Age- and time-dependent mitochondrial genotoxic and myopathic effects of beta-guanidinopropionic acid, a creatine analog, on rodent skeletal muscles - Allen Herbst; Judd M. Aiken; Chiye Kim; Danielle Gushue; Debbie McKenzie; Timothy M. Moore; Jin Zhou; Austin N. Hoang; Solbie Choi; Jonathan Wanagat (GeroScience, 2023)

A sex-stratified analysis of neuroimmune gene expression signatures in Alzheimer’s disease brains - Cristina Sanfilippo; Paola Castrogiovanni; Manlio Vinciguerra; Rosa Imbesi; Martina Ulivieri; Francesco Fazio; Kaj Blennow; Henrik Zetterberg; Michelino Di Rosa (GeroScience, 2023)

Delayed effects of radiation in adipose tissue reflect progenitor damage and not cellular senescence - Alistaire D. Ruggiero; Matthew A. Davis; Ashley T. Davis; Darla DeStephanis; Abigail G. Williams; Ravichandra Vemuri; Katherine M. Fanning; Chrissy Sherrill; J. Mark Cline; David L. Caudell; Kylie Kavanagh (GeroScience, 2023)

The association of measures of body shape and adiposity with incidence of cardiometabolic disease from an ageing perspective - Fleur L. Meulmeester; Ko Willems van Dijk; Simon P. Mooijaart; Diana van Heemst; Raymond Noordam (GeroScience, 2023)
While obesity increases the risk of developing cardiometabolic diseases (CMDs), these associations seem to attenuate with increasing age, albeit studied poorly. The present study aimed to investigate the associations between adiposity and CMDs in sex-specific groups of chronological age and leukocyte telomere length (LTL) as a measure of biological age. We investigated the associations between BMI, a body shape index, waist-to-hip ratio (adjusted for BMI) and total body fat, and incident coronary artery disease (CAD), type 2 diabetes (T2D) and ischemic stroke (IS) in 413,017 European-ancestry participants of the UK Biobank without CMD at baseline. We assessed the change in the associations between adiposity and CMD over strata of increasing chronological age or decreasing LTL. Participants (56% women) had a median (IQR) age of 57.0 (50.0–63.0) years. The median follow-up time was 12 years. People with higher BMI had a higher risk of incident CAD (HR 1.14 (95% confidence interval [CI] 1.13, 1.16)), T2D (HR 1.70 (95% CI 1.68, 1.72)) and IS (HR 1.09 (95% CI 1.06, 1.12)). In groups based on chronological age and LTL, adiposity measures were associated with higher risk of CAD and T2D in both men and women, but these associations attenuated with increasing chronological age ( P interactions < 0.001), but not with decreasing LTL ( P interaction men = 0.85; P interaction women = 0.27). Increased (abdominal) adiposity was associated with higher risk of incident CMDs, which attenuated with increasing chronological age but not with decreasing LTL. Future research may validate these findings using different measures of biological age.

Episodic memory dysfunction and hypersynchrony in brain functional networks in cognitively intact subjects and MCI: a study of 379 individuals - Brenda Chino; Pablo Cuesta; Javier Pacios; Jaisalmer de Frutos-Lucas; Lucía Torres-Simón; Sandra Doval; Alberto Marcos; Ricardo Bruña; Fernando Maestú (GeroScience, 2023)
Delayed recall (DR) impairment is one of the most significant predictive factors in defining the progression to Alzheimer’s disease (AD). Changes in brain functional connectivity (FC) could accompany this decline in the DR performance even in a resting state condition from the preclinical stages to the diagnosis of AD itself, so the characterization of the relationship between the two phenomena has attracted increasing interest. Another aspect to contemplate is the potential moderator role of the APOE genotype in this association, considering the evidence about their implication for the disease. 379 subjects (118 mild cognitive impairment (MCI) and 261 cognitively intact (CI) individuals) underwent an extensive evaluation, including MEG recording. Applying cluster-based permutation test, we identified a cluster of differences in FC and studied which connections drove such an effect in DR. The moderation effect of APOE genotype between FC results and delayed recall was evaluated too. Higher FC in beta band in the right occipital region is associated with lower DR scores in both groups. A significant anteroposterior link emerged in the seed-based analysis with higher values in MCI. Moreover, APOE genotype appeared as a moderator between beta FC and DR performance only in the CI group. An increased beta FC in the anteroposterior brain region appears to be associated with lower memory performance in MCI. This finding could help discriminate the pattern of the progression of healthy aging to MCI and the relation between resting state and memory performance.

Bioenergetic and vascular predictors of potential super-ager and cognitive decline trajectories—a UK Biobank Random Forest classification study - Parvin Mohammadiarvejeh; Brandon S. Klinedinst; Qian Wang; Tianqi Li; Brittany Larsen; Amy Pollpeter; Shannin N. Moody; Sara A. Willette; Jon P. Mochel; Karin Allenspach; Guiping Hu; Auriel A. Willette (GeroScience, 2023)

Neither myonuclear accretion nor a myonuclear domain size ceiling is a feature of the attenuated hypertrophic potential of aged human skeletal muscle - Matthew S. Brook; Daniel J. Wilkinson; Janelle Tarum; Kyle W. Mitchell; Jonathan L. Lund; Bethan E. Phillips; Nathaniel J. Szewczyk; Fawzi Kadi; Paul L. Greenhaff; Ken Smith; Philip J. Atherton (GeroScience, 2023)
Ageing limits growth capacity of skeletal muscle (e.g. in response to resistance exercise), but the role of satellite cell (SC) function in driving this phenomenon is poorly defined. Younger (Y) (~ 23 years) and older (O) men (~ 69 years) (normal-weight BMI) underwent 6 weeks of unilateral resistance exercise training (RET). Muscle biopsies were taken at baseline and after 3-/6-week training. We determined muscle size by fibre CSA (and type), SC number, myonuclei counts and DNA synthesis (via D 2 O ingestion). At baseline, there were no significant differences in fibre areas between Y and O. RET increased type I fibre area in Y from baseline at both 3 weeks and 6 weeks (baseline: 4509 ± 534 µm 2 , 3 weeks; 5497 ± 510 µm 2 P < 0.05, 6 weeks; 5402 ± 352 µm 2 P < 0.05), whilst O increased from baseline at 6 weeks only (baseline 5120 ± 403 µm 2 , 3 weeks; 5606 ± 620 µm 2 , 6 weeks; 6017 ± 482 µm 2 P < 0.05). However, type II fibre area increased from baseline in Y at both 3 weeks and 6 weeks (baseline: 4949 ± 459 µm 2 , 3 weeks; 6145 ± 484 µm 2 ( P < 0.01), 6 weeks; 5992 ± 491 µm 2 ( P < 0.01), whilst O showed no change (baseline 5210 ± 410 µm 2 , 3 weeks; 5356 ± 535 µm 2 ( P = 0.9), 6 weeks; 5857 ± 478 µm 2 ( P = 0.1). At baseline, there were no differences in fibre myonuclei number between Y and O. RET increased type I fibre myonuclei number from baseline in both Y and O at 3 weeks and 6 weeks with RET (younger: baseline 2.47 ± 0.16, 3 weeks; 3.19 ± 0.16 ( P < 0.001), 6 weeks; 3.70 ± 0.29 ( P < 0.0001); older: baseline 2.29 ± 0.09, 3 weeks; 3.01 ± 0.09 ( P < 0.001), 6 weeks; 3.65 ± 0.18 ( P < 0.0001)). Similarly, type II fibre myonuclei number increased from baseline in both Y and O at 3 weeks and 6 weeks (younger: baseline 2.49 ± 0.14, 3 weeks; 3.31 ± 0.21 ( P < 0.001), 6 weeks; 3.86 ± 0.29 ( P < 0.0001); older: baseline 2.43 ± 0.12, 3 weeks; 3.37 ± 0.12 ( P < 0.001), 6 weeks; 3.81 ± 0.15 ( P < 0.0001)). DNA synthesis rates %.d −1 exhibited a main effect of training but no age discrimination. Declines in myonuclei addition do not underlie impaired muscle growth capacity in older humans, supporting ribosomal and proteostasis impairments as we have previously reported.

Cathepsin F is a potential marker for senescent human skin fibroblasts and keratinocytes associated with skin aging - Kento Takaya; Toru Asou; Kazuo Kishi (GeroScience, 2023)
Cellular senescence is characterized by cell cycle arrest and the senescence-associated secretory phenotype (SASP) and can be triggered by a variety of stimuli, including deoxyribonucleic acid (DNA) damage, oxidative stress, and telomere exhaustion. Cellular senescence is associated with skin aging, and identification of specific markers of senescent cells is essential for development of targeted therapies. Cathepsin F (CTSF) has been implicated in dermatitis and various cancers and participates in cell immortalization through its association with Bcl family proteins. It is a candidate therapeutic target to specifically label and eliminate human skin fibroblasts and keratinocytes immortalized by aging and achieve skin rejuvenation. In this study, we investigated whether CTSF is associated with senescence in human fibroblasts and keratinocytes. In senescence models, created using replicative aging, ionizing radiation exposure, and the anticancer drug doxorubicin, various senescence markers were observed, such as senescence-associated β-galactosidase (SA-β-gal) activity, increased SASP gene expression, and decreased uptake of the proliferation marker BrdU. Furthermore, CTSF expression was elevated at the gene and protein levels. In addition, CTSF-positive cells were abundant in aged human epidermis and in some parts of the dermis. In the population of senescent cells with arrested division, the number of CTSF-positive cells was significantly higher than that in the proliferating cell population. These results suggest that CTSF is a candidate for therapeutic modalities targeting aging fibroblasts and keratinocytes.

Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging? - Ramon Casanova; Andrea M. Anderson; Ryan T. Barnard; Jamie N. Justice; Anna Kucharska-Newton; Beverly Gwen Windham; Priya Palta; Rebecca F. Gottesman; Thomas H. Mosley; Timothy M. Hughes; Lynne E. Wagenknecht; Stephen B. Kritchevsky (GeroScience, 2023)

Vitamin D3 promotes longevity in Caenorhabditis elegans - Billy Huggins; Mindy Farris (GeroScience, 2023)

A metabolomic signature of the APOE2 allele - Paola Sebastiani; Zeyuan Song; Dylan Ellis; Qu Tian; Michaela Schwaiger-Haber; Ethan Stancliffe; Michael S. Lustgarten; Cory C. Funk; Priyanka Baloni; Cong-Hui Yao; Shakchhi Joshi; Megan M. Marron; et al. (GeroScience, 2023)

Tissue-specific reductions in mitochondrial efficiency and increased ROS release rates during ageing in zebra finches, Taeniopygia guttata - Pablo Salmón; Caroline Millet; Colin Selman; Pat Monaghan; Neal J. Dawson (GeroScience, 2023)
Mitochondrial dysfunction and oxidative damage have long been suggested as critically important mechanisms underlying the ageing process in animals. However, conflicting data exist on whether this involves increased production of mitochondrial reactive oxygen species (ROS) during ageing. We employed high‐resolution respirometry and fluorometry on flight muscle (pectoralis major) and liver mitochondria to simultaneously examine mitochondrial function and ROS (H 2 O 2 ) release rates in young (3 months) and old (4 years) zebra finches ( Taeniopygia guttata ). Respiratory capacities for oxidative phosphorylation did not differ between the two age groups in either tissue. Respiratory control ratios (RCR) of liver mitochondria also did not differ between the age classes. However, RCR in muscle mitochondria was 55% lower in old relative to young birds, suggesting that muscle mitochondria in older individuals are less efficient. Interestingly, this observed reduction in muscle RCR was driven almost entirely by higher mitochondrial LEAK-state respiration. Maximum mitochondrial ROS release rates were found to be greater in both flight muscle (1.3-fold) and the liver (1.9-fold) of old birds. However, while maximum ROS (H 2 O 2 ) release rates from mitochondria increased with age across both liver and muscle tissues, the liver demonstrated a proportionally greater age-related increase in ROS release than muscle. This difference in age-related increases in ROS release rates between muscle and liver tissues may be due to increased mitochondrial leakiness in the muscle, but not the liver, of older birds. This suggests that age-related changes in cellular function seem to occur in a tissue-specific manner in zebra finches, with flight muscle exhibiting signs of minimising age-related increase in ROS release, potentially to reduce damage to this crucial tissue in older individuals.

Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice - Jessica M. Snyder; Kerriann M. Casey; Andrzej Galecki; David E. Harrison; Hashan Jayarathne; Navasuja Kumar; Francesca Macchiarini; Nadia Rosenthal; Marianna Sadagurski; Adam B. Salmon; Randy Strong; Richard A. Miller; et al. (GeroScience, 2023)
Canagliflozin (Cana), a clinically important anti-diabetes drug, leads to a 14% increase in median lifespan and a 9% increase in the 90th percentile age when given to genetically heterogeneous male mice from 7 months of age, but does not increase lifespan in female mice. A histopathological study was conducted on 22-month-old mice to see if Cana retarded diverse forms of age-dependent pathology. This agent was found to diminish incidence or severity, in male mice only, of cardiomyopathy, glomerulonephropathy, arteriosclerosis, hepatic microvesicular cytoplasmic vacuolation (lipidosis), and adrenal cortical neoplasms. Protection against atrophy of the exocrine pancreas was seen in both males and females. Thus, the extension of lifespan in Cana-treated male mice, which is likely to reflect host- or tumor-mediated delay in lethal neoplasms, is accompanied by parallel retardation of lesions, in multiple tissues, that seldom if ever lead to death in these mice. Canagliflozin thus can be considered a drug that acts to slow the aging process and should be evaluated for potential protective effects against many other late-life conditions.

High polygenic risk score for exceptional longevity is associated with a healthy metabolic profile - Mary Revelas; Anbupalam Thalamuthu; Anna Zettergren; Christopher Oldmeadow; Jenna Najar; Nazib M. Seidu; Nicola J. Armstrong; Carlos Riveros; John B. Kwok; Peter R. Schofield; Julian N. Trollor; Margda Waern; et al. (GeroScience, 2023)
Healthy metabolic measures in humans are associated with longevity. Dysregulation leads to metabolic syndrome (MetS) and negative health outcomes. Recent exceptional longevity (EL) genome wide association studies have facilitated estimation of an individual’s polygenic risk score (PRS) for EL. We tested the hypothesis that individuals with high ELPRS have a low prevalence of MetS. Participants were from five cohorts of middle-aged to older adults. The primary analyses were performed in the UK Biobank (UKBB) ( n = 407,800, 40–69 years). Replication analyses were undertaken using three Australian studies: Hunter Community Study ( n = 2122, 55–85 years), Older Australian Twins Study ( n = 539, 65–90 years) and Sydney Memory and Ageing Study ( n = 925, 70–90 years), as well as the Swedish Gothenburg H70 Birth Cohort Studies ( n = 2273, 70–93 years). MetS was defined using established criteria. Regressions and meta-analyses were performed with the ELPRS and MetS and its components. Generally, MetS prevalence (22–30%) was higher in the older cohorts. In the UKBB, high EL polygenic risk was associated with lower MetS prevalence (OR = 0.94, p = 1.84 × 10 –42 ) and its components ( p < 2.30 × 10 – 8 ). Meta-analyses of the replication cohorts showed nominal associations with MetS ( p = 0.028) and 3 MetS components ( p < 0.05). This work suggests individuals with a high polygenic risk for EL have a healthy metabolic profile promoting longevity.

Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT4R) in the postmortem brains of individuals without cognitive impairment - Caglar Cosarderelioglu; Lolita S. Nidadavolu; Claudene J. George; Ruth Marx-Rattner; Laura Powell; Qian-Li Xue; Jing Tian; Esther S. Oh; Luigi Ferrucci; Pervin Dincer; David A. Bennett; Jeremy D. Walston; et al. (GeroScience, 2023)

Lipidomics profiling of biological aging in American Indians: the Strong Heart Family Study - Pooja Subedi; Helena Palma-Gudiel; Oliver Fiehn; Lyle G. Best; Elisa T. Lee; Barbara V. Howard; Jinying Zhao (GeroScience, 2023)

Metabolic and molecular responses of human patellar tendon to concentric- and eccentric-type exercise in youth and older age - Hannah Crossland; Matthew S. Brook; Jonathan I. Quinlan; Martino V. Franchi; Bethan E. Phillips; Daniel J. Wilkinson; Constantinos N. Maganaris; Paul L. Greenhaff; Nathaniel J. Szewczyk; Kenneth Smith; Marco V. Narici; Philip J. Atherton (GeroScience, 2023)
Exercise training can induce adaptive changes to tendon tissue both structurally and mechanically; however, the underlying compositional changes that contribute to these alterations remain uncertain in humans, particularly in the context of the ageing tendon. The aims of the present study were to determine the molecular changes with ageing in patellar tendons in humans, as well as the responses to exercise and exercise type (eccentric (ECC) and concentric (CON)) in young and old patellar tendon. Healthy younger males (age 23.5 ± 6.1 years; n = 27) and older males (age 68.5 ± 1.9 years; n = 27) undertook 8 weeks of CON or ECC training (3 times per week; at 60% of 1 repetition maximum (1RM)) or no training. Subjects consumed D 2 O throughout the protocol and tendon biopsies were collected after 4 and 8 weeks for measurement of fractional synthetic rates (FSR) of tendon protein synthesis and gene expression. There were increases in tendon protein synthesis following 4 weeks of CON and ECC training ( P < 0.01; main effect by ANOVA), with no differences observed between young and old males, or training type. At the transcriptional level however, ECC in young adults generally induced greater responses of collagen and extracellular matrix-related genes than CON, while older individuals had reduced gene expression responses to training. Different training types did not appear to induce differential tendon responses in terms of protein synthesis, and while tendons from older adults exhibited different transcriptional responses to younger individuals, protein turnover changes with training were similar for both age groups.

Task-based functional connectivity of the Useful Field of View (UFOV) fMRI task - Jessica N. Kraft; Hanna K. Hausman; Cheshire Hardcastle; Alejandro Albizu; Andrew O’Shea; Nicole D. Evangelista; Emanuel M. Boutzoukas; Emily J. Van Etten; Pradyumna K. Bharadwaj; Hyun Song; Samantha G. Smith; Steven DeKosky; et al. (GeroScience, 2023)

High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity - Brenda Gonzalez; Archana Tare; Seungjin Ryu; Simon C. Johnson; Gil Atzmon; Nir Barzilai; Matt Kaeberlein; Yousin Suh (GeroScience, 2023)
Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.

Aging compromises oligodendrocyte precursor cell maturation and efficient remyelination in the monkey brain - Christina Dimovasili; Ashley E. Fair; Isabella R. Garza; Katelyn V. Batterman; Farzad Mortazavi; Tara L. Moore; Douglas L. Rosene (GeroScience, 2023)

Hypothalamic microstructure and function are related to body mass, but not mental or cognitive abilities across the adult lifespan - Melanie Spindler; Christiane M. Thiel (GeroScience, 2023)
Physical, mental, and cognitive resources are essential for healthy aging. Aging impacts on the structural integrity of various brain regions, including the hippocampus. Even though recent rodent studies hint towards a critical role of the hypothalamus, there is limited evidence on functional consequences of age-related changes of this region in humans. Given its central role in metabolic regulation and affective processing and its connections to the hippocampus, it is plausible that hypothalamic integrity and connectivity are associated with functional age-related decline. We used data of n = 369 participants (18–88 years) from the Cambridge Centre for Ageing and Neuroscience repository to determine functional impacts of potential changes in hypothalamic microstructure across the lifespan. First, we identified age-related changes in microstructure as a function of physical, mental, and cognitive health and compared those findings to changes in hippocampal microstructure. Second, we investigated the relationship of hypothalamic microstructure and resting-state functional connectivity and related those changes to age as well as physical health. Our results showed that hypothalamic microstructure is not affected by depressive symptoms (mental health), cognitive performance (cognitive health), and comparatively stable across the lifespan, but affected by body mass (physical health). Furthermore, body mass changes connectivity to limbic regions including the hippocampus, amygdala, and nucleus accumbens, suggesting functional alterations in the metabolic and reward systems. Our results demonstrate that hypothalamic structure and function are affected by body mass, focused on neural density and dispersion, but not inflammation. Still, observed effect sizes were small, encouraging detailed investigations of individual hypothalamic subunits.

Effect of simultaneous exercise and cognitive training on executive functions, baroreflex sensitivity, and pre-frontal cortex oxygenation in healthy older adults: a pilot study - Manon Pellegrini-Laplagne; Olivier Dupuy; Phillipe Sosner; Laurent Bosquet (GeroScience, 2023)

Circulating cell-free DNA in health and disease — the relationship to health behaviours, ageing phenotypes and metabolomics - Laura Kananen; Mikko Hurme; Alexander Bürkle; Maria Moreno-Villanueva; Jürgen Bernhardt; Florence Debacq-Chainiaux; Beatrix Grubeck-Loebenstein; Marco Malavolta; Andrea Basso; Francesco Piacenza; Sebastiano Collino; Efstathios S. Gonos; et al. (GeroScience, 2023)
Circulating cell-free DNA (cf-DNA) has emerged as a promising biomarker of ageing, tissue damage and cellular stress. However, less is known about health behaviours, ageing phenotypes and metabolic processes that lead to elevated cf-DNA levels. We sought to analyse the relationship of circulating cf-DNA level to age, sex, smoking, physical activity, vegetable consumption, ageing phenotypes (physical functioning, the number of diseases, frailty) and an extensive panel of biomarkers including blood and urine metabolites and inflammatory markers in three human cohorts (N = 5385; 17–82 years). The relationships were assessed using correlation statistics, and linear and penalised regressions (the Lasso), also stratified by sex. cf-DNA levels were significantly higher in men than in women, and especially in middle-aged men and women who smoke, and in older more frail individuals. Correlation statistics of biomarker data showed that cf-DNA level was higher with elevated inflammation (C-reactive protein, interleukin-6), and higher levels of homocysteine, and proportion of red blood cells and lower levels of ascorbic acid. Inflammation (C-reactive protein, glycoprotein acetylation), amino acids (isoleucine, leucine, tyrosine), and ketogenesis (3-hydroxybutyrate) were included in the cf-DNA level-related biomarker profiles in at least two of the cohorts. In conclusion, circulating cf-DNA level is different by sex, and related to health behaviour, health decline and metabolic processes common in health and disease. These results can inform future studies where epidemiological and biological pathways of cf-DNA are to be analysed in details, and for studies evaluating cf-DNA as a potential clinical marker.

