Tristetraprolin overexpression drives hematopoietic changes in young and middle-aged mice generating dominant mitigating effects on induced inflammation in murine models - Mayuri Tanaka-Yano; Le Zong; Bongsoo Park; Hagai Yanai; Ferda Tekin-Turhan; Perry J. Blackshear; Isabel Beerman (GeroScience, 2023)
Tristetraprolin (TTP), encoded by Zfp36 in mice, is one of the best-characterized tandem zinc-finger mRNA binding proteins involved in mRNA deadenylation and decay. TTPΔARE mice lack an AU-rich motif in the 3′-untranslated regions of TTP mRNA, leading to increased TTP mRNA stability and more TTP protein, resulting in elevated mRNA decay rates of TTP targets. We examined the effect of TTP overexpression on the hematopoietic system in both young and middle-aged mice using TTPΔARE mice and found alterations in blood cell frequencies, with loss of platelets and B220 cells and gains of eosinophils and T cells. TTPΔARE mice also have skewed primitive populations in the bone marrow, with increases in myeloid-biased hematopoietic stem cells (HSCs) but decreases in granulocyte/macrophage-biased multipotent progenitors (MPP3) in both young and middle-aged mice. Changes in the primitive cells’ frequencies were associated with transcriptional alterations in the TTP overexpression cells specific to age as well as cell type. Regardless of age, there was a consistent elevation of transcripts regulated by TNFα and TGFβ signaling pathways in both the stem and multipotent progenitor populations. HSCs with TTP overexpression had decreased reconstitution potential in murine transplants but generated hematopoietic environments that mitigated the inflammatory response to the collagen antibody-induced arthritis (CAIA) challenge, which models rheumatoid arthritis and other autoimmune disorders. This dampening of the inflammatory response was even present when there was only a small frequency of TTP overexpressing cells present in the middle-aged mice. We provide an analysis of the early hematopoietic compartments with elevated TTP expression in both young and middle-aged mice which inhibits the reconstitution potential of the HSCs but generates a hematopoietic system that provides dominant repression of induced inflammation.

Plasma neurofilament light chain in relation to 10-year change in cognition and neuroimaging markers: a population-based study - Joyce van Arendonk; Frank J. Wolters; Julia Neitzel; Elisabeth J. Vinke; Meike W. Vernooij; Mohsen Ghanbari; M. Arfan Ikram (GeroScience, 2023)
Neurofilament light chain (NfL) is a promising biomarker for risk stratification and disease monitoring of dementia, but its utility in the preclinical disease stage remains uncertain. We determined the association of plasma NfL with (change in) neuroimaging markers and cognition in the population-based Rotterdam Study, using linear and logistic regression and mixed-effects models. Plasma NfL levels were measured using the Simoa NF-light™ assay in 4705 dementia-free participants (mean age 71.9 years, 57% women), who underwent cognitive assessment and brain MRI with repeated assessments over a 10-year follow-up period. Higher plasma NfL was associated with worse cognitive performance at baseline (g-factor: β = − 0.12 (− 0.15; − 0.09), p < 0.001), and accelerated cognitive decline during follow-up on the Stroop color naming task ( β = 0.04 (0.02; 0.06), p < 0.001), with a smaller trend for decline in global cognition (g-factor β = − 0.02 (− 0.04; 0.00), p = 0.044). In the subset of 975 participants with brain MRI, higher NfL was associated with poorer baseline white matter integrity (e.g., global mean diffusivity: β = 0.12 (0.06; 0.19), p < 0.001), with similar trends for volume of white matter hyperintensities ( β = 0.09 (0.02; 0.16), p = 0.011) and presence of lacunes (OR = 1.55 (1.13; 2.14), p = 0.007). Plasma NfL was not associated with volumes or thickness of the total gray matter, hippocampus, or Alzheimer signature regions. In conclusion, higher plasma NfL levels are associated with cognitive decline and larger burden of primarily white matter pathology in the general population.

MiR-425-5p suppression of Crebzf regulates oocyte aging via chromatin modification - Kadiliya Jueraitetibaike; Ting Tang; Rujun Ma; Shanmeizi Zhao; Ronghua Wu; Yang Yang; Xuan Huang; Xi Cheng; Cheng Zhou; Hong Zhang; Lu Zheng; Xie Ge; et al. (GeroScience, 2023)
Female infertility due to declining oocyte quality with age remains a significant challenge for patients and physicians, despite extensive research efforts. Recent studies suggest that microRNAs (miRNAs), which respond to various stressors in the aging process, may provide a promising solution. With the approval of small RNA drugs for clinical use, miRNA-based treatment of oocyte aging appears to be a viable option. Through high-throughput sequencing, miR-425-5p was identified as the only miRNA elevated under natural aging and oxidative stress. Microinjection of inhibitors to inhibit miR-425-5p effectively improved compromised phenotypes of old oocytes in vitro. Further investigation revealed that Crebzf acts as a mediator of miR-425-5p 's age-related functions in old oocytes. In vivo treatment with miR-425-5p antagomirs significantly improved impaired oocyte development in reproductively old females by targeting Crebzf . Single-cell RNA sequencing revealed that Crebzf plays a vital role in regulating mRNAs targeting histone H3, trimethylated lysine 4 (H3K4me3), a crucial marker for transcriptional silencing. Overexpression of miR-425-5p could hinder oocyte maturation by downregulating Crebzf expression and disrupting transcriptional regulation. Our findings provide new insights into the potential of miR-425-5p antagomirs as a treatment for female infertility and highlight an elegant mechanism by which miR-425-5p inhibition of Crebzf inhibits a developmental switch in GV oocytes by regulating a group of histone methyltransferase mRNAs.

Muscle quality, physical performance, and comorbidity are predicted by circulating procollagen type III N-terminal peptide (P3NP): the InCHIANTI follow-up study - Raffaello Pellegrino; Roberto Paganelli; Angelo Di Iorio; Stefania Bandinelli; Antimo Moretti; Giovanni Iolascon; Eleonora Sparvieri; Domiziano Tarantino; Luigi Ferrucci (GeroScience, 2023)
Sarcopenia is characterized by skeletal muscle quantitative and qualitative alterations. A marker of collagen turnover, procollagen type III N-terminal peptide (P3NP), seems to be related to those conditions. This study aims to assess the predictive role of P3NP in muscle density and physical performance changes. In the InCHIANTI study, a representative sample from the registry lists of two towns in Tuscany, Italy, was recruited. Baseline data was collected in 1998, and follow-up visits were conducted every 3 years. Out of the 1453 participants enrolled at baseline, this study includes 1052 participants. According to P3NP median levels, population was clustered in two groups; 544 (51.7%) of the 1052 subjects included were classified in the low median levels (LM-P3NP); at the baseline, they were younger, had higher muscle density, and performed better at the Short Physical Performance Battery (SPPB), compared to the high-median group (HM-P3NP). LM-P3NP cases showed a lower risk to develop liver chronic diseases, CHF, myocardial infarction, and osteoarthritis. HM-P3NP levels were associated with a longitudinal reduction of muscle density, and this effect was potentiated by the interaction between P3NP and leptin. Moreover, variation in physical performance was inversely associated with high level of P3NP, and directly associated with high fat mass, and with the interaction between P3NP and muscle density. Our data indicate that P3NP is associated with the aging process, affecting body composition, physical performance, and clinical manifestations of chronic degenerative age-related diseases.

Associations of plasma NfL, GFAP, and t-tau with cerebral small vessel disease and incident dementia: longitudinal data of the AGES-Reykjavik Study - April C. E. van Gennip; Claudia L. Satizabal; Russell P. Tracy; Sigurdur Sigurdsson; Vilmundur Gudnason; Lenore J. Launer; Thomas T. van Sloten (GeroScience, 2023)
We investigated the associations of plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (t-tau) with markers of cerebral small vessel disease (SVD) and with incident dementia. We also investigated whether associations of NfL, GFAP, and t-tau with incident dementia were explained by SVD. Data are from a random subsample ( n = 1069) of the population-based AGES-Reykjavik Study who underwent brain MRI and in whom plasma NfL, GFAP, and t-tau were measured at baseline (76.1 ± 5.4 years/55.9% women/baseline 2002–2006/follow-up until 2015). A composite SVD burden score was calculated using white matter hyperintensity volume (WMHV), subcortical infarcts, cerebral microbleeds, and large perivascular spaces. Dementia was assessed in a 3-step process and adjudicated by specialists. Higher NfL was associated with a higher SVD burden score. Dementia occurred in 225 (21.0%) individuals. The SVD burden score significantly explained part of the association between NfL and incident dementia. WMHV mostly strongly contributed to the explained effect. GFAP was not associated with the SVD burden score, but was associated with WMHV, and WMHV significantly explained part of the association between GFAP and incident dementia. T-tau was associated with WMHV, but not with incident dementia. In conclusion, the marker most strongly related to SVD is plasma NfL, for which the association with WMHV appeared to explain part of its association with incident dementia. This study suggests that plasma NfL may reflect the contribution of co-morbid vascular disease to dementia. However, the magnitude of the explained effect was relatively small, and further research is required to investigate the clinical implications of this finding.

Associations of healthy aging index and all-cause and cause-specific mortality: a prospective cohort study of UK Biobank participants - Zhenhuang Zhuang; Yimin Zhao; Ninghao Huang; Yueying Li; Wenxiu Wang; Zimin Song; Xue Dong; Wendi Xiao; Jinzhu Jia; Zhonghua Liu; Lu Qi; Tao Huang (GeroScience, 2023)

Associations of sugar-sweetened, artificially sweetened, and naturally sweet juices with Alzheimer’s disease: a prospective cohort study - Yanchun Chen; Yuan Zhang; Hongxi Yang; Huiping Li; Lihui Zhou; Mengnan Zhang; Yaogang Wang (GeroScience, 2023)

Utilizing multimodal approach to identify candidate pathways and biomarkers and predicting frailty syndrome in individuals from UK Biobank - Watson Hua-Sheng Tseng; Amrita Chattopadhyay; Nam Nhut Phan; Eric Y. Chuang; Oscar K. Lee (GeroScience, 2023)

Associations between physical exercise type, fluid intelligence, executive function, and processing speed in the oldest-old (85 +) - Brian Duy Ho; Joseph M. Gullett; Stephen Anton; Mary Kathryn Franchetti; Pradyumna K. Bharadwaj; David A. Raichlen; Gene E. Alexander; Tatjana Rundek; Bonnie Levin; Kristina Visscher; Adam J. Woods; Ronald A. Cohen (GeroScience, 2023)

Prefrontal hemodynamic features of older adults with preserved visuospatial working memory function - Tsz-lok Lee; Zihan Ding; Agnes S. Chan (GeroScience, 2023)
Memory decline has been observed in the aging population and is a risk factor for the later development of dementia. Understanding how memory is preserved in older adults has been an important topic. The present study examines the hemodynamic features of older adults whose memory is comparable with that of young adults. In the present study, 45 younger and 45 older adults performed the visual memory task with various difficulty levels (i.e., the items to be remembered), and their cerebral hemodynamics at each level were measured by functional near-infrared spectroscopy (fNIRS). The results showed that older adults exhibited higher activation than younger adults under more difficult but not easier levels. In addition, older adults whose performance is comparable with that of young adults (i.e., being able to remember six items) showed more right-lateralized activation. However, those unable to do so showed more left-lateralized activation. The results suggested that high-performing older adults possess successful compensatory mechanisms by recruiting cognitive resources in a specialized brain region.

Systemic inflammation and biological aging in the Health and Retirement Study - Helen C. S. Meier; Colter Mitchell; Thomas Karadimas; Jessica D. Faul (GeroScience, 2023)
Chronic, low-level systemic inflammation associated with aging, or inflammaging, is a risk factor for several chronic diseases and mortality. Using data from the Health and Retirement Study, we generated a continuous latent variable for systemic inflammation from seven measured indicators of inflammation and examined associations with another biomarker of biological aging, DNA methylation age acceleration measured by epigenetic clocks, and 4-year mortality ( N = 3,113). We found that greater systemic inflammation was positively associated with DNA methylation age acceleration for 10 of the 13 epigenetic clocks, after adjustment for sociodemographics and chronic disease risk factors. The latent variable for systemic inflammation was associated with 4-year mortality independent of DNA methylation age acceleration and was a better predictor of 4-year mortality than any of the epigenetic clocks examined, as well as mortality risk factors, including obesity and multimorbidity. Inflammaging and DNA methylation age acceleration may represent different biological processes contributing to mortality risk. Leveraging multiple measured inflammation markers to capture inflammaging is important for biology of aging research.

Basal autophagic flux measured in blood correlates positively with age in adults at increased risk of type 2 diabetes - Julien Bensalem; Xiao Tong Teong; Kathryn J. Hattersley; Leanne K. Hein; Célia Fourrier; Kai Liu; Amy T. Hutchison; Leonie K. Heilbronn; Timothy J. Sargeant (GeroScience, 2023)

The multifaceted benefits of walking for healthy aging: from Blue Zones to molecular mechanisms - Zoltan Ungvari; Vince Fazekas-Pongor; Anna Csiszar; Setor K. Kunutsor (GeroScience, 2023)
Physical activity, including walking, has numerous health benefits in older adults, supported by a plethora of observational and interventional studies. Walking decreases the risk or severity of various health outcomes such as cardiovascular and cerebrovascular diseases, type 2 diabetes mellitus, cognitive impairment and dementia, while also improving mental well-being, sleep, and longevity. Dose-response relationships for walking duration and intensity are established for adverse cardiovascular outcomes. Walking’s favorable effects on cardiovascular risk factors are attributed to its impact on circulatory, cardiopulmonary, and immune function. Meeting current physical activity guidelines by walking briskly for 30 min per day for 5 days can reduce the risk of several age-associated diseases. Additionally, low-intensity physical exercise, including walking, exerts anti-aging effects and helps prevent age-related diseases, making it a powerful tool for promoting healthy aging. This is exemplified by the lifestyles of individuals in Blue Zones, regions of the world with the highest concentration of centenarians. Walking and other low-intensity physical activities contribute significantly to the longevity of individuals in these regions, with walking being an integral part of their daily lives. Thus, incorporating walking into daily routines and encouraging walking-based physical activity interventions can be an effective strategy for promoting healthy aging and improving health outcomes in all populations. The goal of this review is to provide an overview of the vast and consistent evidence supporting the health benefits of physical activity, with a specific focus on walking, and to discuss the impact of walking on various health outcomes, including the prevention of age-related diseases. Furthermore, this review will delve into the evidence on the impact of walking and low-intensity physical activity on specific molecular and cellular mechanisms of aging, providing insights into the underlying biological mechanisms through which walking exerts its beneficial anti-aging effects.

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 Martos-Duarte; Luis Perea-Unceta; Carlos Romero-Morales; Helios Pareja-Galeano (GeroScience, 2023)
Physical exercise has demonstrated its effectiveness in the management of the deleterious process of aging. However, it is less studied in institutionalized elderly people. This investigation aims to clarify the benefits of a multicomponent training program in institutionalized older adults. A randomized controlled trial was conducted with institutionalized older adults (≥ 70 years old). Intervention group (IG; N = 18) were submitted to a multicomponent training program based on muscle power training and interval endurance exercise, 2 times/week for 12 weeks. Control group (CG; N = 16) continued their usual mobility exercises. Independence was estimated with the Barthel index, and physical fitness and functional mobility were evaluated by the Short Physical Performance Battery (SPPB), the Timed Up and Go (TUG) test, the 6-min Walking Test (6’WT), the 10-Meter Walking Test (10MWT), hand grip strength dynamometry, and lower limb muscle strength and power. The IG improved, compared with the CG, in TUG scores in -7.43 s (95% IC: 3.28, 11.59; p < 0.001); in 10MWT scores in -5.19 s (95% IC: 1.41, 8.97; p = 0.004) and -4.43 s (95% IC: 1.14, 7.73; p = 0.002), 6’WT scores in + 54.54 m (95% IC: 30.24, 78.84; p < 0.001); and SPPB in + 2.74 points (95% IC: 2.10, 3.37; p < 0.001). Maximum muscle power and maximum strength did not show statistically significant differences. The multicomponent training program based on muscle power and interval endurance exercise was shown to be safe, well tolerated and effective for the improvement of functional mobility and physical fitness, but not for independence in institutionalized older adults.

Pan-primate studies of age and sex - Steve Horvath; Amin Haghani; Joseph A. Zoller; Ake T. Lu; Jason Ernst; Matteo Pellegrini; Anna J. Jasinska; Julie A. Mattison; Adam B. Salmon; Ken Raj; Markus Horvath; Kimberly C. Paul; et al. (GeroScience, 2023)
Age and sex have a profound effect on cytosine methylation levels in humans and many other species. Here we analyzed DNA methylation profiles of 2400 tissues derived from 37 primate species including 11 haplorhine species (baboons, marmosets, vervets, rhesus macaque, chimpanzees, gorillas, orangutan, humans) and 26 strepsirrhine species (suborders Lemuriformes and Lorisiformes). From these we present here, pan-primate epigenetic clocks which are highly accurate for all primates including humans (age correlation R = 0.98). We also carried out in-depth analysis of baboon DNA methylation profiles and generated five epigenetic clocks for baboons (Olive-yellow baboon hybrid), one of which, the pan-tissue epigenetic clock, was trained on seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age. Using the primate data, we characterize the effect of age and sex on individual cytosines in highly conserved regions. We identify 11 sex-related CpGs on autosomes near genes ( POU3F2, CDYL, MYCL, FBXL4, ZC3H10, ZXDC, RRAS, FAM217A, RBM39, GRIA2, UHRF2 ). Low overlap can be observed between age- and sex-related CpGs. Overall, this study advances our understanding of conserved age- and sex-related epigenetic changes in primates, and provides biomarkers of aging for all primates.

Concentrating to avoid falling: interaction between peripheral sensory and central attentional demands during a postural stability limit task in sedentary seniors - Marie Julie Vermette; François Prince; Louis Bherer; Julie Messier (GeroScience, 2023)

Using voice biomarkers for frailty classification - Yael Rosen-Lang; Saad Zoubi; Ron Cialic; Tal Orenstein (GeroScience, 2023)

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT) - Gavin Pharaoh; Varun Kamat; Sricharan Kannan; Rudolph S. Stuppard; Jeremy Whitson; Miguel Martín-Pérez; Wei-Jun Qian; Michael J. MacCoss; Judit Villén; Peter Rabinovitch; Matthew D. Campbell; Ian R. Sweet; et al. (GeroScience, 2023)
Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. Graphical abstract ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H + (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH 2 (flavin adenine dinucleotide), O 2 (oxygen), ELAM (elamipretide), –SH (free thiol), –SSG (glutathionylated protein)

Resting-state fractal brain connectivity is associated with impaired cognitive performance in healthy aging - Akos Czoch; Zalan Kaposzta; Peter Mukli; Orestis Stylianou; Andras Eke; Frigyes Samuel Racz (GeroScience, 2023)
Aging affects cognitive functions even in the absence of ongoing pathologies. The neurophysiological basis of age-related cognitive decline (CD), however, is not completely understood. Alterations in both functional brain connectivity and in the fractal scaling of neuronal dynamics have been linked to aging and cognitive performance. Recently, fractal connectivity (FrC) has been proposed — combining the two concepts — for capturing long-term interactions among brain regions. FrC was shown to be influenced by increased mental workload; however, no prior studies investigated how resting-state FrC relates to cognitive performance and plausible CD in healthy aging. We recruited 19 healthy elderly (HE) and 24 young control (YC) participants, who underwent resting-state electroencephalography (EEG) measurements and comprehensive cognitive evaluation using 7 tests of the Cambridge Neurophysiological Test Automated Battery. FrC networks were reconstructed from EEG data using the recently introduced multiple-resampling cross-spectral analysis (MRCSA). Elderly individuals could be characterized with increased response latency and reduced performance in 4–4 tasks, respectively, with both reaction time and accuracy being affected in two tasks. Auto- and cross-spectral exponents — characterizing regional fractal dynamics and FrC, respectively, — were found reduced in HE when compared to YC over most of the cortex. Additionally, fractal scaling of frontoparietal connections expressed an inverse relationship with task performance in visual memory and sustained attention domains in elderly, but not in young individuals. Our results confirm that the fractal nature of brain connectivity — as captured by MRCSA — is affected in healthy aging. Furthermore, FrC appears as a sensitive neurophysiological marker of age-related CD.

Correction to: Pre-frail older adults show improved cognition with StayFitLonger computerized home–based training: a randomized controlled trial - Sylvie Belleville; M. Cuesta; M. Bieler-Aeschlimann; K. Giacomino; A. Widmer; A. G. Mittaz Hager; D. Perez-Marcos; S. Cardin; B. Boller; N. Bier; M. Aubertin-Leheudre; L. Bherer; et al. (GeroScience, 2023)

Targeting mitochondria in the aged cerebral vasculature with SS-31, a proteomic study of brain microvessels - Abigail Seman; Partha K. Chandra; Stephanie D. Byrum; Samuel G. Mackintosh; Allen J. Gies; David W. Busija; Ibolya Rutkai (GeroScience, 2023)
Cognitive impairment and dementias during aging such as Alzheimer’s disease are linked to functional decline and structural alterations of the brain microvasculature. Although mechanisms leading to microvascular changes during aging are not clear, loss of mitochondria, and reduced efficiency of remaining mitochondria appear to play a major role. Pharmacological agents, such as SS-31, which target mitochondria have been shown to be effective during aging and diseases; however, the benefit to mitochondrial- and non-mitochondrial proteins in the brain microvasculature has not been examined. We tested whether attenuation of aging-associated changes in the brain microvascular proteome via targeting mitochondria represents a therapeutic option for the aging brain. We used aged male (> 18 months) C57Bl6/J mice treated with a mitochondria-targeted tetrapeptide, SS-31, or vehicle saline. Cerebral blood flow (CBF) was determined using laser speckle imaging during a 2-week treatment period. Then, isolated cortical microvessels (MVs) composed of end arterioles, capillaries, and venules were used for Orbitrap Eclipse Tribrid mass spectrometry. CBF was similar among the groups, whereas bioinformatic analysis revealed substantial differences in protein abundance of cortical MVs between SS-31 and vehicle. We identified 6267 proteins, of which 12% were mitochondria-associated. Of this 12%, 107 were significantly differentially expressed and were associated with oxidative phosphorylation, metabolism, the antioxidant defense system, or mitochondrial dynamics. Administration of SS-31 affected many non-mitochondrial proteins. Our findings suggest that mitochondria in the microvasculature represent a therapeutic target in the aging brain, and widespread changes in the proteome may underlie the rejuvenating actions of SS-31 in aging.

Chronological and reproductive aging-associated changes in resistance to oxidative stress in post-reproductive female mice - Tristin L. King; Kaden B. Underwood; Kindra K. Hansen; Michael T. Kinter; Augusto Schneider; Michal M. Masternak; Jeffrey B. Mason (GeroScience, 2023)

Determining the feasibility of characterising cellular senescence in human skeletal muscle and exploring associations with muscle morphology and physical function at different ages: findings from the MASS_Lifecourse Study - Leena Habiballa; Adam Hruby; Antoneta Granic; Richard M. Dodds; Susan J. Hillman; Diana Jurk; João F. Passos; Avan A. Sayer (GeroScience, 2023)
Cellular senescence may be associated with morphological changes in skeletal muscle and changes in physical function with age although there have been few human studies. We aimed to determine the feasibility of characterising cellular senescence in skeletal muscle and explored sex-specific associations between markers of cellular senescence, muscle morphology, and physical function in participants from the MASS_Lifecourse Study. Senescence markers ( p16 , TAF (Telomere-Associated DNA Damage Foci), HMGB1 (High Mobility Group Box 1), and Lamin B1) and morphological characteristics (fibre size, number, fibrosis, and centrally nucleated fibres) were assessed in muscle biopsies from 40 men and women (age range 47–84) using spatially-resolved methods (immunohistochemistry, immunofluorescence, and RNA and fluorescence in situ hybridisation). The associations between senescence, morphology, and physical function (muscle strength, mass, and physical performance) at different ages were explored. We found that most senescence markers and morphological characteristics were weakly associated with age in men but more strongly, although non-significantly, associated with age in women. Associations between senescence markers, morphology, and physical function were also stronger in women for HMGB1 and grip strength ( r = 0.52); TAF, BMI, and muscle mass ( r > 0.4); Lamin B1 and fibrosis ( r = − 0.5); fibre size and muscle mass ( r ≥ 0.4); and gait speed ( r = − 0.5). However, these associations were non-significant. In conclusion, we have demonstrated that it is feasible to characterise cellular senescence in human skeletal muscle and to explore associations with morphology and physical function in women and men of different ages. The findings require replication in larger studies.

