.014), and breast cancer screening ( p = 0.035), and a higher rate of blood pressure measurement ( p = 0.042). Multivariable models indicated that urban residence was positively associated with faecal occult blood testing (OR = 2.32, p = 0.014), but negatively associated with blood pressure (OR = 0.42, p = 0.017) and blood glucose measurements (OR = 0.48, p = 0.009). These findings highlight the influence of residence on health service utilization among older adults in Hungary. Further comprehensive studies are needed to better understand the health needs of the elderly population and to develop policies aimed at promoting healthy aging in CEE countries.

Cellular senescence and frailty: a comprehensive insight into the causal links - Serena Marcozzi; Giorgia Bigossi; Maria Elisa Giuliani; Robertina Giacconi; Francesco Piacenza; Maurizio Cardelli; Dario Brunetti; Agnese Segala; Alessandra Valerio; Enzo Nisoli; Fabrizia Lattanzio; Mauro Provinciali; et al. (GeroScience, 2023)

Characterization of novel mouse models to study the role of necroptosis in aging and age-related diseases - Ramasamy Selvarani; Hoang Van Michelle Nguyen; Nidheesh Thadathil; Roman F. Wolf; Willard M. Freeman; Christopher D. Wiley; Sathyaseelan S. Deepa; Arlan Richardson (GeroScience, 2023)
To study the impact of necroptosis-induced chronic inflammation on age-related diseases and aging, two knockin mouse models ( Ripk3 -KI and Mlkl -KI) were generated that overexpress two genes involved in necroptosis ( Ripk3 or Mlkl ) when crossed to Cre transgenic mice. Crossing Ripk3 -KI or Mlkl -KI mice to albumin-Cre transgenic mice produced hepatocyte specific hRipk3 -KI or hMlkl -KI mice, which express the two transgenes only in the liver. Ripk3 and Mlkl proteins were overexpressed 10- and fourfold, respectively, in the livers of the hRipk3 -KI or hMlkl -KI mice. Treating young (2-month) hRipk3 -KI or hMlkl -KI mice with carbon tetrachloride (CCl 4 ), a chemical inducer of oxidative stress, resulted in increased necroptosis (Mlkl-oligomers) and inflammation in the liver compared to control mice receiving CCl 4 . Mlkl-oligomerization also was significantly increased in old (18-month) hRipk3 -KI and hMlkl -KI mice compared to old control (Cre negative, Ripk3 -KI and Mlkl -KI) mice. The increase in necroptosis was associated with an increase in inflammation, e.g., inflammatory cytokines (TNFα, IL-6) and macrophage markers (F4/80, CD68). Importantly, steatosis (triglycerides) and fibrosis (e.g., picrosirius red staining, hydroxyproline levels, and transcripts for TGFβ, Col1α1, and Col3α1) that increase with age were significantly higher in the livers of the old hRipk3 -KI or hMlkl -KI mice compared to old control mice. In addition, markers of cellular senescence were significantly increased in the livers of the old hRipk3 -KI and hMlkl -KI mice. Thus, the first mouse models have been developed that allow researchers to study the impact of inducing necroptosis in specific cells/tissues on chronic inflammation in aging and age-related diseases.

Application of a mathematical model to clarify the statistical characteristics of a pan-tissue DNA methylation clock - Daigo Okada (GeroScience, 2023)

Hawaiian native herb Mamaki prevents dementia by ameliorating neuropathology and repairing neurons in four different mouse models of neurodegenerative diseases - Tomohiro Umeda; Keiko Shigemori; Rumi Uekado; Kazunori Matsuda; Takami Tomiyama (GeroScience, 2023)

Associations of measured and genetically predicted leukocyte telomere length with vascular phenotypes: a population-based study - Dan Liu; N. Ahmad Aziz; Mohammed Aslam Imtiaz; Gökhan Pehlivan; Monique M. B. Breteler (GeroScience, 2023)
Shorter leukocyte telomere length (LTL) is associated with cardiovascular dysfunction. Whether this association differs between measured and genetically predicted LTL is still unclear. Moreover, the molecular processes underlying the association remain largely unknown. We used baseline data of the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany [56.2% women, age: 55.5 ± 14.0 years (range 30 – 95 years)]. We calculated genetically predicted LTL in 4180 participants and measured LTL in a subset of 1828 participants with qPCR. Using multivariable regression, we examined the association of measured and genetically predicted LTL, and the difference between measured and genetically predicted LTL ( Δ LTL), with four vascular functional domains and the overall vascular health. Moreover, we performed epigenome-wide association studies of three LTL measures. Longer measured LTL was associated with better microvascular and cardiac function. Longer predicted LTL was associated with better cardiac function. Larger Δ LTL was associated with better microvascular and cardiac function and overall vascular health, independent of genetically predicted LTL. Several CpGs were associated ( p < 1e-05) with measured LTL ( n = 5), genetically predicted LTL ( n = 8), and Δ LTL ( n = 27). Genes whose methylation status was associated with Δ LTL were enriched in vascular endothelial signaling pathways and have been linked to environmental exposures, cardiovascular diseases, and mortality. Our findings suggest that non-genetic causes of LTL contribute to microvascular and cardiac function and overall vascular health, through an effect on the vascular endothelial signaling pathway. Interventions that counteract LTL may thus improve vascular function.

Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models - Ka Ka Ting; Paul Coleman; Hani Jieun Kim; Yang Zhao; Jocelyne Mulangala; Ngan Ching Cheng; Wan Li; Dilini Gunatilake; Daniel M. Johnstone; Lipin Loo; G. Gregory Neely; Pengyi Yang; et al. (GeroScience, 2023)
Alzheimer’s disease (AD) is an age-related disease, with loss of integrity of the blood–brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD. Senescent endothelial cells and pericytes are present in APP/PS1 transgenic mice but not in wild-type littermates at the time of amyloid deposition. In vitro, senescent endothelial cells display altered VE-cadherin expression and loss of cell junction formation and increased permeability. Consistent with this, senescent endothelial cells in APP/PS1 mice are present at areas of vascular leak that have decreased claudin-5 and VE-cadherin expression confirming BBB breakdown. Furthermore, single cell sequencing of endothelial cells from APP/PS1 transgenic mice confirms that adhesion molecule pathways are among the most highly altered pathways in these cells. At the pre-plaque stage, the vasculature shows significant signs of breakdown, with a general loss of VE-cadherin, leakage within the microcirculation, and obvious pericyte perturbation. Although senescent vascular cells were not directly observed at sites of vascular leak, senescent cells were close to the leak area. Thus, we would suggest in AD that there is a progressive induction of senescence in constituents of the neurovascular unit contributing to an increasing loss of vascular integrity. Targeting the vasculature early in AD, either with senolytics or with drugs that improve the integrity of the BBB may be valid therapeutic strategies.

Phenoage and longitudinal changes on transthoracic echocardiography in Alström syndrome: a disease of accelerated ageing? - Leena Patel; Ashwin Roy; Amor Mia B Alvior; Mengshi Yuan; Shanat Baig; Karina V. Bunting; James Hodson; Katja Gehmlich; Janet M Lord; Tarekegn Geberhiwot; Richard P. Steeds (GeroScience, 2023)
Alström syndrome (AS) is an ultra-rare disorder characterised by early-onset multi-organ dysfunction, such as insulin resistance, obesity, dyslipidaemia, and renal and cardiovascular disease. The objective is to explore whether AS is a disease of accelerated ageing and whether changes over time on echocardiography could reflect accelerated cardiac ageing. Cross-sectional measurement of Phenoage and retrospective analysis of serial echocardiography were performed between March 2012 and November 2022. The setting is a single national tertiary service jointly run by health service and patient charity. Forty-five adult patients aged over 16 years were included, 64% were male and 67% of White ethnicity. The median Phenoage was 48 years (interquartile range [IQR]: 35–72) in the 34 patients for whom this was calculable, which was significantly higher than the median chronological age of 29 years (IQR: 22–39, p <0.001). Phenoage was higher than chronological age in 85% ( N =29) of patients, with a median difference of +18 years (IQR: +4, +34). On echocardiography, significant decreases were observed over time in left ventricular (LV) size at end-diastole (average of 0.046 cm per year, p <0.001) and end-systole (1.1% per year, p =0.025), with significant increase in posterior wall thickness at end-diastole (0.009 cm per year, p =0.008). LV systolic function measured by global longitudinal strain reduced (0.34 percentage points per year, p =0.020) and E/e’lat increased (2.5% per year, p =0.019). Most AS patients display a higher Phenoage compared to chronological age. Cardiac changes in AS patients were also reflective of accelerated ageing, with a reduction in LV size and increased wall thickening. AS may be a paradigm disease for premature ageing.