Inter- and intra-chromosomal modulators of the APOE ɛ2 and ɛ4 effects on the Alzheimer’s disease risk - Alireza Nazarian; Ian Philipp; Irina Culminskaya; Liang He; Alexander M. Kulminski (GeroScience, 2023)
The mechanisms of incomplete penetrance of risk-modifying impacts of apolipoprotein E ( APOE ) ε2 and ε4 alleles on Alzheimer’s disease (AD) have not been fully understood. We performed genome-wide analysis of differences in linkage disequilibrium (LD) patterns between 6,136 AD-affected and 10,555 AD-unaffected subjects from five independent studies to explore whether the association of the APOE ε2 allele (encoded by rs7412 polymorphism) and ε4 allele (encoded by rs429358 polymorphism) with AD was modulated by autosomal polymorphisms. The LD analysis identified 24 (mostly inter-chromosomal) and 57 (primarily intra-chromosomal) autosomal polymorphisms with significant differences in LD with either rs7412 or rs429358, respectively, between AD-affected and AD-unaffected subjects, indicating their potential modulatory roles. Our Cox regression analysis showed that minor alleles of four inter-chromosomal and ten intra-chromosomal polymorphisms exerted significant modulating effects on the ε2- and ε4-associated AD risks, respectively, and identified ε2-independent (rs2884183 polymorphism, 11q22.3) and ε4-independent (rs483082 polymorphism, 19q13.32) associations with AD. Our functional analysis highlighted ε2- and/or ε4-linked processes affecting the lipid and lipoprotein metabolism and cell junction organization which may contribute to AD pathogenesis. These findings provide insights into the ε2- and ε4-associated mechanisms of AD pathogenesis, underlying their incomplete penetrance.

Changes in cAMP signaling are associated with age-related downregulation of spontaneously beating atrial tissue energetic indices - Noa Kirschner Peretz; Sofia Segal; Rotem Shapira; Ori Shemla; Yevgeniya Lukyanenko; Inbar Brosh; Edward G. Lakatta; Kenta Tsutsui; Yael Yaniv (GeroScience, 2023)

Plant-based diets and risk of frailty in community-dwelling older adults: the Seniors-ENRICA-1 cohort - Javier Maroto-Rodriguez; Mario Delgado-Velandia; Rosario Ortolá; Adrián Carballo-Casla; Esther García-Esquinas; Fernando Rodríguez-Artalejo; Mercedes Sotos-Prieto (GeroScience, 2023)
Frailty is a geriatric syndrome that leads to increased risk of hospitalization, disability, and death. The effect of plant-based diets defined by the quality of their plant foods is unclear. Our objective is to study the association between two plant-based diet indices and the occurrence of frailty among community-dwelling older adults in Spain. We analyzed data from 1880 individuals aged ≥ 60 years from the Spanish Seniors ENRICA-1 cohort. We used a validated diet history to build two indices: (a) the healthful Plant-based Diet Index (hPDI) where healthy plant foods received positive scores, whereas less-healthy plant foods and animal foods received reverse scores; and (b) the unhealthful Plant-based Diet Index (uPDI), with positive scores to less-healthy plant foods and reverse scores to animal and healthy plant foods. Incident frailty was defined with the Fried phenotype. Study associations were summarized with odds ratios (OR) and 95% confidence intervals (CI) obtained from multivariable logistic models. After 3.3 years of follow-up, 136 incident frailty cases were ascertained. Comparing the highest vs. the lowest tertile of adherence, the OR [95% CI] for frailty was 0.43 (0.25–0.74; p- trend = .003) for the hPDI, and 2.89 (1.73–4.84; p- trend < .001) for the uPDI. Higher consumption of healthy plant foods was inversely associated with frailty (0.39 [0.23–0.66; p -trend < 0.001]); higher consumption of unhealthy plant foods was associated with higher frailty risk (2.40 [1.23–4.71; p -trend = .01]). In older adults, the hPDI was associated with lower risk of frailty, while the opposite was found for the uPDI.

The association between aging-related monocyte transcriptional networks and comorbidity burden: the Multi-Ethnic Study of Atherosclerosis (MESA) - Jingzhong Ding; Kurt Lohman; Anthony Molina; Osvaldo Delbono; Alain Bertoni; Steven Shea; Wendy Post; Xiuqing Guo; R. Graham Barr; Ani W. Manichaikul; James S. Pankow; Jerome I. Rotter; et al. (GeroScience, 2023)

Attentional focus effect on dual-task walking in Parkinson’s disease with and without freezing of gait - Yu-An Chen; Ruey-Meei Wu; Chen-Hsing Sheu; Chin-Hsien Lin; Cheng-Ya Huang (GeroScience, 2023)

The PICLS high-throughput screening method for agents extending cellular longevity identifies 2,5-anhydro-D-mannitol as novel anti-aging compound - Mohammad Alfatah; Frank Eisenhaber (GeroScience, 2023)
Although aging is the biggest risk factor for human chronic (cancer, diabetic, cardiovascular, and neurodegenerative) diseases, few interventions are known besides caloric restriction and a small number of drugs (with substantial side effects) that directly address aging. Thus, there is an urgent need for new options that can generally delay aging processes and prevent age-related diseases. Cellular aging is at the basis of aging processes. Chronological lifespan (CLS) of yeast Saccharomyces cerevisiae is the well-established model system for investigating the interventions of human post-mitotic cellular aging. CLS is defined as the number of days cells remain viable in a stationary phase. We developed a new, cheap, and fast quantitative method for measuring CLS in cell cultures incubated together with various chemical agents and controls on 96-well plates. Our PICLS protocol with (1) the use of propidium iodide for fluorescent-based cell survival reading in a microplate reader and (2) total cell count measurement via OD600nm absorption from the same plate provides real high-throughput capacity. Depending on logistics, large numbers of plates can be processed in parallel so that the screening of thousands of compounds becomes feasible in a short time. The method was validated by measuring the effect of rapamycin and calorie restriction on yeast CLS. We utilized this approach for chemical agent screening. We discovered the anti-aging/geroprotective potential of 2,5-anhydro-D-mannitol (2,5-AM) and suggest its usage individually or in combination with other anti-aging interventions.

Aging: working memory capacity and spatial strategies in a virtual orientation task - Joaquín Castillo Escamilla; Irene León Estrada; Manuel Alcaraz-Iborra; José Manuel Cimadevilla Redondo (GeroScience, 2023)

Retrospective reports of socioeconomic disadvantage in childhood and mortality risk: are associations consistent across measures and sex? - Amanda E. Ng; Rodman Turpin; Eric M. Connor; Natalie Slopen (GeroScience, 2023)

Modulation of nigral dopamine signaling mitigates parkinsonian signs of aging: evidence from intervention with calorie restriction or inhibition of dopamine uptake - Michael F. Salvatore; Ella A. Kasanga; D. Parker Kelley; Katy E. Venable; Tamara R. McInnis; Mark A. Cantu; Jennifer Terrebonne; Kathryn Lanza; Samantha M. Meadows; Ashley Centner; Christopher Bishop; Donald K. Ingram (GeroScience, 2023)

Circulating interleukin-37 declines with aging in healthy humans: relations to healthspan indicators and IL37 gene SNPs - Vienna E. Brunt; Akpevweoghene P. Ikoba; Brian P. Ziemba; Dov B. Ballak; Alexander Hoischen; Charles A. Dinarello; Marissa A. Ehringer; Douglas R. Seals (GeroScience, 2023)

Efficient representations of binarized health deficit data: the frailty index and beyond - Glen Pridham; Kenneth Rockwood; Andrew Rutenberg (GeroScience, 2023)

Comprehensive longitudinal non-invasive quantification of healthspan and frailty in a large cohort (n = 546) of geriatric C57BL/6 J mice - Serena Marcozzi; Giorgia Bigossi; Maria Elisa Giuliani; Robertina Giacconi; Maurizio Cardelli; Francesco Piacenza; Fiorenza Orlando; Agnese Segala; Alessandra Valerio; Enzo Nisoli; Dario Brunetti; Annibale Puca; et al. (GeroScience, 2023)

Strength gains after 12 weeks of resistance training correlate with neurochemical markers of brain health in older adults: a randomized control 1H-MRS study - Samrat Sheoran; Wouter A. J. Vints; Kristina Valatkevičienė; Simona Kušleikienė; Rymantė Gleiznienė; Vida J. Česnaitienė; Uwe Himmelreich; Oron Levin; Nerijus Masiulis (GeroScience, 2023)
Physical exercise is considered a potent countermeasure against various age-associated physiological deterioration processes. We therefore assessed the effect of 12 weeks of resistance training on brain metabolism in older adults (age range: 60–80 years). Participants either underwent two times weekly resistance training program which consisted of four lower body exercises performed for 3 sets of 6–10 repetitions at 70–85% of 1 repetition maximum ( n = 20) or served as the passive control group ( n = 21). The study used proton magnetic resonance spectroscopy to quantify the ratio of total N-acetyl aspartate, total choline, glutamate-glutamine complex, and myo-inositol relative to total creatine (tNAA/tCr, tCho/tCr, Glx/tCr, and mIns/tCr respectively) in the hippocampus (HPC), sensorimotor (SM1), and prefrontal (dlPFC) cortices. The peak torque (PT at 60°/s) of knee extension and flexion was assessed using an isokinetic dynamometer. We used repeated measures time × group ANOVA to assess time and group differences and correlation coefficient analyses to examine the pre-to-post change (∆) associations between PT and neurometabolite variables. The control group showed significant declines in tNAA/tCr and Glx/tCr of SM1, and tNAA/tCr of dlPFC after 12 weeks, which were not seen in the experimental group. A significant positive correlation was found between ∆PT knee extension and ∆SM1 Glx/tCr, ∆dlPFC Glx/tCr and between ∆PT knee flexion and ∆dlPFC mIns/tCr in the experimental group. Overall, findings suggest that resistance training seems to elicit alterations in various neurometabolites that correspond to exercise-induced “preservation” of brain health, while simultaneously having its beneficial effect on augmenting muscle functional characteristics in older adults.