A simple framework to distinguish ‘individualistic’ from a ‘uniform rate’ of ageing within or between study populations - Hans Degens; Gladys L. Onambélé-Pearson (GeroScience, 2023)
Ageing is accompanied by a progressive decline in physiological functions. It is often argued that the rate of ageing differs between people and is ‘highly individualistic’. This view is not unequivocally shared, and others have argued that the rate of ageing is rather ‘uniform’. Distinguishing conclusively between these views requires longitudinal data, but these are difficult to obtain as they require decades of data collection from individuals. Here, a simple framework is proposed to assess in cross-sectional data whether in a given population the rate is ‘highly individualistic’ or rather ‘uniform’. It is illustrated that an age-related decrease in the standard deviation (SD) of a certain parameter combined with a non-changing coefficient of variation (COVAR) reflects a ‘uniform’ rate of ageing, whilst an increase or decrease in COVAR with or without a concomitant increase in SD reflects a ‘highly individualistic’ rate of ageing. This framework is applied to some published data, focussing on muscle strength, power and physical function for the sake of illustration, and it is suggested that most studies do in fact show a ‘highly individualistic’ rate of ageing, perhaps apart from a ‘uniform’ rate of ageing in master athletes.

The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery - Mitchell B. Lee; Benjamin Blue; Michael Muir; Matt Kaeberlein (GeroScience, 2023)

Cognitive and physical age gaps in relation to mild cognitive impairment and behavioral phenotypes - Junhong Yu; Ted Kheng Siang Ng; Rathi Mahendran (GeroScience, 2023)

SIRT1 safeguards adipogenic differentiation by orchestrating anti-oxidative responses and suppressing cellular senescence - An Yu; Ruofan Yu; Haiying Liu; Chenliang Ge; Weiwei Dang (GeroScience, 2023)

Psychological resilience and competence: key promoters of successful aging and flourishing in late life - Virág Zábó; Anna Csiszar; Zoltan Ungvari; György Purebl (GeroScience, 2023)
Many individuals, both in the public and within the field of psychology, often perceive aging as a burden that negatively impacts intellectual and mental health. Our present study aims to challenge this notion by identifying the crucial components of positive mental health in later life. These components not only promote positive mental health but also actively contribute to it, even under difficult circumstances. To accomplish this, we first offer a concise review of well-being and mental health models that highlight the psychological aspects of flourishing in late life. We then introduce a psychological competence-based model for positive mental health, which aligns with the concept of positive aging. Subsequently, we present a measurement tool suitable for practical applications. Finally, we provide a comprehensive overview of positive aging, drawing on methodological guidelines and existing research findings concerning sustainable positive mental health in later life. We examine the evidence indicating that psychological resilience (the capacity to adapt and recover from adversity or stress) and competence (skills and abilities to effectively cope with challenges across various life domains) significantly contribute to slowing down biological aging processes. Furthermore, we discuss insights into the relationship between psychological factors and aging derived from research on Blue Zones (regions characterized by a higher proportion of individuals experiencing longer, healthier lives).

Effective virus-specific T-cell therapy for high-risk SARS-CoV-2 infections in hematopoietic stem cell transplant recipients: initial case studies and literature review - László Gopcsa; Marienn Réti; Hajnalka Andrikovics; Ilona Bobek; Gabriella Bekő; Judit Bogyó; Andrea Ceglédi; Katalin Dobos; Laura Giba-Kiss; István Jankovics; Orsolya Kis; Botond Lakatos; et al. (GeroScience, 2023)
The COVID-19 pandemic has exacerbated mortality rates among immunocompromised patients, accentuating the need for novel, targeted therapies. Transplant recipients, with their inherent immune vulnerabilities, represent a subgroup at significantly heightened risk. Current conventional therapies often demonstrate limited effectiveness in these patients, calling for innovative treatment approaches. In immunocompromised transplant recipients, several viral infections have been successfully treated by adoptive transfer of virus-specific T-cells (VST). This paper details the successful application of SARS-CoV-2-specific memory T-cell therapy, produced by an interferon-γ cytokine capture system (CliniMACS® Prodigy device), in three stem cell transplant recipients diagnosed with COVID-19 (case 1: alpha variant, cases 2 and 3: delta variants). These patients exhibited persistent SARS-CoV-2 PCR positivity accompanied by bilateral pulmonary infiltrates and demonstrated only partial response to standard treatments. Remarkably, all three patients recovered and achieved viral clearance within 3 to 9 weeks post-VST treatment. Laboratory follow-up investigations identified an increase in SARS-CoV-2-specific T-cells in two of the cases. A robust anti-SARS-CoV-2 S (S1/S2) IgG serological response was also recorded, albeit with varying titers. The induction of memory T-cells within the CD4 + compartment was confirmed, and previously elevated interleukin-6 (IL-6) and IL-8 levels normalized post-VST therapy. The treatment was well tolerated with no observed adverse effects. While the need for specialized equipment and costs associated with VST therapy present potential challenges, the limited treatment options currently available for COVID-19 within the allogeneic stem cell transplant population, combined with the risk posed by emerging SARS-CoV-2 mutations, underscore the potential of VST therapy in future clinical practice. This therapeutic approach may be particularly beneficial for elderly patients with multiple comorbidities and weakened immune systems.

Deprescribing in cardiometabolic conditions in older patients: a systematic review - Elizabeth Hickman; Mansha Seawoodharry; Clare Gillies; Kamlesh Khunti; Samuel Seidu (GeroScience, 2023)
We conduct a systematic review to investigate current deprescribing practices and evaluate outcomes and adverse events with deprescribing of preventive medications in older patients with either an end-of-life designation or residing in long-term care facilities with cardiometabolic conditions. Studies were identified using a literature search of MEDLINE, EMBASE, Web of Science, clinicaltrials.gov.uk, CINAHLS, and the Cochrane Register from inception to March 2022. Studies reviewed included observational studies and randomised control trials (RCTs). Data was extracted on baseline characteristics, deprescribing rates, adverse events and outcomes, and quality of life indicators, and was discussed using a narrative approach. Thirteen studies were identified for inclusion. Deprescribing approaches included complete withdrawal, dose reduction or tapering, or switching to an alternative medication, for at least one preventive medication. Deprescribing success rates ranged from 27 to 94.7%. The studies reported no significant changes in laboratory values or adverse outcomes but did find mixed outcomes for hospitalisations and a slight increase in mortality rates when comparing the intervention and control groups. Lack of good-quality randomised control trials suggests that deprescribing in the older population residing in long-term care facilities with cardiometabolic conditions and multimorbidity is feasible when controlled and regularly monitored by an appropriate healthcare clinician, and that the benefits outweigh the potential harm in this cohort of patients. Due to the limited evidence and the heterogeneity of studies, a meta-analysis was not performed and as such further research is required to assess the benefits of deprescribing in this patient population. Systematic review registration: PROSPERO CRD42021291061.

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)

Sexually dimorphic effects of methionine sulfoxide reductase A (MsrA) on murine longevity and health span during methionine restriction - Kevin M. Thyne; Adam B. Salmon (GeroScience, 2023)

Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension - Tomoya Shintani; Hideya Shintani; Masashi Sato; Hisashi Ashida (GeroScience, 2023)
Calorie restriction (CR) can prolong human lifespan, but enforcing long-term CR is difficult. Thus, a drug that reproduces the effects of CR without CR is required. More than 10 drugs have been listed as CR mimetics (CRM), and some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, whereas the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Intriguingly, recent reports have revealed the beneficial effects of CRMs on the body such as improving the host body condition via intestinal bacteria and their metabolites. This beneficial effect of gut microbiota may lead to lifespan extension. Thus, CRMs may have a dual effect on longevity. However, no reports have collectively discussed them as CRMs; hence, our knowledge about CRM and its physiological effects on the host remains fragmentary. This study is the first to present and collectively discuss the accumulative evidence of CRMs improving the gut environments for healthy lifespan extension, after enumerating the latest scientific findings related to the gut microbiome and CR. The conclusion drawn from this discussion is that CRM may partially extend the lifespan through its effect on the gut microbiota. CRMs increase beneficial bacteria abundance by decreasing harmful bacteria rather than increasing the diversity of the microbiome. Thus, the effect of CRMs on the gut could be different from that of conventional prebiotics and seemed similar to that of next-generation prebiotics.

Mapping cellular senescence networks in human diabetic foot ulcers - Grace T. Yu; Dileep D. Monie; Sundeep Khosla; Tamar Tchkonia; James L. Kirkland; Saranya P. Wyles (GeroScience, 2023)

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 Ferruci; Beate R. Ritz; Alexandra M. Binder; Steve Horvath (GeroScience, 2023)
Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations. We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort, the Baltimore Longitudinal Study of Aging, and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sex Hormone Binding Globulin (SHBG) was associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11). SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1. Graphical Abstract

Serum factors mediate changes in mitochondrial bioenergetics associated with diet and exercise interventions - Jenny L. Gonzalez-Armenta; Jaclyn Bergstrom; Jingyun Lee; Cristina M. Furdui; Barbara J. Nicklas; Anthony J. A. Molina (GeroScience, 2023)
Mitochondrial improvements resulting from behavioral interventions, such as diet and exercise, are systemic and apparent across multiple tissues. Here, we test the hypothesis that factors present in serum, and therefore circulating throughout the body, can mediate changes in mitochondrial function in response to intervention. To investigate this, we used stored serum from a clinical trial comparing resistance training (RT) and RT plus caloric restriction (RT + CR) to examine effects of blood borne circulating factors on myoblasts in vitro. We report that exposure to dilute serum is sufficient to mediate bioenergetic benefits of these interventions. Additionally, serum-mediated bioenergetic changes can differentiate between interventions, recapitulate sex differences in bioenergetic responses, and is linked to improvements in physical function and inflammation. Using metabolomics, we identified circulating factors associated with changes in mitochondrial bioenergetics and the effects of interventions. This study provides new evidence that circulating factors play a role in the beneficial effects of interventions that improve healthspan among older adults. Understanding the factors that drive improvements in mitochondrial function is a key step towards predicting intervention outcomes and developing strategies to countermand systemic age-related bioenergetic decline.

Early life thymectomy induces arterial dysfunction in mice - David J. Buckley; Sunita Sharma; Blessy Joseph; Alia H. Fayyaz; Alexandra Canizales; Konner J. Terrebonne; Daniel W. Trott (GeroScience, 2023)

Specific nasopharyngeal Corynebacterium strains serve as gatekeepers against SARS-CoV-2 infection - Dora Szabo; Eszter Ostorhazi; Balazs Stercz; Nora Makra; Kinga Penzes; Katalin Kristof; Istvan Antal; Janos M. Rethelyi; Reka I. Zsigmond; Ede Birtalan; Bela Merkely; Laszlo Tamas (GeroScience, 2023)
The SARS-CoV-2 virus is still causing a worldwide problem. The virus settles primarily on the nasal mucosa, and the infection and its course depend on individual susceptibility. Our aim was to investigate the nasopharynx composition’s role in the individual susceptibility. During the first phase of SARS-CoV-2 pandemic, nasopharyngeal microbiome samples of close contact unvaccinated patients were investigated by 16S rRNA analysis and by culturing. The whole genome of cultured Corynebacteria was sequenced. The relative expression of ACE2, TMPRSS2, and cathepsin L on Caco-2 cells and the strength of S1-ACE2 binding were determined in the presence of Corynebacteria . From 55 close contacts exposed to identical SARS-CoV-2 exposure, 26 patients became infected and 29 remained uninfected. The nasopharyngeal microbiome analysis showed significantly higher abundance of Corynebacteria in uninfected group. Corynebacterium accolens could be cultivated only from uninfected individuals and Corynebacterium propinquum from both infected and uninfected. Corynebacteria from uninfected patient significantly reduced the ACE2 and cathepsin L expression. C. accolens significantly reduced the TMPRSS2 expression compared to other Corynebacteria . Furthermore, Corynebacterium spp. weakened the binding of the S1-ACE2. Most C. accolens isolates harbored the TAG lipase LipS1 gene. Based on these results, the presence of Corynebacterium spp. in the nasopharyngeal microbiota, especially C. accolens strains, could reduce the individual susceptibility to SARS-CoV-2 infection by several mechanisms: by downregulation the ACE2, the TMPRSS2 receptors, and cathepsin L in the host; through the inhibition of S1-ACE2 binding; and lipase production. These results suggest the use of C. accolens strains as probiotics in the nasopharynx in the future.

Imaging the time course, morphology, neuronal tissue compression, and resolution of cerebral microhemorrhages in mice using intravital two-photon microscopy: insights into arteriolar, capillary, and venular origin - Janet Faakye; Ádám Nyúl-Tóth; Rafal Gulej; Boglarka Csik; Stefano Tarantini; Santny Shanmugarama; Calin Prodan; Peter Mukli; Andriy Yabluchanskiy; Shannon Conley; Peter Toth; Anna Csiszar; et al. (GeroScience, 2023)

Investigating the associations between upper limb motor function and cognitive impairment: a scoping review - Kaylee D. Rudd; Katherine Lawler; Michele L. Callisaya; Jane Alty (GeroScience, 2023)
Upper limb motor function is a potential new biomarker of cognitive impairment and may aid discrimination from healthy ageing. However, it remains unclear which assessments to use. This study aimed to explore what methods have been used and to describe associations between upper limb function and cognitive impairment. A scoping review was conducted using PubMed, CINAHL and Web of Science. A systematic search was undertaken, including synonyms for key concepts ‘upper limb’, ‘motor function’ and ‘cognitive impairment’. Selection criteria included tests of upper limb motor function and impaired cognition in adults. Analysis was by narrative synthesis. Sixty papers published between 1998 and 2022, comprising 41,800 participants, were included. The most common assessment tasks were finger tapping, Purdue Pegboard Test and functional tasks such as writing. Protocols were diverse in terms of equipment used and recording duration. Most participants were recruited from clinical settings. Alzheimer’s Disease was the most common cause of cognitive impairment. Results were mixed but, generally, slower speed, more errors, and greater variability in upper limb movement variables was associated with cognitive impairment. This review maps the upper limb motor function assessments used and summarises the available evidence on how these associate with cognitive impairment. It identifies research gaps and may help guide protocols for future research. There is potential for upper limb motor function to be used in assessments of cognitive impairment.

Greater myofibrillar protein synthesis following weight-bearing activity in obese old compared with non-obese old and young individuals - Paul T. Morgan; Benoit Smeuninx; Ryan N. Marshall; Marie Korzepa; Jonathan I. Quinlan; Jamie S. McPhee; Leigh Breen (GeroScience, 2023)
The mechanisms through which obesity impacts age-related muscle mass regulation are unclear. In the present study, rates of integrated myofibrillar protein synthesis (iMyoPS) were measured over 48-h prior-to and following a 45-min treadmill walk in 10 older-obese (O-OB, body fat[%]: 33 ± 3%), 10 older-non-obese (O-NO, 20 ± 3%), and 15 younger-non-obese (Y-NO, 13 ± 5%) individuals. Surface electromyography was used to determine thigh muscle “activation”. Quadriceps cross-sectional area (CSA), volume, and intramuscular thigh fat fraction (ITFF) were measured by magnetic resonance imaging. Quadriceps maximal voluntary contraction (MVC) was measured by dynamometry. Quadriceps CSA and volume were greater (muscle volume, Y-NO: 1182 ± 232 cm 3 ; O-NO: 869 ± 155 cm 3 ; O-OB: 881 ± 212 cm 3 , P < 0.01) and ITFF significantly lower ( m. vastus lateralis, Y-NO: 3.0 ± 1.0%; O-NO: 4.0 ± 0.9%; O-OB: 9.1 ± 2.6%, P ≤ 0.03) in Y-NO compared with O-NO and O-OB, with no difference between O-NO and O-OB in quadriceps CSA and volume. ITFF was significantly higher in O-OB compared with O-NO. Relative MVC was lower in O-OB compared with Y-NO and O-NO (Y-NO: 5.5 ± 1.6 n·m/kg −1 ; O-NO: 3.9 ± 1.0 n·m/kg −1 ; O-OB: 2.9 ± 1.1 n·m/kg −1 , P < 0.0001). Thigh muscle “activation” during the treadmill walk was greater in O-OB compared with Y-NO and O-NO (Y-NO: 30.5 ± 13.5%; O-NO: 35.8 ± 19.7%; O-OB: 68.3 ± 32.3%, P < 0.01). Habitual iMyoPS did not differ between groups, whereas iMyoPS was significantly elevated over 48-h post-walk in O-OB (+ 38.6 ± 1.2%·day −1 , P < 0.01) but not Y-NO or O-NO (+ 11.4 ± 1.1%·day −1 and + 17.1 ± 1.1%·day −1 , respectively, both P > 0.271). Equivalent muscle mass in O-OB may be explained by the muscle anabolic response to weight-bearing activity, whereas the age-related decline in indices of muscle quality appears to be exacerbated in O-OB and warrants further exploration.

Amyloid beta accumulation in TgF344-AD rats is associated with reduced cerebral capillary endothelial Kir2.1 expression and neurovascular uncoupling - Xing Fang; Jane J. Border; Patrice L. Rivers; Huawei Zhang; Jan Michael Williams; Fan Fan; Richard J. Roman (GeroScience, 2023)

Nonlinear changes in pupillary attentional orienting responses across the lifespan - Elizabeth Riley; Hamid Turker; Dongliang Wang; Khena M Swallow; Adam K Anderson; Eve De Rosa (GeroScience, 2023)
The cognitive aging process is not necessarily linear. Central task-evoked pupillary responses, representing a brainstem-pupil relationship, may vary across the lifespan. Thus we examined, in 75 adults ranging in age from 19 to 86, whether task-evoked pupillary responses to an attention task may serve in as an index of cognitive aging. This is because the locus coeruleus (LC), located in the brainstem, is not only among the earliest sites of degeneration in pathological aging, but also supports both attentional and pupillary behaviors. We assessed brief, task-evoked phasic attentional orienting to behaviorally relevant and irrelevant auditory tones, stimuli known specifically to recruit the LC in the brainstem and evoke pupillary responses. Due to potential nonlinear changes across the lifespan, we used a novel data-driven analysis on 6 dynamic pupillary behaviors on 10% of the data to reveal cut off points that best characterized the three age bands: young (19–41 years old), middle aged (42–68 years old), and older adults (69 + years old). Follow-up analyses on independent data, the remaining 90%, revealed age-related changes such as monotonic decreases in tonic pupillary diameter and dynamic range, along with curvilinear phasic pupillary responses to the behaviorally relevant target events, increasing in the middle-aged group and then decreasing in the older group. Additionally, the older group showed decreased differentiation of pupillary responses between target and distractor events. This pattern is consistent with potential compensatory LC activity in midlife that is diminished in old age, resulting in decreased adaptive gain. Beyond regulating responses to light, pupillary dynamics reveal a nonlinear capacity for neurally mediated gain across the lifespan, thus providing evidence in support of the LC adaptive gain hypothesis.

Mild exercise improves executive function with increasing neural efficiency in the prefrontal cortex of older adults - Kyeongho Byun; Kazuki Hyodo; Kazuya Suwabe; Takemune Fukuie; Min-seong Ha; Chorphaka Damrongthai; Ryuta Kuwamizu; Hikaru Koizumi; Michael A. Yassa; Hideaki Soya (GeroScience, 2023)
This study examined whether a 3-month mild-exercise intervention could improve executive function in healthy middle-aged and older adults in a randomized control trial. Ultimately, a total of 81 middle-aged and older adults were randomly assigned to either an exercise group or a control group. The exercise group received 3 months of mild cycle exercise intervention (3 sessions/week, 30–50 min/session). The control group was asked to behave as usual for the intervention period. Before and after the intervention, participants did color-word matching Stroop tasks (CWST), and Stroop interference (SI)-related reaction time (RT) was assessed as an indicator of executive function. During the CWST, prefrontal activation was monitored using functional near-infrared spectroscopy (fNIRS). SI-related oxy-Hb changes and SI-related neural efficiency (NE) scores were assessed to examine the underlying neural mechanism of the exercise intervention. Although the mild-exercise intervention significantly decreased SI-related RT, there were no significant effects of exercise intervention on SI-related oxy-Hb changes or SI-related NE scores in prefrontal subregions. Lastly, changes in the effects of mild exercise on NE with advancing age were examined. The 81 participants were divided into two subgroups (younger-aged subgroup [YA], older-aged subgroup [OA], based on median age [68 years.]). Interestingly, SI-related RT significantly decreased, and SI-related NE scores in all ROIs of the prefrontal cortex significantly increased only in the OA subgroup. These results reveal that a long-term intervention of very light-intensity exercise has a positive effect on executive function especially in older adults, possibly by increasing neural efficiency in the prefrontal cortex.

Deconstructing heterogeneity of replicative senescence in human mesenchymal stem cells at single cell resolution - Atefeh Taherian Fard; Hannah C. Leeson; Julio Aguado; Giovanni Pietrogrande; Dominique Power; Cecilia Gómez-Inclán; Huiwen Zheng; Christopher B. Nelson; Farhad Soheilmoghaddam; Nick Glass; Malindrie Dharmaratne; Ebony R. Watson; et al. (GeroScience, 2023)
Following prolonged cell division, mesenchymal stem cells enter replicative senescence, a state of permanent cell cycle arrest that constrains the use of this cell type in regenerative medicine applications and that in vivo substantially contributes to organismal ageing. Multiple cellular processes such as telomere dysfunction, DNA damage and oncogene activation are implicated in promoting replicative senescence, but whether mesenchymal stem cells enter different pre-senescent and senescent states has remained unclear. To address this knowledge gap, we subjected serially passaged human ESC-derived mesenchymal stem cells (esMSCs) to single cell profiling and single cell RNA-sequencing during their progressive entry into replicative senescence. We found that esMSC transitioned through newly identified pre-senescent cell states before entering into three different senescent cell states. By deconstructing this heterogeneity and temporally ordering these pre-senescent and senescent esMSC subpopulations into developmental trajectories, we identified markers and predicted drivers of these cell states. Regulatory networks that capture connections between genes at each timepoint demonstrated a loss of connectivity, and specific genes altered their gene expression distributions as cells entered senescence. Collectively, this data reconciles previous observations that identified different senescence programs within an individual cell type and should enable the design of novel senotherapeutic regimes that can overcome in vitro MSC expansion constraints or that can perhaps slow organismal ageing.

Prediction of cognitive performance differences in older age from multimodal neuroimaging data - Camilla Krämer; Johanna Stumme; Lucas da Costa Campos; Paulo Dellani; Christian Rubbert; Julian Caspers; Svenja Caspers; Christiane Jockwitz (GeroScience, 2023)
Differences in brain structure and functional and structural network architecture have been found to partly explain cognitive performance differences in older ages. Thus, they may serve as potential markers for these differences. Initial unimodal studies, however, have reported mixed prediction results of selective cognitive variables based on these brain features using machine learning (ML). Thus, the aim of the current study was to investigate the general validity of cognitive performance prediction from imaging data in healthy older adults. In particular, the focus was with examining whether (1) multimodal information, i.e., region-wise grey matter volume (GMV), resting-state functional connectivity (RSFC), and structural connectivity (SC) estimates, may improve predictability of cognitive targets, (2) predictability differences arise for global cognition and distinct cognitive profiles, and (3) results generalize across different ML approaches in 594 healthy older adults (age range: 55–85 years) from the 1000BRAINS study. Prediction potential was examined for each modality and all multimodal combinations, with and without confound (i.e., age, education, and sex) regression across different analytic options, i.e., variations in algorithms, feature sets, and multimodal approaches (i.e., concatenation vs. stacking). Results showed that prediction performance differed considerably between deconfounding strategies. In the absence of demographic confounder control, successful prediction of cognitive performance could be observed across analytic choices. Combination of different modalities tended to marginally improve predictability of cognitive performance compared to single modalities. Importantly, all previously described effects vanished in the strict confounder control condition. Despite a small trend for a multimodal benefit, developing a biomarker for cognitive aging remains challenging.