The microarchitecture and chemical composition of the femur neck of senescent female rats after different physical training protocols - Rafael Augusto dos Santos Silva; Melise Jacon Peres-Ueno; Angela Cristina Nicola; Luis Fernando Gadioli Santos; Fernanda Fernandes-Breitenbach; Rafael Jesus Gonçalves Rubira; Rafael Pereira; Antônio Hernandes Chaves-Neto; Rita Cássia Menegati Dornelles (GeroScience, 2023)

Changes in oral health during aging in a novel non-human primate model - Parveez Ahamed Abdul-Azees; Hanzhou Wang; Yong-Hee P. Chun; Jason Pizzini; David D. Dean; Kelly R. Reveles; Milos Marinkovic; Xiao-Dong Chen; Adam B. Salmon; Chih-Ko Yeh (GeroScience, 2023)

Cellular metabolic pathways of aging in dogs: could p53 and SIRT1 be at play? - Ana Gabriela Jiménez; Kailey D. Paul; Mitchel Benson; Sahil Lalwani; William Cipolli (GeroScience, 2023)

The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic - Viktor J. Horvath; Magdolna Békeffy; Zsuzsanna Németh; Emese Szelke; Vince Fazekas-Pongor; Noémi Hajdu; Márk M. Svébis; József Pintér; Beatrix A. Domján; Szilvia Mészáros; Anna E. Körei; Árpád Kézdi; et al. (GeroScience, 2023)
The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients ( n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021–15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30 day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52–55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39–1.23) to booster vaccination (OR 0.31, 95% CI 0.13–0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission.

Senescence, regulators of alternative splicing and effects of trametinib treatment in progeroid syndromes - Laura R. Bramwell; Lorna W. Harries (GeroScience, 2023)
Progeroid syndromes such as Hutchinson Gilford Progeroid syndrome (HGPS), Werner syndrome (WS) and Cockayne syndrome (CS), result in severely reduced lifespans and premature ageing. Normal senescent cells show splicing factor dysregulation, which has not yet been investigated in syndromic senescent cells. We sought to investigate the senescence characteristics and splicing factor expression profiles of progeroid dermal fibroblasts. Natural cellular senescence can be reversed by application of the senomorphic drug, trametinib, so we also investigated its ability to reverse senescence characteristics in syndromic cells. We found that progeroid cultures had a higher senescence burden, but did not always have differences in levels of proliferation, DNA damage repair and apoptosis. Splicing factor gene expression appeared dysregulated across the three syndromes. 10 µM trametinib reduced senescent cell load and affected other aspects of the senescence phenotype (including splicing factor expression) in HGPS and Cockayne syndromes. Werner syndrome cells did not demonstrate changes in in senescence following treatment. Splicing factor dysregulation in progeroid cells provides further evidence to support this mechanism as a hallmark of cellular ageing and highlights the use of progeroid syndrome cells in the research of ageing and age-related disease. This study suggests that senomorphic drugs such as trametinib could be a useful adjunct to therapy for progeroid diseases.

Comparative analysis of the molecular and physiological consequences of constitutive SKN-1 activation - Carmen M. Ramos; Sean P. Curran (GeroScience, 2023)
Molecular homeostats play essential roles across all levels of biological organization to ensure a return to normal function after responding to abnormal internal and environmental events. SKN-1 is an evolutionarily conserved cytoprotective transcription factor that is integral for the maintenance of cellular homeostasis upon exposure to a variety of stress conditions. Despite the essentiality of turning on SKN-1/NRF2 in response to exogenous and endogenous stress, animals with chronic activation of SKN-1 display premature loss of health with age, and ultimately, diminished lifespan. Previous genetic models of constitutive SKN-1 activation include gain-of-function alleles of skn-1 and loss-of-function alleles of wdr-23 that impede the turnover of SKN-1 by the ubiquitin proteasome. Here, we define a novel gain-of-function mutation in the xrep-4 locus that results in constitutive activation of SKN-1 in the absence of stress. Although each of these genetic mutations results in continuously unregulated transcriptional output from SKN-1, the physiological consequences of each model on development, stress resistance, reproduction, lipid homeostasis, and lifespan are distinct. Here, we provide a comprehensive assessment of the differential healthspan impacts across multiple models of constitutive SKN-1 activation. Although our results reveal the universal need to reign in the uncontrolled activity of cytoprotective transcription factors, we also define the unique signatures of each model of constitutive SKN-1 activation, which provides innovative solutions for the design of molecular “off-switches” of unregulated transcriptional homeostats.

Bleomycin-treated myoblasts undergo p21-associated cellular senescence and have severely impaired differentiation - Michael Kamal; Sophie Joanisse; Gianni Parise (GeroScience, 2023)

Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors - Blaise L. Mariner; Antonio S. Rodriguez; Olivia C. Heath; Mark A. McCormick (GeroScience, 2023)
We have recently shown that multiple tRNA synthetase inhibitors can greatly increase lifespan in multiple models by acting through the conserved transcription factor ATF4. Here, we show that these compounds, and several others of the same class, can greatly upregulate mammalian ATF4 in cells in vitro, in a dose dependent manner. Further, RNASeq analysis of these cells pointed toward changes in protein turnover. In subsequent experiments here we show that multiple tRNA synthetase inhibitors can greatly upregulate activity of the ubiquitin proteasome system (UPS) in cells in an ATF4-dependent manner. The UPS plays an important role in the turnover of many damaged or dysfunctional proteins in an organism. Increasing UPS activity has been shown to enhance the survival of Huntington’s disease cell models, but there are few known pharmacological enhancers of the UPS. Additionally, we see separate ATF4 dependent upregulation of macroautophagy upon treatment with tRNA synthetase inhibitors. Protein degradation is an essential cellular process linked to many important human diseases of aging such as Alzheimer’s disease and Huntington’s disease. These drugs’ ability to enhance proteostasis more broadly could have wide-ranging implications in the treatment of important age-related neurodegenerative diseases.

Functional network disorganization and cognitive decline following fractionated whole-brain radiation in mice - Benjamin A. Seitzman; Francisco J. Reynoso; Timothy J. Mitchell; Annie R. Bice; Anmol Jarang; Xiaodan Wang; Cedric Mpoy; Lori Strong; Buck E. Rogers; Carla M. Yuede; Joshua B. Rubin; Stephanie M. Perkins; et al. (GeroScience, 2023)
Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain’s functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of temporally evolving neural dynamics as they relate to cerebral hemodynamics for bridging with human studies. In order to adequately study the underlying mechanisms of RT-induced cognitive dysfunction, the development of clinically mimetic RT protocols in animal models is needed. To address these challenges, we developed a fractionated whole-brain RT protocol (3Gy/day for 10 days) and applied longitudinal wide field optical imaging (WFOI) of neural and hemodynamic brain activity at 1, 2, and 3 months post RT. At each time point, mice were subject to repeated behavioral testing across a variety of sensorimotor and cognitive domains. Disruptions in cortical neuronal and hemodynamic activity observed 1 month post RT were significantly worsened by 3 months. While broad changes were observed in functional brain organization post RT, brain regions most impacted by RT occurred within those overlapping with the mouse default mode network and other association areas similar to prior reports in human subjects. Further, significant cognitive deficits were observed following tests of novel object investigation and responses to auditory and contextual cues after fear conditioning. Our results fill a much-needed gap in understanding the effects of whole-brain RT on systems level brain organization and how RT affects neuronal versus hemodynamic signaling in the cortex. Having established a clinically-relevant injury model, future studies can examine therapeutic interventions designed to reduce neuroinflammation-based injury following RT. Given the overlap of sequelae that occur following RT with and without chemotherapy, these tools can also be easily incorporated to examine chemotherapy-related cognitive impairment.

Sex differences in biological aging and the association with clinical measures in older adults - Aung Zaw Zaw Phyo; Peter D. Fransquet; Jo Wrigglesworth; Robyn L. Woods; Sara E. Espinoza; Joanne Ryan (GeroScience, 2023)
Females live longer than males, and there are sex disparities in physical health and disease incidence. However, sex differences in biological aging have not been consistently reported and may differ depending on the measure used. This study aimed to determine the correlations between epigenetic age acceleration (AA), and other markers of biological aging, separately in males and females. We additionally explored the extent to which these AA measures differed according to socioeconomic characteristics, clinical markers, and diseases. Epigenetic clocks (HorvathAge, HannumAge, PhenoAge, GrimAge, GrimAge2, and DunedinPACE) were estimated in blood from 560 relatively healthy Australians aged ≥ 70 years (females, 50.7%) enrolled in the ASPREE study. A system-wide deficit accumulation frailty index (FI) composed of 67 health-related measures was generated. Brain age and subsequently brain-predicted age difference (brain-PAD) were estimated from neuroimaging. Females had significantly reduced AA than males, but higher FI, and there was no difference in brain-PAD. FI had the strongest correlation with DunedinPACE (range r : 0.21 to 0.24 in both sexes). Brain-PAD was not correlated with any biological aging measures. Significant correlations between AA and sociodemographic characteristics and health markers were more commonly found in females (e.g., for DunedinPACE and systolic blood pressure r = 0.2, p < 0.001) than in males. GrimAA and Grim2AA were significantly associated with obesity and depression in females, while in males, hypertension, diabetes, and chronic kidney disease were associated with these clocks, as well as DunedinPACE. Our findings highlight the importance of considering sex differences when investigating the link between biological age and clinical measures.