CCA identifies a neurophysiological marker of adaptation capacity that is reliably linked to internal locus of control of cognition in amnestic MCI - Lizbeth Peralta-Malváez; Adam Turnbull; Mia Anthony; Ehsan Adeli; F. Vankee Lin (GeroScience, 2023)

Accelerated ageing and coronary microvascular dysfunction in chronic heart failure in Tgαq*44 mice - Piotr Berkowicz; Justyna Totoń-Żurańska; Grzegorz Kwiatkowski; Agnieszka Jasztal; Tamás Csípő; Kamil Kus; Urszula Tyrankiewicz; Anna Orzyłowska; Paweł Wołkow; Attila Tóth; Stefan Chlopicki (GeroScience, 2023)
Age represents a major risk factor in heart failure (HF). However, the mechanisms linking ageing and HF are not clear. We aimed to identify the functional, morphological and transcriptomic changes that could be attributed to cardiac ageing in a model of slowly progressing HF in Tgαq*44 mice in reference to the cardiac ageing process in FVB mice. In FVB mice, ageing resulted in the impairment of diastolic cardiac function and in basal coronary flow (CF), perivascular and interstitial fibrosis without changes in the cardiac activity of angiotensin-converting enzyme (ACE) or aldosterone plasma concentration. In Tgαq*44 mice, HF progression was featured by the impairment of systolic and diastolic cardiac function and in basal CF that was associated with a distinct rearrangement of the capillary architecture, pronounced perivascular and interstitial fibrosis, progressive activation of cardiac ACE and systemic angiotensin-aldosterone-dependent pathways. Interestingly, cardiac ageing genes and processes were represented in Tgαq*44 mice not only in late but also in early phases of HF, as evidenced by cardiac transcriptome analysis. Thirty-four genes and 8 biological processes, identified as being ageing related, occurred early and persisted along HF progression in Tgαq*44 mice and were mostly associated with extracellular matrix remodelling and fibrosis compatible with perivascular fibrosis resulting in coronary microvascular dysfunction (CMD) in Tgαq*44 mice. In conclusion, accelerated and persistent cardiac ageing contributes to the pathophysiology of chronic HF in Tgαq*44 mice. In particular, prominent perivascular fibrosis of microcirculation resulting in CMD represents an accelerated cardiac ageing phenotype that requires targeted treatment in chronic HF.

The combination of hyperventilation test and graph theory parameters to characterize EEG changes in mild cognitive impairment (MCI) condition - Francesca Miraglia; Chiara Pappalettera; Valeria Guglielmi; Alessia Cacciotti; Rosa Manenti; Elda Judica; Fabrizio Vecchio; Paolo Maria Rossini (GeroScience, 2023)

A new set of estimated cardiorespiratory fitness equations are associated with cognitive performance in older adults - Daniel Velázquez-Díaz; Cristina Cadenas-Sanchez; Flor Abril Molina-Guzmán; Jesús Alfredo Sáenz-Carrasco; Javier J. Gonzalez-Rosa; Kirk I. Erickson; Ana Carbonell-Baeza; David Jiménez-Pavón (GeroScience, 2023)
This study aimed to develop new equations to estimate cardiorespiratory fitness specifically for older adults and, secondly, to analyze the associations of cardiorespiratory fitness, both objectively measured and estimated using new equations, with cognitive performance. Ninety-two older adults (41 females, 65–75 years) from baseline data of a randomized controlled trial were analyzed (“ClinicalTrials.gov” Identifier: NCT03923712). Participants completed 4 measurement sessions including (i) physiological and health indicators in a laboratory setting, (ii) field-based fitness tests, (iii) sociodemographic and physical activity questionnaires, and (iv) a battery of neuropsychological tests to evaluate cognitive performance. The main findings were as follows: (i) a set of new equations with good predictive value for estimated cardiorespiratory fitness were developed (74–87%), using different scenarios of complexity and/or equipment requirements, and (ii) higher estimated cardiorespiratory fitness, even using its simplest equation (eCRF = − 1261.99 + 1.97 × 6 min walking test (m) + 1.12 × bioimpedance basal metabolic rate (kcal/day) + 5.25 × basal heart rate (bpm)), was associated with better cognitive performance evaluated by several neuropsychological tests (i.e., language, cognitive flexibility, fluency, attention, and working memory), similar to using objectively measured cardiorespiratory fitness. In summary, a new set of estimated cardiorespiratory fitness equations have been developed with predictive values ranging from 74 to 87% that could be used based on necessity, availability of equipment, resources, or measurement context. Moreover, similar to objectively measured cardiorespiratory fitness, this measure of estimated cardiorespiratory fitness was positively associated with performance on language, fluency, cognitive flexibility, attention, and working memory, independently of sex, age, and education level.

Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics - Yueyue Gao; Tong Wu; Xianan Tang; Jingyi Wen; Yan Zhang; Jinjin Zhang; Shixuan Wang (GeroScience, 2023)
Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such injury. Cellular senescence can be induced by chemotherapeutic agents in multiple organs and may corrode the structure and function of normal tissues. We hypothesized that the widely used first-line chemotherapy drug, doxorubicin, could increase senescent cell burden in normal ovarian tissue during the therapeutic process and that elimination of senescent cells with senolytics would ameliorate doxorubicin-induced ovarian injury. Here, we demonstrated an accumulation of cellular senescence in doxorubicin-treated ovaries through detecting p16 and p21 expression levels and senescence-associated β-galactosidase (SA-β-gal) activity as well as senescence-associated secretory phenotype (SASP) factors. Short-term intervention with the classic senolytic combination dasatinib and quercetin (DQ) or fisetin significantly reduced the load of senescent cells in ovaries after doxorubicin treatment. However, neither DQ nor fisetin alleviated doxorubicin-related ovarian dysfunction. Further experiments showed that ovarian apoptosis and fibrosis following doxorubicin exposure could not be improved by senolytics. Collectively, our study shows that senolytic treatment can eliminate accumulated senescent cells, but cannot reverse the massive follicle loss and ovarian stromal fibrosis caused by doxorubicin, suggesting that cellular senescence may not be one of the key mechanisms in doxorubicin-induced ovarian injury.

Baseline and usual cardiorespiratory fitness and the risk of chronic kidney disease: A prospective study and meta-analysis of published observational cohort studies - Setor K. Kunutsor; Nzechukwu M. Isiozor; Jonathan Myers; Samuel Seidu; Kamlesh Khunti; Jari A. Laukkanen (GeroScience, 2023)
Chronic kidney disease (CKD) is a global public health burden but is largely preventable. Few studies have reported an association between high levels of cardiorespiratory fitness (CRF) and decreased risk of CKD. However, some relevant aspects of the association, such as the dose-response relationship and the long-term relevance of CRF levels to CKD, have yet to be addressed. We, therefore, aimed to quantify the nature and magnitude of the association between CRF and CKD in a cohort of 2099 men aged 42-61 years with normal kidney function at baseline. CRF was directly measured using a respiratory gas exchange analyzer during cardiopulmonary exercise testing. Hazard ratios (HRs) (95% CIs) were estimated for the incidence of CKD. Correction for within-person variability was made using data from repeat measurements of CRF taken 11 years after baseline. A total of 197 CKD events were recorded during a median follow-up of 25.8 years. The age-adjusted regression dilution ratio for CRF was 0.59 (95% CI: 0.53-0.65). The risk of CKD decreased in a graded fashion with increasing CRF. Comparing extreme tertiles of CRF, the HR (95% CI) for CKD was 0.67 (0.46-0.97) following adjustment for several established and emerging risk factors. The corresponding adjusted HR (95% CI) was 0.51 (0.27-0.96) following correction for within-person variability. In a meta-analysis of five population-based cohort studies (including the current study) comprising 32,447 participants and 4,043 CKD cases, the fully-adjusted risk ratios (95% CIs) for CKD comparing extreme tertiles of baseline and long-term CRF values were 0.58 (0.46-0.73) and 0.40 (0.27-0.59), respectively. Findings from a new prospective study and pooled analysis of previous studies plus the new study indicate that high CRF levels are strongly and independently associated with a reduced risk of CKD and consistent with a linear dose-response relationship. Using single baseline measurements of CRF to investigate the association between CRF and CKD risk could considerably underestimate the true association.

Testing the evidence that lifespan-extending compound interventions are conserved across laboratory animal model species - Michael Bene; Adam B. Salmon (GeroScience, 2023)

Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis in a sex-specific manner - Lukas Stilgenbauer; Juliana Bezerra Medeiros de Lima; Lucas Kniess Debarba; Manal Khan; Lisa Koshko; John J. Kopchick; Andrzej Bartke; Augusto Schneider; Marianna Sadagurski (GeroScience, 2023)

T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults - Mladen Jergović; Makiko Watanabe; Ruchika Bhat; Christopher P. Coplen; Sandip A. Sonar; Rachel Wong; Yvonne Castaneda; Lisa Davidson; Mrinalini Kala; Rachel C. Wilson; Homer L. Twigg; Kenneth Knox; et al. (GeroScience, 2023)

Hippocampal neurochemicals are associated with exercise group and intensity, psychological health, and general cognition in older adults - Line S. Reitlo; Jelena M. Mihailovic; Dorthe Stensvold; Ulrik Wisløff; Fahmeed Hyder; Asta Kristine Håberg (GeroScience, 2023)
Based on the premise that physical activity/exercise impacts hippocampal structure and function, we investigated if hippocampal metabolites for neuronal viability and cell membrane density (i.e., N-acetyl aspartate (NAA), choline (Cho), creatine (Cr)) were higher in older adults performing supervised exercise compared to following national physical activity guidelines. Sixty-three participants (75.3 ± 1.9 years after 3 years of intervention) recruited from the Generation 100 study (NCT01666340_date:08.16.2012) were randomized into a supervised exercise group (SEG) performing twice weekly moderate- to high-intensity training, and a control group (CG) following national physical activity guidelines of ≥ 30-min moderate physical activity ≥ 5 days/week. Hippocampal body and head volumes and NAA, Cho, and Cr levels were acquired at 3T with magnetic resonance imaging and spectroscopic imaging. Sociodemographic data, peak oxygen uptake (VO 2peak ), exercise characteristics, psychological health, and cognition were recorded. General linear models were used to assess group differences and associations corrected for age, sex, education, and hippocampal volume. Both groups adhered to their training, where SEG trained at higher intensity. SEG had significantly lower NAA/Cr in hippocampal body than CG ( p = 0.04). Across participants, higher training intensity was associated with lower Cho/Cr in hippocampal body ( p < 0.001). Change in VO 2peak , increasing VO 2peak from baseline to 3 years, or VO 2peak at 3 years were not associated with hippocampal neurochemicals. Lower NAA/Cr in hippocampal body was associated with poorer psychological health and slightly higher cognitive scores. Thus, following the national physical activity guidelines and not training at the highest intensity level were associated with the best neurochemical profile in the hippocampus at 3 years.

The aging of the immune system and its implications for transplantation - Kathryn E. McGovern; Sandip A. Sonar; Makiko Watanabe; Christopher P. Coplen; Christine M. Bradshaw; Janko Ž. Nikolich (GeroScience, 2023)

Understanding changes in mental health symptoms from young-old to old-old adults by sex using multiple-group latent transition analysis - Se Hee Min; Maxim Topaz; Chiyoung Lee; Rebecca Schnall (GeroScience, 2023)

Genes encoding agrin (AGRN) and neurotrypsin (PRSS12) are associated with muscle mass, strength and plasma C-terminal agrin fragment concentration - Jedd Pratt; Laura Whitton; Anthony Ryan; Thorhildur Juliusdottir; Jackie Dolan; Judith Conroy; Marco Narici; Giuseppe De Vito; Colin Boreham (GeroScience, 2023)
Although physiological data suggest that neuromuscular junction (NMJ) dysfunction is a principal mechanism underpinning sarcopenia, genetic studies have implicated few genes involved in NMJ function. Accordingly, we explored whether genes encoding agrin ( AGRN ) and neurotrypsin ( PRSS12 ) were associated with sarcopenia phenotypes: muscle mass, strength and plasma C-terminal agrin fragment (CAF). PhenoScanner was used to determine if AGRN and/or PRSS12 variants had previously been implicated with sarcopenia phenotypes. For replication, we combined genotype from whole genome sequencing with phenotypic data from 6715 GenoFit participants aged 18–83 years. Dual energy X-ray absorptiometry assessed whole body lean mass (WBLM) and appendicular lean mass (ALM), hand dynamometry determined grip strength and ELISA measured plasma CAF in a subgroup ( n = 260). Follow-up analyses included eQTL analyses, carrier analyses, single-variant and gene-burden tests. rs2710873 ( AGRN ) and rs71608359 ( PRSS12 ) associate with muscle mass and strength phenotypes, respectively, in the UKBB ( p = 8.9 × 10 −6 and p = 8.4 × 10 −6 ) and GenoFit cohort ( p = 0.019 and p = 0.014). rs2710873 and rs71608359 are eQTLs for AGRN and PRSS12 , respectively, in ≥ three tissues. Compared to non-carriers, carriers of rs2710873 had 4.0% higher WBLM and ALM (both p < 0.001), and 9.5% lower CAF concentrations ( p < 0.001), while carriers of rs71608359 had 2.3% lower grip strength ( p = 0.034). AGRN and PRSS12 are associated with muscle strength and mass in single-variant analyses, while PRSS12 has further associations with muscle strength in gene-burden tests. Our findings provide novel evidence of the relevance of AGRN and PRSS12 to sarcopenia phenotypes and support existing physiological data illustrating the importance of the NMJ in maintaining muscle health during ageing.