Age-related changes in energy metabolism in peripheral mononuclear blood cells (PBMCs) and the brains of cognitively healthy seniors - Carmina V. Silaidos; Martina Reutzel; Lena Wachter; Fabian Dieter; Nasir Ludin; Werner F. Blum; Stefan A. Wudy; Silke Matura; Ulrich Pilatus; Elke Hattingen; Johannes Pantel; Gunter P. Eckert (GeroScience, 2023)
Mitochondrial dysfunction is a hallmark of cellular senescence and many age-related neurodegenerative diseases. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cerebral energy metabolites in young and older sex-matched, physically and mentally healthy volunteers. Cross-sectional observational study involving 65 young (26.0 ± 0.49 years) and 65 older (71.7 ± 0.71 years) women and men recruited. Cognitive health was evaluated using established psychometric methods (MMSE, CERAD). Blood samples were collected and analyzed, and fresh peripheral blood mononuclear cells (PBMCs) were isolated. Mitochondrial respiratory complex activity was measured using a Clarke electrode. Adenosine triphosphate (ATP) and citrate synthase activity (CS) were determined by bioluminescence and photometrically. N-aspartyl-aspartate (tNAA), ATP, creatine (Cr), and phosphocreatine (PCr) were quantified in brains using 1 H- and 31 P-magnetic resonance spectroscopic imaging (MRSI). Levels of insulin-like growth factor 1 (IGF-1) were determined using a radio-immune assay (RIA). Complex IV activity (CIV) (− 15%) and ATP levels (− 11%) were reduced in PBMCs isolated from older participants. Serum levels of IGF-1 were significantly reduced (− 34%) in older participants. Genes involved in mitochondrial activity, antioxidant mechanisms, and autophagy were unaffected by age. tNAA levels were reduced (− 5%), Cr (+ 11%), and PCr (+ 14%) levels were increased, and ATP levels were unchanged in the brains of older participants. Markers of energy metabolism in blood cells did not significantly correlate with energy metabolites in the brain. Age-related bioenergetic changes were detected in peripheral blood cells and the brains of healthy older people. However, mitochondrial function in peripheral blood cells does not reflect energy related metabolites in the brain. While ATP levels in PBMCs may be be a valid marker for age-related mitochondrial dysfunction in humans, cerebral ATP remained constant.

Curcumin-rich curry consumption and life expectancy: Singapore longitudinal ageing study - Tze Pin Ng; Shwe Zin Nyunt; Qi Gao; Xinyi Gwee; Denise Qian Ling Chua; Keng Bee Yap (GeroScience, 2023)

Age-related decline of various cognitive functions in well-experienced male rats treated with the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP) - Aliz Judit Ernyey; Ferenc Kassai; Kata Kozma; Imola Plangár; Zsuzsa Somfai; Ildikó Miklya; István Gyertyán (GeroScience, 2023)
Aging-associated cognitive disorders lack proper medication. To meet this need translation-wise, modification of the animal models is also required. In the present study, effect of the putative anti-aging compound (2 R )-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP, a deprenyl derivative) on age-related cognitive decline was investigated in experienced, aged Long-Evans rats. During their lifetime, animals had acquired knowledge in various cognitive assays. Their performance in these tests was then parallel followed from the age of 27 months until their death meanwhile half of them were treated with BPAP. Cognitive performance in various tasks showed different sensitivities/resistances to age-related impairment. Pot jumping performance (motor skill-learning) started to impair first, at 21 months of age, followed by decreasing performance in five-choice serial reaction time task (attention) at 26 months. Navigation performance in Morris water maze (spatial learning) started to decline at 31 months. Performance in a cooperation task (social cognition) started to decline the latest, at 34 months. Our findings suggest that in this process, the primary factor was the level of motivation to be engaged with the task and not losing the acquired knowledge. The average lifespan of the tested rat population was 36 months. BPAP could not improve the cognitive performance; neither could it prolong lifespan. A possible reason might be that dietary restriction and lifelong cognitive engagement had beneficial effects on cognitive capabilities and lifespan creating a “ceiling effect” for further improvement. The results confirmed that experienced animals provide a translationally relevant model to study age-related cognitive decline and measure the effect of putative anti-aging compounds.

Sexual dimorphic metabolic and cognitive responses of C57BL/6 mice to Fisetin or Dasatinib and quercetin cocktail oral treatment - Yimin Fang; David Medina; Robert Stockwell; Sam McFadden; Kathleen Quinn; Mackenzie R. Peck; Andrzej Bartke; Kevin N. Hascup; Erin R. Hascup (GeroScience, 2023)
Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4–13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma, tissue specific markers of senescence-associated secretory phenotype (SASP), and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D + Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Graphical Abstract Male and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4–13 months of age. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. Females treated with D + Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. No effects were observed in females treated with Fisetin or males treated with D + Q.

Serum neurofilament light and white matter characteristics in the general population: a longitudinal analysis - Marco Hermesdorf; Niklas Wulms; Aleksandra Maceski; David Leppert; Pascal Benkert; Heinz Wiendl; Jens Kuhle; Klaus Berger (GeroScience, 2023)
Neurofilament light polypeptide (NfL) is a component of the neuronal cytoskeleton and particularly abundant in large-caliber axons. When axonal injury occurs, NfL is released and reaches the cerebrospinal fluid and the blood. Associations between NfL and white matter alterations have previously been observed in studies based on patients with neurological diseases. The current study aimed to explore the relationship between serum NfL (sNfL) and white matter characteristics in a population-based sample. The cross-sectional associations between sNfL as dependent variable, fractional anisotropy (FA), and white matter lesion (WML) volume were analyzed with linear regression models in 307 community-dwelling adults aged between 35 and 65 years. These analyses were repeated with additional adjustment for the potential confounders age, sex, and body mass index (BMI). Longitudinal associations over a mean follow-up of 5.39 years were analyzed with linear mixed models. The unadjusted cross-sectional models yielded significant associations between sNfL, WML volume, and FA, respectively. However, after the adjustment for confounders, these associations did not reach significance. In the longitudinal analyses, the findings corroborated the baseline findings showing no significant associations between sNfL and white matter macrostructure and microstructure beyond the effects of age. In synopsis with previous studies in patients with acute neurological diseases showing a significant association of sNfL with white matter changes beyond the effects of age, the present results based on a sample from the general population suggest the perspective that changes in sNfL reflect age-related effects that also manifest in altered white matter macrostructure and microstructure.

Periodontal disease as a model to study chronic inflammation in aging - Martinna Bertolini; Daniel Clark (GeroScience, 2023)

Electroencephalogram-based objective assessment of cognitive function level associated with age-related hearing loss - Ran Zhao; Tao Yue; Zihao Xu; Yunqi Zhang; Yubo Wu; Yanru Bai; Guangjian Ni; Dong Ming (GeroScience, 2023)

Coordinated transcriptional upregulation of oxidative metabolism proteins in long-lived endocrine mutant mice - Ahmed M. Elmansi; Richard A. Miller (GeroScience, 2023)

Physical activity intensity, frequency, duration, volume and the risk of possible sarcopenia in middle-aged and older adults - Xiaoguang Zhao; Hongjun Zhang; Jiabin Yu; Zhexiao Zhou; Jin Wang (GeroScience, 2023)

DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging - Joseph A. Zoller; Eleftheria Parasyraki; Ake T. Lu; Amin Haghani; Christof Niehrs; Steve Horvath (GeroScience, 2023)
To address how conserved DNA methylation-based epigenetic aging is in diverse branches of the tree of life, we generated DNA methylation data from African clawed frogs ( Xenopus laevis ) and Western clawed frogs ( Xenopus tropicalis ) and built multiple epigenetic clocks. Dual species clocks were developed that apply to both humans and frogs (human-clawed frog clocks), supporting that epigenetic aging processes are evolutionary conserved outside mammals. Highly conserved positively age-related CpGs are located in neural-developmental genes such as uncx , tfap2d as well as nr4a2 implicated in age-associated disease. We conclude that signatures of epigenetic aging are evolutionary conserved between frogs and mammals and that the associated genes relate to neural processes, altogether opening opportunities to employ Xenopus as a model organism to study aging.

Impact of influenza, herpes zoster, and pneumococcal vaccinations on the incidence of cardiovascular events in subjects aged over 65 years: a systematic review - Alexandra Addario; Thomas Célarier; Bienvenu Bongue; Nathalie Barth; Gaëtan Gavazzi; Elisabeth Botelho-Nevers (GeroScience, 2023)

Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design - Alistaire D. Ruggiero; Ravichandra Vemuri; Megan Blawas; Masha Long; Darla DeStephanis; Abigail G. Williams; Haiying Chen; Jamie N. Justice; Shannon L. Macauley; Steven M. Day; Kylie Kavanagh (GeroScience, 2023)

Safety outcomes of direct oral anticoagulants in older adults with atrial fibrillation: a systematic review and meta-analysis of (subgroup analyses from) randomized controlled trials - Katharina Doni; Stefanie Bühn; Alina Weise; Nina-Kristin Mann; Simone Hess; Andreas Sönnichsen; Susanna Salem; Dawid Pieper; Petra Thürmann; Tim Mathes (GeroScience, 2023)
Balancing stroke prevention and risk of bleeding in patients with atrial fibrillation (AF) is challenging. Direct oral anticoagulants (DOACs) are by now considered standard of care for treating patients with AF in international guidelines. Our objective was to assess the safety of long-term intake of DOACs in older adults with AF. We included RCTs in elderly (≥ 65 years) patients with AF. A systematic search in MEDLINE and EMBASE was performed on 19 April 2022. For determination of risk of bias, the RoB 2 tool was applied. We pooled outcomes using random-effects meta-analyses. The quality of evidence was assessed using GRADE. Eleven RCTs with a total of 63,374 patients were identified. Two RCTs compared apixaban with either warfarin or aspirin, four edoxaban with either placebo, aspirin, or vitamin K antagonists (VKAs), two dabigatran with warfarin and three rivaroxaban with warfarin. DOACs probably reduce mortality in elderly patients with AF (HR 0.89 95%CI 0.77 to 1.02). Low-dose DOACs likely reduce bleeding compared to VKAs (HR ranged from 0.47 to 1.01). For high-dose DOACS the risk of bleeding varied widely (HR ranged from 0.80 to 1.40). We found that low-dose DOACs probably decrease mortality in AF patients. Moreover, apixaban and probably edoxaban are associated with fewer major or clinically relevant bleeding (MCRB) events compared to VKAs. For dabigatran and rivaroxaban, the risk of MCRB varies depending on dose. Moreover, subgroup analyses indicate that in the very old (≥ 85) the risk for MCRB events might be increased when using DOACs. Registration: PROSPERO: CRD42020187876.

A metabolomic signature of decelerated physiological aging in human plasma - Georges E. Janssens; Lotte Grevendonk; Bauke V. Schomakers; Ruben Zapata Perez; Michel van Weeghel; Patrick Schrauwen; Joris Hoeks; Riekelt H. Houtkooper (GeroScience, 2023)
The degenerative processes that occur during aging increase the risk of disease and impaired health. Meanwhile, interventions that target aging to promote healthy longevity are gaining interest, both academically and in the public. While nutritional and physical interventions exist, efficacy is often difficult to determine. It is therefore imperative that an aging score measuring the biological aging process is available to the wider public. However, simple, interpret, and accessible biological aging scores are lacking. Here, we developed PhysiAge, a physiological aging score based on five accessible parameters that have influence on or reflect the aging process: (1) average daily step count, (2) blood glucose, (3) systolic blood pressure, (4) sex, and (5) age. Here, we found that compared to calendar age alone, PhysiAge better predicts mortality, as well as established muscle aging markers such as decrease in NAD + levels, increase in oxidative stress, and decline in physical functioning. In order to demonstrate the usefulness of PhysiAge in identifying relevant factors associated with decelerated aging, we calculated PhysiAges for a cohort of aged individuals and obtained mass spectrometry-based blood plasma metabolomic profiles for each individual. Here, we identified a metabolic signature of decelerated aging, which included components of the TCA cycle, including malate, citrate, and isocitrate. Higher abundance of these metabolites was associated with decelerated aging, in line with supplementation studies in model organisms. PhysiAge represents an accessible way for people to track and intervene in their aging trajectories, and identifies a metabolic signature of decelerated aging in human blood plasma, which can be further studied for its causal involvement in human aging.

Correction to: Altered T cell infiltration and enrichment of leukocyte regulating pathways within aged skeletal muscle are associated with impaired muscle function following influenza infection - Spencer R. Keilich; Andreia N. Cadar; Darcy T. Ahern; Blake L. Torrance; Erica C. Lorenzo; Dominique E. Martin; Laura Haynes; Jenna M. Bartley (GeroScience, 2023)

Correction to: Capturing postural blood pressure dynamics with near‑infrared spectroscopy‑measured cerebral oxygenation - Marjolein Klop; Rianne A. A. de Heus; Andrea B. Maier; Anne van Alphen; Marianne J. Floor‑Westerdijk; Mathijs Bronkhorst; René J. F. Melis; Carel G. M. Meskers; Jurgen A. H. R. Claassen; Richard J. A. van Wezel (GeroScience, 2023)

Spousal multimorbidity and depressive symptoms among older Indian couples: Do one’s own health status and sex matter? - Soohyeon Ko; Sungchul Park; Jinho Kim; S. V. Subramanian; Rockli Kim (GeroScience, 2023)

“Impact of aging on maximal oxygen uptake adjusted for lower limb lean mass, total body mass, and absolute values in runners” - Aldo Seffrin; Lavínia Vivan; Vinícius Ribeiro dos Anjos Souza; Ronaldo Alves da Cunha; Claudio Andre Barbosa de Lira; Rodrigo Luiz Vancini; Katja Weiss; Beat Knechtle; Marilia Santos Andrade (GeroScience, 2023)
Performance in endurance sports decreases with aging, which has been primarily attributed to cardiovascular and musculoskeletal aging; however, there is still no clear information on the factors that are most affected by aging. The aim of this study was to compare two groups of runners (< 50 and > 50 years of age) according to their absolute, weight-adjusted maximal oxygen uptake (V̇O 2 max ), lower limb lean mass-adjusted V̇O 2 max , ventilatory threshold, and respiratory compensation point (RCP). A total of 78 male recreational long-distance runners were divided into Group 1 (38.12 ± 6.87 years) and Group 2 (57.55 ± 6.14 years). Participants were evaluated for body composition, V̇O 2 max , VT, and RCP. Group 1 showed higher absolute and body mass-adjusted V̇O 2 max (4.60 ± 0.57 l·min −1 and 61.95 ± 8.25 ml·kg −1 ·min −1 , respectively) than Group 2 (3.77 ± 0.56 l·min −1 and 51.50 ± 10.22 ml·kg −1 ·min −1 , respectively), indicating a significant difference ( p < 0.001, d = − 1.46 and p < 0.001, d = − 1.16). Correspondingly, Group 1 showed a significantly higher lower limb lean mass–adjusted V̇O 2 max (251.72 ± 29.60 ml·kgLM −1 ·min −1 ) than Group 2 (226.36 ± 43.94 ml·kgLM −1 ·min −1 ) ( p = 0.008, d = − 0.71). VT (%V̇O 2 max ) ( p = 0.19, d = 0.19) and RCP (%V̇O 2 max ) ( p = 0.24, d = 0.22) did not differ between the groups. These findings suggest that both variables that are limited by central or peripheral conditions are negatively affected by aging, but the magnitude of the effect is higher in variables limited by central conditions. These results contribute to our understanding of how aging affects master runners.

Coronary and carotid artery dysfunction and KV7 overexpression in a mouse model of Hutchinson-Gilford progeria syndrome - Álvaro Macías; Rosa M. Nevado; Cristina González-Gómez; Pilar Gonzalo; María Jesús Andrés-Manzano; Beatriz Dorado; Ignacio Benedicto; Vicente Andrés (GeroScience, 2023)
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease caused by expression of progerin, a lamin A variant that is also expressed at low levels in non-HGPS individuals. Although HGPS patients die predominantly from myocardial infarction and stroke, the mechanisms that provoke pathological alterations in the coronary and cerebral arteries in HGPS remain ill defined. Here, we assessed vascular function in the coronary arteries (CorAs) and carotid arteries (CarAs) of progerin-expressing Lmna G609G/G609G mice (G609G), both in resting conditions and after hypoxic stimulus. Wire myography, pharmacological screening, and gene expression studies demonstrated vascular atony and stenosis, as well as other functional alterations in progeroid CorAs and CarAs and aorta. These defects were associated with loss of vascular smooth muscle cells and overexpression of the K V 7 family of voltage-dependent potassium channels. Compared with wild-type controls, G609G mice showed reduced median survival upon chronic isoproterenol exposure, a baseline state of chronic cardiac hypoxia characterized by overexpression of hypoxia-inducible factor 1α and 3α genes, and increased cardiac vascularization. Our results shed light on the mechanisms underlying progerin-induced coronary and carotid artery disease and identify K V 7 channels as a candidate target for the treatment of HGPS.

Low circulating adropin concentrations predict increased risk of cognitive decline in community-dwelling older adults - Geetika Aggarwal; John E. Morley; Bruno Vellas; Andrew D. Nguyen; Andrew A. Butler; Sophie Guyonnet; Isabelle Carrié; Lauréane Brigitte; Catherine Faisant; Françoise Lala; Julien Delrieu; Hélène Villars; et al. (GeroScience, 2023)
The secreted peptide adropin is highly expressed in human brain tissues and correlates with RNA and proteomic risk indicators for dementia. Here we report that plasma adropin concentrations predict risk for cognitive decline in the Multidomain Alzheimer Preventive Trial (ClinicalTrials.gov Identifier, NCT00672685; mean age 75.8y, SD = 4.5 years, 60.2% female, n = 452). Cognitive ability was evaluated using a composite cognitive score (CCS) that assessed four domains: memory, language, executive function, and orientation. Relationships between plasma adropin concentrations and changes in CCS (∆CCS) were examined using Cox Proportional Hazards Regression, or by grouping into tertiles ranked low to high by adropin values and controlling for age, time between baseline and final visits, baseline CCS, and other risk factors (e.g., education, medication, APOE4 status). Risk of cognitive decline (defined as a ∆CCS of − 0.3 or more) decreased with increasing plasma adropin concentrations (hazard ratio = 0.873, 95% CI 0.780–0.977, P = 0.018). Between adropin tertiles, ∆CCS was significantly different ( P = 0.01; estimated marginal mean ± SE for the 1st to 3rd tertile, − 0.317 ± 0.064; − 0.275 ± 0.063; − 0.042 ± 0.071; n = 133,146, and 130, respectively; P < 0.05 for 1st vs. 2nd and 3rd adropin tertiles). Normalized plasma Aß 42/40 ratio and plasma neurofilament light chain, indicators of neurodegeneration, were significantly different between adropin tertile. These differences were consistent with reduced risk of cognitive decline with higher plasma adropin levels. Overall, these results suggest cognitive decline is reduced in community-dwelling older adults with higher circulating adropin levels. Further studies are needed to determine the underlying causes of the relationship and whether increasing adropin levels can delay cognitive decline.

Are statins making older persons weaker? A discontinuation study of muscular side effects - Morten Bruun Korsholm; Thea Winther Pødenphanth; Sofie Kirstine Strømgaard; Linda Wiuff Petersen; Christina Alexandersen; Sarah Samama Hoffmann; Hanne K. Rasmusen; Charlotte Suetta; Kirsten Damgaard; Eckart Pressel; Flemming Dela (GeroScience, 2023)
Thirteen percent of the Danish population are treated with a statin—half of these are in primary prevention, and most are > 65 years old. Statins have known muscular side effects (i.e., myalgia) correlated to reduced muscle performance. This study examines if years of statin treatment in older people introduce subclinical muscle discomfort and loss of muscle mass and strength. In total, 98 participants (71.1 ± 3.6 years (mean ± SD)), who were in primary prevention treatment for elevated plasma cholesterol with a statin, were included in this study. Statin treatment was discontinued for 2 months and then re-introduced for 2 months. Primary outcomes included muscle performance and myalgia. Secondary outcomes included lean mass and plasma cholesterol. Functional muscle capacity measured as a 6-min walk test increased after discontinuation (from 542 ± 88 to 555 ± 91 m, P < 0.05) and remained increased after re-introduction (557 ± 94 m). Similar significant results were found with a chair stand test (15.7 ± 4.3 to 16.3 ± 4.9 repetitions/30 s) and a quadriceps muscle test. Muscle discomfort during rest did not change significantly with discontinuation (visual analog scale from 0.9 ± 1.7 to 0.6 ± 1.4) but increased ( P < 0.05) with the re-introduction (to 1.2 ± 2.0) and muscle discomfort during activity decreased ( P < 0.05) with discontinuation (from 2.5 ± 2.6 to 1.9 ± 2.3). After 2 weeks of discontinuation, low-density lipoprotein cholesterol increased from 2.2 ± 0.5 to 3.9 ± 0.8 mM and remained elevated until the re-introduction of statins ( P < 0.05). Significant and lasting improvements in muscle performance and myalgia were found at the discontinuation and re-introduction of statins. The results indicate a possible statin-related loss of muscle performance in older persons that needs further examination.

Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol - Elena Sandalova; Jorming Goh; Zi Xiang Lim; Zhi Meng Lim; Diogo Barardo; Rajkumar Dorajoo; Brian K. Kennedy; Andrea B. Maier (GeroScience, 2023)
Targeting molecular processes of aging will enable people to live healthier and longer lives by preventing age-related diseases. Geroprotectors are compounds with the potential to increase healthspan and lifespan. Even though many of them have been tested in animal models, the translation to humans is limited. Alpha-Ketoglutarate (AKG) has been studied widely in model animals, but there are few studies testing its geroprotective properties in humans. ABLE is a double blinded placebo-controlled randomized trial (RCT) of 1 g sustained release Ca-AKG versus placebo for 6 months of intervention and 3 months follow up including 120 40–60-year-old healthy individuals with a higher DNA methylation age compared to their chronological age. The primary outcome is the decrease in DNA methylation age from baseline to the end of the intervention. A total of 120 participants will be randomized to receive either sustained release Ca-AKG or placebo. Secondary outcomes include changes in the inflammatory and metabolic parameters in blood, handgrip strength and leg extension strength, arterial stiffness, skin autofluorescence, and aerobic capacity from baseline to 3 months, 6 months, and 9 months. This study will recruit middle-aged participants with an older DNA methylation age compared to their chronological age, and test whether supplementation with Ca-AKG can reduce DNA methylation age. This study is unique in its inclusion of biologically older participants.

Cystine rather than cysteine is the preferred substrate for β-elimination by cystathionine γ-lyase: implications for dietary methionine restriction - Thomas M. Jeitner; Juan A. Azcona; Gene P. Ables; Diana Cooke; Mark C. Horowitz; Pradeep Singh; James M. Kelly; Arthur J. L. Cooper (GeroScience, 2023)
Dietary methionine restriction (MR) increases longevity by improving health. In experimental models, MR is accompanied by decreased cystathionine β-synthase activity and increased cystathionine γ-lyase activity. These enzymes are parts of the transsulfuration pathway which produces cysteine and 2-oxobutanoate. Thus, the decrease in cystathionine β-synthase activity is likely to account for the loss of tissue cysteine observed in MR animals. Despite this decrease in cysteine levels, these tissues exhibit increased H 2 S production which is thought to be generated by β-elimination of the thiol moiety of cysteine, as catalyzed by cystathionine β-synthase or cystathionine γ-lyase. Another possibility for this H 2 S production is the cystathionine γ-lyase-catalyzed β-elimination of cysteine persulfide from cystine, which upon reduction yields H 2 S and cysteine. Here, we demonstrate that MR increases cystathionine γ-lyase production and activities in the liver and kidneys, and that cystine is a superior substrate for cystathionine γ-lyase catalyzed β-elimination as compared to cysteine. Moreover, cystine and cystathionine exhibit comparable K cat / K m values (6000 M −1 s −1 ) as substrates for cystathionine γ-lyase-catalyzed β-elimination. By contrast, cysteine inhibits cystathionine γ-lyase in a non-competitive manner ( K i ~ 0.5 mM), which limits its ability to function as a substrate for β-elimination by this enzyme. Cysteine inhibits the enzyme by reacting with its pyridoxal 5′-phosphate cofactor to form a thiazolidine and in so doing prevents further catalysis. These enzymological observations are consistent with the notion that during MR cystathionine γ-lyase is repurposed to catabolize cystine and thereby form cysteine persulfide, which upon reduction produces cysteine.