The effects of a new immersive multidomain training on cognitive, dual-task and physical functions in older adults - Néva Béraud-Peigné; Pauline Maillot; Alexandra Perrot (GeroScience, 2023)

Sex difference in brain functional connectivity of hippocampus in Alzheimer’s disease - Jordan Williamson; Shirley A. James; Peter Mukli; Andriy Yabluchanskiy; Dee H. Wu; William Sonntag; Yuan Yang (GeroScience, 2023)

Differential behavioral aging trajectories according to body size, expected lifespan, and head shape in dogs - Borbála Turcsán; Enikő Kubinyi (GeroScience, 2023)
The twofold life expectancy difference between dog breeds predicts differential behavioral and cognitive aging patterns between short- and long-lived dogs. To investigate this prediction, we conducted a cross-sectional analysis using survey data from over 15,000 dogs. We examined the effect of expected lifespan and three related factors (body size, head shape, and purebred status) on the age trajectory of various behavioral characteristics and the prevalence of canine cognitive dysfunction (CCD). Our findings reveal that, although age-related decline in most behavioral characteristics began around 10.5 years of age, the proportion of dogs considered “old” by their owners began to increase uniformly around 6 years of age. From the investigated factors, only body size had a systematic, although not gradual, impact on the aging trajectories of all behavioral characteristics. Dogs weighing over 30 kg exhibited an earlier onset of decline by 2–3 years and a slower rate of decline compared to smaller dogs, probably as a byproduct of their faster age-related physical decline. Larger sized dogs also showed a lower prevalence of CCD risk in their oldest age group, whereas smaller-sized dogs, dolichocephalic breeds, and purebreds had a higher CCD risk prevalence. The identification of differential behavioral and cognitive aging trajectories across dog groups, and the observed associations between body size and the onset, rate, and degree of cognitive decline in dogs have significant translational implications for human aging research, providing valuable insights into the interplay between morphology, physiological ageing, and cognitive decline, and unravelling the trade-off between longevity and relative healthspan.

Artificial light and neurodegeneration: does light pollution impact the development of Alzheimer’s disease? - Julia Karska; Szymon Kowalski; Anna Gładka; Anna Brzecka; Marta Sochocka; Donata Kurpas; Jan Aleksander Beszłej; Jerzy Leszek (GeroScience, 2023)
Two multidimensional problems of recent times — Alzheimer’s disease and light pollution — seem to be more interrelated than previously expected. A series of studies in years explore the pathogenesis and the course of Alzheimer’s disease, yet the mechanisms underlying this pathology remain not fully discovered and understood. Artificial lights which accompany civilization on a daily basis appear to have more detrimental effects on both environment and human health than previously anticipated. Circadian rhythm is affected by inappropriate lighting conditions in particular. The consequences are dysregulation of the sleep-wake cycle, gene expression, neuronal restructuring, brain’s electricity, blood flow, metabolites’ turnover, and gut microbiota as well. All these phenomena may contribute to neurodegeneration and consequently Alzheimer’s disease. There is an increasing number of research underlining the complexity of the correlation between light pollution and Alzheimer’s disease; however, additional studies to enhance the key tenets are required for a better understanding of this relationship.

Deep neural network-estimated age using optical coherence tomography predicts mortality - Ruiye Chen; Shiran Zhang; Guankai Peng; Wei Meng; Grace Borchert; Wei Wang; Zhen Yu; Huan Liao; Zongyuan Ge; Mingguang He; Zhuoting Zhu (GeroScience, 2023)
The concept of biological age has emerged as a measurement that reflects physiological and functional decline with ageing. Here we aimed to develop a deep neural network (DNN) model that predicts biological age from optical coherence tomography (OCT). A total of 84,753 high-quality OCT images from 53,159 individuals in the UK Biobank were included, among which 12,631 3D-OCT images from 8,541 participants without any reported medical conditions at baseline were used to develop an age prediction model. For the remaining 44,618 participants, OCT age gap, the difference between the OCT-predicted age and chronological age, was calculated for each participant. Cox regression models assessed the association between OCT age gap and mortality. The DNN model predicted age with a mean absolute error of 3.27 years and showed a strong correlation of 0.85 with chronological age. After a median follow-up of 11.0 years (IQR 10.9–11.1 years), 2,429 deaths (5.44%) were recorded. For each 5-year increase in OCT age gap, there was an 8% increased mortality risk (hazard ratio [HR] = 1.08, CI:1.02–1.13, P = 0.004). Compared with an OCT age gap within ± 4 years, OCT age gap less than minus 4 years was associated with a 16% decreased mortality risk (HR = 0.84, CI: 0.75–0.94, P = 0.002) and OCT age gap more than 4 years showed an 18% increased risk of death incidence (HR = 1.18, CI: 1.02–1.37, P = 0.026). OCT imaging could serve as an ageing biomarker to predict biological age with high accuracy and the OCT age gap, defined as the difference between the OCT-predicted age and chronological age, can be used as a marker of the risk of mortality.

Brain age prediction across the human lifespan using multimodal MRI data - Sihai Guan; Runzhou Jiang; Chun Meng; Bharat Biswal (GeroScience, 2023)

Differential predictability of cognitive profiles from brain structure in older males and females - Christiane Jockwitz; Camilla Krämer; Paulo Dellani; Svenja Caspers (GeroScience, 2023)
Structural brain imaging parameters may successfully predict cognitive performance in neurodegenerative diseases but mostly fail to predict cognitive abilities in healthy older adults. One important aspect contributing to this might be sex differences. Behaviorally, older males and females have been found to differ in terms of cognitive profiles, which cannot be captured by examining them as one homogenous group. In the current study, we examined whether the prediction of cognitive performance from brain structure, i.e. region-wise grey matter volume (GMV), would benefit from the investigation of sex-specific cognitive profiles in a large sample of older adults (1000BRAINS; N = 634; age range 55–85 years). Prediction performance was assessed using a machine learning (ML) approach. Targets represented a) a whole-sample cognitive component solution extracted from males and females, and b) sex-specific cognitive components. Results revealed a generally low predictability of cognitive profiles from region-wise GMV. In males, low predictability was observed across both, the whole sample as well as sex-specific cognitive components. In females, however, predictability differences across sex-specific cognitive components were observed, i.e. visual working memory (WM) and executive functions showed higher predictability than fluency and verbal WM. Hence, results accentuated that addressing sex-specific cognitive profiles allowed a more fine-grained investigation of predictability differences, which may not be observable in the prediction of the whole-sample solution. The current findings not only emphasize the need to further investigate the predictive power of each cognitive component, but they also emphasize the importance of sex-specific analyses in older adults.

Data-driven transcriptomics analysis identifies PCSK9 as a novel key regulator in liver aging - Muhammad Arif; Csaba Matyas; Partha Mukhopadhyay; Burhan Yokus; Eszter Trojnar; Janos Paloczi; Bruno Paes-Leme; Suxian Zhao; Falk W. Lohoff; György Haskó; Pal Pacher (GeroScience, 2023)

Blood biomarker profiles and exceptional longevity: comparison of centenarians and non-centenarians in a 35-year follow-up of the Swedish AMORIS cohort - Shunsuke Murata; Marcus Ebeling; Anna C. Meyer; Katharina Schmidt-Mende; Niklas Hammar; Karin Modig (GeroScience, 2023)
Comparing biomarker profiles measured at similar ages, but earlier in life, among exceptionally long-lived individuals and their shorter-lived peers can improve our understanding of aging processes. This study aimed to (i) describe and compare biomarker profiles at similar ages between 64 and 99 among individuals eventually becoming centenarians and their shorter-lived peers, (ii) investigate the association between specific biomarker values and the chance of reaching age 100, and (iii) examine to what extent centenarians have homogenous biomarker profiles earlier in life. Participants in the population-based AMORIS cohort with information on blood-based biomarkers measured during 1985–1996 were followed in Swedish register data for up to 35 years. We examined biomarkers of metabolism, inflammation, liver, renal, anemia, and nutritional status using descriptive statistics, logistic regression, and cluster analysis. In total, 1224 participants (84.6% females) lived to their 100th birthday. Higher levels of total cholesterol and iron and lower levels of glucose, creatinine, uric acid, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase, and total iron-binding capacity were associated with reaching 100 years. Centenarians overall displayed rather homogenous biomarker profiles. Already from age 65 and onwards, centenarians displayed more favorable biomarker values in commonly available biomarkers than individuals dying before age 100. The differences in biomarker values between centenarians and non-centenarians more than one decade prior death suggest that genetic and/or possibly modifiable lifestyle factors reflected in these biomarker levels may play an important role for exceptional longevity.

Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release - Sharmin Aktar; Farhana Ferdousi; Shinji Kondo; Tamami Kagawa; Hiroko Isoda (GeroScience, 2023)
In recent years, exploring natural compounds with functional properties to ameliorate aging-associated cognitive decline has become a research priority to ensure healthy aging. In the present study, we investigated the effects of Trigonelline (TG), a plant alkaloid, on memory and spatial learning in 16-week-old senescence-accelerated mouse model SAMP8 using an integrated approach for cognitive and molecular biology aspects. After 30 days of oral administration of TG at the dose of 5 mg/kg/day, the mice were trained in Morris Water Maze task. TG-treated SAMP8 mice exhibited significant improvement in the parameters of escape latency, distance moved, and annulus crossing index. Next, we performed a whole-genome transcriptome profiling of the mouse hippocampus using microarrays. Gene ontology analyses showed that a wide range of biological processes, including nervous system development, mitochondrial function, ATP synthesis, and several signaling pathways related to inflammation, autophagy, and neurotransmitter release, were significantly enriched in TG-treated SAMP8 compared to nontreated. Further, a nonlinear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP), was applied to identify clusters of functions that revealed TG primarily regulated pathways related to inflammation, followed by those involved in neurotransmitter release. In addition, a protein–protein interaction network analysis indicated that TG may exert its biological effects through negatively modulating Traf6-mediated NF-κB activation. Finally, ELISA test showed that TG treatment significantly decreased proinflammatory cytokines- TNFα and IL6 and increased neurotransmitters- dopamine, noradrenaline, and serotonin in mouse hippocampus. Altogether, our integrated bio-cognitive approach highlights the potential of TG in alleviating age-related memory and spatial impairment.

Associations of circulating GDF15 with combined cognitive frailty and depression in older adults of the MARK-AGE study - Bastian Kochlik; Catrin Herpich; María Moreno-Villanueva; Susanne Klaus; Ursula Müller-Werdan; Birgit Weinberger; Simone Fiegl; Olivier Toussaint; Florence Debacq-Chainiaux; Christiane Schön; Jürgen Bernhard; Nicolle Breusing; et al. (GeroScience, 2023)
Growth differentiation factor-15 (GDF15) might be involved in the development of cognitive frailty and depression. Therefore, we evaluated cross-sectional associations of plasma GDF15 with combined cognitive-frailty-and-depression in older (i.e. ≥ 55 years) and younger adults of the MARK-AGE study. In the present work, samples and data of MARK-AGE (“European study to establish bioMARKers of human AGEing“) participants ( N = 2736) were analyzed. Cognitive frailty was determined by the global cognitive functioning score (GCF) and depression by the Self-Rating Depression Scale (SDS score). Adults were classified into three groups: (I) neither-cognitive-frailty-nor-depression, (II) either-cognitive-frailty-or-depression or (III) both-cognitive-frailty-and-depression. Cross-sectional associations were determined by unadjusted and by age, BMI, sex, comorbidities and hsCRP-adjusted linear and logistic regression analyses. Cognitive frailty, depression, age and GDF15 were significantly related within the whole study sample. High GDF15 levels were significantly associated with both-cognitive-frailty-and-depression (adjusted β = 0.177 [0.044 – 0.310], p = 0.009), and with low GCF scores and high SDS scores. High GDF15 concentrations and quartiles were significantly associated with higher odds to have both-cognitive-frailty-and-depression (adjusted odds ratio = 2.353 [1.267 – 4.372], p = 0.007; and adjusted odds ratio = 1.414 [1.025 – 1.951], p = 0.035, respectively) independent of age, BMI, sex, comorbidities and hsCRP. These associations remained significant when evaluating older adults. We conclude that plasma GDF15 concentrations are significantly associated with combined cognitive-frailty-and-depression status and, with cognitive frailty and depressive symptoms separately in old as well as young community-dwelling adults.

Regional differences in the link between water exchange rate across the blood–brain barrier and cognitive performance in normal aging - Valentinos Zachariou; Colleen Pappas; Christopher E. Bauer; Xingfeng Shao; Peiying Liu; Hanzhang Lu; Danny J. J. Wang; Brian T. Gold (GeroScience, 2023)
The blood–brain barrier (BBB) undergoes functional changes with aging which may contribute to cognitive decline. A novel, diffusion prepared arterial spin labeling-based MRI technique can measure the rate of water exchange across the BBB ( k w ) and may thus be sensitive to age-related alterations in water exchange at the BBB. However, studies investigating relationships between k w and cognition have reported different directions of association. Here, we begin to investigate the direction of associations between k w and cognition in different brain regions, and their possible underpinnings, by evaluating links between k w , cognitive performance, and MRI markers of cerebrovascular dysfunction and/or damage. Forty-seven healthy older adults (age range 61–84) underwent neuroimaging to obtain whole-brain measures of k w , cerebrovascular reactivity (CVR), and white matter hyperintensity (WMH) volumes. Additionally, participants completed uniform data set (Version 3) neuropsychological tests of executive function (EF) and episodic memory (MEM). Voxel-wise linear regressions were conducted to test associations between k w and cognitive performance, CVR, and WMH volumes. We found that k w in the frontoparietal brain regions was positively associated with cognitive performance but not with CVR or WMH volumes. Conversely, k w in the basal ganglia was negatively associated with cognitive performance and CVR and positively associated with regional, periventricular WMH volume. These regionally dependent associations may relate to different physiological underpinnings in the relationships between k w and cognition in neocortical versus subcortical brain regions in older adults.

Salidroside promotes healthy longevity by interfering with HSP90 activity - Jianfei Zhang; Zhiquan Li; Jiangbo Song; Lei Zhou; Xin Chen; Wen Ge; Tianyi Dong; Yuxin Luo; Ting Mao; Zheng Li; Duan Tan; Lene Juel Rasmussen; et al. (GeroScience, 2023)

Associations between psychological resilience and epigenetic clocks in the health and retirement study - Aijie Zhang; Yasi Zhang; Yaxian Meng; Qianqian Ji; Meijie Ye; Liqiong Zhou; Miao Liu; Chao Yi; Ida K. Karlsson; Fang Fang; Sara Hägg; Yiqiang Zhan (GeroScience, 2023)

Dorsal and ventral fronto-amygdala networks underlie risky decision-making in age-related cognitive decline - Ping Ren; Manxiu Ma; Yuchuan Zhuang; Jiayin Huang; Meiling Tan; Donghui Wu; Guozhi Luo (GeroScience, 2023)
Older adults often have difficulty in making decisions under uncertainty, increasing the risk of financial exploitation. However, it is still under investigation about the extent to which cognitive decline influences risky decision-making and the underlying neural correlates. We hypothesized that the individual differences of risk-taking behavior depend on cognitive integrity, in which the dorsal and ventral fronto-amygdala connectivity would play dissociable roles. In the current study, thirty-six young and 51 older adults were tested with the Iowa gambling task combing resting-state and task-related functional magnetic resonance imaging. The results showed significant changes in behaviors and the fronto-amygdala network in older adults relative to young adults. More importantly, age-effect on risk-taking behaviors was remarkably different in cognitively normal and impaired older adults. In resting-state analysis, task performance was positively correlated with the ventral fronto-amygdala connectivity and negatively correlated with the dorsal fronto-amygdala connectivity in cognitively impaired older adults, compared with cognitively normal individuals. Furthermore, task-related analysis confirmed the relationships between dorsal/ventral fronto-amygdala network and risk-taking behaviors depending on cognitive integrity. These findings indicate that the fronto-amygdala network is crucial for understanding altered risky decision-making in aging, suggesting dissociable contributions of the dorsal and ventral pathways in the context of cognitive decline.

Geroprotective interventions converge on gene expression programs of reduced inflammation and restored fatty acid metabolism - Tomer Landsberger; Ido Amit; Uri Alon (GeroScience, 2023)
Understanding the mechanisms of geroprotective interventions is central to aging research. We compare four prominent interventions: senolysis, caloric restriction, in vivo partial reprogramming, and heterochronic parabiosis. Using published mice transcriptomic data, we juxtapose these interventions against normal aging. We find a gene expression program common to all four interventions, in which inflammation is reduced and several metabolic processes, especially fatty acid metabolism, are increased. Normal aging exhibits the inverse of this signature across multiple organs and tissues. A similar inverse signature arises in three chronic inflammation disease models in a non-aging context, suggesting that the shift in metabolism occurs downstream of inflammation. Chronic inflammation is also shown to accelerate transcriptomic age. We conclude that a core mechanism of geroprotective interventions acts through the reduction of inflammation with downstream effects that restore fatty acid metabolism. This supports the notion of directly targeting genes associated with these pathways to mitigate age-related deterioration.