Optimising the selection of outcomes for healthy ageing trials: a mixed methods study - Muslim Abbas Syed; Olalekan Lee Aiyegbusi; Eliot Marston; Janet M. Lord; Harriet Teare; Melanie Calvert (GeroScience, 2022)
Advancing age is associated with chronic diseases which are the largest cause of death and disability in developed countries. With increasing life expectancy and an ageing population, there is a need to conduct trials to extend healthy ageing, including targeting biological ageing processes, and prevent ageing-related diseases. The main objectives of the study are as follows: (i) to review outcome measures utilised in healthy ageing trials focusing on pharmacological therapies, nutritional supplements and medical devices; (ii) to summarise the views of key stakeholders on outcome selection for healthy ageing trials. An analysis of records from the Clinicaltrials.gov database pertaining to healthy ageing trials from inception to May 2022 was conducted. In addition, the findings of a workshop attended by key stakeholders at the 2022 annual UKSPINE conference were qualitatively analysed. Substantial heterogeneity was found in the interventions evaluated and the outcomes utilised by the included studies. Recruitment of participants with diverse backgrounds and the confounding effects of multi-morbidity in older adults were identified as the main challenges of measuring outcomes in healthy ageing trials by the workshop participants. The development of a core outcome set for healthy ageing trials can aid comparability across interventions and within different settings. The workshop provided an important platform to garner a range of perspectives on the challenges with measuring outcomes in this setting. It is critical to initiate such discussions to progress this field and provide practical answers to how healthy ageing trials are designed and structured in the future.

Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study - Roger A. Fielding; Elizabeth J. Atkinson; Zaira Aversa; Thomas A. White; Amanda A. Heeren; Sara J. Achenbach; Michelle M. Mielke; Steven R. Cummings; Marco Pahor; Christiaan Leeuwenburgh; Nathan K. LeBrasseur (GeroScience, 2022)
Cellular senescence is a plausible mediator of age-associated declines in physical performance. To test this premise, we examined cross-sectional associations between circulating components of the senescence-associated secretory phenotype (SASP) and measures of physical function and muscle strength in 1377 older adults. We showed significant associations between multiple SASP proteins and the short physical performance battery (SPPB), its subcomponents (gait speed, balance, chair rise time), and 400-m walk time. Activin A, ICAM1, MMP7, VEGFA, and eotaxin showed strong associations based on gradient boost machine learning (GBM), and, when combined with other proteins, effectively identified participants at the greatest risk for mobility disability (SPPB score $$\le$$ ≤ 7). Senescence biomarkers were also associated with lower grip strength, and GBM identified PARC, ADAMTS13, and RANTES as top candidates in females, and MMP2, SOST, and MCP1 in males. These findings highlight an association between senescence biomarkers and physical performance in older adults. ClinicalTrials.gov Identifier: NCT01072500.

Aging results in DNA damage and telomere dysfunction that is greater in endothelial versus vascular smooth muscle cells and is exacerbated in atheroprone regions - Samuel I. Bloom; Jordan R. Tucker; Jisok Lim; Tyler G. Thomas; Gregory J. Stoddard; Lisa A. Lesniewski; Anthony J. Donato (GeroScience, 2022)

Elamipretide effects on the skeletal muscle phosphoproteome in aged female mice - Matthew D. Campbell; Miguel Martín-Pérez; Jarrett D. Egertson; Matthew J. Gaffrey; Lu Wang; Theo Bammler; Peter S. Rabinovitch; Michael MacCoss; Wei-Jun Qian; Judit Villen; David Marcinek (GeroScience, 2022)
The age-related decline in skeletal muscle mass and function is known as sarcopenia. Sarcopenia progresses based on complex processes involving protein dynamics, cell signaling, oxidative stress, and repair. We have previously found that 8-week treatment with elamipretide improves skeletal muscle function, reverses redox stress, and restores protein S-glutathionylation changes in aged female mice. This study tested whether 8-week treatment with elamipretide also affects global phosphorylation in skeletal muscle consistent with functional improvements and S-glutathionylation. Using female 6–7-month-old mice and 28–29-month-old mice, we found that phosphorylation changes did not relate to S-glutathionylation modifications, but that treatment with elamipretide did partially reverse age-related changes in protein phosphorylation in mouse skeletal muscle.

Endpoints for geroscience clinical trials: health outcomes, biomarkers, and biologic age - Steven R. Cummings; Stephen B. Kritchevsky (GeroScience, 2022)
Treatments that target fundamental processes of aging are expected to delay several aging-related conditions simultaneously. Testing the efficacy of these treatments for potential anti-aging benefits will require clinical trials with endpoints that reflect the potential benefits of slowing processes of aging. There are several potential types of endpoints to capture the benefits of slowing a process of aging, and a consensus is needed to standardize and compare the results of these trials and to guide the analysis of observational data to support trial planning. Using biomarkers instead of clinical outcomes would substantially reduce the size and the duration of clinical trials. This requires validation of surrogate markers showing that treatment induced change in the marker reliably predicts the magnitude of change in the clinical outcome. The surrogate marker must also reflect the biological mechanism for the effect of treatment on the clinical outcome. “Biological age” is a superficially attractive marker for such trials. However, it is essential to establish that treatment induced change in biological age reliably predict the magnitude of benefits in the clinical outcome. Reaching consensus on clinical outcomes for geroscience trials and then validating potential surrogate biomarkers requires time, effort, and coordination that will be worthwhile to develop surrogate outcomes that can be trusted to efficiently test the value of many anti-aging treatments under development.

Research priorities for measuring biologic age: summary and future directions from the Research Centers Collaborative Network Workshop - Tina E. Brinkley; Jamie N. Justice; Shubhashrita Basu; Scott R. Bauer; Kah Poh Loh; Peter Mukli; Ted Kheng Siang Ng; Indira C. Turney; Luigi Ferrucci; Steven R. Cummings; Stephen B. Kritchevsky (GeroScience, 2022)
Biologic aging reflects the genetic, molecular, and cellular changes underlying the development of morbidity and mortality with advancing chronological age. As several potential mechanisms have been identified, there is a growing interest in developing robust measures of biologic age that can better reflect the underlying biology of aging and predict age-related outcomes. To support this endeavor, the Research Centers Collaborative Network (RCCN) conducted a workshop in January 2022 to discuss emerging concepts in the field and identify opportunities to move the science forward. This paper presents workshop proceedings and summarizes the identified research needs, priorities, and recommendations for measuring biologic age. The highest priorities identified were the need for more robust measures, longitudinal studies, multidisciplinary collaborations, and translational approaches.

Using blood test parameters to define biological age among older adults: association with morbidity and mortality independent of chronological age validated in two separate birth cohorts - Johanna Drewelies; Gizem Hueluer; Sandra Duezel; Valentin Max Vetter; Graham Pawelec; Elisabeth Steinhagen-Thiessen; Gert G. Wagner; Ulman Lindenberger; Christina M. Lill; Lars Bertram; Denis Gerstorf; Ilja Demuth (GeroScience, 2022)
Biomarkers defining biological age are typically laborious or expensive to assess. Instead, in the current study, we identified parameters based on standard laboratory blood tests across metabolic, cardiovascular, inflammatory, and kidney functioning that had been assessed in the Berlin Aging Study (BASE) ( n = 384) and Berlin Aging Study II (BASE-II) ( n = 1517). We calculated biological age using those 12 parameters that individually predicted mortality hazards over 26 years in BASE. In BASE, older biological age was associated with more physician-observed morbidity and higher mortality hazards, over and above the effects of chronological age, sex, and education. Similarly, in BASE-II, biological age was associated with physician-observed morbidity and subjective health, over and above the effects of chronological age, sex, and education as well as alternative biomarkers including telomere length, DNA methylation age, skin age, and subjective age but not PhenoAge. We discuss the importance of biological age as one indicator of aging.

Evolution, epidemiology, geographical distribution, and mutational landscape of newly emerging monkeypox virus - Chiranjib Chakraborty; Manojit Bhattacharya; Ashish Ranjan Sharma; Kuldeep Dhama (GeroScience, 2022)

Old plasma dilution reduces human biological age: a clinical study - Daehwan Kim; Dobri D. Kiprov; Connor Luellen; Michael Lieb; Chao Liu; Etsuko Watanabe; Xiaoyue Mei; Kaitlin Cassaleto; Joel Kramer; Michael J. Conboy; Irina M. Conboy (GeroScience, 2022)
This work extrapolates to humans the previous animal studies on blood heterochronicity and establishes a novel direct measurement of biological age. Our results support the hypothesis that, similar to mice, human aging is driven by age-imposed systemic molecular excess, the attenuation of which reverses biological age, defined in our work as a deregulation (noise) of 10 novel protein biomarkers. The results on biological age are strongly supported by the data, which demonstrates that rounds of therapeutic plasma exchange (TPE) promote a global shift to a younger systemic proteome, including youthfully restored pro-regenerative, anticancer, and apoptotic regulators and a youthful profile of myeloid/lymphoid markers in circulating cells, which have reduced cellular senescence and lower DNA damage. Mechanistically, the circulatory regulators of the JAK-STAT, MAPK, TGF-beta, NF-κB, and Toll-like receptor signaling pathways become more youthfully balanced through normalization of TLR4, which we define as a nodal point of this molecular rejuvenation. The significance of our findings is confirmed through big-data gene expression studies.