Executive function mediates age-related variation in social integration in female vervet monkeys (Chlorocebus sabaeus) - Jacob D. Negrey; Brett M. Frye; Suzanne Craft; Thomas C. Register; Mark G. Baxter; Matthew J. Jorgensen; Carol A. Shively (GeroScience, 2023)

Unique trans-kingdom microbiome structural and functional signatures predict cognitive decline in older adults - Diptaraj S. Chaudhari; Shalini Jain; Vinod K. Yata; Sidharth P. Mishra; Ambuj Kumar; Amoy Fraser; Judyta Kociolek; Mariana Dangiolo; Amanda Smith; Adam Golden; Michal M. Masternak; Peter Holland; et al. (GeroScience, 2023)
The prevalence of age-related cognitive disorders/dementia is increasing, and effective prevention and treatment interventions are lacking due to an incomplete understanding of aging neuropathophysiology. Emerging evidence suggests that abnormalities in gut microbiome are linked with age-related cognitive decline and getting acceptance as one of the pillars of the Geroscience hypothesis. However, the potential clinical importance of gut microbiome abnormalities in predicting the risk of cognitive decline in older adults is unclear. Till now the majority of clinical studies were done using 16S rRNA sequencing which only accounts for analyzing bacterial abundance, while lacking an understanding of other crucial microbial kingdoms, such as viruses, fungi, archaea, and the functional profiling of the microbiome community. Utilizing data and samples of older adults with mild cognitive impairment (MCI; n = 23) and cognitively healthy controls ( n = 25). Our whole-genome metagenomic sequencing revealed that the gut of older adults with MCI harbors a less diverse microbiome with a specific increase in total viruses and a decrease in bacterial abundance compared with controls. The virome, bacteriome, and microbial metabolic signatures were significantly distinct in subjects with MCI versus controls. Selected bacteriome signatures show high predictive potential of cognitive dysfunction than virome signatures while combining virome and metabolic signatures with bacteriome boosts the prediction power. Altogether, the results from our pilot study indicate that trans-kingdom microbiome signatures are significantly distinct in MCI gut compared with controls and may have utility for predicting the risk of developing cognitive decline and dementia- debilitating public health problems in older adults.

DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation - Matyas Jokai; Ferenc Torma; Kristen M. McGreevy; Erika Koltai; Zoltan Bori; Gergely Babszki; Peter Bakonyi; Zoltan Gombos; Bernadett Gyorgy; Dora Aczel; Laszlo Toth; Peter Osvath; et al. (GeroScience, 2023)
DNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm)-based biomarkers that reflect the individual aging process. Here, we examine the relationship between physical fitness and DNAm-based biomarkers in adults aged 33–88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO 2 max ( ρ = 0.2, p = 6.4E − 4, r = 0.19, p = 1.2E − 3), Jumpmax ( p = 0.11, p = 5.5E − 2, r = 0.13, p = 2.8E − 2), Gripmax ( ρ = 0.17, p = 3.5E − 3, r = 0.16, p = 5.6E − 3), and HDL levels ( ρ = 0.18, p = 1.95E − 3, r = 0.19, p = 1.1E − 3) are associated with better verbal short-term memory. In addition, verbal short-term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration ( ρ : − 0.18, p = 0.0017). DNAmFitAge can distinguish high-fitness individuals from low/medium-fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high-fit males and females (1.5 and 2.0 years younger, respectively). Our research shows that regular physical exercise contributes to observable physiological and methylation differences which are beneficial to the aging process. DNAmFitAge has now emerged as a new biological marker of quality of life.

Associations between PBMC whole genome transcriptome, muscle strength, muscle mass, and physical performance in healthy home-dwelling older women - Ana R. S. de Sousa; Inger Ottestad; Gyrd O. Gjevestad; Kirsten B. Holven; Stine M. Ulven; Jacob J. Christensen (GeroScience, 2023)
Increasing age is accompanied by many changes, including declining functional skeletal muscle health and immune dysfunction. Peripheral blood mononuclear cells (PBMCs) are circulating cells that assemble an immune response, but their whole genome transcriptome has not been studied in the context of age-related muscle health. Consequently, this article explored associations between three muscle variables indicative of functional muscle health — maximum handgrip strength (muscle strength), appendicular skeletal muscle mass index (ASMI, muscle mass), and gait speed (physical performance) — and two groups of bioinformatics-generated PBMC gene expression features (gene expression–estimated leukocyte subset proportions and gene clusters). We analyzed cross-sectional data from 95 home-dwelling healthy women ≥ 70 years, using “cell-type identification by estimating relative subsets of RNA transcripts” (CIBERSORT) to estimate leukocyte subset proportions and “weighted correlation network analysis” (WGCNA) to generate gene clusters. Associations were studied using linear regression models and relevant gene clusters were subjected to gene set enrichment analysis using gene ontology. Gait speed and ASMI associated with CIBERSORT-estimated monocyte proportions ( β = − 0.090, 95% CI = (− 0.146, − 0.034), p -value = 0.002 for gait speed, and β = − 0.206, 95% CI = (− 0.385, − 0.028), p -value = 0.024 for ASMI), and gait speed associated with CIBERSORT-estimated M2 macrophage proportions ( β = − 0.026, 95% CI = (− 0.043, − 0.008), p -value = 0.004). Furthermore, maximum handgrip strength associated with nine WGCNA gene clusters, enriched in processes related to immune function and skeletal muscle cells ( β in the range − 0.007 to 0.008, p -values < 0.05). These results illustrate interactions between skeletal muscle and the immune system, supporting the notion that age-related functional muscle health and the immune system are closely linked.

Remote monitoring technologies for measuring cardiovascular functions in community-dwelling adults: a systematic review - Jessica K. Lu; Marcella Sijm; Georges E. Janssens; Jorming Goh; Andrea B. Maier (GeroScience, 2023)
Remote monitoring technologies (RMTs) allow continuous, unobtrusive, and real-time monitoring of the cardiovascular system. An overview of existing RMTs measuring cardiovascular physiological variables is lacking. This systematic review aimed to describe RMTs measuring cardiovascular functions in community-dwelling adults. An electronic search was conducted via PubMed, EMBASE, and Cochrane Library from January 1, 2020, to April 7, 2022. Articles reporting on non-invasive RMTs used unsupervised in community-dwelling adults were included. Reviews and studies in institutionalized populations were excluded. Two reviewers independently assessed the studies and extracted the technologies used, cardiovascular variables measured, and wearing locations of RMTs. Validation of the RMTs was examined based on the COSMIN tool, and accuracy and precision were presented. This systematic review was registered with PROSPERO (CRD42022320082). A total of 272 articles were included representing 322,886 individuals with a mean or median age from 19.0 to 88.9 years (48.7% female). Of all 335 reported RMTs containing 216 distinct devices, photoplethysmography was used in 50.3% of RMTs. Heart rate was measured in 47.0% of measurements, and the RMT was worn on the wrist in 41.8% of devices. Nine devices were reported in more than three articles, of which all were sufficiently accurate, six were sufficiently precise, and four were commercially available in December 2022. The top four most reported technologies were AliveCor KardiaMobile®, Fitbit Charge 2, and Polar H7 and H10 Heart Rate Sensors. With over 200 distinct RMTs reported, this review provides healthcare professionals and researchers an overview of available RMTs for monitoring the cardiovascular system.

Targeted metabolomics reveals plasma biomarkers and metabolic alterations of the aging process in healthy young and older adults - Paniz Jasbi; Janko Nikolich-Žugich; Jeffrey Patterson; Kenneth S. Knox; Yan Jin; George M. Weinstock; Patricia Smith; Homer L. Twigg; Haiwei Gu (GeroScience, 2023)

Evaluation of off-label rapamycin use to promote healthspan in 333 adults - Tammi L. Kaeberlein; Alan S. Green; George Haddad; Johnny Hudson; Anar Isman; Andy Nyquist; Bradley S. Rosen; Yousin Suh; Sajad Zalzala; Xingyu Zhang; Mikhail V. Blagosklonny; Jonathan Y. An; et al. (GeroScience, 2023)

Resilience, aging, and response to radiation exposure (RARRE) in nonhuman primates: a resource review - George W. Schaaf; Jamie N. Justice; Ellen E. Quillen; J. Mark Cline (GeroScience, 2023)

Exploring the possible causal effects of cardiac blood biomarkers in dementia and cognitive performance: a Mendelian randomization study - Michelle H. Zonneveld; Stella Trompet; J. Wouter Jukema; Raymond Noordam (GeroScience, 2023)
Prospective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring possible causality. We aimed to assess the causal associations of these cardiac blood biomarkers with dementia and cognition using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e −7 ) for troponin T and I, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth-differentiation factor 15 (GDF15) were obtained from previously-performed genome-wide association studies of predominantly European ancestry. Summary statistics for gene-outcome associations in European-ancestry participants, for the two-sample MR analyses, were obtained for general cognitive performance ( n = 257,842) and dementia ( n = 111,326 clinically diagnosed and “proxy” AD cases, and 677,663 controls). Two-sample MR analyses were performed using inverse variance-weighted (IWV) analyses. Sensitivity analyses to evaluate horizontal pleiotropy included weighted median estimator, MR-Egger, and MR using cis-SNPs only. Using IVW, we did not find evidence for possible causal associations between genetically influenced cardiac biomarkers with cognition and dementia. For example, per standard deviation (SD) higher cardiac blood biomarker, the odds ratio for risk of dementia was 1.06 (95%CI 0.90; 1.21) for troponin T, 0.98 (95%CI 0.72; 1.23) for troponin I, 0.97 (95%CI 0.90; 1.06) for NT-proBNP and 1.07 (95%CI 0.93; 1.21) for GDF15. Sensitivity analyses showed higher GDF15 was significantly associated with higher dementia risk and worse cognitive function. We did not find strong evidence that cardiac biomarkers causally influence dementia risk. Future research should aim at elucidating the biological pathways through which cardiac blood biomarkers associate with dementia.

Lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of prostate carcinogenesis - Elisabete Nascimento-Gonçalves; Fernanda Seixas; Carlos Palmeira; Gabriela Martins; Carolina Fonseca; José Alberto Duarte; Ana I. Faustino-Rocha; Bruno Colaço; Maria João Pires; Maria João Neuparth; Daniel Moreira-Gonçalves; Margarida Fardilha; et al. (GeroScience, 2023)
This work aimed to understand how lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of PCa. Fifty-five male Wistar rats were divided into four groups: control sedentary, control exercised, induced PCa sedentary and induced PCa exercised. Exercised animals were trained in a treadmill for 53 weeks. Pca induction consisted on the sequential administration of flutamide, N-methyl-N-nitrosourea and testosterone propionate implants. Serum concentrations of C-reactive protein (CRP) and tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) were not different among groups. Peripheral levels of γδ T cells were higher in Pca exercised group than in the PCa sedentary group ( p < 0.05). Exercise training also induced Oestrogen Receptor (ESR1) upregulation and Mitogen-activated Protein Kinase 13 (MAPK13) downregulation, changed the content of the phosphorylated (at Ser-104) form of this receptor (coded by the gene ESR1) and seemed to increase Erα phosphorylation and activity in exercised PCa rats when compared with sedentary PCa rats. Our data highlight the exercise-induced remodelling of peripheral lymphocyte subpopulations and lymphocyte infiltration in prostate tissue. Moreover, exercise training promotes the remodelling prostate signalome in this rat model of prostate carcinogenesis.

Neurophysiological markers of successful learning in healthy aging - Dawid Strzelczyk; Simon P. Kelly; Nicolas Langer (GeroScience, 2023)
The capacity to learn and memorize is a key determinant for the quality of life but is known to decline to varying degrees with age. However, neural correlates of memory formation and the critical features that determine the extent to which aging affects learning are still not well understood. By employing a visual sequence learning task, we were able to track the behavioral and neurophysiological markers of gradual learning over several repetitions, which is not possible in traditional approaches that utilize a remember vs. forgotten comparison. On a neurophysiological level, we focused on two learning-related centro-parietal event-related potential (ERP) components: the expectancy-driven P300 and memory-related broader positivity (BP). Our results revealed that although both age groups showed significant learning progress, young individuals learned faster and remembered more stimuli than older participants. Successful learning was directly linked to a decrease of P300 and BP amplitudes. However, young participants showed larger P300 amplitudes with a sharper decrease during the learning, even after correcting for an observed age-related longer P300 latency and increased P300 peak variability. Additionally, the P300 amplitude predicted learning success in both age groups and showed good test–retest reliability. On the other hand, the memory formation processes, reflected by the BP amplitude, revealed a similar level of engagement in both age groups. However, this engagement did not translate into the same learning progress in the older participants. We suggest that the slower and more variable timing of the stimulus identification process reflected in the P300 means that despite the older participants engaging the memory formation process, there is less time for it to translate the categorical stimulus location information into a solidified memory trace. The results highlight the important role of the P300 and BP as a neurophysiological marker of learning and may enable the development of preventive measures for cognitive decline.

Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice - Gozde Yildirim; Edmara T. P. Bergamo; Sher Bahadur Poudel; Ryan R. Ruff; Manisha Dixit; Bin Hu; Dindo Q. Mijares; Lukasz Witek; Carolyn Chlebek; David E. Harrison; Randy Strong; Richard A. Miller; et al. (GeroScience, 2023)

Combining exercise with cognitive training and vitamin D3 to improve functional brain connectivity (FBC) in older adults with mild cognitive impairment (MCI). Results from the SYNERGIC trial - Nick W. Bray; Frederico Pieruccini-Faria; Suzanne T. Witt; Robert Bartha; Timothy J. Doherty; Lindsay S. Nagamatsu; Quincy J. Almeida; Teresa Liu-Ambrose; Laura E. Middleton; Louis Bherer; Manuel Montero-Odasso (GeroScience, 2023)

Exposure factors associated with dementia among older adults in Iceland: the AGES-Reykjavik study - Vaka Valsdóttir; Brynja Björk Magnúsdóttir; Haukur Freyr Gylfason; Milan Chang; Thor Aspelund; Vilmundur Gudnason; Lenore J. Launer; María K. Jónsdóttir (GeroScience, 2023)

Devo-Aging: Intersections Between Development and Aging - Carlos Giovanni Silva-García (GeroScience, 2023)
There are two fundamental questions in developmental biology. How does a single fertilized cell give rise to a whole body? and how does this body later produce progeny? Synchronization of these embryonic and postembryonic developments ensures continuity of life from one generation to the next. An enormous amount of work has been done to unravel the molecular mechanisms behind these processes, but more recently, modern developmental biology has been expanded to study development in wider contexts, including regeneration, environment, disease, and even aging. However, we have just started to understand how the mechanisms that govern development also regulate aging. This review discusses examples of signaling pathways involved in development to elucidate how their regulation influences healthspan and lifespan. Therefore, a better knowledge of developmental signaling pathways stresses the possibility of using them as innovative biomarkers and targets for aging and age-related diseases.

Unraveling effects of anti-aging drugs on C. elegans using liposomes - Aihan Zhang; Kuei Ching Hsiung; Carina C. Kern; Yuting Wang; Anna L. Girtle; Nuo Xu; David Gems (GeroScience, 2023)
Liposome-mediated delivery is a possible means to overcome several shortcomings with C. elegans as a model for identifying and testing drugs that retard aging. These include confounding interactions between drugs and the nematodes’ bacterial food source and failure of drugs to be taken up into nematode tissues. To explore this, we have tested liposome-mediated delivery of a range of fluorescent dyes and drugs in C. elegans . Liposome encapsulation led to enhanced effects on lifespan, requiring smaller quantities of compounds, and enhanced uptake of several dyes into the gut lumen. However, one dye (Texas red) did not cross into nematode tissues, showing that liposomes cannot ensure the uptake of all compounds. Of six compounds previously reported to extend lifespan (vitamin C, N -acetylcysteine, glutathione (GSH), trimethadione, thioflavin T (ThT), and rapamycin), this effect was reproduced for the latter four in a condition-dependent manner. For GSH and ThT, antibiotics abrogated life extension, implying a bacterially mediated effect. With GSH, this was attributable to reduced early death from pharyngeal infection and associated with alterations of mitochondrial morphology in a manner suggesting a possible innate immune training effect. By contrast, ThT itself exhibited antibiotic effects. For rapamycin, significant increases in lifespan were only seen when bacterial proliferation was prevented. These results document the utility and limitations of liposome-mediated drug delivery for C. elegans . They also illustrate how nematode-bacteria interactions can determine the effects of compounds on C. elegans lifespan in a variety of ways.

Skeletal and cardiac muscle have different protein turnover responses in a model of right heart failure - Danielle R. Bruns; Benjamin D. McNair; Frederick F. Peelor; Agnieszka K. Borowik; Atul Pranay; Aykhan Yusifov; Benjamin F. Miller (GeroScience, 2023)

Moderate protein intake percentage in mice for maintaining metabolic health during approach to old age - Yoshitaka Kondo; Hitoshi Aoki; Masato Masuda; Hiroki Nishi; Yoshihiro Noda; Fumihiko Hakuno; Shin-Ichiro Takahashi; Takuya Chiba; Akihito Ishigami (GeroScience, 2023)
Nutritional requirements for maintaining metabolic health may vary with each life stage, such as young, middle, and old age. To investigate the appropriate ratio of nutrients, particularly proteins, for maintaining metabolic health while approaching old age, young (6-month-old) and middle-aged (16-month-old) mice were fed isocaloric diets with varying protein percentages (5%, 15%, 25%, 35%, and 45% by calorie ratio) for two months. The low-protein diet developed mild fatty liver, with middle-aged mice showing more lipids than young mice, whereas the moderate-protein diet suppressed lipid contents and lowered the levels of blood glucose and lipids. Self-organizing map (SOM) analysis revealed that plasma amino acid profiles differed depending on age and difference in protein diet and were associated with hepatic triglyceride and cholesterol levels. Results indicate that the moderate protein intake percentages (25% and 35%) are required for maintaining metabolic health in middle-aged mice, which is similar to that in young mice.

The interplay between circulating high-density lipoprotein, age and fracture risk: a new cohort study and systematic meta-analysis - Setor K. Kunutsor; Jari A. Laukkanen (GeroScience, 2023)
Previous findings on the association between high-density lipoprotein cholesterol (HDL-C) and fracture have yielded inconsistent results and it is unclear if the association varies with age and sex. We sought to evaluate the prospective association between HDL-C levels and fracture risk and assess if the association is modified by age and sex. Circulating HDL-C levels were measured at baseline in a population-based sample of 2,448 men aged 42–61 years. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs. Incident fractures ( n = 134) occurred during a median follow-up of 25.7 years. In analysis adjusted for several risk factors, the HR (95% CI) for fractures was 1.00 (0.85–1.20) per 1 standard deviation (SD) increase in HDL-C levels . Comparing the extreme tertiles of HDL-C levels, the corresponding adjusted HR (95% CI) was 0.94 (0.62–1.45). In a meta-analysis of eight cohort studies (including the current study) comprising 74,378 participants and 4,621 fracture cases, the fully-adjusted risk estimate (95% CI) for fracture was 1.03 (0.96–1.10) per 1SD increase in HDL-C levels and 1.05 (0.92–1.20) comparing extreme tertiles of HDL-C. The pooled risk estimate (95% CIs) for fracture per 1SD increase were 1.09 (1.01–1.17) and 0.98 (0.93–1.04) for age groups ≥ 60 and < 60 years, respectively, and the corresponding risks comparing the extreme tertiles of HDL-C levels were 1.21 (1.09–1.33) and 0.95 (0.85–1.07) ( p -value for interaction < 0.05). Age may modify the association between HDL-C levels and fracture risk – an increased fracture risk associated with increased HDL-C levels is only evident in older age (≥ 60 years).

Applying systems thinking to unravel the mechanisms underlying orthostatic hypotension related fall risk - Liping Wang; Anouschka C. Pronk; Eveline P. van Poelgeest; Robert Briggs; Jurgen A.H.R. Claassen; Sofie Jansen; Marjolein Klop; Frederik J. de Lange; Carel C.G.M. Meskers; Vincent J. J. Odekerken; Stephen J. Payne; Marijke C. Trappenburg; et al. (GeroScience, 2023)
Orthostatic hypotension (OH) is an established and common cardiovascular risk factor for falls. An in-depth understanding of the various interacting pathophysiological pathways contributing to OH-related falls is essential to guide improvements in diagnostic and treatment opportunities. We applied systems thinking to multidisciplinary map out causal mechanisms and risk factors. For this, we used group model building (GMB) to develop a causal loop diagram (CLD). The GMB was based on the input of experts from multiple domains related to OH and falls and all proposed mechanisms were supported by scientific literature. Our CLD is a conceptual representation of factors involved in OH-related falls, and their interrelatedness. Network analysis and feedback loops were applied to analyze and interpret the CLD, and quantitatively summarize the function and relative importance of the variables. Our CLD contains 50 variables distributed over three intrinsic domains (cerebral, cardiovascular, and musculoskeletal), and an extrinsic domain (e.g., medications). Between the variables, 181 connections and 65 feedback loops were identified. Decreased cerebral blood flow, low blood pressure, impaired baroreflex activity, and physical inactivity were identified as key factors involved in OH-related falls, based on their high centralities. Our CLD reflects the multifactorial pathophysiology of OH-related falls. It enables us to identify key elements, suggesting their potential for new diagnostic and treatment approaches in fall prevention. The interactive online CLD renders it suitable for both research and educational purposes and this CLD is the first step in the development of a computational model for simulating the effects of risk factors on falls.

Neuronal properties of pyramidal cells in lateral prefrontal cortex of the aging rhesus monkey brain are associated with performance deficits on spatial working memory but not executive function - Tara L. Moore; Maria Medalla; Sara Ibañez; Klaus Wimmer; Chromewell A. Mojica; Ronald J. Killiany; Mark B. Moss; Jennifer I. Luebke; Douglas L. Rosene (GeroScience, 2023)

Sex-specific alteration in human muscle transcriptome with age - Mohini Gharpure; Jie Chen; Resheek Nerella; Sagar Vyavahare; Sandeep Kumar; Carlos M. Isales; Mark Hamrick; Satish Adusumilli; Sadanand Fulzele (GeroScience, 2023)

Advancing age increases the size and severity of spontaneous atheromas in mouse models of atherosclerosis - Venkateswara R. Gogulamudi; Jessica R. Durrant; Adelola O. Adeyemo; Huynh Mi Ho; Ashley E. Walker; Lisa A. Lesniewski (GeroScience, 2023)
Using multiple mouse models, we explored the impact of aging on the size and severity of atherosclerotic lesions. In young, middle-aged and old apolipoprotein E knockout mice (ApoE −/− ) fed an atherogenic diet (AD) for 3–8 weeks, plaque/atheroma formation in the descending aorta and aortic root, and atheroma development in the carotid in response to partial carotid ligation (PCL) were assessed. Total and LDL cholesterol, and triglycerides were higher in old compared to both other age groups, regardless of AD duration. Aortic plaque burden increased with AD duration in all ages. The size and plaque morphology grade of aortic root atheromas was higher with age; however, there was no effect of age on the size or severity of carotid atheromas after PCL. We additionally induced hyperlipidemia in young and old C57BL/6 mice by adeno-associated virus mediated upregulation of LDL receptor regulator, Pcsk9, and 5 weeks of AD. Despite lower cholesterol in old compared to young Pcsk9 mice, there was a greater size and severity of aortic root atheromas in old mice. However, like the ApoE −/− mice, there was no effect of age on size or severity of PCL-induced carotid artery atheromas in Pcsk9 mice. Together, these results suggest that aging increases the size and severity of spontaneous aortic atheromas.

Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan - Cheryl Zi Jin Phua; Xiaqing Zhao; Lesly Turcios-Hernandez; Morrigan McKernan; Morteza Abyadeh; Siming Ma; Daniel Promislow; Matt Kaeberlein; Alaattin Kaya (GeroScience, 2023)
Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 167 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strain’s proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes.

Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction - Bilal Bawamia; Luke Spray; Vincent K. Wangsaputra; Karim Bennaceur; Sharareh Vahabi; Konstantinos Stellos; Ehsan Kharatikoopaei; Emmanuel Ogundimu; Chris P. Gale; Bernard Keavney; Rebecca Maier; Helen Hancock; et al. (GeroScience, 2023)
Myocardial infarction (MI) accelerates immune ageing characterised by lymphopenia, expansion of terminally differentiated CD8 + T-lymphocytes (CD8 + T EMRA ) and inflammation. Pre-clinical data showed that TA-65, an oral telomerase activator, reduced immune ageing and inflammation after MI. We conducted a double blinded randomised controlled pilot trial evaluating the use of TA-65 to reduce immune cell ageing in patients following MI. Ninety MI patients aged over 65 years were randomised to either TA-65 (16 mg daily) or placebo for 12 months. Peripheral blood leucocytes were analysed by flow cytometry. The pre-defined primary endpoint was the proportion of CD8 + T-lymphocytes which were CD8 + T EMRA after 12 months. Secondary outcomes included high-sensitivity C-reactive protein (hsCRP) levels. Median age of participants was 71 years. Proportions of CD8 + T EMRA did not differ after 12 months between treatment groups. There was a significant increase in mean total lymphocyte count in the TA-65 group after 12 months (estimated treatment effect: + 285 cells/μl (95% CI: 117–452 cells/ μ l, p < 0.004), driven by significant increases from baseline in CD3 + , CD4 + , and CD8 + T-lymphocytes, B-lymphocytes and natural killer cells. No increase in lymphocyte populations was seen in the placebo group. At 12 months, hsCRP was 62% lower in the TA-65 group compared to placebo (1.1 vs. 2.9 mg/L). Patients in the TA-65 arm experienced significantly fewer adverse events (130 vs. 185, p = 0.002). TA-65 did not alter CD8 + T EMRA but increased all major lymphocyte subsets and reduced hsCRP in elderly patients with MI after 12 months.