Physiological phenotypes have optimal values relevant to healthy aging: sweet spots deduced from the Canadian Longitudinal Study on Aging - Olga Vishnyakova; Xiaowei Song; Kenneth Rockwood; Lloyd T. Elliott; Angela Brooks-Wilson (GeroScience, 2023)
Previous observations on a group of exceptionally healthy “Super-Seniors” showed a lower variance of multiple physiological measures relevant for health than did a less healthy group of the same age. The finding was interpreted as the healthier individuals having physiological measurement values closer to an optimal level, or “sweet spot.” Here, we tested the generalizability of the sweet-spot hypothesis in a larger community sample, comparing differences in the variance between healthier and less healthy groups. We apply this method to the Canadian Longitudinal Study on Aging (CLSA) comprehensive cohort of 30,097 participants aged 45 to 85 years with deep phenotype data. Data from both sexes and four age ranges were analyzed. Five instruments were used to represent different aspects of health, physical, and cognitive functioning. We tested 231 phenotypic measures for lower variance in the most healthy vs. least healthy quartile of each sex and age group, as classified by the five instruments. Segmented regression was used to determine sex-specific optimal values. One hundred forty-two physiological measures (61%) showed lower variance in the healthiest than in the least healthy group, in at least one sex and age group. The difference in variance was most significant for hemoglobin A1c and was also significant for many body composition measurements, but not for bone mineral density. Ninety-four phenotypes showed a nonmonotonic relationship with health, consistent with the idea of a sweet spot; for these, we determined optimal values and 95% confidence intervals that were generally narrower than the ranges of current clinical reference intervals. These findings for sweet spot discovery validate the proposed approach for identifying traits important for healthy aging.

FABP7 drives an inflammatory response in human astrocytes and is upregulated in Alzheimer’s disease - Haylee L. Hamilton; Noah A. Kinscherf; Garrett Balmer; Mariana Bresque; Shahriar M. Salamat; Marcelo R. Vargas; Mariana Pehar (GeroScience, 2023)
Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. In partnership with microglial cells, astrocytes are key players in the regulation of neuroinflammation. Fatty acid binding protein 7 (FABP7) belongs to a family of conserved proteins that regulate lipid metabolism, energy homeostasis, and inflammation. FABP7 expression is largely restricted to astrocytes and radial glia-like cells in the adult central nervous system. We observed that treatment of primary hippocampal astrocyte cultures with amyloid β fragment 25–35 (Aβ 25–35 ) induces FABP7 upregulation. In addition, FABP7 expression is upregulated in the brain of APP/PS1 mice, a widely used AD mouse model. Co-immunostaining with specific astrocyte markers revealed increased FABP7 expression in astrocytes. Moreover, astrocytes surrounding amyloid plaques displayed increased FABP7 staining when compared to non-plaque-associated astrocytes. A similar result was obtained in the brain of AD patients. Whole transcriptome RNA sequencing analysis of human astrocytes differentiated from induced pluripotent stem cells (i-astrocytes) overexpressing FABP7 identified 500 transcripts with at least a 2-fold change in expression. Gene Ontology enrichment analysis identified (i) positive regulation of cytokine production and (ii) inflammatory response as the top two statistically significant overrepresented biological processes. We confirmed that wild-type FABP7 overexpression induces an NF-κB-driven inflammatory response in human i-astrocytes. On the other hand, the expression of a ligand-binding impaired mutant FABP7 did not induce NF-κB activation. Together, our results suggest that the upregulation of FABP7 in astrocytes could contribute to the neuroinflammation observed in AD.

Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures - Tamas Pandics; David Major; Vince Fazekas-Pongor; Zsofia Szarvas; Anna Peterfi; Peter Mukli; Rafal Gulej; Anna Ungvari; Monika Fekete; Anna Tompa; Stefano Tarantini; Andriy Yabluchanskiy; et al. (GeroScience, 2023)
The aging population worldwide is facing a significant increase in age-related non-communicable diseases, including cardiovascular and brain pathologies. This comprehensive review paper delves into the impact of the exposome, which encompasses the totality of environmental exposures, on unhealthy aging. It explores how environmental factors contribute to the acceleration of aging processes, increase biological age, and facilitate the development and progression of a wide range of age-associated diseases. The impact of environmental factors on cognitive health and the development of chronic age-related diseases affecting the cardiovascular system and central nervous system is discussed, with a specific focus on Alzheimer’s disease, Parkinson’s disease, stroke, small vessel disease, and vascular cognitive impairment (VCI). Aging is a major risk factor for these diseases. Their pathogenesis involves cellular and molecular mechanisms of aging such as increased oxidative stress, impaired mitochondrial function, DNA damage, and inflammation and is influenced by environmental factors. Environmental toxicants, including ambient particulate matter, pesticides, heavy metals, and organic solvents, have been identified as significant contributors to cardiovascular and brain aging disorders. These toxicants can inflict both macro- and microvascular damage and many of them can also cross the blood–brain barrier, inducing neurotoxic effects, neuroinflammation, and neuronal dysfunction. In conclusion, environmental factors play a critical role in modulating cardiovascular and brain aging. A deeper understanding of how environmental toxicants exacerbate aging processes and contribute to the pathogenesis of neurodegenerative diseases, VCI, and dementia is crucial for the development of preventive strategies and interventions to promote cardiovascular, cerebrovascular, and brain health. By mitigating exposure to harmful environmental factors and promoting healthy aging, we can strive to reduce the burden of age-related cardiovascular and brain pathologies in the aging population.

Comparing the associations between muscle strength, walking speed, and mortality in community-dwelling older adults of two birth cohorts born 28 years apart - Kaisa Koivunen; Erja Portegijs; Laura Karavirta; Taina Rantanen (GeroScience, 2023)
Reduced age-specific mortality and increased muscle strength and walking speed of current older adults may have altered the relationships between these factors as more people may be above the reserve capacity threshold. We compared the cross-sectional associations between muscle strength and walking speed, and the associations of muscle strength and walking speed with five-year mortality between two population-based cohorts of 75- and 80-year-old people born 28 years apart. Maximal isometric grip and knee extension strength and walking speed were measured in 2017–2018 ( n = 726). Mortality was ascertained from registers. The associations were compared with data of same-aged people studied in 1989–1990 with identical protocols ( n = 500). The knee extension strength-walking speed relationship showed plateauing at higher strength levels among the later-born men, whereas the earlier-born men and women of both cohorts with lower strength levels were on the linear part of the curve. In the later-born women with lower five-year mortality rate (1.16 vs. 5.88 per 100 person-years), the association between grip strength and mortality was markedly different from the earlier cohort (HR 1.13 [95% CI 0.47–2.70] vs. 0.57 [0.37–0.86]). For knee extension strength and walking speed, the mortality hazards were similar between the cohorts, although statistically non-significant in the later-born women. In men, the later-born cohort showed similar associations as observed in the earlier-born cohort despite having lower mortality rate (2.93 vs. 6.44). Current older adults have more functional reserve that will likely help them to maintain walking ability for longer while also contributing to better survival.

Distinct subsets of anti-pulmonary autoantibodies correlate with disease severity and survival in severe COVID-19 patients - Emese Tóth; Miklós Fagyas; Béla Nagy; Ivetta Mányiné Siket; Blanka Szőke; Lilla Mártha; Mohamed Mahdi; Gábor Erdősi; Zsófia Pólik; János Kappelmayer; Zoltán Papp; Attila Borbély; et al. (GeroScience, 2023)
Autoantibodies targeting the lung tissue were identified in severe COVID-19 patients in this retrospective study. Fifty-three percent of 104 patients developed anti-pulmonary antibodies, the majority of which were IgM class, suggesting that they developed upon infection with SARS-CoV-2. Anti-pulmonary antibodies correlated with worse pulmonary function and a higher risk of multiorgan failure that was further aggravated if 3 or more autoantibody clones were simultaneously present (multi-producers). Multi-producer patients were older than the patients with less or no autoantibodies. One of the identified autoantibodies (targeting a pulmonary protein of ~ 50 kDa) associated with worse clinical outcomes, including mortality. In summary, severe COVID-19 is associated with the development of lung-specific autoantibodies, which may worsen the clinical outcome. Tissue proteome-wide tests, such as the ones applied here, can be used to detect autoimmunity in the post-COVID state to identify the cause of symptoms and to reveal a new target for treatment.

Proteomic changes induced by longevity-promoting interventions in mice - Adam R. Burns; Jack Wiedrick; Alicia Feryn; Michal Maes; Mukul K. Midha; David H. Baxter; Seamus R. Morrone; Timothy J. Prokop; Charu Kapil; Michael R. Hoopmann; Ulrike Kusebauch; Eric W. Deutsch; et al. (GeroScience, 2023)

Involvement of ApoE4 in dementia with Lewy bodies in the prodromal and demented stages: evaluation of the Strasbourg cohort - Olivier Bousiges; Benjamin Cretin; Candice Muller; Anne Botzung; Lea Sanna; Pierre Anthony; Nathalie Philippi; Catherine Demuynck; Frédéric Blanc (GeroScience, 2023)

Metabolic biomarkers using nuclear magnetic resonance metabolomics assay for the prediction of aging-related disease risk and mortality: a prospective, longitudinal, observational, cohort study based on the UK Biobank - Jie Lian; Varut Vardhanabhuti (GeroScience, 2023)

Endocytosis and Alzheimer’s disease - Łukasz Zadka; Marta Sochocka; Naomi Hachiya; Justyna Chojdak-Łukasiewicz; Piotr Dzięgiel; Egbert Piasecki; Jerzy Leszek (GeroScience, 2023)
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia. The pathogenesis of AD still remains unclear, including two main hypotheses: amyloid cascade and tau hyperphosphorylation. The hallmark neuropathological changes of AD are extracellular deposits of amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Endocytosis plays an important role in a number of cellular processes including communication with the extracellular environment, nutrient uptake, and signaling by the cell surface receptors. Based on the results of genetic and biochemical studies, there is a link between neuronal endosomal function and AD pathology. Taking this into account, we can state that in the results of previous research, endolysosomal abnormality is an important cause of neuronal lesions in the brain. Endocytosis is a central pathway involved in the regulation of the degradation of amyloidogenic components. The results of the studies suggest that a correlation between alteration in the endocytosis process and associated protein expression progresses AD. In this article, we discuss the current knowledge about endosomal abnormalities in AD.