Increased pulse wave velocity is related to impaired working memory and executive function in older adults with metabolic syndrome - Jigar Gosalia; Polly S. Montgomery; Shangming Zhang; William A. Pomilla; Ming Wang; Menglu Liang; Anna Csiszar; Zoltan Ungvari; Andriy Yabluchanskiy; David N. Proctor; Andrew W. Gardner (GeroScience, 2022)

Microbiota mitochondria disorders as hubs for early age-related macular degeneration - János Fehér; Ágnes Élő; Lilla István; Zoltán Zsolt Nagy; Zsolt Radák; Gianluca Scuderi; Marco Artico; Illés Kovács (GeroScience, 2022)
Age-related macular degeneration (AMD) is a progressive neurodegenerative disease affecting the central area (macula lutea) of the retina. Research on the pathogenic mechanism of AMD showed complex cellular contribution governed by such risk factors as aging, genetic predisposition, diet, and lifestyle. Recent studies suggested that microbiota is a transducer and a modifier of risk factors for neurodegenerative diseases, and mitochondria may be one of the intracellular targets of microbial signaling molecules. This review explores studies supporting a new concept on the contribution of microbiota—mitochondria disorders to AMD. We discuss metabolic, vascular, immune, and neuronal mechanism in AMD as well as key alterations of photoreceptor cells, retinal pigment epithelium (RPE), Bruch’s membrane, choriocapillaris endothelial, immune, and neuronal cells. Special attention was paid to alterations of mitochondria contact sites (MCSs), an organelle network of mitochondria, endoplasmic reticulum, lipid droplets (LDs), and peroxisomes being documented based on our own electron microscopic findings from surgically removed human eyes. Morphometry of Bruch’s membrane lipids and proteoglycans has also been performed in early AMD and aged controls. Microbial metabolites (short-chain fatty acids, polyphenols, and secondary bile acids) and microbial compounds (lipopolysaccharide, peptidoglycan, and bacterial DNA)—now called postbiotics—in addition to local effects on resident microbiota and mucous membrane, regulate systemic metabolic, vascular, immune, and neuronal mechanisms in normal conditions and in various common diseases. We also discuss their antioxidant, anti-inflammatory, and metabolic effects as well as experimental and clinical observations on regulating the main processes of photoreceptor renewal, mitophagy, and autophagy in early AMD. These findings support an emerging concept that microbiota-mitochondria disorders may be a crucial pathogenic mechanism of early AMD; and similarly, to other age-related neurodegenerative diseases, new treatment approaches should be targeted at these disorders.

Cognition and brain health among older adults in Iceland: the AGES-Reykjavik study - Vaka Valsdóttir; Brynja Björk Magnúsdóttir; Milan Chang; Sigurdur Sigurdsson; Vilmundur Gudnason; Lenore J. Launer; María K. Jónsdóttir (GeroScience, 2022)

Amyloid $$\upbeta$$ (1–42) peptide impairs mitochondrial respiration in primary human brain microvascular endothelial cells: impact of dysglycemia and pre-senescence - Siva S. V. P. Sakamuri; Venkata N. Sure; Xiaoying Wang; Gregory Bix; Vivian A. Fonseca; Ricardo Mostany; Prasad V. G. Katakam (GeroScience, 2022)

DNA methylation trajectories and accelerated epigenetic aging in incident type 2 diabetes - Eliza Fraszczyk; Chris H. L. Thio; Paul Wackers; Martijn E. T. Dollé; Vincent W. Bloks; Hennie Hodemaekers; H. Susan Picavet; Marjolein Stynenbosch; W. M. Monique Verschuren; Harold Snieder; Annemieke M. W. Spijkerman; Mirjam Luijten (GeroScience, 2022)

Unbiased proteomic analysis of extracellular vesicles secreted by senescent human vascular smooth muscle cells reveals their ability to modulate immune cell functions - Agata Głuchowska; Dominik Cysewski; Monika Baj-Krzyworzeka; Rafał Szatanek; Kazimierz Węglarczyk; Paulina Podszywałow-Bartnicka; Piotr Sunderland; Ewa Kozłowska; Małgorzata A. Śliwińska; Michał Dąbrowski; Ewa Sikora; Grażyna Mosieniak (GeroScience, 2022)
Atherosclerosis, a common age-related disease, is characterized by intense immunological activity. Atherosclerotic plaque is composed of endothelial cells, vascular smooth muscle cells (VSMCs), lipids and immune cells infiltrating from the blood. During progression of the disease, VSMCs undergo senescence within the plaque and secrete SASP (senescence-associated secretory phenotype) factors that can actively modulate plaque microenvironment. We demonstrated that senescent VSMCs secrete increased number of extracellular vesicles (senEVs). Based on unbiased proteomic analysis of VMSC-derived EVs and of the soluble fraction of SASP (sSASP), more than 900 proteins were identified in each of SASP compartments. Comparison of the composition of VMSC-derived EVs with the SASP atlas revealed several proteins, including Serpin Family F Member 1 (SERPINF1) and Thrombospondin 1 (THBS1), as commonly upregulated components of EVs secreted by senescent VSMCs and fibroblasts. Among soluble SASP factors, only Growth Differentiation Factor 15 (GDF15) was universally increased in the secretome of senescent VSMCs, fibroblasts, and epithelial cells. Bioinformatics analysis of EV proteins distinguished functionally organized protein networks involved in immune cell function regulation. Accordingly, EVs released by senescent VSMCs induced secretion of IL-17, INFγ, and IL-10 by T cells and of TNFα produced by monocytes. Moreover senEVs influenced differentiation of monocytes favoring mix M1/M2 polarization with proinflammatory characteristics. Altogether, our studies provide a complex, unbiased analysis of VSMC SASP and prove that EVs derived from senescent VSMCs influence the cytokine milieu by modulating immune cell activity. Our results strengthen the role of senescent cells as an important inducer of inflammation in atherosclerosis.

GH deficiency confers protective advantages against Alzheimer’s disease through rescued miRNA expression profile in APP/PS1 mice - Sarah Noureddine; Tatiana Saccon; Trina Rudeski-Rohr; Adam Gesing; Jeffrey B. Mason; Augusto Schneider; Joseph Dhabhi; Kendra L. Puig; Sharlene Rakoczy; Holly M. Brown-Borg; Michal M. Masternak (GeroScience, 2022)

Age-related decline in circulating IGF-1 associates with impaired neurovascular coupling responses in older adults - Luca Toth; Andras Czigler; Emoke Hegedus; Hedvig Komaromy; Krisztina Amrein; Endre Czeiter; Andriy Yabluchanskiy; Akos Koller; Gergely Orsi; Gabor Perlaki; Attila Schwarcz; Andras Buki; et al. (GeroScience, 2022)
Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) to the increased oxygen and energy requirements of active brain regions via neurovascular coupling (NVC) contributes to the genesis of age-related cognitive impairment. Aging is associated with marked deficiency in the vasoprotective hormone insulin-like growth factor-1 (IGF-1). Preclinical studies on animal models of aging suggest that circulating IGF-1 deficiency is causally linked to impairment of NVC responses. The present study was designed to test the hypotheses that decreases in circulating IGF-1 levels in older adults also predict the magnitude of age-related decline of NVC responses. In a single-center cross-sectional study, we enrolled healthy young ( n = 31, 11 female, 20 male, mean age: 28.4 + / − 4.2 years) and aged volunteers ( n = 32, 18 female, 14 male, mean age: 67.9 + / − 4.1 years). Serum IGF-1 level, basal CBF (phase contrast magnetic resonance imaging (MRI)), and NVC responses during the trail making task (with transcranial Doppler sonography) were assessed. We found that circulating IGF-1 levels were significantly decreased with age and associated with decreased basal CBF. Age-related decline in IGF-1 levels predicted the magnitude of age-related decline in NVC responses. In conclusion, our study provides additional evidence in support of the concept that age-related circulating IGF-1 deficiency contributes to neurovascular aging, impairing CBF and functional hyperemia in older adults.

Biomarkers of aging in real life: three questions on aging and the comprehensive geriatric assessment - Marta Zampino; M. Cristina Polidori; Luigi Ferrucci; Desmond O’Neill; Alberto Pilotto; Manfred Gogol; Laurence Rubenstein (GeroScience, 2022)
Measuring intrinsic, biological age is a central question in medicine, which scientists have been trying to answer for decades. Age manifests itself differently in different individuals, and chronological age often does not reflect such heterogeneity of health and function. We discuss here the value of measuring age and aging using the comprehensive geriatric assessment (CGA), cornerstone of geriatric medicine, and operationalized assessment tools for prognosis. Specifically, we review the benefits of employing the multidimensional prognostic index (MPI), which collects information about eight domains relevant for the global assessment of the older person (functional and cognitive status, nutrition, mobility and risk of pressure sores, multi-morbidity, polypharmacy, and co-habitation), in the evaluation of the functional status, and in the prediction of health outcomes for older adults. Further integration of biological markers of aging into multidimensional prognostic tools is warranted, as well as actions which could facilitate prognostic assessments for older persons in all healthcare settings.

The role of age-associated autonomic dysfunction in inflammation and endothelial dysfunction - Yunqiu Jiang; Andriy Yabluchanskiy; Jielin Deng; Faris A. Amil; Sunny S. Po; Tarun W. Dasari (GeroScience, 2022)

Renoprotective effects of empagliflozin in type 1 and type 2 models of diabetic nephropathy superimposed with hypertension - Jan M. Williams; Sydney R. Murphy; Wenjie Wu; Jane J. Border; Fan Fan; Richard J. Roman (GeroScience, 2022)

Emergence of heartbeat frailty in advanced age I: perspectives from life-long EKG recordings in adult mice - Jack M. Moen; Christopher H. Morrell; Michael G. Matt; Ismayil Ahmet; Syevda Tagirova; Moran Davoodi; Michael Petr; Shaquille Charles; Rafael de Cabo; Yael Yaniv; Edward G. Lakatta (GeroScience, 2022)
The combined influences of sinoatrial nodal (SAN) pacemaker cell automaticity and its response to autonomic input determine the heart’s beating interval variability and mean beating rate. To determine the intrinsic SAN and autonomic signatures buried within EKG RR interval time series change in advanced age, we measured RR interval variability before and during double autonomic blockade at 3-month intervals from 6 months of age until the end of life in long-lived (those that achieved the total cohort median life span of 24 months and beyond) C57/BL6 mice. Prior to 21 months of age, time-dependent changes in intrinsic RR interval variability and mean RR interval were relatively minor. Between 21 and 30 months of age, however, marked changes emerged in intrinsic SAN RR interval variability signatures, pointing to a reduction in the kinetics of pacemaker clock mechanisms, leading to reduced synchronization of molecular functions within and among SAN cells. This loss of high-frequency signal processing within intrinsic SAN signatures resulted in a marked increase in the mean intrinsic RR interval. The impact of autonomic signatures on RR interval variability were net sympathetic and partially compensated for the reduced kinetics of the intrinsic SAN RR interval variability signatures, and partially, but not completely, shifted the EKG RR time series intervals to a more youthful pattern. Cross-sectional analyses of other subsets of C57/BL6 ages indicated that at or beyond the median life span of our longitudinal cohort, noncardiac, constitutional, whole-body frailty was increased, energetic efficiency was reduced, and the respiratory exchange ratio increased. We interpret the progressive reduction in kinetics in intrinsic SAN RR interval variability signatures in this context of whole-body frailty beyond 21 months of age to be a manifestation of “heartbeat frailty.”