Could olfactory identification be a prognostic factor in detecting cognitive impairment risk in the elderly? - Alice Helena Delgado-Lima; Jaime Bouhaben; Sergio Martínez-Zujeros; Beatriz Pallardo-Rodil; Javier Gómez-Pavón; María Luisa Delgado-Losada (GeroScience, 2023)
Aging contributes to the deterioration of the olfactory system in humans. Several studies indicate that the olfactory identification test alone may function as a screening test for olfactory dysfunction and they are more feasible to apply in clinical practice. Olfactory identification may be a predictor for cognitive impairment. Multiple studies have considered the use of odor identification as a measure to identify the conversion from normality to mild cognitive impairment or dementia. The objectives were (i) to elucidate the associations between cognitive status and olfactory identification performance in aging; (ii) understand the predictive value of olfactory capacity in identifying subjects with cognitive impairment risk; and (iii) to study how cognitive status and olfactory identification relate with other variables of wellness in aging, such as functional capabilities and clinical measures. For this purpose, a group of 149 participants (77.15 ± 7.29 years; 73 women of 76.7 ± 8 years and 76 men of 77.6 ± 6.52 years) were recruited and were subjected to a sociodemographic questionnaire, a psychological screening tool of general cognitive status, an olfactory identification evaluation, and clinical measures. The participants were divided into groups based on their cutoff scores of previous scientific reports about the Spanish version of Montreal Cognitive Assessment. Our results indicate an age-associated decline in olfactory identification ability and intensity of odor perception. The predictive ability of olfactory identification scores for the risk of mild and severe impairment is around 80%. Olfactory identification decreases with cognitive function. Performance in odor identification is associated with impairment of episodic memory and executive functions. These findings further our current understanding of the association between cognition and olfaction, and support olfactory assessment in screening those at higher risk of dementia.

cAMP signaling affects age-associated deterioration of pacemaker beating interval dynamics - Sofia Segal; Ori Shemla; Rotem Shapira; Noa Kirschner Peretz; Yevgeniya Lukyanenko; Inbar Brosh; Joachim Behar; Edward G. Lakatta; Kenta Tsutsui; Yael Yaniv (GeroScience, 2023)

Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies - Christopher Cherry; James I. Andorko; Kavita Krishnan; Joscelyn C. Mejías; Helen Hieu Nguyen; Katlin B. Stivers; Elise F. Gray-Gaillard; Anna Ruta; Jin Han; Naomi Hamada; Masakazu Hamada; Ines Sturmlechner; et al. (GeroScience, 2023)

Chow diet in mouse aging studies: nothing regular about it - Jennifer Lee; Chloe Purello; Sarah L. Booth; Brian Bennett; Christopher D. Wiley; Ron Korstanje (GeroScience, 2023)
Chow diet is used in the majority of rodent studies and, although assumed to be standardized for dietary source and nutritional contents, it varies widely across commercial formulations. Similarly, current approaches to study aging in rodents involve a single-diet formulation across the lifespan and overlook age-specific nutritional requirements, which may have long-term effects on aging processes. Together, these nutrition-based disparities represent major gaps in geroscience research, affecting the interpretation and reproducibility of the studies. This perspective aims to raise awareness on the importance of rodent diet formulation and proposes that geroscientists include detailed descriptions of all experimental diets and feeding protocols. Detailed reporting of diets will enhance rigor and reproducibility of aging rodent studies and lead to more translational outcomes in geroscience research.

Autonomic dysfunction is associated with the development of arterial stiffness: the Whitehall II cohort - Jonas R. Schaarup; Martin S. Christensen; Adam Hulman; Christian S. Hansen; Dorte Vistisen; Adam G. Tabák; Daniel R. Witte; Lasse Bjerg (GeroScience, 2023)

Protectin DX as a therapeutic strategy against frailty in mice - Laís R. Perazza; Adam C. Gower; Holly M. Brown-Borg; Paola Divieti Pajevic; LaDora V. Thompson (GeroScience, 2023)
Frailty in aging is driven by the dysregulation of multiple biological pathways. Protectin DX (PDX) is a docosahexaenoic acid (DHA)-derived molecule that alleviates many chronic inflammatory disorders, but its potential effects on frailty remain unknown. Our goal is to identify age-related impairments in metabolic systems and to evaluate the therapeutic potential of PDX on frailty, physical performance, and health parameters. A set of 22-month-old C57BL/6 male and female mice were assigned to vehicle (Old) or PDX daily gavage treatment for 9 weeks, whereas 6-month-old (Adult) mice received only vehicle. Forelimb and hindlimb strength, endurance, voluntary wheel activity and walking speed determined physical performance and were combined with a frailty index score and body weight loss to determine frailty status. Our data shows that old vehicle-treated mice from both sexes had body weight loss paralleling visceromegaly, and Old females also had impaired insulin clearance as compared to the Adult group. Aging was associated with physical performance decline together with higher odds of frailty development. There was also age-driven mesangial expansion and glomerular hypertrophy as well as bone mineral density loss. All of the in vivo and in vitro impairments observed with aging co-occurred with upregulation of inflammatory pathways and Myc signaling as well as downregulation of genes related to adipogenesis and oxidative phosphorylation in liver. PDX attenuated the age-driven physical performance (strength, exhaustion, walking speed) decline, promoted robustness, prevented bone losses and partially reversed changes in hepatic expression of Myc targets and metabolic genes. In conclusion, our data provides evidence of the beneficial therapeutic effect of PDX against features of frailty in mice. Further studies are warranted to investigate the mechanisms of action and the potential for human translation.

Longitudinal lipidomic signatures of all-cause and CVD mortality in American Indians: findings from the Strong Heart Study - Guanhong Miao; Oliver Fiehn; Kimberly M. Malloy; Ying Zhang; Elisa T. Lee; Barbara V. Howard; Jinying Zhao (GeroScience, 2023)

Rapamycin restores peripheral blood flow in aged mice and in mouse models of atherosclerosis and Alzheimer’s disease - Candice E. Van Skike; Nicholas DeRosa; Veronica Galvan; Stacy A. Hussong (GeroScience, 2023)

A decade of aging in healthy older adults: longitudinal findings on cerebrovascular and cognitive health - Ralf W. J. Weijs; Madelijn H. Oudegeest-Sander; Janneke I. A. Vloet; Maria T. E. Hopman; Jurgen A. H. R. Claassen; Dick H. J. Thijssen (GeroScience, 2023)
Research suggests an association between cerebrovascular health and cognitive decline, but previous work is limited by its cross-sectional nature or short (< 1–2 years) follow-up. Our aim was to examine, across 10 years of follow-up in healthy older adults, changes in cerebrovascular health and their relationship with subjective memory complaints as an early marker of cognitive decline. Between 2008 and 2010, twenty-eight healthy older adults (69 ± 4 years) underwent baseline blood pressure and transcranial Doppler measurements to assess middle cerebral artery blood velocity (MCAv), cerebrovascular resistance index (CVRi), and measures of cerebral autoregulation (CA). After 9–12 years of follow-up, these measurements were repeated, and presence of memory complaints was evaluated. Linear mixed-model analyses explored effects of aging on cerebrovascular parameters and whether memory complaints were associated with cerebrovascular changes. Across a median follow-up of 10.9 years, no changes in MCAv, CVRi, or CA were found. At baseline, these parameters were not different between subjects with ( n = 15) versus without ( n = 13) memory complaints. During follow-up, subjects with memory complaints showed larger decreases in MCAv (− 10% versus + 9%, P = 0.041) and increases in CVRi (+ 26% versus − 9%, P = 0.029) compared to other peers without memory complaints, but no distinct changes in CA parameters ( P > 0.05). Although a decade of aging does not lead to deterioration in cerebral blood flow or autoregulation, our findings suggest that reductions in cerebral blood flow and increases in cerebrovascular resistance are associated with early subjective cognitive decline.

Plasma metabolomic signatures of dual decline in memory and gait in older adults - Qu Tian; Michelle D. Shardell; Pei-Lun Kuo; Toshiko Tanaka; Eleanor M. Simonsick; Ruin Moaddel; Susan M. Resnick; Luigi Ferrucci (GeroScience, 2023)
Older adults experiencing dual decline in memory and gait have greater dementia risk than those with memory or gait decline only, but mechanisms are unknown. Dual decline may indicate specific pathophysiological pathways to dementia which can be reflected by circulating metabolites. We compared longitudinal changes in plasma metabolite biomarkers of older adults with and without dual decline in the Baltimore Longitudinal Study of Aging (BLSA). Participants were grouped into 4 phenotypes based on annual rates of decline in verbal memory and gait speed: no decline in memory or gait, memory decline only, gait decline only, and dual decline. Repeated measures of plasma metabolomics were measured by biocrates p500 kit during the same time of memory and gait assessments. In BLSA, 18 metabolites differed across groups ( q -value < 0.05). Metabolites differentially abundant were enriched for lysophosphatidylcholines (lysoPC C18:0,C16:0,C17:0,C18:1,C18:2), ceramides (d18:2/24:0,d16:1/24:0,d16:1/23:0), and amino acids (glycine) classes. Compared to no decline, the dual decline group showed greater declines in lysoPC C18:0, homoarginine synthesis, and the metabolite module containing mostly triglycerides, and showed a greater increase in indoleamine 2,3-dioxygenase (IDO) activity. Metabolites distinguishing dual decline and no decline groups were implicated in metabolic pathways of the aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, histidine metabolism, and sphingolipid metabolism. Older adults with dual decline exhibit the most extensive alterations in metabolic profiling of lysoPCs, ceramides, IDO activity, and homoarginine synthesis. Alterations in these metabolites may indicate mitochondrial dysfunction, compromised immunity, and elevated burden of cardiovascular and kidney pathology.

Circulating polyunsaturated fatty acids, fish oil supplementation, and risk of incident dementia: a prospective cohort study of 440,750 participants - Yu He; Shu-Yi Huang; Hui-Fu Wang; Wei Zhang; Yue-Ting Deng; Ya-Ru Zhang; Qiang Dong; Jian-Feng Feng; Wei Cheng; Jin-Tai Yu (GeroScience, 2023)

Capturing postural blood pressure dynamics with near-infrared spectroscopy-measured cerebral oxygenation - Marjolein Klop; Rianne A. A. de Heus; Andrea B. Maier; Anne van Alphen; Marianne J. Floor-Westerdijk; Mathijs Bronkhorst; René J. F. Melis; Carel G. M. Meskers; Jurgen A. H. R. Claassen; Richard J. A. van Wezel (GeroScience, 2023)
Orthostatic hypotension (OH) is highly prevalent in older adults and associated with dizziness, falls, lower physical and cognitive function, cardiovascular disease, and mortality. OH is currently diagnosed in a clinical setting with single-time point cuff measurements. Continuous blood pressure (BP) devices can measure OH dynamics but cannot be used for daily life monitoring. Near-infrared spectroscopy (NIRS) has potential diagnostic value in measuring cerebral oxygenation continuously over a longer time period, but this needs further validation. This study aimed to compare NIRS-measured (cerebral) oxygenation with continuous BP and transcranial Doppler-measured cerebral blood velocity (CBv) during postural changes. This cross-sectional study included 41 participants between 20 and 88 years old. BP, CBv, and cerebral (long channels) and superficial (short channels) oxygenated hemoglobin (O 2 Hb) were measured continuously during various postural changes. Pearson correlations between BP, CBv, and O 2 Hb were calculated over curves and specific characteristics (maximum drop amplitude and recovery). BP and O 2 Hb only showed good curve-based correlations (0.58–0.75) in the initial 30 s after standing up. Early (30–40 s) and 1-min BP recovery associated significantly with O 2 Hb, but no consistent associations were found for maximum drop amplitude and late (60–175 s) recovery values. Associations between CBv and O 2 Hb were poor, but stronger for long-channel than short-channel measurements. BP associated well with NIRS-measured O 2 Hb in the first 30 s after postural change. Stronger associations for CBv with long-channel O 2 Hb suggest that long-channel NIRS specifically reflects cerebral blood flow during postural transitions, necessary to better understand the consequences of OH such as intolerance symptoms.

Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging - Bowen Tang; Xia Li; Yunzhang Wang; Arvid Sjölander; Kristina Johnell; Madhav Thambisetty; Luigi Ferrucci; Chandra A. Reynolds; Deborah Finkel; Juulia Jylhävä; Nancy L. Pedersen; Sara Hägg (GeroScience, 2023)
Aging is a major risk factor for many chronic diseases. This study aimed to examine the effects of antihypertensive, lipid-lowering, and antidiabetic drugs on biological aging. We included 672 participants and 2746 repeated measurements from the Swedish Adoption/Twin Study of Aging. Self-reported medicine uses were categorized into antidiabetic, antihypertensive, and lipid-lowering drugs. A total of 12 biomarkers for biological aging (BA biomarkers) were included as outcomes. Conditional generalized estimating equations were applied conditioning on individuals to estimate the drug effect on BA biomarker level within the same person when using or not using the drug. Chronological age, body mass index, smoking status, number of multiple medication uses, blood pressure, blood glucose level, and apoB/apoA ratio were adjusted for as covariates in the model. Overall, using antihypertensive drugs was associated with a decrease in one DNA-methylation age (PCGrimAge: beta = − 0.39, 95%CI = − 0.67 to − 0.12). When looking into drug subcategories, calcium channel blockers (CCBs) were associated with a decrease in several DNA-methylation ages (PCHorvathAge beta = − 1.28, 95%CI = − 2.34 to − 0.21; PCSkin&bloodAge beta = − 1.34, 95%CI = − 2.61 to − 0.07; PCPhenoAge beta = − 1.74, 95%CI = − 2.58 to − 0.89; PCGrimAge beta = − 0.57, 95%CI = − 0.96 to − 0.17) and in functional biological ages (functional age index beta = − 2.18, 95%CI = − 3.65 to − 0.71; frailty index beta = − 1.31, 95%CI = − 2.43 to − 0.18). However, the results within other drug subcategories were inconsistent. Calcium channel blockers may decrease biological aging captured by the BA biomarkers measured at epigenetic and functional level. Future studies are warranted to confirm these effects and understand the underlying biological mechanisms.

Geroprotective interventions in the 3xTg mouse model of Alzheimer’s disease - Michelle M. Sonsalla; Dudley W. Lamming (GeroScience, 2023)

Associations of a biopsychosocial frailty phenotype with all-cause dementia, Alzheimer’s disease, vascular dementia, and other dementias: the Italian PRoject on the Epidemiology of Alzheimer’s disease (IPREA) - Emanuele Scafato; Vincenzo Solfrizzi; Carlo Custodero; Giovanna Casieri; Claudia Falco; Rosselia Maggipinto; Claudia Gandin; Lucia Galluzzo; Silvia Ghirini; Alice Matone; Vittorio Dibello; Rodolfo Sardone; et al. (GeroScience, 2023)

The transcription regulator ATF4 is a mediator of skeletal muscle aging - Matthew J. Miller; George R. Marcotte; Nathan Basisty; Cameron Wehrfritz; Zachary C. Ryan; Matthew D. Strub; Andrew T. McKeen; Jennifer I. Stern; Karl A. Nath; Blake B. Rasmussen; Andrew R. Judge; Birgit Schilling; et al. (GeroScience, 2023)
Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass. Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults.

Low neighborhood deprivation buffers against hippocampal neurodegeneration, white matter hyperintensities, and poorer cognition - Chin Hong Tan; Jacinth J. X. Tan (GeroScience, 2023)

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer’s disease - Ricardo A. Santana Martínez; Priyanka D. Pinky; Benjamin A. Harlan; Gregory J. Brewer (GeroScience, 2023)
Increased interest in the aging and Alzheimer’s disease (AD)-related impairments in autophagy in the brain raise important questions about regulation and treatment. Since many steps in endocytosis and autophagy depend on GTPases, new measures of cellular GTP levels are needed to evaluate energy regulation in aging and AD. The recent development of ratiometric GTP sensors (GEVALS) and findings that GTP levels are not homogenous inside cells raise new issues of regulation of GTPases by the local availability of GTP. In this review, we highlight the metabolism of GTP in relation to the Rab GTPases involved in formation of early endosomes, late endosomes, and lysosomal transport to execute the autophagic degradation of damaged cargo. Specific GTPases control macroautophagy (mitophagy), microautophagy, and chaperone-mediated autophagy (CMA). By inference, local GTP levels would control autophagy, if not in excess. Additional levels of control are imposed by the redox state of the cell, including thioredoxin involvement. Throughout this review, we emphasize the age-related changes that could contribute to deficits in GTP and AD. We conclude with prospects for boosting GTP levels and reversing age-related oxidative redox shift to restore autophagy. Therefore, GTP levels could regulate the numerous GTPases involved in endocytosis, autophagy, and vesicular trafficking. In aging, metabolic adaptation to a sedentary lifestyle could impair mitochondrial function generating less GTP and redox energy for healthy management of amyloid and tau proteostasis, synaptic function, and inflammation.

Altered T cell infiltration and enrichment of leukocyte regulating pathways within aged skeletal muscle are associated impaired muscle function following influenza infection - Spencer R. Keilich; Andreia N. Cadar; Darcy T. Ahern; Blake L. Torrance; Erica C. Lorenzo; Dominique E. Martin; Laura Haynes; Jenna M. Bartley (GeroScience, 2023)

Urolithin A reduces amyloid-beta load and improves cognitive deficits uncorrelated with plaque burden in a mouse model of Alzheimer’s disease - Josué Ballesteros-Álvarez; Wynnie Nguyen; Renuka Sivapatham; Anand Rane; Julie K. Andersen (GeroScience, 2023)
In the present study, we investigated the effects of urolithin A (UA), a metabolite generated from ellagic acid via its metabolism by gut bacteria, as an autophagy activator with potential neuroprotective activity. WT and 3xTg-AD mice were administered long-term intermittent dietary supplementation with UA. UA was found to prevent deficits in spatial memory, cued fear response, and exploratory behavior in this model. It also decreased the Aβ plaque burden in areas of the hippocampus where these protein deposits are prominent in the model. Interestingly, correlation analyses demonstrate that Aβ plaque burden positively correlates with enhanced spatial memory in 3xTg-AD mice on a control diet but not in those supplemented with UA. In contrast, Aβ42 abundance in cortical and hippocampal homogenates negatively correlate with spatial memory in UA-fed mice. Our data suggest that plaque formation may be a protective mechanism against neurodegeneration and cognitive decline and that targeting the generation of proteotoxic Aβ species might be a more successful approach in halting disease progression. UA was also found to extend lifespan in normal aging mice. Mechanistically, we demonstrate that UA is able to induce autophagy and to increase Aβ clearance in neuronal cell lines. In summary, our studies reveal UA, likely via its actions as a autophagy inducer, is capable of removing Aβ from neurons and its dietary administration prevents the onset of cognitive deficits associated with pathological Aβ deposition in the 3xTg-AD mouse model as well as extending lifespan in normal aging mice.

Rapid emergence of transcriptional heterogeneity upon molecular stress predisposes cells to two distinct states of senescence - Nikolay Burnaevskiy; Junko Oshima; Alexander R. Mendenhall (GeroScience, 2023)

Recapitulation of anti-aging phenotypes by global, but not by muscle-specific, deletion of PAPP-A in mice - Xinna Li; Mary Hager; Madaline McPherson; Michael Lee; Riha Hagalwadi; Mary E. Skinner; David Lombard; Richard A. Miller (GeroScience, 2023)

Frailty and functional brain connectivity (FBC) in older adults with mild cognitive impairment (MCI): baseline results from the SYNERGIC Trial - Nick W. Bray; Frederico Pieruccini-Faria; Suzanne T. Witt; Kenneth Rockwood; Robert Bartha; Timothy J. Doherty; Lindsay S. Nagamatsu; Quincy J. Almeida; Teresa Liu-Ambrose; Laura E. Middleton; Louis Bherer; Manuel Montero-Odasso (GeroScience, 2023)

Approximate entropy analysis across electroencephalographic rhythmic frequency bands during physiological aging of human brain - Chiara Pappalettera; Alessia Cacciotti; Lorenzo Nucci; Francesca Miraglia; Paolo Maria Rossini; Fabrizio Vecchio (GeroScience, 2023)

Human centenarian–associated SIRT6 mutants modulate hepatocyte metabolism and collagen deposition in multilineage hepatic 3D spheroids - Jan Frohlich; Marco Raffaele; Helena Skalova; Eric Leire; Illar Pata; Pille Pata; Vera Gorbunova; Manlio Vinciguerra (GeroScience, 2023)

Changes in hippocampal volume during a preceding 10-year period do not correlate with cognitive performance and hippocampal blood‒brain barrier permeability in cognitively normal late-middle-aged men - Aftab Bakhtiari; Mark B. Vestergaard; Krisztina Benedek; Birgitte Fagerlund; Erik Lykke Mortensen; Merete Osler; Martin Lauritzen; Henrik B. W. Larsson; Ulrich Lindberg (GeroScience, 2023)
Hippocampal blood–brain barrier (BBB) permeability may increase in normal healthy ageing and contribute to neurodegenerative disease. To examine this hypothesis, we investigated the correlation between blood–brain barrier (BBB) permeability, regional brain volume, memory functions and health and lifestyle factors in The Metropolit 1953 Danish Male Birth Cohort. We used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a gadolinium-based contrast agent to assess BBB permeability in 77 participants in the cohort. BBB permeability was measured as K i values in the hippocampus, thalamus and white matter. Over a 10-year period, we observed progressive atrophy of both the left and right hippocampus ( p = 0.001). There was no significant correlation between current BBB permeability and hippocampal volume, prior atrophy or cognition. The hippocampus volume ratio was associated with better visual and verbal memory scores ( p < 0.01). Regional BBB differences revealed higher K i values in the hippocampus and white matter than in the thalamus ( p < 0.001). Participants diagnosed with type II diabetes had significantly higher BBB permeability in the white matter ( p = 0.015) and thalamus ( p = 0.016), which was associated with a higher Fazekas score ( p = 0.024). We do not find evidence that BBB integrity is correlated with age-related hippocampal atrophy or cognitive functions. The association between diabetes, white matter hyperintensities and increased BBB permeability is consistent with the idea that cerebrovascular disease compromises BBB integrity. Our findings suggest that the hippocampus is particularly prone to age-related atrophy, which may explain some of the cognitive changes that accompany older age, but this prior atrophy is not correlated with current BBB permeability.

Liver alterations and detection of SARS-CoV-2 RNA and proteins in COVID-19 autopsies - Adrián Pesti; Krisztina Danics; Tibor Glasz; Tibor Várkonyi; Tamás Barbai; Andrea Reszegi; Ilona Kovalszky; István Vályi-Nagy; Deján Dobi; Gábor Lotz; Zsuzsa Schaff; András Kiss (GeroScience, 2023)
The most severe alterations in Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection are seen in the lung. However, other organs also are affected. Here, we report histopathologic findings in the liver and detection of viral proteins and RNA in COVID-19 autopsies performed at the Semmelweis University (Budapest, Hungary). Between March 2020 through March 2022, 150 autopsies on patients who died of COVID-19 were analyzed. Cause-of-death categories were formed based on the association with SARS-CoV-2 as strong, contributive, or weak. Samples for histopathologic study were obtained from all organs, fixed in formalin, and embedded in paraffin (FFPE). Immunohistochemical study (IHC) to detect SARS-CoV-2 spike protein and nucleocapsid protein (NP), CD31, claudin-5, factor VIII, macrosialin (CD68), and cytokeratin 7, with reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization (ISH, RNAscope®) for SARS-CoV-2 RNA were conducted using FFPE samples of livers taken from 20 autopsies performed ≤ 2 days postmortem. All glass slides were scanned; the digital images were evaluated by semiquantitative scoring and scores were analyzed statistically. Steatosis, single-cell and focal/zonal hepatocyte necrosis, portal fibrosis, and chronic inflammation were found in varying percentages. Sinusoidal ectasia, endothelial cell disruption, and fibrin-filled sinusoids were seen in all cases; these were assessed semiquantitatively for severity (SEF scored). SEF scores did not correlate with cause-of-death categories ( p = 0.92) or with severity of lung alterations ( p = 0.96). SARS-CoV-2 RNA was detected in 13/20 cases by PCR and in 9/20 by ISH, with IHC demonstration of spike protein in 4/20 cases and NP in 15/20. Viral RNA and proteins were located in endothelial and Kupffer cells, and in portal macrophages, but not in hepatocytes and cholangiocytes. In conclusion, endothelial damage (SEF scores) was the most common alteration in the liver and was a characteristic, but not specific alteration in COVID-19, suggesting an important role in the pathogenesis of COVID-19-associated liver disease. Detection of SARS-CoV-2 RNA and viral proteins in liver non-parenchymal cells suggests that while the most extended primary viral cytotoxic effect occurs in the lung, viral components are present in other organs too, as in the liver. The necrosis/apoptosis and endothelial damage associated with viral infection in COVID-19 suggest that those patients who survive more severe COVID-19 may face prolonged liver repair and accordingly should be followed regularly in the post-COVID period.