In-vivo screening implicates endoribonuclease Regnase-1 in modulating senescence-associated lysosomal changes - Richard Venz; Anita Goyala; Abel Soto-Gamez; Tugce Yenice; Marco Demaria; Collin Y. Ewald (GeroScience, 2023)
Accumulation of senescent cells accelerates aging and age-related diseases, whereas preventing this accumulation extends the lifespan in mice. A characteristic of senescent cells is increased staining with β-galactosidase (β-gal) ex vivo. Here, we describe a progressive accumulation of β-gal staining in the model organism C. elegans during aging. We show that distinct pharmacological and genetic interventions targeting the mitochondria and the mTORC1 to the nuclear core complex axis, the non-canonical apoptotic, and lysosomal-autophagy pathways slow the age-dependent accumulation of β-gal. We identify a novel gene, rege-1/Regnase-1/ZC3H12A/MCPIP1 , modulating β-gal staining via the transcription factor ets-4/SPDEF . We demonstrate that knocking down Regnase-1 in human cell culture prevents senescence-associated β-gal accumulation. Our data provide a screening pipeline to identify genes and drugs modulating senescence-associated lysosomal phenotypes.

Elimination of senescent cells by treatment with Navitoclax/ABT263 reverses whole brain irradiation-induced blood-brain barrier disruption in the mouse brain - Rafal Gulej; Ádám Nyúl-Tóth; Chetan Ahire; Jordan DelFavero; Priya Balasubramanian; Tamas Kiss; Stefano Tarantini; Zoltan Benyo; Pal Pacher; Boglarka Csik; Andriy Yabluchanskiy; Peter Mukli; et al. (GeroScience, 2023)

Serum methylmalonic acid concentrations at breast cancer diagnosis significantly correlate with clinical frailty - Qi Wu; Sigrid Hatse; Cindy Kenis; Juan Fernández-García; Patricia Altea-Manzano; Jaak Billen; Mélanie Planque; Anke Vandekeere; Yentl Lambrechts; François Richard; Kevin Punie; Patrick Neven; et al. (GeroScience, 2023)

Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults - Wan-Hsuan Lu; Sophie Guyonnet; Laurent O. Martinez; Alexandre Lucas; Angelo Parini; Bruno Vellas; Philipe de Souto Barreto (GeroScience, 2023)

Signs of aging in midlife: physical function and sex differences in microbiota - Roy Tzemah-Shahar; Sondra Turjeman; Efrat Sharon; Gila Gamliel; Hagit Hochner; Omry Koren; Maayan Agmon (GeroScience, 2023)

Sex-dependent associations of plasma high-density lipoprotein cholesterol and mortality risk in healthy older men and women: two prospective cohort studies - Sultana Monira Hussain; Andrew M Tonkin; Gerald F Watts; Paul Lacaze; Chenglong Yu; Lawrence J Beilin; Zhen Zhou; Anne B Newman; Johannes T Neumann; Cammie Tran; John J McNeil (GeroScience, 2023)
The relationship between high plasma high-density lipoprotein cholesterol (HDL-C) and cause and mortality are not well established in healthy older people. This study examined the associations between HDL-C levels and mortality in initially healthy older men and women. This analysis included participants from the Aspirin in Reducing Events in the Elderly (ASPREE; n =18,668) trial and a matched cohort from the UK Biobank (UKB; n =62,849 ≥65 years). Cox regression was used to examine hazard ratios between HDL-C categories <1.03 mmol/L, 1.03–1.55 mmol/L (referent category), 1.55–2.07 mmol/L, and >2.07 mmol/L and all-cause, cancer, cardiovascular disease (CVD), and “non-cancer non-CVD” mortality. Genetic contributions were assessed using a polygenic score for HDL-C. Among ASPREE participants (aged 75±5 years), 1836 deaths occurred over a mean follow-up of 6.3±1.8 years. In men, the highest category of HDL-C levels was associated with increased risk of all-cause (HR 1.60, 95% CI 1.26–2.03), cancer (HR 1.37, 95% CI 0.96–2.00), and “non-cancer non-CVD” mortality (HR 2.35, 95% CI 1.41–3.42) but not CVD mortality (HR 1.08, 95% CI 0.60–1.94). The associations were replicated among UKB participants (aged 66.9±1.5 years), including 8739 deaths over a mean follow-up of 12.7±0.8 years. There was a non-linear association between HDL-C levels and all-cause and cause-specific mortality. The association between HDL-C levels and mortality was unrelated to variations in the HDL-C polygenic score. No significant association was found between HDL-C levels and mortality in women. Higher HDL-C levels are associated with increased risk from cancer and “non-cancer non-CVD” mortality in healthy older men but no such relationship was observed in women.

Glucose metabolism in posterior cingulate cortex has supplementary value to predict the progression of cognitively unimpaired to dementia due to Alzheimer’s disease: an exploratory study of 18F-FDG-PET - Qi Zhang; Chunqiu Fan; Luyao Wang; Taoran Li; Min Wang; Ying Han; Jiehui Jiang; Michael W. Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; et al. (GeroScience, 2023)

DNA methylation age acceleration contributes to the development and prediction of non-alcoholic fatty liver disease - Mingfeng Xia; Wenran Li; Huandong Lin; Hailuan Zeng; Shuai Ma; Qi Wu; Hui Ma; Xiaoming Li; Baishen Pan; Jian Gao; Yu Hu; Yun Liu; et al. (GeroScience, 2023)
Non-alcoholic fatty liver disease (NAFLD) is prevalent in the aging society. Despite body weight reduction, the prevalence of NAFLD has been increasing with aging for unknown reasons. Here, we investigate the association of DNA methylation age acceleration, a hallmark of aging, with risk of NAFLD. Genome-wide DNA methylation profiles were measured in 95 participants who developed type 2 diabetes during 4-year follow-up, and 356 randomly sampled participants from Shanghai Changfeng Study. DNA methylation age was calculated using the Horvath’s method, and liver fat content (LFC) was measured using a quantitative ultrasound method. Subjects with highest tertile of DNA methylation age acceleration (≥ 9.5 years) had significantly higher LFC (7.2% vs 3.1%, P = 0.008) but lower body fat percentage (29.7% vs 33.0%, P = 0.032) than those with lowest tertile of DNA methylation age acceleration (< 4.0 years). After adjustment for age, sex, alcohol drinking, cigarette smoking, BMI, waist circumference, and different type blood cell counts, the risk of NAFLD was still significantly increased in the highest tertile group (OR, 4.55; 95% CI, 1.06–19.61). Even in subjects with similar LFC at baseline, DNA methylation age acceleration was associated with higher increase in LFC (4.0 ± 10.7% vs 0.9 ± 9.5%, P = 0.004) after a median of 4-year follow-up. Further analysis found that 6 CpGs of Horvath age predictors were associated with longitudinal changes in LFC after multivariate adjustment and located on genes that might lead to fat redistribution from peripheral adipose to liver. Combination of the key CpG methylation related to liver fat content with conventional risk factors improves the performance for NAFLD prediction. Graphical Abstract

Caspase 5 depletion is linked to hyper-inflammatory response and progeroid syndrome - Fuki M. Hisama; Renuka Kandhaya Pillai; Julia Sidorova; Karynne Patterson; Carolina Gokingco; Michal Yacobi-Bach; Junko Oshima (GeroScience, 2023)
A progeroid family was found to harbor a pathogenic variant in the CASP5 gene that encodes inflammatory caspase 5. Caspase 5-depleted fibroblasts exhibited hyper-activation of inflammatory cytokines in response to pro-inflammatory stimuli. Long-term intermittent hyper-inflammatory response is likely the cause of the accelerated aging phenotype comprised of earlier onset of common aging diseases, supporting inflammaging as a potential common disease mechanism of progeroid syndromes and possibly normative aging.