Use of convalescent plasma therapy in hospitalised adult patients with non-critical COVID-19: a focus on the elderly from Hungary - Noemi Kiss-Dala; Balint Gergely Szabo; Botond Lakatos; Marienn Reti; Janos Szlavik; Istvan Valyi-Nagy (GeroScience, 2022)
Convalescent plasma therapy might be a feasible option for treatment of novel infections. During the early phases of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, several promising results were published with convalescent plasma therapy, followed by more disappointing findings of randomised controlled trials. In our single-centre, open-label, prospective, cohort study, we assessed the findings of 180 patients treated with convalescent plasma during the first four waves of the pandemic in Hungary. The primary outcome was all-cause mortality; secondary outcomes were clinical improvement and need for intensive care unit admission by day 28. Subgroup analysis comparing elderly and non-elderly (less than 65 years of age) was performed. Twenty (11.4%) patients died by day 28, at significantly higher rates in the elderly subgroup (3 vs. 17, p < 0.01). One hundred twenty-eight (72.7%) patients showed clinical improvement, and 15 (8.5%) were transferred to the intensive care unit until day 28. Non-elderly patients showed clinical improvement by day 28 in significantly higher rates (improvement 74 vs. 54, no improvement 15 vs. 11, worsening or death 4 vs. 18 patients, p < 0.01). In conclusion, we found similar clinical outcome results as randomised controlled trials, and the impact of risk factors for unfavourable clinical outcomes among patients in the elderly population.

Decreased lifespan in female “Munchkin” actors from the cast of the 1939 film version of The Wizard of Oz does not support the hypothesis linking hypopituitary dwarfism to longevity - Vince Fazekas-Pongor; Anna Péterfi; Dávid Major; Zsófia Szarvas; Monika Fekete; Adam G. Tabak; Anna Csiszar; William E. Sonntag; Steven N. Austad; Zoltan I. Ungvari (GeroScience, 2022)

Henipaviruses: an expanding global public health concern? - Jorge Quarleri; Verónica Galvan; M. Victoria Delpino (GeroScience, 2022)

The majority of severe COVID-19 patients develop anti-cardiac autoantibodies - Miklós Fagyas; Béla Nagy; Arnold Péter Ráduly; Ivetta Siket Mányiné; Lilla Mártha; Gábor Erdősi; Sándor Sipka; Enikő Enyedi; Attila Ádám Szabó; Zsófia Pólik; János Kappelmayer; Zoltán Papp; et al. (GeroScience, 2022)
Severe cases of COVID-19 are characterized by an inflammatory burst, which is accompanied by multiorgan failure. The elderly population has higher risk for severe or fatal outcome for COVID-19. Inflammatory mediators facilitate the immune system to combat viral infection by producing antibodies against viral antigens. Several studies reported that the pro-inflammatory state and tissue damage in COVID-19 also promotes autoimmunity by autoantibody generation. We hypothesized that a subset of these autoantibodies targets cardiac antigens. Here we aimed to detect anti-cardiac autoantibodies in severe COVID-19 patients during hospitalization. For this purpose, 104 COVID-19 patients were recruited, while 40 heart failure patients with dilated cardiomyopathy and 20 patients with severe aortic stenosis served as controls. Patients were tested for anti-cardiac autoantibodies, using human heart homogenate as a bait. Follow-up samples were available in 29 COVID-19 patients. Anti-cardiac autoantibodies were detected in 68% (71 out of 104) of severe COVID-19 patients. Overall, 39% of COVID-19 patients had anti-cardiac IgG autoantibodies, while 51% had anti-cardiac autoantibodies of IgM isotype. Both IgG and IgM anti-cardiac autoantibodies were observed in 22% of cases, and multiple cardiac antigens were targeted in 38% of COVID-19 patients. These anti-cardiac autoantibodies targeted a diverse set of myocardial proteins, without apparent selectivity. As controls, heart failure patients (with dilated cardiomyopathy) had similar occurrence of IgG (45%, p = 0.57) autoantibodies, while significantly lower occurrence of IgM autoantibodies (30%, p = 0.03). Patients with advanced aortic stenosis had significantly lower number of both IgG (11%, p = 0.03) and IgM (10%, p < 0.01) type anti-cardiac autoantibodies than that in COVID-19 patients. Furthermore, we detected changes in the anti-cardiac autoantibody profile in 7 COVID-19 patients during hospital treatment. Surprisingly, the presence of these anti-cardiac autoantibodies did not affect the clinical outcome and the prevalence of the autoantibodies did not differ between the elderly (over 65 years) and the patients younger than 65 years of age. Our results demonstrate that the majority of hospitalized COVID-19 patients produce novel anti-cardiac IgM autoantibodies. COVID-19 also reactivates resident IgG autoantibodies. These autoantibodies may promote autoimmune reactions, which can complicate post-COVID recuperation, contributing to post-acute sequelae of COVID-19 (long COVID).

Is “cellular senescence” a misnomer? - David Gems; Carina C. Kern (GeroScience, 2022)
One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends lifespan in mice. This implied that accumulation of senescent cells promotes late-life diseases, particularly through action of senescent cell secretions (the senescence-associated secretory phenotype, or SASP). But what exactly is a senescent cell? Subsequent to the initial characterization of cellular senescence, it became clear that, prior to aging, this phenomenon is in fact adaptive. It supports tissue remodeling functions in a variety of contexts, including embryogenesis, parturition, and acute inflammatory processes that restore normal tissue architecture and function, such as wound healing, tissue repair after infection, and amphibian limb regeneration. In these contexts, such cells are normal and healthy and not in any way senescent in the true sense of the word, as originally meant by Hayflick. Thus, it is misleading to refer to them as “senescent.” Similarly, the common assertion that senescent cells accumulate with age due to stress and DNA damage is no longer safe, particularly given their role in inflammation—a process that becomes persistent in later life. We therefore suggest that it would be useful to update some terminology, to bring it into line with contemporary understanding, and to avoid future confusion. To open a discussion of this issue, we propose replacing the term cellular senescence with remodeling activation , and SASP with RASP (remodeling-associated secretory phenotype).

Replenishment of myeloid-derived suppressor cells (MDSCs) overrides CR-mediated protection against tumor growth in a murine model of triple-negative breast cancer - Laura C. D. Pomatto-Watson; Monica Bodogai; Melissa Carpenter; Dolly Chowdhury; Priya Krishna; Sandy Ng; Oye Bosompra; Jonathan Kato; Sarah Wong; Carlos Reyes-Sepulveda; Michel Bernier; Nathan L. Price; et al. (GeroScience, 2022)

A comprehensive analysis of the mutational landscape of the newly emerging Omicron (B.1.1.529) variant and comparison of mutations with VOCs and VOIs - Chiranjib Chakraborty; Manojit Bhattacharya; Ashish Ranjan Sharma; Kuldeep Dhama; Govindasamy Agoramoorthy (GeroScience, 2022)

Different patterns of excess all-cause mortality by age and sex in Hungary during the 2nd and 3rd waves of the COVID-19 pandemic - Vince Fazekas-Pongor; Zsófia Szarvas; Norbert D. Nagy; Anna Péterfi; Zoltán Ungvári; Viktor J. Horváth; Szilvia Mészáros; Adam G. Tabák (GeroScience, 2022)

Aging alters antiviral signaling pathways resulting in functional impairment in innate immunity in response to pattern recognition receptor agonists - Jennifer Connors; Bhavani Taramangalam; Gina Cusimano; Matthew R. Bell; Stephanie M. Matt; Kaitlyn Runner; Peter J. Gaskill; Victor DeFilippis; Janko Nikolich-Žugich; Michele A. Kutzler; Elias K. Haddad (GeroScience, 2022)
The progressive impairment of immunity to pathogens and vaccines with aging is a significant public health problem as the world population shifts to an increased percentage of older adults (> 65). We have previously demonstrated that cells obtained from older volunteers have delayed and defective induction of type I interferons and T cell and B cell helper cytokines in response to TLR ligands when compared to those from adult subjects. However, the underlying intracellular mechanisms are not well described. Herein, we studied two critical pathways important in the production of type I interferon (IFN), the interferon response factor 7 (pIRF7), and TANK-binding kinase (pTBK-1). We show a decrease in pIRF7 and pTBK-1 in cross-priming dendritic cells (cDC1s), CD4 + T cell priming DCs (cDC2s), and CD14 dim CD16 + vascular patrolling monocytes from older adults ( n = 11) following stimulation with pathway-specific agonists in comparison with young individuals ( n = 11). The decrease in these key antiviral pathway proteins correlates with decreased phagocytosis, suggesting impaired function in Overall, our findings describe molecular mechanisms which explain the innate functional impairment in older adults and thus could inform us of novel approaches to restore these defects. Graphical abstract

Continent-wide evolutionary trends of emerging SARS-CoV-2 variants: dynamic profiles from Alpha to Omicron - Chiranjib Chakraborty; Manojit Bhattacharya; Ashish Ranjan Sharma; Kuldeep Dhama; Sang-Soo Lee (GeroScience, 2022)

Evidence for preserved insulin responsiveness in the aging rat brain - Matthew G. Engel; Jeremy Smith; Kai Mao; Gabriela Farias Quipildor; Min-Hui Cui; Maria Gulinello; Craig A. Branch; Samuel E. Gandy; Derek M. Huffman (GeroScience, 2022)
Insulin appears to exert salutary effects in the central nervous system (CNS). Thus, brain insulin resistance has been proposed to play a role in brain aging and dementia but is conceptually complex and unlikely to fit classic definitions established in peripheral tissues. Thus, we sought to characterize brain insulin responsiveness in young (4–5 months) and old (24 months) FBN male rats using a diverse set of assays to determine the extent to which insulin effects in the CNS are impaired with age. When performing hyperinsulinemic-euglycemic clamps in rats, intracerebroventricular (ICV) infusion of insulin in old animals improved peripheral insulin sensitivity by nearly two-fold over old controls and comparable to young rats, suggesting preservation of this insulin-triggered response in aging per se ( p < 0.05). We next used an imaging-based approach by comparing ICV vehicle versus insulin and performed resting state functional magnetic resonance imaging (rs-fMRI) to evaluate age- and insulin-related changes in network connectivity within the default mode network. In aging, lower connectivity between the mesial temporal (MT) region and other areas, as well as reduced MT signal complexity, was observed in old rats, which correlated with greater cognitive deficits in old. Despite these stark differences, ICV insulin failed to elicit any significant alteration to the BOLD signal in young rats, while a significant deviation of the BOLD signal was observed in older animals, characterized by augmentation in regions of the septal nucleus and hypothalamus, and reduction in thalamus and nucleus accumbens. In contrast, ex vivo stimulation of hippocampus with 10 nM insulin revealed increased Akt activation in young ( p < 0.05), but not old rats. Despite similar circulating levels of insulin and IGF-1, cerebrospinal fluid concentrations of these ligands were reduced with age. Thus, these data highlight the complexity of capturing brain insulin action and demonstrate preserved or heightened brain responses to insulin with age, despite dampened canonical signaling, thereby suggesting impaired CNS input of these ligands may be a feature of reduced brain insulin action, providing further rationale for CNS replacement strategies.