Resistance to mild cold stress is greater in both wild-type and long-lived GHR-KO female mice - Yimin Fang; David Medina; Robert Stockwell; Samuel McFadden; Erin R. Hascup; Kevin N. Hascup; Andrzej Bartke (GeroScience, 2023)

The effect of a digital health coaching and health education protocol on cognition in adults at-risk for Alzheimer’s - Anthony Campitelli; Joshua L. Gills; Megan D. Jones; Sally Paulson; Jennifer Myers; Kelsey Bryk; Erica N. Madero; Jordan M. Glenn; Charlie H. Rodgers; Jenova A. Kempkes; Michelle Gray (GeroScience, 2023)
Several modifiable lifestyle factors have been linked to cognitive ability and the risk of developing Alzheimer’s disease and related dementias (ADRD). Health coaching (HC) is an intervention that addresses lifestyle factors associated with cognition. The effectiveness of an HC protocol was evaluated and compared with a health education (HE) intervention, representing the current standard of care, in a sample of 216 adults between the ages of 45 and 75 years who were at-risk for developing ADRD. Outcomes examined were global cognition, neuropsychological cognition, and Alzheimer’s risk. HC participants received personalized coaching from a health coach focusing on nutrition, physical activity, sleep, stress, social engagement, and cognitive activity. HE participants received biweekly education materials focusing on the same modifiable lifestyle factors addressed by HC. Participants were assessed at baseline and again 4 months later. Self-reported global cognition scores improved only in the HC group (16.18 to 15.52, p = .03) and neuropsychological cognitive ability improved in the HE group (104.48 to 108.76, p < .001). When non-adherence in the HC group was accounted for, however, the mean change in neuropsychological score was similar between groups ( p > .05), self-reported global cognition demonstrated an even larger mean improvement in the HC group (16.20 to 15.41, p = .01), and the HC group saw an improvement in ADRD protective risk score (− 10.39 to − 11.45, p = .007). These results indicate that HC and HE can both improve cognition, but HC may be more effective and may yield increased protection against ADRD risk.

The potential of hyperbaric oxygen as a therapy for neurodegenerative diseases - Paapa Mensah-Kane; Nathalie Sumien (GeroScience, 2023)

Dilated hypertrophic phenotype of the carotid artery is associated with accelerated age-associated central arterial stiffening - Majd AlGhatrif; Edward G. Lakatta; Christopher H. Morrell; Danilo Alunni Fegatelli; Edoardo Fiorillo; Michele Marongiu; David Schlessinger; Francesco Cucca; Angelo Scuteri (GeroScience, 2023)

Network analyses unveil ageing-associated pathways evolutionarily conserved from fungi to animals - Jérôme Teulière; Charles Bernard; Eduardo Corel; François-Joseph Lapointe; Johannes Martens; Philippe Lopez; Eric Bapteste (GeroScience, 2023)

Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment - Veronika S. Urban; Andrea Cegledi; Gabor Mikala (GeroScience, 2023)
Multiple myeloma (MM) is an incurable plasma cell malignancy, which is predominantly a disease of older adults (the median age at diagnosis is 70 years). The slow progression from asymptomatic stages and the late-onset of MM suggest fundamental differences compared to many other hematopoietic system-related malignancies. The concept discussed in this review is that age-related changes at the level of terminally differentiated plasma cells act as the main risk factors for the development of MM. Epigenetic and genetic changes that characterize both MM development and normal aging are highlighted. The relationships between cellular aging processes, genetic mosaicism in plasma cells, and risk for MM and the stochastic processes contributing to clonal selection and expansion of mutated plasma cells are investigated. In line with the DNA damage accumulation theory of aging, in this review, the evolution of monoclonal gammopathy to symptomatic MM is considered. Therapeutic consequences of age-dependent comorbidities that lead to frailty and have fundamental influence on treatment outcome are described. The importance of considering geriatric states when planning the life-long treatment course of an elderly MM patient in order to achieve maximal therapeutic benefit is emphasized.

Progerin induces a phenotypic switch in vascular smooth muscle cells and triggers replication stress and an aging-associated secretory signature - Nuria Coll-Bonfill; Urvashi Mahajan; Elena V. Shashkova; Chien-Jung Lin; Robert P. Mecham; Susana Gonzalo (GeroScience, 2023)

Morusin and mulberrin extend the lifespans of yeast and C. elegans via suppressing nutrient-sensing pathways - Pingkang Xu; Qimin Chen; Xiaoman Chen; Hao Qi; Yuyan Yang; Weiqi Li; Xin Yang; Amelia Gunawan; Shuoyu Chen; Huimin Zhang; Han-Ming Shen; Dejian Huang; et al. (GeroScience, 2023)

The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner - Ping Li; Maria F. Newhardt; Satoshi Matsuzaki; Craig Eyster; Atul Pranay; Frederick F. Peelor; Albert Batushansky; Caroline Kinter; Kumar Subramani; Sandeep Subrahmanian; Jasimuddin Ahamed; Pengchun Yu; et al. (GeroScience, 2023)
SIRT3 is a longevity factor that acts as the primary deacetylase in mitochondria. Although ubiquitously expressed, previous global SIRT3 knockout studies have shown primarily a cardiac-specific phenotype. Here, we sought to determine how specifically knocking out SIRT3 in cardiomyocytes (SIRTcKO mice) temporally affects cardiac function and metabolism. Mice displayed an age-dependent increase in cardiac pathology, with 10-month-old mice exhibiting significant loss of systolic function, hypertrophy, and fibrosis. While mitochondrial function was maintained at 10 months, proteomics and metabolic phenotyping indicated SIRT3 hearts had increased reliance on glucose as an energy substrate. Additionally, there was a significant increase in branched-chain amino acids in SIRT3cKO hearts without concurrent increases in mTOR activity. Heavy water labeling experiments demonstrated that, by 3 months of age, there was an increase in protein synthesis that promoted hypertrophic growth with a potential loss of proteostasis in SIRT3cKO hearts. Cumulatively, these data show that the cardiomyocyte-specific loss of SIRT3 results in severe pathology with an accelerated aging phenotype.

Biomarkers of mitochondrial dysfunction and inflammaging in older adults and blood pressure variability - Leonardo Bencivenga; Mathilde Strumia; Yves Rolland; Laurent Martinez; Philippe Cestac; Sophie Guyonnet; Sandrine Andrieu; Angelo Parini; Alexandre Lucas; Bruno Vellas; Philipe De Souto Barreto; Laure Rouch; et al. (GeroScience, 2023)

Handgrip strength is associated with learning and verbal fluency in older men without dementia: insights from the NHANES - Konstantinos Prokopidis; Panagiotis Giannos; Theocharis Ispoglou; Ben Kirk; Oliver C. Witard; Yannis Dionyssiotis; David Scott; Helen Macpherson; Gustavo Duque; Masoud Isanejad (GeroScience, 2023)
Low handgrip strength, a hallmark measure of whole-body strength, has been linked with greater odds of cognitive decline and dementia; however, conflicting findings, which could be due to population characteristics and choice of tools, such for the assessment of handgrip strength and cognitive function domains, also exist. Therefore, we examined the relationship of handgrip strength with a comprehensive list of tests to assess domains of cognitive function using a representative sample of US older men and women without neurodegenerative disorders such as dementia. We analyzed cross-sectional data from the US National Health and Nutrition Examination Survey (NHANES) between 2011 and 2014, with a study cohort of 777 older adults (380 men and 397 women) above 60 years of age. Handgrip strength was assessed using a handgrip dynamometer, while cognitive function was assessed through the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word List Learning Test (WLLT), Word List Recall Test (WLRT), Intrusion Word Count Test (WLLT-IC and WLRT-IC), the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Sex-stratified multiple linear regression analyses were performed upon covariate adjustment for age, ethnicity, socio-economic status, education, medical history, body mass index, physical activity, energy, protein, and alcohol intake. Maximal handgrip strength was positively associated with cognitive function scores, including CERAD WLLT ( P = 0.009, R 2 = 0.146) and AFT ( P = 0.022, R 2 = 0.024) in older men, but not in women (CERAD WLLT: P = 0.253, AFT: P = 0.370). No significant associations with CERAD WLLRT (men: P = 0.057, women: P = 0.976), WLLT-IC (men: P = 0.671, women: P = 0.869), WLLRT-IC (men: P = 0.111, women: P = 0.861), and DSST (men: P = 0.108, women: P = 0.091) were observed. Dose–response curves exhibited a prominent linear relationship between all significant associations after covariate adjustment, with no indication of a plateau in these relationships. In conclusion, higher handgrip strength was independently associated with better learning ability for novel verbal information and verbal fluency in US men over the age of 60 and without dementia. Longitudinal studies are required to confirm whether muscle strength independently predicts cognitive function changes in older adults in a sex-specific manner, and whether this connection is affirmed to the possibility of reverse causation due to declines in physical activity levels in the preclinical phase of dementia.

Age-associated changes in circulatory fatty acids: new insights on adults and long-lived individuals - Sawan Ali; Anna Aiello; Tiziana Zotti; Giulia Accardi; Gaetano Cardinale; Pasquale Vito; Anna Calabrò; Mattia Emanuela Ligotti; Mariano Intrieri; Graziamaria Corbi; Calogero Caruso; Giuseppina Candore; et al. (GeroScience, 2023)

Focus group study on perceptions and information needs regarding vaccines targeting the older population: a cross-country comparison in four European countries - Manuela Dominique Wennekes; Renske Eilers; Antonella Caputo; Amandine Gagneux-Brunon; Riccardo Gavioli; Francesco Nicoli; Zoltán Vokó; Aura Timen; Amandine Gagneux-Brunon; Anna Czwarno; Antonella Caputo; Atika Abelin; et al. (GeroScience, 2023)
The increasing life expectancy leads to more older adults suffering from infectious diseases. Vaccines are available against diverse infections such as influenza, pneumococcal disease, herpes zoster and tetanus. However, vaccine acceptance is crucial for optimal preventive effect. The objective of the study is to perform a cross-country analysis of the perceptions and decision-making behaviour of older adults regarding vaccinations and their information needs. Focus groups with older adults were conducted in four countries: France, Hungary, Italy and the Netherlands. Data were analysed using thematic analysis. Demographic characteristics of participants were gathered with a questionnaire. Influenza and tetanus vaccines were commonly known, as was the disease influenza. On the contrary, the awareness of the vaccines against pneumococcal disease and herpes zoster were low. Participants also expressed a need for more information on vaccines, such as possible side effects, contra-indications and duration of protection, emphasizing that information is a condition for decision-making on vaccination. General practitioners were found to be the most important in information provision on vaccines. Perceptions on vaccines, such as effectiveness, side effects and safety, as well as perceptions on infectious diseases, such as severity, susceptibility and experiencing an infectious disease, played a role in the decision-making of older adults on vaccines. More awareness of the information needs among older adults with regard to vaccines should be raised among general practitioners and other healthcare providers. This requires appropriate knowledge about the vaccines among healthcare providers as well as communication skills to meet the information needs of older adults.

Fast and slow skeletal myosin binding protein-C and aging - L. R. Perazza; G. Wei; L. V. Thompson (GeroScience, 2023)
Aging is associated with skeletal muscle strength decline and cardiac diastolic dysfunction. The structural arrangements of the sarcomeric proteins, such as myosin binding protein-C (MyBP-C) are shown to be pivotal in the pathogenesis of diastolic dysfunction. Yet, the role of fast (fMyBP-C) and slow (sMyBP-C) skeletal muscle MyBP-C remains to be elucidated. Herein, we aimed to characterize MyBP-C and its paralogs in the fast tibialis anterior (TA) muscle from adult and old mice. Immunoreactivity preparations showed that the relative abundance of the fMyBP-C paralog was greater in the TA of both adult and old, but no differences were noted between groups. We further found that the expression level of cardiac myosin binding protein-C (cMyBP-C), an important modulator of cardiac output, was lowered by age. Standard SDS-PAGE along with Pro-Q Diamond phosphoprotein staining did not identify age-related changes in phosphorylated MyBP-C proteins from TA and cardiac muscles; however, it revealed that MyBP-C paralogs in fast skeletal and cardiac muscle were highly phosphorylated. Mass spectrometry further identified glycogen phosphorylase, desmin, actin, troponin T, and myosin regulatory light chain 2 as phosphorylated myofilament proteins in both ages. MyBP-C protein-bound carbonyls were determined using anti-DNP immunostaining and found the carbonyl level of fMyBP-C, sMyBP-C, and cMyBP-C to be similar between old and adult animals. In summary, our data showed some differences regarding the MyBP-C paralog expression and identified an age-related reduction of cMyBP-C expression. Future studies are needed to elucidate which are the age-driven post-translational modifications in the MyBP-C paralogs.

Causal influences of salience/cerebellar networks on dorsal attention network subserved age-related cognitive slowing - Clive H. Y. Wong; Jiao Liu; Jing Tao; Li-dian Chen; Huan-ling Yuan; Mabel N. K. Wong; Yan-wen Xu; Tatia M. C. Lee; Chetwyn C. H. Chan (GeroScience, 2023)
Age-related cognitive slowing is a prominent precursor of cognitive decline. Functional neuroimaging studies found that cognitive processing speed is associated with activation and coupling among frontal, parietal and cerebellar brain networks. However, how the reciprocal influences of inter- and intra-network coupling mediate age-related decline in processing speed remains insufficiently studied. This study examined how inter- and intra-brain network influences mediate age-related slowing. We were interested in the fronto-insular salience network (SN), frontoparietal dorsal attention network (DAN), cerebellar network (CN) and default mode network (DMN). Reaction time (RT) and functional MRI data from 84 participants (aged 18–75) were collected while they were performing the Arrow Task in visual or audial forms. At the subject level, effective connectivities (ECs) were estimated with regression dynamic causal modelling. At the group level, structural equation models (SEMs) were used to model latent speed based on age and the EC mediators. Age was associated with decreased speed and increased inter-network effective connectivity. The CN exerting influence on the DAN (CN → DAN EC) mediated, while the SN → DAN EC suppressed age-related slowing. The DMN and intra-network ECs did not seem to play significant roles in slowing due to ageing. Inter-network connectivity from the CN and SN to the DAN contributes to age-related slowing. The seemingly antagonizing influences of the CN and SN indicate that increased task-related automaticity and decreased effortful control on top-down attention would promote greater speed in older individuals.

Familial aggregation of the aging process: biological age measured in young adult offspring as a predictor of parental mortality - Ilona Shapiro; Daniel W. Belsky; Salomon Israel; Iaroslav Youssim; Yechiel Friedlander; Hagit Hochner (GeroScience, 2023)

Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis - Eleanor J. Phillips; Mirre J. P. Simons (GeroScience, 2023)
Dietary restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR, and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice ( n = 1223 from 23 studies comprising 46 effect sizes involving DR ( n = 17) and rapamycin treatment ( n = 29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR = − 0.72; CI = − 1.17, -0.28; p = 0.0015). In contrast, DR reduced post-infection survival (lnHR = 0.80; CI = 0.08, 1.52; p = 0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower ( p < 0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR, our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.

Carotid disease, cognition, and aging: time to redefine asymptomatic disease? - Christina M. Lineback; Brian Stamm; Farzaneh Sorond; Fan Z. Caprio (GeroScience, 2023)

The Instrumented Stand and Walk (ISAW) test to predict falls in older men - Fay B. Horak; Amy Laird; Patricia Carlson-Kuhta; Melanie Abrahamson; Martina Mancini; Eric S. Orwoll; Jodi A. Lapidus; Vrutangkumar V. Shah (GeroScience, 2023)
Objective measures of balance and gait have the potential to improve prediction of future fallers because balance and gait impairments are common precursors. We used the Instrumented Stand and Walk Test (ISAW) with wearable, inertial sensors to maximize the domains of balance and gait evaluated in a short test. We hypothesized that ISAW objective measures across a variety of gait and balance domains would improve fall prediction beyond history of falls and better than gait speed or dual-task cost on gait-speed. We recruited 214 high-functioning older men (mean 82 years), of whom 91 participants (42.5%) had one or more falls in the 12 months following the ISAW test. The ISAW test involved 30 s of stance followed by a 7-m walk, turn, and return. We examined regression models for falling using 17 ISAW metrics, with and without age and fall history, and characterize top-performing models by AUC and metrics included. The ISAW test improved distinguishing between future fallers and non-fallers compared to age and history of falls, alone (AUC improved from 0.69 to 0.75). Models with 1 ISAW metric usually included a postural sway measure, models with 2 ISAW measures included a turning measure, models with 3 ISAW measures included a gait variability measure, and models with 4 or 5 measures added a gait initiation measure. Gait speed and dual-task cost did not distinguish between fallers and non-fallers in this high-functioning cohort. The best fall-prediction models support the notion that older people may fall due to a variety of balance and gait impairments.

A long-term obesogenic high-fat diet in mice partially dampens the anti-frailty benefits of late-life intermittent fasting - Yoko O. Henderson; Nazmin Bithi; Jie Yang; Christopher Link; Aili Zhang; Benjamin Baron; Eran Maina; Christopher Hine (GeroScience, 2023)
The global obesity pandemic coupled with ever-growing life expectancies equates to hundreds of millions of individuals with potentially longer but not healthier lives. Aging is one of the risk factors for numerous maladies such as metabolic disorder and frailty, which are exacerbated under obesity. Thus, therapeutic approaches that address obesity to ultimately improve affected individuals’ quality of life and extend their lifespan are needed. We previously reported that the every other day (EOD) fasting initiated late-life improved metabolic, musculoskeletal, and cognitive endpoints in standard rodent diet-fed mice. In the present study, using the same dietary intervention methodology, we tested if 2.5 months of EOD fasting could improve metabolic, physiological, and cognitive endpoints in mice after an 18 month obesogenic high-fat diet (HFD). The positive effects of EOD fasting were generally consistent across the endpoints; EOD fasting decreased total body mass, maintained more %lean mass, improved glucose tolerance and utilization, and improved neuromuscular function. In contrast to our previous study, grip strength, hippocampal-dependent memory, and renal hydrogen sulfide (H 2 S) production were not improved by the HFD EOD fasting. Thus, efficacy for late-life initiated intermittent fasting to improve specific frailty markers may be partially dependent on nutritional compositions of the diet.

Remember NIBS? tACS improves memory performance in elders with subjective memory complaints - Sahereh Varastegan; Reza Kazemi; Reza Rostami; Sanaz Khomami; Ahmad Zandbagleh; Abed L. Hadipour (GeroScience, 2023)

Longitudinal association of executive function and structural network controllability in the aging brain - Rongxiang Tang; Jeremy A. Elman; Carol E. Franz; Anders M. Dale; Lisa T. Eyler; Christine Fennema-Notestine; Donald J. Hagler; Michael J. Lyons; Matthew S. Panizzon; Olivia K. Puckett; William S. Kremen (GeroScience, 2023)
Executive function encompasses effortful cognitive processes that are particularly susceptible to aging. Functional brain networks supporting executive function—such as the frontoparietal control network and the multiple demand system—have been extensively investigated. However, it remains unclear how structural networks facilitate and constrain the dynamics of functional networks to contribute to aging-related executive function declines. We examined whether changes in structural network modal controllability—a network’s ability to facilitate effortful brain state transitions that support cognitive functions—are associated with changes in executive function cross-sectionally and longitudinally. Diffusion-weighted imaging and neuropsychological testing were conducted at two time points (Time 1: ages 56 to 66, N = 172; Time 2: ages 61 to 70, N = 267) in community-dwelling men from the Vietnam Era Twin Study of Aging. An executive function factor score was computed from six neuropsychological tasks. Structural networks constructed from white matter connectivity were used to estimate modal controllability in control network and multiple demand system. We showed that higher modal controllability in control network and multiple demand system was associated with better executive function at Time 2, after controlling for age, young adult general cognitive ability, and physical health status. Moreover, changes in executive function over a period of 5 to 6 years (Time 1-Time 2, N = 105) were associated with changes in modal controllability of the multiple demand system and weakly in the control network over the same time period. These findings suggest that changes in the ability of structural brain networks in facilitating effortful brain state transitions may be a key neural mechanism underlying aging-related executive function declines and cognitive aging.

Pre-frail older adults show improved cognition with StayFitLonger computerized home–based training: a randomized controlled trial - Sylvie Belleville; M. Cuesta; M. Bieler-Aeschlimann; K. Giacomino; A. Widmer; A. G. Mittaz Hager; D. Perez-Marcos; S. Cardin; B. Boller; N. Bier; M. Aubertin-Leheudre; L. Bherer; et al. (GeroScience, 2023)
Multidomain interventions have shown tremendous potential for improving cognition in older adults. It is unclear if multidomain interventions can be delivered remotely and whether remote intervention is beneficial for older adults who are vulnerable or at risk of cognitive decline. In a 26-week multi-site, home-based, double-blind, randomized controlled trial, 120 cognitively healthy older adults (75 robust, 45 pre-frail; age range = 60–94) recruited from Switzerland, Canada, and Belgium were randomized to receive either the StayFitLonger (SFL) computerized multidomain training program or an active control intervention. Delivered on tablets, the SFL intervention combined adapted physical exercises (strength, balance, and mobility), cognitive training (divided attention, problem solving, and memory), opportunities for social and contributive interactions, and psychoeducation. The active control intervention provided basic mobilization exercises and access to video games. Cognitive outcomes were global cognition ( Z -scores of attention, verbal fluency, and episodic memory for nondemented older adults; ZAVEN), memory, executive function, and processing speed. Linear mixed model analyses indicated improved performance on the ZAVEN global cognition score in the SFL group but not in the active control group. Stratified analyses by frailty status revealed improved ZAVEN global cognition and processing speed scores following SFL in the pre-frail group but not in the robust group. Overall, the study indicates that a computerized program providing a multidomain intervention at home can improve cognition in older adults. Importantly, pre-frail individuals, who are at higher risk of cognitive decline, seem to benefit more from the intervention. Trial registration: ClinicalTrials.gov, NCT037519 Registered on January 22, 2020—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04237519 .

Poliomyelitis is a current challenge: long-term sequelae and circulating vaccine-derived poliovirus - Jorge Quarleri (GeroScience, 2023)

Oral frailty indicators to target major adverse health-related outcomes in older age: a systematic review - Vittorio Dibello; Frank Lobbezoo; Madia Lozupone; Rodolfo Sardone; Andrea Ballini; Giuseppe Berardino; Anita Mollica; Hélio José Coelho-Júnior; Giovanni De Pergola; Roberta Stallone; Antonio Dibello; Antonio Daniele; et al. (GeroScience, 2023)

Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project - Emily E. Bray; David A. Raichlen; Kiersten K. Forsyth; Daniel E. L. Promislow; Gene E. Alexander; Evan L. MacLean; Joshua M. Akey; Brooke Benton; Elhanan Borenstein; Marta G. Castelhano; Amanda E. Coleman; Kate E. Creevy; et al. (GeroScience, 2023)

How size and genetic diversity shape lifespan across breeds of purebred dogs - Cornelia Kraus; Noah Snyder-Mackler; Daniel E. L. Promislow (GeroScience, 2023)

Potassium-chelating drug sodium polystyrene sulfonate enhances lysosomal function and suppresses proteotoxicity - Cyrene Arputhasamy; Anna C. Foulger; Mark Lucanic; Anand Rane; Minna Schmidt; Theo Garrett; Michael Broussalian; Elena Battistoni; Rachel B. Brem; Gordon J. Lithgow; Manish Chamoli; Julie K. Andersen (GeroScience, 2023)

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome - Miriam Díez-Díez; Marta Amorós-Pérez; Jorge de la Barrera; Enrique Vázquez; Ana Quintas; Domingo A. Pascual-Figal; Ana Dopazo; Fátima Sánchez-Cabo; Monica E. Kleinman; Leslie B. Gordon; Valentín Fuster; Vicente Andrés; et al. (GeroScience, 2023)
Clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in cancer-related genes in blood cells in the absence of hematological cancer, has recently emerged as an important risk factor for several age-related conditions, especially cardiovascular disease. CHIP is strongly associated with normal aging, but its role in premature aging syndromes is unknown. Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare genetic condition driven by the accumulation of a truncated form of the lamin A protein called progerin. HGPS patients exhibit several features of accelerated aging and typically die from cardiovascular complications in their early teens. Previous studies have shown normal hematological parameters in HGPS patients, except for elevated platelets, and low levels of lamin A expression in hematopoietic cells relative to other cell types in solid tissues, but the prevalence of CHIP in HGPS remains unexplored. To investigate the potential role of CHIP in HGPS, we performed high-sensitivity targeted sequencing of CHIP-related genes in blood DNA samples from a cohort of 47 HGPS patients. As a control, the same sequencing strategy was applied to blood DNA samples from middle-aged and elderly individuals, expected to exhibit a biological age and cardiovascular risk profile similar to HGPS patients. We found that CHIP is not prevalent in HGPS patients, in marked contrast to our observations in individuals who age normally. Thus, our study unveils a major difference between HGPS and normal aging and provides conclusive evidence that CHIP is not frequent in HGPS and, therefore, is unlikely to contribute to the pathophysiology of this accelerated aging syndrome.