Assessment of cerebral autoregulatory function and inter-hemispheric blood flow in older adults with internal carotid artery stenosis using transcranial Doppler sonography-based measurement of transient hyperemic response after carotid artery compression - Rita Magyar-Stang; Hanga Pál; Borbála Csányi; Anna Gaál; Zsuzsanna Mihály; Zsófia Czinege; Tamas Csipo; Zoltan Ungvari; Péter Sótonyi; Andrea Varga; Tamás Horváth; Dániel Bereczki; et al. (GeroScience, 2023)
Unhealthy vascular aging promotes atherogenesis, which may lead to significant internal carotid artery stenosis (CAS) in 5 to 7.5% of older adults. The pathogenic factors that promote accelerated vascular aging and CAS also affect the downstream portion of the cerebral microcirculation in these patients. Primary treatments of significant CAS are eversion endarterectomy or endarterectomy with patch plasty. Factors that determine adequate hemodynamic compensation and thereby the clinical consequences of CAS as well as medical and surgical complications of carotid reconstruction surgery likely involve the anatomy of the circle of Willis (CoW), the magnitude of compensatory inter-hemispheric blood flow, and the effectiveness of cerebral microcirculatory blood flow autoregulation. This study aimed to test two hypotheses based on this theory. First, we hypothesized that patients with symptomatic and asymptomatic CAS would exhibit differences in autoregulatory function and inter-hemispheric blood flow. Second, we predicted that anatomically compromised CoW would associate with impaired inter-hemispheric blood flow compensation. We enrolled older adults with symptomatic or asymptomatic internal CAS (>70% NASCET criteria; n = 46) and assessed CoW integrity by CT angiography. We evaluated transient hyperemic responses in the middle cerebral arteries (MCA) after common carotid artery compression (CCC; 10 s) by transcranial Doppler sonography (TCD). We compared parameters reflecting autoregulatory function (e.g., transient hyperemic response ratio [THRR], return to baseline time [RTB], changes of vascular resistance) and inter-hemispheric blood flow (residual blood flow velocity). Our findings revealed that CAS was associated with impaired cerebral vascular reactivity. However, we did not observe significant differences in autoregulatory function or inter-hemispheric blood flow between patients with symptomatic and asymptomatic CAS. Moreover, anatomically compromised CoW did not significantly affect these parameters. Notably, we observed an inverse correlation between RTB and THRR, and 49% of CAS patients exhibited a delayed THRR, which associated with decreased inter-hemispheric blood flow. Future studies should investigate how TCD-based evaluation of autoregulatory function and inter-hemispheric blood flow can be used to optimize surgical techniques and patient selection for internal carotid artery revascularization.

Insights into ageing rates comparison across tissues from recalibrating cerebellum DNA methylation clock - Yucheng Wang; Olivia A. Grant; Xiaojun Zhai; Klaus D. Mcdonald-Maier; Leonardo C. Schalkwyk (GeroScience, 2023)
DNA methylation (DNAm)-based age clocks have been studied extensively as a biomarker of human ageing and a risk factor for age-related diseases. Despite different tissues having vastly different rates of proliferation, it is still largely unknown whether they age at different rates. It was previously reported that the cerebellum ages slowly; however, this claim was drawn from a single clock using a relatively small sample size and so warrants further investigation. We collected the largest cerebellum DNAm dataset ( N = 752) to date. We found the respective epigenetic ages are all severely underestimated by six representative DNAm age clocks, with the underestimation effects more pronounced in the four clocks whose training datasets do not include brain-related tissues. We identified 613 age-associated CpGs in the cerebellum, which accounts for only 14.5% of the number found in the middle temporal gyrus from the same population ( N = 404). From the 613 cerebellum age-associated CpGs, we built a highly accurate age prediction model for the cerebellum named CerebellumClock specific (Pearson correlation=0.941, MAD=3.18 years). Ageing rate comparisons based on the two tissue-specific clocks constructed on the 201 overlapping age-associated CpGs support the cerebellum has younger DNAm age. Nevertheless, we built BrainCortexClock to prove a single DNAm clock is able to unbiasedly estimate DNAm ages of both cerebellum and cerebral cortex, when they are adequately and equally represented in the training dataset. Comparing ageing rates across tissues using DNA methylation multi-tissue clocks is flawed. The large underestimation of age prediction for cerebellums by previous clocks mainly reflects the improper usage of these age clocks. There exist strong and consistent ageing effects on the cerebellar methylome, and we suggest the smaller number of age-associated CpG sites in cerebellum is largely attributed to its extremely low average cell replication rates.

A revisiting of “the hallmarks of aging” in domestic dogs: current status of the literature - Ana Gabriela Jiménez (GeroScience, 2023)

Examining racial differences in the network structure and properties of specific cognitive domains among older adults - Se Hee Min; Rebecca Schnall; Chiyoung Lee; Maxim Topaz (GeroScience, 2023)

The use of assistive devices and social engagement among older adults: heterogeneity by type of social engagement and gender - HyunJee Park; Jinho Kim (GeroScience, 2023)

Effects of a brief HIIT intervention on cognitive performance in older women - Amani M. Norling; Adam Gerstenecker; Mark S. Bolding; Lawrence Ver Hoef; Thomas Buford; Randall Walden; Hongyu An; Chunwei Ying; Terina Myers; Benjamin S. Jones; Victor Del Bene; Ronald M. Lazar (GeroScience, 2023)

Mediterranean lifestyle index and 24-h systolic blood pressure and heart rate in community-dwelling older adults - Irene Talavera-Rodríguez; José R. Banegas; Juan J. de la Cruz; David Martínez-Gómez; Miguel Ruiz-Canela; Rosario Ortolá; Maria S. Hershey; Fernando Rodríguez Artalejo; Mercedes Sotos-Prieto (GeroScience, 2023)
Specific foods, nutrients, dietary patterns, and physical activity are associated with lower blood pressure (BP) and heart rate (HR), but little is known about the joint effect of lifestyle factors captured in a multidimensional score. We assessed the association of a validated Mediterranean-lifestyle (MEDLIFE) index with 24-h-ambulatory BP and HR in everyday life among community-living older adults. Data were taken from 2,184 individuals (51% females, mean age: 71.4 years) from the Seniors-ENRICA-2 cohort. The MEDLIFE index consisted of 29 items arranged in three blocks: 1) Food consumption; 2) Dietary habits; and 3) Physical activity, rest, and conviviality. A higher MEDLIFE score (0–29 points) represented a better Mediterranean lifestyle adherence. 24-h-ambulatory BP and HR were obtained with validated oscillometric devices. Analyses were performed with linear regression adjusted for the main confounders. The MEDLIFE-highest quintile (vs Q1) was associated with lower nighttime systolic BP (SBP) (-3.17 mmHg [95% CI: -5.25, -1.08]; p-trend = 0.011), greater nocturnal-SBP fall (1.67% [0.51, 2.83]; p-trend = 0.052), and lower HR (-2.04 bpm [daytime], -2.33 bpm [nighttime], and -1.93 bpm [24-h]; all p -trend < 0.001). Results were similar for each of the three blocks of MEDLIFE and by hypertension status (yes/no). Among older adults, higher adherence to MEDLIFE was associated with lower nighttime SBP, greater nocturnal-SBP fall, and lower HR in their everyday life. These results suggest a synergistic BP-related protection from the components of the Mediterranean lifestyle. Future studies should determine whether these results replicate in older adults from other Mediterranean and non-Mediterranean countries.

Personalization matters: the effect of sex in multivitamin-multimineral-based cancer prevention - Julij Šelb; Filip Cvetko; Leon Deutsch; Leon Bedrač; Enej Kuščer; Andrea Britta Maier (GeroScience, 2023)
The prevention of non-communicable diseases like cancer contributes to healthy aging. Dietary supplements might support such prevention; their effect likely depends on the personal characteristics of the individuals receiving them. To evaluate the influence of sex on reducing cancer incidence with multivitamin-multimineral (MVM) supplementation, sex-specific results of the efficacy of MVM supplementation for cancer prevention were collected and meta-analyzed (using fixed effect (FE) and random effect (RE) models). Three trials included in the “US Preventive Services Task Force Recommendation Statement Report regarding Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer” were used, namely, COSMOS, SU.VI.MAX, and PHS2. A total of 28,558 men and 20,542 women were included. Multivitamin-multimineral supplementation significantly reduced cancer incidence in the entire population (HR 0.93 [95% CI, 0.88–0.99], FE and RE); sex-specific meta-analysis showed beneficial effects of supplementation in men (HR 0.91 [95% CI, 0.85–0.97] (FE)/0.88 [95% CI, 0.77–1.01] (RE)); however, there was no effect in women (HR 1.00 [95% CI, 0.88–1.14], FR and RE); ( P difference = 0.17). Sex could influence the effect of MVM supplementation in reducing cancer incidence, with supplementation being effective only in male individuals. These results might be informative for future research and public health policy makers.

Geroprotective potential of microbiome modulators in the Caenorhabditis elegans model - Brandi C. Miller; Megha Mathai; Hariom Yadav; Shalini Jain (GeroScience, 2023)
Aging is associated with cellular and physiological changes, which significantly reduce the quality of life and increase the risk for disease. Geroprotectors improve lifespan and slow the progression of detrimental aging-related changes such as immune system senescence, mitochondrial dysfunction, and dysregulated nutrient sensing and metabolism. Emerging evidence suggests that gut microbiota dysbiosis is a hallmark of aging-related diseases and microbiome modulators, such as probiotics (live bacteria) or postbiotics (non-viable bacteria/bacterial byproducts) may be promising geroprotectors. However, because they are strain-specific, the geroprotective effects of probiotics and postbiotics remain poorly understood and understudied. Drosophila melanogaster , Caenorhabditis elegans , and rodents are well-validated preclinical models for studying lifespan and the role of probiotics and/or postbiotics, but each have their limitations, including cost and their translation to human aging biology. C. elegans is an excellent model for large-scale screening to determine the geroprotective potential of drugs or probiotics/postbiotics due to its short lifecycle, easy maintenance, low cost, and homology to humans. The purpose of this article is to review the geroprotective effects of microbiome modulators and their future scope, using C. elegans as a model. The proposed geroprotective mechanisms of these probiotics and postbiotics include delaying immune system senescence, preventing or reducing mitochondrial dysfunction, and regulating food intake (dietary restriction) and metabolism. More studies are warranted to understand the geroprotective potential of probiotics and postbiotics, as well as other microbiome modulators, like prebiotics and fermented foods, and use them to develop effective therapeutics to extend lifespan and reduce the risk of debilitating aging-related diseases.