Modeling human gray hair by irradiation as a valuable tool to study aspects of tissue aging - Da-mao Dai; Ye He; Qing Guan; Zhe-xiang Fan; Yunmin Zhu; Jin Wang; Shulian Wu; Jian Chen; Demengjie Le; Zhi-qi Hu; Qian Qu; Yong Miao (GeroScience, 2023)

Can frailty scores predict the incidence of cancer? Results from two large population-based studies - Jonathan K. L. Mak; Ralf Kuja-Halkola; Yunzhang Wang; Sara Hägg; Juulia Jylhävä (GeroScience, 2023)
While chronological age is the single biggest risk factor for cancer, it is less clear whether frailty, an age-related state of physiological decline, may also predict cancer incidence. We assessed the associations of frailty index (FI) and frailty phenotype (FP) scores with the incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, melanoma) in 453,144 UK Biobank (UKB) and 36,888 Screening Across the Lifespan Twin study (SALT) participants, who aged 38–73 years and had no cancer diagnosis at baseline. During a median follow-up of 10.9 and 10.7 years, 53,049 (11.7%) and 4,362 (11.8%) incident cancers were documented in UKB and SALT, respectively. Using multivariable-adjusted Cox models, we found a higher risk of any cancer in frail vs. non-frail UKB participants, when defined by both FI (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 1.17–1.28) and FP (HR = 1.16; 95% CI = 1.11–1.21). The FI in SALT similarly predicted risk of any cancer (HR = 1.31; 95% CI = 1.15–1.49). Moreover, frailty was predictive of lung cancer in UKB, although this association was not observed in SALT. Adding frailty scores to models including age, sex, and traditional cancer risk factors resulted in little improvement in C-statistics for most cancers. In a within-twin-pair analysis in SALT, the association between FI and any cancer was attenuated within monozygotic but not dizygotic twins, indicating that it may partly be explained by genetic factors. Our findings suggest that frailty scores are associated with the incidence of any cancer and lung cancer, although their clinical utility for predicting cancers may be limited.

Kinetic proteomics identifies targeted changes in liver metabolism and the ribo-interactome by dietary sulfur amino acid restriction - William O. Jonsson; Agnieszka K. Borowik; Atul Pranay; Michael T. Kinter; Emily T. Mirek; Jordan L. Levy; Elizabeth M. Snyder; Benjamin F. Miller; Tracy G. Anthony (GeroScience, 2023)
Dietary sulfur amino acid restriction (SAAR) protects against diet-induced obesity, extends healthspan, and coincides with an overall reduction in hepatic protein synthesis. To explore the underpinnings of SAAR-induced slowed growth and its impact on liver metabolism and proteostasis, we resolved changes in hepatic mRNA and protein abundances and compared synthesis rates of individual liver proteins. To achieve this, adult male mice were provided deuterium-labeled drinking water while freely consuming either a regular-fat or high-fat diet that was SAA restricted. Livers from these mice and their respective dietary controls were used to conduct transcriptomic, proteomic, and kinetic proteomic analyses. We found that remodeling of the transcriptome by SAAR was largely agnostic to dietary fat content. Shared signatures included activation of the integrated stress response alongside alterations in metabolic processes impacting lipids, fatty acids, and amino acids. Changes to the proteome correlated poorly with the transcriptome, and yet, functional clustering of kinetic proteomic changes in the liver during SAAR revealed that the management of fatty acids and amino acids were altered to support central metabolism and redox balance. Dietary SAAR also strongly influenced the synthesis rates of ribosomal proteins and ribosome-interacting proteins regardless of dietary fat. Taken together, dietary SAAR alters the transcriptome and proteome in the liver to safely manage increased fatty acid flux and energy use and couples this with targeted changes in the ribo-interactome to support proteostasis and slowed growth.

Effect of Nrf2 loss on senescence and cognition of tau-based P301S mice - Ruben Riordan; Wang Rong; Zhen Yu; Grace Ross; Juno Valerio; Jovita Dimas-Muñoz; Valeria Heredia; Kathy Magnusson; Veronica Galvan; Viviana I. Perez (GeroScience, 2023)

Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome - Martí Llaurador-Coll; Santiago Rios; Jesus F. García-Gavilán; Nancy Babio; Elisabet Vilella; Jordi Salas-Salvadó (GeroScience, 2023)
Cognitive impairment is present in a broad spectrum of medical conditions and in aging. Here, we aimed to identify plasma proteins related to cognitive function in a sample of older adults with overweight/obesity and metabolic syndrome. A total of 129 subjects (mean age 64.7 years; 36% females) were grouped according to low (l-GCF, N =65) or high (h-GCF, N =64) global cognitive function and matched according to education, sex, age, and body mass index. Cognitive performance was assessed using neuropsychological tests. Plasma levels of 92 neurology-related proteins were assessed using a proximity extension assay. An elastic net regression analysis was used to identify proteins more associated with cognitive performance. Additionally, the protein expression levels were compared between the two groups by means of a t -test with false discovery rate correction. Pearson correlations were used to assess associations between the protein levels and scores from the neurocognitive tests. Six proteins (alpha-2-MRAP, HAGH, Siglec-9, MDGA1, IL12, and EDA2R) were identified as potential contributors to cognitive performance, remaining significantly increased in l-GCF compared to h-GCF participants after correction for multiple testing. Negative correlations ( r = −0.23 to −0.18, i.e., lower protein levels, higher cognitive function) were found between global cognitive function and Siglec-9, NMNAT1, HAGH, LXN, gal-8, alpha-2-MRAP, IL12, PDGF-R-alpha, NAAA, EDA2R, CLEC1B, and LAT. Mini-mental state examination z scores showed the strongest correlations with protein levels, specifically negative correlations with CLEC1b, LXN, LAT, PLXNB3, NMNAT1, gal-8, HAGH, NAAA, CTSS, EZR, KYNU, MANF ( r =−0.38 to −0.26) and a positive correlation with ADAM23 ( r = 0.26). In summary, we identified several plasma proteins that were significantly associated with cognitive performance in older adults with obesity and metabolic syndrome, although further research is needed to replicate the results in larger samples and to include a predictive perspective.

Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity - Eric Dec; James Clement; Kaiyang Cheng; George M. Church; Michael B. Fossel; David H. Rehkopf; Luis Rosero-Bixby; Michael S. Kobor; David TS. Lin; Ake T. Lu; Zhe Fei; Wei Guo; et al. (GeroScience, 2023)
Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated ( r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.

Older mice show decreased regeneration of neuromuscular junctions following lengthening contraction-induced injury - Thomas A. Paul; Peter C. Macpherson; Tara L. Janetzke; Carol S. Davis; Malcolm J. Jackson; Anne McArdle; Susan V. Brooks (GeroScience, 2023)

Exploring the secrets of super-aging: a UK Biobank study on brain health and cognitive function - Brandon S. Klinedinst; Mihir K. Kharate; Parvin Mohammadiarvejeh; Mohammad Fili; Amy Pollpeter; Brittany A. Larsen; Shannin Moody; Qian Wang; Karin Allenspach; Jonathan P. Mochel; Auriel A. Willette (GeroScience, 2023)

Longitudinal characterization of cerebral hemodynamics in the TgF344-AD rat model of Alzheimer’s disease - Xing Fang; Chengyun Tang; Huawei Zhang; Jane J. Border; Yedan Liu; Seung Min Shin; Hongwei Yu; Richard J. Roman; Fan Fan (GeroScience, 2023)

Ketogenic diets initiated in late mid-life improved measures of spatial memory in male mice - Zeyu Zhou; Kyoungmi Kim; Jon J. Ramsey; Jennifer M. Rutkowsky (GeroScience, 2023)
Studies have shown ketogenic diets (KD) started from early middle-age improved health span and longevity in mice. KDs started later in life or administered intermittently may be more feasible and promote compliance. Therefore, this study sought to test if continuous or intermittent KDs started in late-middle-aged mice would improve cognition and motor function at advanced age. Eighteen-month-old male C57BL/6JN mice were assigned to an isocaloric control (CD), KD, or intermittent ketogenic (IKD, 3-day KD/week) diet. A panel of behavior tests were performed to assess cognitive and motor functions with aging. Y-maze alternation rate was higher for both IKD and KD mice at 23 months of age and for KD mice at 26 months indicating an improved spatial working memory. Twenty-six-month-old KD mice also showed better spatial learning memory in Barnes maze when compared to the CD. Improved grid wire hang performance was observed in aged IKD and KD versus CD mice indicating better muscle endurance under isometric contraction. A reduced level of circulating proinflammatory cytokines in aged KD (IL-6 and TNF-α) and IKD (IL-6) mice may contribute to the phenotypic improvements observed with these interventions. This study demonstrates that when initiated at late-middle age, the KD improved measures of spatial memory and grid wire hang performance in aged male mice, with IKD showing results intermediate to the CD and KD groups.

Association between cardiovascular health metrics and retinal ageing - Ruiye Chen; Jinyi Xu; Xianwen Shang; Gabriella Bulloch; Mingguang He; Wei Wang; Zhuoting Zhu (GeroScience, 2023)
The study aims to investigate associations between cardiovascular health (CVH) metrics and retinal ageing indexed by retinal age gap. A total of 26,354 participants from the UK Biobank study with available CVH metrics and qualified retinal imaging were included in the present analysis. CVH included 7 metrics (smoking, physical activity, diet, body mass index [BMI], total cholesterol, blood pressure [BP], blood glucose). These were summarized to classify the overall CVH as poor (0–7), intermediate (8–10) or ideal (11–14). Retinal age gap was defined as the difference between biological age predicted by fundus images and chronological age. Accelerated and non-accelerated retinal ageing was defined if retinal age gap was in the upper or lower 50% quantiles of the study population, respectively. Linear and logistic regression models estimated the association of overall CVH and each metric of CVH with retinal age gap respectively. Our results showed that in the fully adjusted model, each one-unit score increase in overall CVH was negatively associated with retinal age gap (odds ratio [OR] = 0.89, 95% confidence interval [CI]: 0.87-0.92, P < 0.001). Compared with poor overall CVH, people with intermediate and ideal overall CVH had significantly lower retinal age gap (OR = 0.76, 95%CI: 0.67–0.85, P < 0.001; OR = 0.58, 95%CI: 0.50–0.67, P < 0.001). Similar associations were found between overall CVH and accelerated retinal ageing. CVH metrics including smoking, BMI, BP, and blood glucose were also significantly associated with higher retinal age gap. Taken together, we found a significant and inverse dose-response association between CVH metrics and retinal age gap, indicating that maintaining healthy metrics especially smoking, BMI, BP, and blood glucose may be crucial to slow down biological ageing.

A genome-wide association study of frailty identifies significant genetic correlation with neuropsychiatric, cardiovascular, and inflammation pathways - Yixuan Ye; Rommell B. Noche; Natalia Szejko; Cameron P. Both; Julian N. Acosta; Audrey C. Leasure; Stacy C. Brown; Kevin N. Sheth; Thomas M. Gill; Hongyu Zhao; Guido J. Falcone (GeroScience, 2023)

Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice - Xinna Li; Madaline McPherson; Mary Hager; Michael Lee; Peter Chang; Richard A. Miller (GeroScience, 2023)

Ovarian aging in humans: potential strategies for extending reproductive lifespan - Marcelo Borges Cavalcante; Olga Goiana Martins Sampaio; Fernanda Eunice Araújo Câmara; Augusto Schneider; Bianca Machado de Ávila; Juliane Prosczek; Michal M. Masternak; Adriana Rolim Campos (GeroScience, 2023)

Assessing tolerability and physiological responses to 17α-estradiol administration in male rhesus macaques - Michael B. Stout; Kelli L. Vaughan; Jose V. V. Isola; Shivani N. Mann; Bayli Wellman; Jessica M. Hoffman; Hunter L. Porter; Willard M. Freeman; Julie A. Mattison (GeroScience, 2023)

Banking on a new understanding: translational opportunities from veterinary biobanks - D. LaLonde-Paul; L. Mouttham; Joshua M. Akey; Brooke Benton; Elhanan Borenstein; Amanda E. Coleman; Kate E. Creevy; Kyle Crowder; Matthew D. Dunbar; Virginia R. Fajt; Annette L. Fitzpatrick; Unity Jeffery; et al. (GeroScience, 2023)

Proteomic basis of mortality resilience mediated by FOXO3 longevity genotype - Timothy A. Donlon; Brian J. Morris; Randi Chen; Eunjung Lim; Eric K. Morgen; Kristen Fortney; Naisha Shah; Kamal H. Masaki; Bradley J. Willcox (GeroScience, 2023)
FOXO3 is a ubiquitous transcription factor expressed in response to cellular stress caused by nutrient deprivation, inflammatory cytokines, reactive oxygen species, radiation, hypoxia, and other factors. We showed previously that the association of inherited FOXO3 variants with longevity was the result of partial protection against mortality risk posed by aging-related life-long stressors, particularly cardiometabolic disease. We then referred to the longevity-associated genotypes as conferring “mortality resilience.” Serum proteins whose levels change with aging and are associated with mortality risk may be considered as “stress proteins.” They may serve as indirect measures of life-long stress. Our aims were to (1) identify stress proteins that increase with aging and are associated with an increased risk of mortality, and (2) to determine if FOXO3 longevity/resilience genotype dampens the expected increase in mortality risk they pose. A total of 4500 serum protein aptamers were quantified using the Somalogic SomaScan proteomics platform in the current study of 975 men aged 71–83 years. Stress proteins associated with mortality were identified. We then used age-adjusted multivariable Cox models to investigate the interaction of stress protein with FOXO3 longevity-associated rs12212067 genotypes. For all the analyses, the p values were corrected for multiple comparisons by false discovery rate. This led to the identification of 44 stress proteins influencing the association of FOXO3 genotype with reduced mortality. Biological pathways were identified for these proteins. Our results suggest that the FOXO3 resilience genotype functions by reducing mortality in pathways related to innate immunity, bone morphogenetic protein signaling, leukocyte migration, and growth factor response.

Results of a systematic review and meta-analysis of early studies on ivermectin in SARS-CoV-2 infection - Zsuzsanna Ragó; Barbara Tóth; Ágnes Szalenko-Tőkés; Zsolt Bella; Fanni Dembrovszky; Nelli Farkas; Szabolcs Kiss; Péter Hegyi; Mária Matuz; Noémi Tóth; Imre Hegedüs; Domokos Máthé; et al. (GeroScience, 2023)
Ivermectin, an antiparasitic drug, has been repurposed for COVID-19 treatment during the SARS-CoV-2 pandemic. Although its antiviral efficacy was confirmed early in vitro and in preclinical studies, its clinical efficacy remained ambiguous. Our purpose was to assess the efficacy of ivermectin in terms of time to viral clearance based on the meta-analysis of available clinical trials at the closing date of the data search period, one year after the start of the pandemic. This meta-analysis was reported by following the PRISMA guidelines and by using the PICO format for formulating the question. The study protocol was registered on PROSPERO. Embase, MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), bioRvix, and medRvix were searched for human studies of patients receiving ivermectin therapy with control groups. No language or publication status restrictions were applied. The search ended on 1/31/2021 exactly one year after WHO declared the public health emergency on novel coronavirus. The meta-analysis of three trials involving 382 patients revealed that the mean time to viral clearance was 5.74 days shorter in case of ivermectin treatment compared to the control groups [WMD = −5.74, 95% CI (−11.1, −0.39), p = 0.036]. Ivermectin has significantly reduced the time to viral clearance in mild to moderate COVID-19 diseases compared to control groups. However, more eligible studies are needed for analysis to increase the quality of evidence of ivermectin use in COVID-19.

Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction - Brandon J. Berry; Evan Mjelde; Fatima Carreno; Kathryn Gilham; Emily J. Hanson; Emily Na; Matt Kaeberlein (GeroScience, 2023)

Increased α-2,6 sialic acid on microglia in amyloid pathology is resistant to oseltamivir - Caitlyn Fastenau; Jessica L. Wickline; Sabrina Smith; Kristian F. Odfalk; Leigh Solano; Kevin F. Bieniek; Sarah C. Hopp (GeroScience, 2023)

Mitochondrial proton leak in cardiac aging - Xingyun Qi; Nancy J. Rusch; Jiaojiao Fan; Christoph J. Mora; Lixin Xie; Shengyu Mu; Peter S. Rabinovitch; Huiliang Zhang (GeroScience, 2023)

Discovery and ranking of the most robust prognostic biomarkers in serous ovarian cancer - Balázs Győrffy (GeroScience, 2023)
Progress in ovarian cancer treatment lags behind other tumor types. With diagnosis usually at an advanced stage, there is a high demand for reliable prognostic biomarkers capable of the selection of effective chemo- and targeted therapies. Our goal was to establish a large-scale transcriptomic database and use it to uncover and rank survival-associated genes. Ovarian cancer cohorts with transcriptome-level gene expression data and clinical follow-up were identified from public repositories. All samples were normalized and entered into an integrated database. Cox univariate survival analysis was performed for all genes and was followed by multivariate analysis for selected genes involving clinical and pathological variables. False discovery rate was computed for multiple hypothesis testing and a 1% cutoff was used to determine statistical significance. The complete integrated database comprises 1816 samples from 17 datasets. Altogether, 2468 genes were correlated to progression-free survival (PFS), and 704 genes were correlated with overall survival (OS). The most significant genes were WBP1L, ASAP3, CNNM2, and NCAPH2 for progression-free survival and CSE1L, NUAK1, ALPK2, and SHKBP1 for overall survival. Genes significant for PFS were also preferentially significant for predicting OS as well. All data including HR and p values as well as the used cutoff values for all genes for both PFS and OS are provided to enable the ranking of future biomarker candidates across all genes. Our results help to prioritize genes and to neglect those which are most likely to fail in studies aiming to establish new clinically useful biomarkers and therapeutic targets in serous ovarian cancer.

The impacts of social determinants of health and cardiometabolic factors on cognitive and functional aging in Colombian underserved populations - Hernando Santamaria-Garcia; Sebastian Moguilner; Odir Antonio Rodriguez-Villagra; Felipe Botero-Rodriguez; Stefanie Danielle Pina-Escudero; Gary O’Donovan; Cecilia Albala; Diana Matallana; Michael Schulte; Andrea Slachevsky; Jennifer S. Yokoyama; Katherine Possin; et al. (GeroScience, 2023)
Global initiatives call for further understanding of the impact of inequity on aging across underserved populations. Previous research in low- and middle-income countries (LMICs) presents limitations in assessing combined sources of inequity and outcomes (i.e., cognition and functionality). In this study, we assessed how social determinants of health (SDH), cardiometabolic factors (CMFs), and other medical/social factors predict cognition and functionality in an aging Colombian population. We ran a cross-sectional study that combined theory- (structural equation models) and data-driven (machine learning) approaches in a population-based study ( N = 23,694; M = 69.8 years) to assess the best predictors of cognition and functionality. We found that a combination of SDH and CMF accurately predicted cognition and functionality, although SDH was the stronger predictor. Cognition was predicted with the highest accuracy by SDH, followed by demographics, CMF, and other factors. A combination of SDH, age, CMF, and additional physical/psychological factors were the best predictors of functional status. Results highlight the role of inequity in predicting brain health and advancing solutions to reduce the cognitive and functional decline in LMICs.

Remission of insomnia in older adults treated with cognitive behavioral therapy for insomnia (CBT-I) reduces p16INK4a gene expression in peripheral blood: secondary outcome analysis from a randomized clinical trial - Judith E. Carroll; Richard Olmstead; Steve W. Cole; Elizabeth C. Breen; Jesusa M. Arevalo; Michael R. Irwin (GeroScience, 2023)
Late life insomnia may increase risk for accelerated biological aging. Intervening to treat insomnia may provide protection from biological aging by reducing the prevalence of senescent cells in the immune system, as indicated by gene expression of a marker of cellular senescence, p16 INK4a . In the present study, we determine whether treatment of insomnia in older adults with cognitive behavioral therapy for insomnia (CBT-I) would reduce p16 INK4a gene expression in peripheral blood mononuclear cells (PBMC), compared to a sleep education therapy (SET), an active comparator condition. Secondly, we investigate the relationship between sustained insomnia remission and reduced expression of p16 INK4a . Participants 60 + years old with insomnia were enrolled in a randomized controlled trial and assigned to CBT-I or SET. Analyses of 231 older adults (CBT-I = 119; SET = 112) examine baseline, post (2 months), and 24 months gene expression of p16 INK4a . Compared to baseline, expression of p16 INK4a increased in the SET group over 24 months ( P = 0.03), but showed no change in the CBT-I group. Those who received CBT-I and experienced sustained remission of insomnia had a significant decline in p16 INK4a expression by 24 months compared to baseline ( P = 0.02). Individuals not sustaining remission of insomnia exhibited overall increase expression of p16 INK4a by 24 months ( P = 0.03). In older adults with insomnia, p16 INK4a increases over 24 months, while CBT-I treatment of insomnia mitigates the increase in p16 INK4a . Further, sustained remission of insomnia using CBT-I leads to a decrease in p16 INK4a . These results suggest that behavioral interventions that are effective at treating insomnia might reduce the population of senescent cells in circulating blood.

Intermittent treatment with elamipretide preserves exercise tolerance in aged female mice - Matthew D. Campbell; Ashton T. Samuelson; Ying Ann Chiao; Mariya T. Sweetwyne; Warren C. Ladiges; Peter S. Rabinovitch; David J. Marcinek (GeroScience, 2023)

Ultra-processed food consumption and nutritional frailty in older age - Roberta Zupo; Rossella Donghia; Fabio Castellana; Ilaria Bortone; Sara De Nucci; Annamaria Sila; Rossella Tatoli; Luisa Lampignano; Giancarlo Sborgia; Francesco Panza; Madia Lozupone; Giuseppe Colacicco; et al. (GeroScience, 2023)
Frailty is a multidisciplinary public health issue and nutrition is key concern. Given the scientific consistency about inflammation as shared pathway to poor nutrition and frailty, food processing seems a suitable target to gain evidence in frailty prevention nutrition settings. This study aimed to assess diet in relation to nutritional frailty using the NOVA classification. Browsing the dataset of the Salus in Apulia, 2185 older adults were found to have completed the nutritional assessment, providing eligible data for this study goal. A validated construct, based on the co-presence of physical frailty by CHS criteria plus nutritional imbalance, was applied to characterize nutritional frailty phenotypes. Using the NOVA classification, daily food and beverage intakes from an 85-item self-administered FFQ were assigned to three categories, and effect sizes were tested among groups according to nutritional frailty status (presence/absence). Raw and adjusted logistic regression models were run to assess associations between NOVA food categories by quintiles of daily exposure (very-low, low, mild, moderate, high) and nutritional frailty. Nutritional frailty prevalence was 27%, being more frequent in males. Eating more unprocessed or minimally processed foods was inversely related to nutritional frailty, even after adjustment (OR: 0.10, 95%CI 0.07–0.16), showing a downward ORs behavior toward lower consumption quintiles. Listing in the quintile of moderate consumption of processed foods meant a nearly 50% increase in nutritional frailty probability (OR: 1.46, 95%CI 1.03–2.06), while the probability was double for the highest quintile against the lowest (OR: 3.22, 95%CI 2.27–4.58). A growing probability of nutritional frailty was found for increasing consumption of ultra-processed foods, but significance was lacking. The contribution of food processing to poor nutrition needs to be considered when promoting a better understanding of effective nutritional screening in aging. Therefore, food processing should be accounted for when composing diet guidelines for the older population within the framework of multidisciplinary efforts to ease the frailty healthcare burden.

Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo - Amanda J. Stock; Saipriya Ayyar; Amogh Kashyap; Yunong Wang; Hagai Yanai; Matthew F. Starost; Mayuri Tanaka-Yano; Monica Bodogai; Chongkui Sun; Yajun Wang; Yi Gong; Chandrakala Puligilla; et al. (GeroScience, 2023)
Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null ( Tert −/− ) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert −/− mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert −/− hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert −/− transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.