Correction to: Microglial MHC‑I induction with aging and Alzheimer’s is conserved in mouse models and humans - Collyn M. Kellogg; Kevin Pham; Adeline H. Machalinski; Hunter L. Porter; Harris E. Blankenship; Kyla B. Tooley; Michael B. Stout; Heather C. Rice; Amanda L. Sharpe; Michael J. Beckstead; Ana J. Chucair‑Elliott; Sarah R. Ocañas; et al. (GeroScience, 2023)

Association of spermidine blood levels with microstructure of sleep—implications from a population-based study - Silke M. Wortha; Juliane Schulz; Jevri Hanna; Claudia Schwarz; Beate Stubbe; Stefan Frenzel; Robin Bülow; Nele Friedrich; Matthias Nauck; Henry Völzke; Ralf Ewert; Antje Vogelgesang; et al. (GeroScience, 2023)
Deteriorations in slow wave sleep (SWS) have been linked to brain aging and Alzheimer’s disease (AD), possibly due to its key role in clearance of amyloid-beta and tau (Aß/tau), two pathogenic hallmarks of AD. Spermidine administration has been shown to improve sleep quality in animal models. So far, the association between spermidine levels in humans and parameters of SWS physiology are unknown but may be valuable for therapeutic strategies. Data from 216 participants (age range 50–81 years) of the population-based Study of Health in Pomerania TREND were included in our analysis. We investigated associations between spermidine plasma levels, key parameters of sleep macroarchitecture and microarchitecture that were previously associated with AD pathology, and brain health measured via a marker of structural brain atrophy (AD score). Higher spermidine levels were significantly associated with lower coupling between slow oscillations and spindle activity. No association was evident for SWS, slow oscillatory, and spindle activity throughout non-rapid eye movement sleep. Furthermore, elevated spermidine blood levels were significantly associated with a higher AD score, while sleep markers revealed no association with AD score. The association between higher spermidine levels and brain health was not mediated by coupling between slow oscillations and spindle activity. We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. Future studies need to evaluate whether sleep, spermidine, and Aß/tau deposition are interrelated and whether sleep may play a mediating role.

Association of growth and differentiation factor-15 with coronary artery calcium score and ankle-brachial index in a middle-aged and elderly Caucasian population sample free of manifest cardiovascular disease - Loretta Zsuzsa Kiss; Balázs Bence Nyárády; Éva Pállinger; Árpád Lux; Ádám Levente Jermendy; Csaba Csobay-Novák; Pál Soós; Zsolt Szelid; Orsolya Láng; László Kőhidai; Elek Dinya; Edit Dósa; et al. (GeroScience, 2023)
Growth and differentiation factor-15 (GDF-15) is a stress-associated cytokine of the transforming growth factor-β superfamily. The inflammatory and angiogenic effects of GDF-15 in atherosclerosis are controversial, and its correlation with the long asymptomatic phase of the disease is not well understood. Coronary artery calcium score (CACS) and ankle-brachial index (ABI) are sensitive markers of subclinical atherosclerosis. To date, only a few studies have examined the impact of GDF-15 on coronary artery calcification, and the association between GDF-15 and ABI has not been evaluated. Therefore, we aimed to investigate the possible relationship between serum GDF-15 concentrations and CACS and ABI in a Caucasian population sample of middle-aged (35–65 years) and elderly (> 65 years) people. In addition to recording demographic and anthropometric characteristics, atherosclerotic risk factors, and laboratory tests including serum HDL-cholesterol, LDL-cholesterol, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP); GDF-15 level, cardiac computed tomography, and ABI measurements were also performed. A total of 269 asymptomatic individuals (men, n = 125; median age, 61.5 [IQR, 12.7] years) formed the basis of this study. Participants were divided into two groups according to their age (middle-aged, n = 175 and elderly, n = 94). Hypertension and diabetes mellitus were significantly more prevalent and CACS values and HbA1c, NT-proBNP, and GDF-15 levels were significantly higher (all p < 0.001) in the elderly group compared to the middle-aged group. Multivariate ridge regression analysis revealed a significant positive association between GDF-15 and CACS (middle-aged group: β = 0.072, p = 0.333; elderly group: β = 0.148, p = 0.003), and between GDF-15 and ABI (middle-aged group: β = 0.062, p = 0.393; elderly group: β = 0.088, p = 0.041) only in the elderly group. Our results show that GDF-15 is not only a useful biomarker of inflammation but can also predict early signs of asymptomatic atherosclerosis, especially in elderly people with chronic systemic inflammation associated with aging (inflammaging).

Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants - Meiruo Xiang; Luke C. Pilling; David Melzer; Ben Kirk; Gustavo Duque; Rui Liu; George A. Kuchel; Andrew R. Wood; Brad Metcalf; Breno S. Diniz; Melvyn Hillsdon; Chia-Ling Kuo (GeroScience, 2023)
Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD. Data were from the UK Biobank participants with well-calibrated accelerometer data for at least 6.5 days ( n = 54,180). Relative mean LTL at baseline (5–6 years prior to aPA assessment) was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction (qPCR) technology, by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). aPA measures included total number of events (at least 10-s continued physical activity > 32 milligravities [mg]), total volume, mean duration, mean intensity, and peak intensity of all events. LTL, aPA measures, and their interactions were associated with incident CHD (mean follow-up 6.8 years) using Cox proportional hazards models adjusting for covariates. Longer LTL (relative to the sample distribution) was associated with reduced incidence of CHD (adjusted hazard ratio [aHR] = 0.94 per standard deviation [SD] increase in LTL, [95% CI, 0.90 to 0.99], P = .010). Incidence of CHD was reduced by higher total volume of aPA (aHR = 0.82 per SD increase in LTL, [95% CI, 0.71 to 0.95], P = .010) but increased by higher total number of events (aHR = 1.11 per SD increase in LTL, [95% CI, 1.02 to 1.21], P = .020) after controlling for other aPA measures and covariates. However, none of the interactions between LTL and aPA measures was statistically significant ( P = .171).

Age- and gender-related dispersion of brain networks across the lifespan - Qing Wang; Lingyu Qi; Cancan He; Haixia Feng; Chunming Xie; Chao-Gan Yan; Xiao Chen; Le Li; Francisco Xavier Castellanos; Tong-Jian Bai; Ning-Xuan Chen; Wei Chen; et al. (GeroScience, 2023)

Sex-specific preservation of neuromuscular function and metabolism following systemic transplantation of multipotent adult stem cells in a murine model of progeria - Seth D. Thompson; Kelsey L. Barrett; Chelsea L. Rugel; Robin Redmond; Alexia Rudofski; Jacob Kurian; Jodi L. Curtin; Sudarshan Dayanidhi; Mitra Lavasani (GeroScience, 2023)
Onset and rates of sarcopenia, a disease characterized by a loss of muscle mass and function with age, vary greatly between sexes. Currently, no clinical interventions successfully arrest age-related muscle impairments since the decline is frequently multifactorial. Previously, we found that systemic transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) isolated from young mice—but not old—extends the health-span in DNA damage mouse models of progeria, a disease of accelerated aging. Additionally, induced neovascularization in the muscles and brain—where no transplanted cells were detected—strongly suggests a systemic therapeutic mechanism, possibly activated through circulating secreted factors. Herein, we used ZMPSTE24-deficient mice, a lamin A defect progeria model, to investigate the ability of young MDSPCs to preserve neuromuscular tissue structure and function. We show that progeroid ZMPST24-deficient mice faithfully exhibit sarcopenia and age-related metabolic dysfunction. However, systemic transplantation of young MDSPCs into ZMPSTE24-deficient progeroid mice sustained healthy function and histopathology of muscular tissues throughout their 6-month life span in a sex-specific manner. Indeed, female—but not male—mice systemically transplanted with young MDSPCs demonstrated significant preservation of muscle endurance, muscle fiber size, mitochondrial respirometry, and neuromuscular junction morphometrics. These novel findings strongly suggest that young MDSPCs modulate the systemic environment of aged animals by secreted rejuvenating factors to maintain a healthy homeostasis in a sex-specific manner and that the female muscle microenvironment remains responsive to exogenous regenerative cues in older age. This work highlights the age- and sex-related differences in neuromuscular tissue degeneration and the future prospect of preserving health in older adults with systemic regenerative treatments.