Soluble and insoluble protein aggregates, endoplasmic reticulum stress, and vascular dysfunction in Alzheimer’s disease and cardiovascular diseases - Emily W. Waigi; R. Clinton Webb; Melissa A. Moss; Mark J. Uline; Cameron G. McCarthy; Camilla Ferreira Wenceslau (GeroScience, 2023)

Accelerated epigenetic aging in older adults with HIV disease: associations with serostatus, HIV clinical factors, and health literacy - Steven Paul Woods; Antonio L. Teixeira; Lais B. Martins; Gabriel R. Fries; Gabriela D. Colpo; Natalia P. Rocha (GeroScience, 2023)

Sex differences in skeletal muscle-aging trajectory: same processes, but with a different ranking - Jelle C.B.C. de Jong; Brecht J. Attema; Marjanne D. van der Hoek; Lars Verschuren; Martien P.M. Caspers; Robert Kleemann; Feike R. van der Leij; Anita M. van den Hoek; Arie G. Nieuwenhuizen; Jaap Keijer (GeroScience, 2023)
Sex differences in muscle aging are poorly understood, but could be crucial for the optimization of sarcopenia-related interventions. To gain insight into potential sex differences in muscle aging, we recruited young (23 ± 2 years, 13 males and 13 females) and old (80 ± 3.5 years, 28 males and 26 females) participants. Males and females in both groups were highly matched, and vastus lateralis muscle parameters of old versus young participants were compared for each sex separately, focusing on gene expression. The overall gene expression profiles separated the sexes, but similar gene expression patterns separated old from young participants in males and females. Genes were indeed regulated in the same direction in both sexes during aging; however, the magnitude of differential expression was sex specific. In males, oxidative phosphorylation was the top-ranked differentially expressed process, and in females, this was cell growth mediated by AKT signaling. Findings from RNA-seq data were studied in greater detail using alternative approaches. In addition, we confirmed our data using publicly available data from three independent human studies. In conclusion, top-ranked pathways differ between males and females, but were present and altered in the same direction in both sexes. We conclude that the same processes are associated with skeletal muscle aging in males and females, but the differential expression of those processes in old vs. young participants is sex specific.

Long-term outcome of cardiac resynchronization therapy patients in the elderly - Anett Behon; Eperke Dóra Merkel; Walter Richard Schwertner; Luca Katalin Kuthi; Boglárka Veres; Richard Masszi; Attila Kovács; Bálint Károly Lakatos; Endre Zima; László Gellér; Annamária Kosztin; Béla Merkely (GeroScience, 2023)
Heart failure (HF) is a leading cause of mortality and hospitalization in the elderly. However, data are scarce about their response to device treatment such as cardiac resynchronization therapy (CRT). We aimed to evaluate the age-related differences in the effectiveness of CRT, procedure-related complications, and long-term outcome. Between 2000 and 2020, 2656 patients undergoing CRT implantation were registered and analyzed retrospectively. Patients were divided into 3 groups according to their age: group I, < 65; group II, 65–75; and group III, > 75 years. The primary endpoint was the echocardiographic response defined as a relative increase > 15% in left ventricular ejection fraction (LVEF) within 6 months, and the secondary endpoint was the composite of all-cause mortality, heart transplantation, or left ventricular assist device implantation. Procedure-related complications were also assessed. After implantation, LVEF showed significant improvement both in the total cohort [28% ( IQR 24/33) vs. 35% ( IQR 28/40); p < 0.01)] and in each subgroup (27% vs. 34%; p < 0.01, 29% vs. 35%; p < 0.01, 30% vs. 35%; p < 0.01). Response rate was similar in the 3 groups (64% vs. 62% vs. 56%; p = 0.41). During the follow-up, 1574 (59%) patients died. Kaplan–Meier curves revealed a significantly lower survival rate in the older groups (log-rank p < 0.001). The cumulative complication rates were similar among the three age groups (27% vs. 28% vs. 24%; p = 0.15). Our results demonstrate that CRT is as effective and safe therapy in the elderly as for young ones. The present data suggest that patients with appropriate indications benefit from CRT in the long term, regardless of age.

Measurements of cerebral microvascular blood flow, oxygenation, and morphology in a mouse model of whole-brain irradiation-induced cognitive impairment by two-photon microscopy and optical coherence tomography: evidence for microvascular injury in the cerebral white matter - Baoqiang Li; Andriy Yabluchanskiy; Stefano Tarantini; Srinivasa Rao Allu; Ikbal Şencan-Eğilmez; Ji Leng; Mohammed Ali H. Alfadhel; Jason E. Porter; Buyin Fu; Chongzhao Ran; Sefik Evren Erdener; David A. Boas; et al. (GeroScience, 2023)

Glycocalyx-targeted therapy ameliorates age-related arterial dysfunction - Daniel R. Machin; Daniel W. Trott; Venkateswara R. Gogulamudi; Md. Torikul Islam; Samuel I. Bloom; Hans Vink; Lisa A. Lesniewski; Anthony J. Donato (GeroScience, 2023)

Sex-specific relationships between obesity, physical activity, and gray and white matter volume in cognitively unimpaired older adults - Brittany Intzandt; Safa Sanami; Julia Huck; Anne Labonté; Alexa Pichet Binette; Axel Mathieu; Cynthia Picard; Doris Dea; Claudio Cuello; Alan Evans; Christine Tardif; Gerhard Mulhaup; et al. (GeroScience, 2023)

Evaluating instruments for assessing healthspan: a multi-center cross-sectional study on health-related quality of life (HRQL) and frailty in the companion dog - Frances L. Chen; Tarini V. Ullal; Jessica L. Graves; Ellen R. Ratcliff; Alexander Naka; Brennen McKenzie; Tennery A. Carttar; Kaitlyn M. Super; Jessica Austriaco; Sunny Y. Weber; Julie Vaughn; Michael L. LaCroix-Fralish (GeroScience, 2023)
Developing valid tools that assess key determinants of canine healthspan such as frailty and health-related quality of life (HRQL) is essential to characterizing and understanding aging in dogs. Additionally, because the companion dog is an excellent translational model for humans, such tools can be applied to evaluate gerotherapeutics and investigate mechanisms underlying longevity in both dogs and humans. In this multi-center, cross-sectional study, we investigated the use of a clinical questionnaire (Canine Frailty Index; CFI; Banzato et al., 2019) to assess frailty and an owner assessment tool (VetMetrica HRQL) to evaluate HRQL in 451 adult companion dogs. Results demonstrated validity of the tools by confirming expectations that frailty score increases and HRQL scores deteriorate with age. CFI scores were significantly higher (higher frailty) and HRQL scores significantly lower (worse HRQL) in old dogs (≥ 7 years of age) compared to young dogs (≥ 2 and < 6 years of age). Body size (small < 11.3 kg (25 lbs) or large > 22.7 kg (50 lbs)) was not associated with CFI or total HRQL score. However, older, larger dogs showed faster age-related decline in HRQL scores specific to owner-reported activity and comfort. Findings suggest that the clinician-assessed CFI and owner-reported VetMetrica HRQL are useful tools to evaluate two determinants of healthspan in dogs: the accumulation of frailty and the progressive decline in quality of life. Establishing tools that operationalize the assessment of canine healthspan is critical for the advancement of geroscience and the development of gerotherapeutics that benefit both human and veterinary medicine. Graphical abstract

Power and distribution of evoked gamma oscillations in brain aging and cognitive performance - Aftab Bakhtiari; Jacob Petersen; Olalla Urdanibia-Centelles; Mostafa Mehdipour Ghazi; Birgitte Fagerlund; Erik Lykke Mortensen; Merete Osler; Martin Lauritzen; Krisztina Benedek (GeroScience, 2023)

Correction to: Differential plasma protein expression after ingestion of essential amino acid-based dietary supplement versus whey protein in low physical functioning older adults - Gohar Azhar; Ambika Verma; Xiaomin Zhang; Amanda Pangle; Pankaj Patyal; Wei Zhang; Yingni Che; Karen Coker; Robert R. Wolfe; Jeanne Y. Wei (GeroScience, 2023)

Cardiovascular correlates of epigenetic aging across the adult lifespan: a population-based study - Dan Liu; N. Ahmad Aziz; Gökhan Pehlivan; Monique M. B. Breteler (GeroScience, 2023)
Individuals with a similar chronological age can exhibit marked differences in cardiovascular risk profiles, but it is unknown whether this variation is related to different rates of biological aging. Therefore, we investigated the relation between nine domains of cardiovascular function and four epigenetic age acceleration estimators (i.e., AgeAccel.Horvath, AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim), derived from DNA methylation profiles. Among 4194 participants (mean age 54.2 years (range 30.0–95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany, epigenetic age acceleration increased by 0.19–1.84 years per standard deviation (SD) increase in cardiovascular risk across multiple domains, including measures of kidney function, adiposity, and a composite cardiovascular risk score. Measures of inflammation and glucose homeostasis were associated with AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim, but not with AgeAccel.Horvath. Moreover, effect sizes were larger for AgeAccelPheno and AgeAccelGrim than for AgeAccel.Horvath and AgeAccel.Hannum. Similarly, epigenetic age acceleration increased by 0.15–0.81 years per SD increase in markers of vascular function (blood pressure, arterial stiffness, and hemodynamic measures), whereas better endothelial function was only associated with lower AgeAccelGrim. Most effects on epigenetic age acceleration were independent, which suggests they independently contribute to different rates of biological aging.

The cerebellum is causally involved in episodic memory under aging - Jorge Almeida; Ana R. Martins; Lénia Amaral; Daniela Valério; Qasim Bukhari; Guilherme Schu; Joana Nogueira; Mónica Spínola; Ghazaleh Soleimani; Filipe Fernandes; Ana R. Silva; Felipe Fregni; et al. (GeroScience, 2023)
Episodic memory decline is a major signature of both normal and pathological aging. Many neural regions have been implicated in the processes subserving both episodic memory and typical aging decline. Here, we demonstrate that the cerebellum is causally involved episodic memory under aging. We show that a 12-day neurostimulation program delivered to the right cerebellum led to improvements in episodic memory performance under healthy aging that long outlast the stimulation period — healthy elderly individuals show episodic memory improvement both immediately after the intervention program and in a 4-month follow-up. These results demonstrate the causal relevance of the cerebellum in processes associated with long-term episodic memory, potentially highlighting its role in regulating and maintaining cognitive processing. Moreover, they point to the importance of non-pharmacological interventions that prevent or diminish cognitive decline in healthy aging.

The puzzle of underreporting disability among tribal population in India: is it a statistical artifact or reality? - Neha Kumari; Nandita Saikia; S. V. Subramanian (GeroScience, 2023)

George M. Martin: tribute and personal remembrance - Steven N. Austad (GeroScience, 2023)

Plasma microglial-derived extracellular vesicles are increased in frail patients with Mild Cognitive Impairment and exert a neurotoxic effect - C. Visconte; M.T. Golia; C. Fenoglio; M. Serpente; M. Gabrielli; M. Arcaro; F. Sorrentino; M. Busnelli; A. Arighi; G. Fumagalli; E. Rotondo; P. Rossi; et al. (GeroScience, 2023)
Extracellular vesicles (EVs) are mediators of cellular communication that can be released by almost all cell types in both physiological and pathological conditions and are present in most biological fluids. Such characteristics make them attractive in the research of biomarkers for age-related pathological conditions. Based on this, the aim of the present study was to examine the changes in EV concentration and size in the context of frailty, a geriatric syndrome associated with a progressive physical and cognitive decline. Specifically, total EVs and neural and microglial-derived EVs (NDVs and MDVs respectively) were investigated in plasma of frail and non-frail controls (CTRL), mild cognitive impairment (MCI) subjects, and in Alzheimer’s disease (AD) patients. Results provided evidence that AD patients displayed diminished NDV concentration (3.61 × 10 9 ± 1.92 × 10 9 vs 7.16 × 10 9 ± 4.3 × 10 9 particles/ml) and showed high diagnostic performance. They are able to discriminate between AD and CTRL with an area under the curve of 0.80, a sensitivity of 78.95% and a specificity of 85.7%, considering the cut-off of 5.27 × 10 9 particles/ml. Importantly, we also found that MDV concentration was increased in frail MCI patients compared to CTRL (5.89 × 10 9 ± 3.98 × 10 9 vs 3.16 × 10 9 ± 3.04 × 10 9 particles/ml, P < 0.05) and showed high neurotoxic effect on neurons. MDV concentration discriminate frail MCI vs non-frail CTRL (AUC = 0.76) with a sensitivity of 80% and a specificity of 70%, considering the cut-off of 2.69 × 10 9 particles/ml. Altogether, these results demonstrated an alteration in NDV and MDV release during cognitive decline, providing important insight into the role of EVs in frailty status.

Differential plasma protein expression after ingestion of essential amino acid-based dietary supplement verses whey protein in low physical functioning older adults - Gohar Azhar; Ambika Verma; Xiaomin Zhang; Amanda Pangle; Pankaj Patyal; Wei Zhang; Yingni Che; Karen Coker; Robert R. Wolfe; Jeanne Y. Wei (GeroScience, 2023)
In a recent randomized, double-blind, placebo-controlled trial, we were able to demonstrate the superiority of a dietary supplement composed of essential amino acids (EAAs) over whey protein, in older adults with low physical function. In this paper, we describe the comparative plasma protein expression in the same subject groups of EAAs vs whey. The plasma proteomics data was generated using SOMA scan assay. A total of twenty proteins were found to be differentially expressed in both groups with a 1.5-fold change. Notably, five proteins showed a significantly higher fold change expression in the EAA group which included adenylate kinase isoenzyme 1, casein kinase II 2-alpha, Nascent polypeptide-associated complex subunit alpha, peroxiredoxin-1, and peroxiredoxin-6. These five proteins might have played a significant role in providing energy for the improved cardiac and muscle strength of older adults with LPF. On the other hand, fifteen proteins showed slightly lower fold change expression in the EAA group. Some of these 15 proteins regulate metabolism and were found to be associated with inflammation or other comorbidities. Gene Ontology (GO) enrichment analysis showed the association of these proteins with several biological processes. Furthermore, protein–protein interaction network analysis also showed distinct networks between upregulated and downregulated proteins. In conclusion, the important biological roles of the upregulated proteins plus better physical function of participants in the EAAs vs whey group demonstrated that EAAs have the potential to improve muscle strength and physical function in older adults. This study was registered with ClinicalTrials.gov: NCT03424265 “Nutritional interventions in heart failure.”

Long-term prognostic value of left atrial longitudinal strain in an elderly community-based cohort - Fjolla Zhubi Bakija; Zsolt Bagyura; Alexandra Fábián; Andrea Ferencz; Loretta Kiss; Orsolya Szenczi; Réka Vadas; Edit Dósa; Dat Tin Nguyen; Csaba Csobay-Novák; Ádám L. Jermendy; Zsolt Szelid; et al. (GeroScience, 2023)
Despite the well-known importance of left atrial (LA) mechanics in diastolic function, data are scarce regarding the prognostic power of LA longitudinal strain and its potential added value in the risk stratification of an elderly population. Accordingly, our aim was to determine the long-term prognostic importance of 2D speckle-tracking echocardiography-derived peak atrial longitudinal strain (PALS) in a community-based screening sample. Three hundred and fourteen volunteers were retrospectively identified from a population-based screening program (mean age 62 ± 11 years; 58% female) with a median follow-up of 9.5 years. All subjects who participated in the screening program underwent 2D echocardiography to measure left ventricular (LV) ejection fraction (EF), global longitudinal strain (GLS), and PALS, as well as low-dose cardiac CT to determine the Agatston score. The primary endpoint was all-cause mortality. Thirty-nine subjects (12.4%) met the primary endpoint. Subjects with adverse outcomes had significantly lower LV GLS (dead vs. alive; − 19.2 ± 4.3 vs. − 20.6 ± 3.5%, p < 0.05) and PALS (32.3 ± 12.0 vs. 41.8 ± 14.2%, p < 0.001), whereas LV EF did not show a difference between the two groups (51.1 ± 7.0 vs. 52.1 ± 6.2, %, p = NS). By multivariable Cox regression analysis, PALS was found to be a significant predictor of adverse outcomes independent of LV GLS, and Agatston and Framingham scores. In subjects with PALS values below the standard cut-off of 39%, the risk of all-cause mortality was almost 2.5 times higher (hazard ratio: 2.499 [95% confidence interval: 1.334–4.682], p < 0.05). Beyond the assessment of LV EF and LV GLS, PALS offers incremental value in cardiovascular risk stratification in a community-based elderly cohort. PALS was found to be a significant and independent predictor of long-term mortality among other classical cardiovascular risk estimators.

The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial - Lin Yi; Andrea B. Maier; Rongsheng Tao; Zhigang Lin; Aditi Vaidya; Sohal Pendse; Sornaraja Thasma; Niranjan Andhalkar; Ganesh Avhad; Vidyadhar Kumbhar (GeroScience, 2023)
In animal studies, β-nicotinamide mononucleotide (NMN) supplementation increases nicotinamide adenine dinucleotide (NAD) concentrations and improves healthspan and lifespan with great safety. However, it is unclear if these effects can be transferred to humans. This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial included 80 middle-aged healthy adults being randomized for a 60-day clinical trial with once daily oral dosing of placebo, 300 mg, 600 mg, or 900 mg NMN. The primary objective was to evaluate blood NAD concentration with dose-dependent regimens. The secondary objectives were to assess the safety and tolerability of NMN supplementation, next to the evaluation of clinical efficacy by measuring physical performance (six-minute walking test), blood biological age (Aging.Ai 3.0 calculator), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and subjective general health assessment [36-Item Short Form Survey Instrument (SF-36)]. Statistical analysis was performed using the Per Protocol analysis with significant level set at p = 0.05. All 80 participants completed the trial without trial protocol violation. Blood NAD concentrations were statistically significantly increased among all NMN-treated groups at day 30 and day 60 when compared to both placebo and baseline (all p ≤ 0.001). Blood NAD concentrations were highest in the groups taking 600 mg and 900 mg NMN. No safety issues, based on monitoring adverse events (AEs), laboratory and clinical measures, were found, and NMN supplementation was well tolerated. Walking distance increase during the six-minute walking test was statistically significantly higher in the 300 mg, 600 mg, and 900 mg groups compared to placebo at both days 30 and 60 (all p < 0.01), with longest walking distances measured in the 600 mg and 900 mg groups. The blood biological age increased significantly in the placebo group and stayed unchanged in all NMN-treated groups at day 60, which resulted in a significant difference between the treated groups and placebo (all p < 0.05). The HOMA-IR showed no statistically significant differences for all NMN-treated groups as compared to placebo at day 60. The change of SF-36 scores at day 30 and day 60 indicated statistically significantly better health of all three treated groups when compared to the placebo group ( p < 0.05), except for the SF-36 score change in the 300 mg group at day 30. NMN supplementation increases blood NAD concentrations and is safe and well tolerated with oral dosing up to 900 mg NMN daily. Clinical efficacy expressed by blood NAD concentration and physical performance reaches highest at a dose of 600 mg daily oral intake. This trial was registered with ClinicalTrials.gov, NCT04823260, and Clinical Trial Registry - India, CTRI/2021/03/032421.

White matter hyperintensity load varies depending on subjective cognitive decline criteria - Cassandra Morrison; Mahsa Dadar; Sylvia Villeneuve; Simon Ducharme; D. Louis Collins (GeroScience, 2023)

Data-driven health deficit assessment improves a frailty index’s prediction of current cognitive status and future conversion to dementia: results from ADNI - Andreas Engvig; Luigi A. Maglanoc; Nhat Trung Doan; Lars T. Westlye (GeroScience, 2023)
Frailty is a dementia risk factor commonly measured by a frailty index (FI). The standard procedure for creating an FI requires manually selecting health deficit items and lacks criteria for selection optimization. We hypothesized that refining the item selection using data-driven assessment improves sensitivity to cognitive status and future dementia conversion, and compared the predictive value of three FIs: a standard 93-item FI was created after selecting health deficit items according to standard criteria (FI s ) from the ADNI database. A refined FI (FI r ) was calculated by using a subset of items, identified using factor analysis of mixed data (FAMD)-based cluster analysis. We developed both FIs for the ADNI1 cohort ( n = 819). We also calculated another standard FI (FI c ) developed by Canevelli and coworkers. Results were validated in an external sample by pooling ADNI2 and ADNI-GO cohorts ( n = 815). Cluster analysis yielded two clusters of subjects, which significantly (p FDR < .05) differed on 26 health items, which were used to compute FI r . The data-driven subset of items included in FI r covered a range of systems and included well-known frailty components, e.g., gait alterations and low energy. In prediction analyses, FI r outperformed FI s and FI c in terms of baseline cognition and future dementia conversion in the training and validation cohorts. In conclusion, the data show that data-driven health deficit assessment improves an FI's prediction of current cognitive status and future dementia, and suggest that the standard FI procedure needs to be refined when used for dementia risk assessment purposes.

Understanding heterogeneity of responses to, and optimizing clinical efficacy of, exercise training in older adults: NIH NIA Workshop summary - Melissa L. Erickson; Jacob M. Allen; Daniel P. Beavers; Linda M. Collins; Karina W. Davidson; Kirk I. Erickson; Karyn A. Esser; Matthijs K. C. Hesselink; Kerrie L. Moreau; Eric B. Laber; Charlotte A. Peterson; Courtney M. Peterson; et al. (GeroScience, 2023)
Exercise is a cornerstone of preventive medicine and a promising strategy to intervene on the biology of aging. Variation in the response to exercise is a widely accepted concept that dates back to the 1980s with classic genetic studies identifying sequence variations as modifiers of the VO 2 max response to training. Since that time, the literature of exercise response variance has been populated with retrospective analyses of existing datasets that are limited by a lack of statistical power from technical error of the measurements and small sample sizes, as well as diffuse outcomes, very few of which have included older adults. Prospective studies that are appropriately designed to interrogate exercise response variation in key outcomes identified a priori and inclusive of individuals over the age of 70 are long overdue. Understanding the underlying intrinsic (e.g., genetics and epigenetics) and extrinsic (e.g., medication use, diet, chronic disease) factors that determine robust versus poor responses to various exercise factors will be used to improve exercise prescription to target the pillars of aging and optimize the clinical efficacy of exercise training in older adults. This review summarizes the proceedings of the NIA-sponsored workshop entitled, “Understanding Heterogeneity of Responses to, and Optimizing Clinical Efficacy of, Exercise Training in Older Adults” and highlights the importance and current state of exercise response variation research, particularly in older adults, prevailing challenges, and future directions.

Topographical differences in white matter hyperintensity burden and cognition in aging, MCI, and AD - Farooq Kamal; Cassandra Morrison; Josefina Maranzano; Yashar Zeighami; Mahsa Dadar (GeroScience, 2023)

Age-dependent association of clonal hematopoiesis with COVID-19 mortality in patients over 60 years - Marta Del Pozo-Valero; Marta Corton; Rosario López-Rodríguez; Ignacio Mahillo-Fernández; Javier Ruiz-Hornillos; Pablo Minguez; Cristina Villaverde; María Elena Pérez-Tomás; María Barreda-Sánchez; Esther Mancebo; Lidia Fernández-Caballero; Ruth Fernández Sanchez; et al. (GeroScience, 2023)
Clonal hematopoiesis, especially that of indeterminate potential (CHIP), has been associated with age-related diseases, such as those contributing to a more severe COVID-19. Four studies have attempted to associate CHIP with COVID-19 severity without conclusive findings. In the present work, we explore the association between CHIP and COVID-19 mortality. Genomic DNA extracted from peripheral blood of COVID-19 patients ( n = 241 deceased, n = 239 survivors) was sequenced with the Myeloid Solutions™ panel of SOPHiA Genetics. The association between clonality and age and clonality and mortality was studied using logistic regression models adjusted for sex, ethnicity, and comorbidities. The association with mortality was performed with patients stratified into four groups of age according to the quartiles of the distribution: 60–74 years, 75–84 years, 85–91 years, and 92–101 years. Clonality was found in 38% of the cohort. The presence of CHIP variants, but not the number, significantly increased with age in the entire cohort of COVID-19 patients, as well as in the group of survivors ( p < 0.001). When patients were stratified by age and the analysis adjusted, CHIP classified as pathogenic/likely pathogenic was significantly more represented in deceased patients compared with survivors in the group of 75–84 years (34.6% vs 13.7%, p = 0.020). We confirmed the well-established linear relationship between age and clonality in the cohort of COVID-19 patients and found a significant association between pathogenic/likely pathogenic CHIP and mortality in patients from 75 to 84 years that needs to be further validated.