Which components of the Mediterranean diet are associated with dementia? A UK Biobank cohort study - Ivelina Dobreva; Louise Marston; Naaheed Mukadam (GeroScience, 2022)
Cohort studies suggest that the Mediterranean diet is associated with better global cognition in older adults, slower cognitive decline and lower risk of dementia. However, little is known about the relative contribution of each component of the Mediterranean diet to dementia risk or whether the diet’s effects are due to one or more specific food components. We aimed to examine whether Mediterranean diet components are associated with all-cause dementia risk in the UK BioBank cohort. Participants joined the UK Biobank study from 2006 to 2010 and were followed until December 2020. 249,511 participants, who were at least 55 years old, without dementia at baseline were included. We used self-reported consumption of food groups, considered part of the Mediterranean diet including fruit, vegetables, processed meat, unprocessed red meat and unprocessed poultry, fish, cheese, wholegrains. Incident dementia was ascertained through electronic linkage to primary care records, hospital and mortality records or self-report. In this study with a total follow-up of 2,868,824 person-years (median 11.4), after adjusting for all covariates and other food groups, moderate fish consumption of between 2.0 and 3.9 times a week was associated with decreased risk of dementia (HR 0.84, 95%CI 0.71–0.98) compared to no consumption. Additionally, fruit consumption of between 1.0 and 1.9 servings a day was associated with reduced dementia risk (HR 0.85, 95%CI 0.74–0.99) compared to no consumption. No other Mediterranean diet components were associated with dementia risk suggesting that fish consumption may drive the beneficial effects seen from the Mediterranean diet. Further study of potential mechanisms and diet-based intervention trials are needed to establish this.

Brain age estimation reveals older adults’ accelerated senescence after traumatic brain injury - Anar Amgalan; Alexander S. Maher; Satyaki Ghosh; Helena C. Chui; Paul Bogdan; Andrei Irimia (GeroScience, 2022)

SARS-CoV-2 infection in HIV-infected patients: potential role in the high mutational load of the Omicron variant emerging in South Africa - Katalin Réka Tarcsai; Oliga Corolciuc; Attila Tordai; József Ongrádi (GeroScience, 2022)
A new variant of SARS-CoV-2 named Omicron (B.1.1.529) was isolated from an HIV-infected patient in Botswana, South Africa, in November 2021. Whole genome sequencing revealed a multitude of mutations and its relationship to the mutation-rich Alpha variant that had been isolated from a cancer patient. It is conceivable that very high prevalence of HIV-infected individuals as susceptible hosts in South Africa and their immunocompromised state may predispose for accumulation of coronavirus mutations. Coronaviruses uniquely code for an N-terminal 3′ to 5′exonuclease (ExoN, nsp14) that removes mismatched nucleotides paired by the RNA dependent RNA polymerase. Its activity depends preferably on Mg 2+ and other divalent cations (manganese, cobalt and zinc). On the contrary, methyl transferase activity of non-structural protein (nsp) 14 and nsp16 both complexed with nsp10 requires Mn 2+ . Enzymes in successive stages of HIV infections require the same cations. In HIV-infected organisms, a subsequent coronavirus infection encounters with altered homeostasis of the body including relative starvation of divalent cations induced by interleukin production of HIV-infected cells. It is hypothesized that selective diminished efficacy of ExoN in the absence of sufficient amount of magnesium may result in the accumulation of mutations. Unusual mutations and recombinations of heterologous viruses detected in AIDS patients also suggest that long-lasting persistence of superinfecting viruses may also contribute to the selection of genetic variants. Non-nucleoside reverse transcriptase inhibitors partially restore divalent cations’ equilibrium. As a practical approach, implementation of highly active antiretroviral therapy against HIV replication and vaccination against coronaviruses may be a successful strategy to reduce the risk of selection of similar mutants.

Proteomic features of skeletal muscle adaptation to resistance exercise training as a function of age - Colleen S. Deane; Bethan E. Phillips; Craig R. G. Willis; Daniel J. Wilkinson; Ken Smith; Nahoko Higashitani; John P. Williams; Nathaniel J. Szewczyk; Philip J. Atherton; Atsushi Higashitani; Timothy Etheridge (GeroScience, 2022)
Resistance exercise training (RET) can counteract negative features of muscle ageing but older age associates with reduced adaptive capacity to RET. Altered muscle protein networks likely contribute to ageing RET adaptation; therefore, associated proteome-wide responses warrant exploration. We employed quantitative sarcoplasmic proteomics to compare age-related proteome and phosphoproteome responses to RET. Thigh muscle biopsies were collected from eight young (25 ± 1.1 years) and eight older (67.5 ± 2.6 years) adults before and after 20 weeks supervised RET. Muscle sarcoplasmic fractions were pooled for each condition and analysed using Isobaric Tags for Relative and Absolute Quantification (iTRAQ) labelling, tandem mass spectrometry and network-based hub protein identification. Older adults displayed impaired RET-induced adaptations in whole-body lean mass, body fat percentage and thigh lean mass ( P > 0.05). iTRAQ identified 73 differentially expressed proteins with age and/or RET. Despite possible proteomic stochasticity, RET improved ageing profiles for mitochondrial function and glucose metabolism (top hub; PYK (pyruvate kinase)) but failed to correct altered ageing expression of cytoskeletal proteins (top hub; YWHAZ (14–3-3 protein zeta/delta)). These ageing RET proteomic profiles were generally unchanged or oppositely regulated post-RET in younger muscle. Similarly, RET corrected expression of 10 phosphoproteins altered in ageing, but these responses were again different vs. younger adults. Older muscle is characterised by RET-induced metabolic protein profiles that, whilst not present in younger muscle, improve untrained age-related proteomic deficits. Combined with impaired cytoskeletal adhesion responses, these results provide a proteomic framework for understanding and optimising ageing muscle RET adaptation.

Monkeypox: considerations for the understanding and containment of the current outbreak in non-endemic countries - Jorge Quarleri; M. Victoria Delpino; Verónica Galvan (GeroScience, 2022)

Evidence that conserved essential genes are enriched for pro-longevity factors - Naci Oz; Elena M. Vayndorf; Mitsuhiro Tsuchiya; Samantha McLean; Lesly Turcios-Hernandez; Jason N. Pitt; Benjamin W. Blue; Michael Muir; Michael G. Kiflezghi; Alexander Tyshkovskiy; Alexander Mendenhall; Matt Kaeberlein; et al. (GeroScience, 2022)
At the cellular level, many aspects of aging are conserved across species. This has been demonstrated by numerous studies in simple model organisms like Saccharomyces cerevisiae , Caenorhabdits elegans , and Drosophila melanogaster . Because most genetic screens examine loss of function mutations or decreased expression of genes through reverse genetics, essential genes have often been overlooked as potential modulators of the aging process. By taking the approach of increasing the expression level of a subset of conserved essential genes, we found that 21% of these genes resulted in increased replicative lifespan in S. cerevisiae . This is greater than the ~ 3.5% of genes found to affect lifespan upon deletion, suggesting that activation of essential genes may have a relatively disproportionate effect on increasing lifespan. The results of our experiments demonstrate that essential gene overexpression is a rich, relatively unexplored means of increasing eukaryotic lifespan.

Systemic inflammatory markers in relation to cognitive function and measures of brain atrophy: a Mendelian randomization study - Jiao Luo; Saskia le Cessie; Gerard Jan Blauw; Claudio Franceschi; Raymond Noordam; Diana van Heemst (GeroScience, 2022)
Observational studies have implied associations between multiple cytokines and cognitive decline, anti-inflammatory drugs however did not yield any protective effects on cognitive decline. We aimed to assess the associations of systemic inflammation, as measured by multiple cytokine and growth factor, with cognitive performance and brain atrophy using two-sample Mendelian randomization (MR). Independent genetic instruments ( p < 5e − 8 and p < 5e − 6) for 41 systemic inflammatory markers were retrieved from a genome-wide association study conducted in 8293 Finnish participants. Summary statistics for gene-outcome associations were obtained for cognitive performance ( N = 257,841) and for brain atrophy measures of cerebral cortical surface area and thickness ( N = 51,665) and hippocampal volume ( N = 33,536). To rule out the heterogeneity in the cognitive performance, we additionally included three domains: the fluid intelligence score ( N = 108,818), prospective memory result ( N = 111,099), and reaction time ( N = 330,069). Main results were computed by inverse-variance weighting; sensitivity analyses taking pleiotropy and invalid instruments into account were performed by using weighted-median estimator, MR-Egger, and MR PRESSO. After correcting for multiple testing using false discovery rate, only genetically predicted (with p < 5e − 6 threshold) per-SD (standard deviation) higher IL-8 was associated with − 0.103 (− 0.155, − 0.051, p adjusted = 0.004) mm 3 smaller hippocampal volume and higher intelligence fluid score [ β : 0.103 SD (95% CI: 0.042, 0.165), p adjusted = 0.041]. Sensitivity analyses generally showed similar results, and no pleiotropic effect, heterogeneity, or possible reverse causation was detected. Our results suggested a possible causal association of high IL-8 levels with better cognitive performance but smaller hippocampal volume among the general healthy population, highlighting the complex role of inflammation in dementia-related phenotypes. Further research is needed to elucidate mechanisms underlying these associations.

Inhibition of the 3-mercaptopyruvate sulfurtransferase—hydrogen sulfide system promotes cellular lipid accumulation - Giovanna Casili; Elisa Randi; Theodora Panagaki; Karim Zuhra; Maria Petrosino; Csaba Szabo (GeroScience, 2022)
H 2 S is generated in the adipose tissue by cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase (3-MST). H 2 S plays multiple roles in the regulation of various metabolic processes, including insulin resistance. H 2 S biosynthesis also occurs in adipocytes. Aging is known to be associated with a decline in H 2 S. Therefore, the question arises whether endogenous H 2 S deficiency may affect the process of adipocyte maturation and lipid accumulation. Among the three H 2 S-generating enzymes, the role of 3-MST is the least understood in adipocytes. Here we tested the effect of the 3-MST inhibitor 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE) and the H 2 S donor (GYY4137) on the differentiation and adipogenesis of the adipocyte-like cells 3T3-L1 in vitro. 3T3-L1 cells were differentiated into mature adipocytes in the presence of GYY4137 or HMPSNE. HMPSNE significantly enhanced lipid accumulation into the maturing adipocytes. On the other hand, suppressed lipid accumulation was observed in cells treated with the H 2 S donor. 3-MST inhibition increased, while H 2 S donation suppressed the expression of various H 2 S-producing enzymes during adipocyte differentiation. 3-MST knockdown also facilitated adipocytic differentiation and lipid uptake. The underlying mechanisms may involve impairment of oxidative phosphorylation and fatty acid oxidation as well as the activation of various differentiation-associated transcription factors. Thus, the 3-MST/H 2 S system plays a tonic role in suppressing lipid accumulation and limiting the differentiation of adipocytes. Stimulation of 3-MST activity or supplementation of H 2 S—which has been recently linked to various experimental therapeutic approaches during aging—may be a potential experimental approach to counteract adipogenesis.

Subclinical cognitive deficits are associated with reduced cerebrovascular response to visual stimulation in mid-sixties men - Mark Bitsch Vestergaard; Ulrich Lindberg; Maria Højberg Knudsen; Olalla Urdanibia-Centelles; Aftab Bakhtiari; Erik Lykke Mortensen; Merete Osler; Birgitte Fagerlund; Krisztina Benedek; Martin Lauritzen; Henrik Bo Wiberg Larsson (GeroScience, 2022)
Reduced cerebrovascular response to neuronal activation is observed in patients with neurodegenerative disease. In the present study, we examined the correlation between reduced cerebrovascular response to visual activation (ΔCBF Vis.Act ) and subclinical cognitive deficits in a human population of mid-sixties individuals without neurodegenerative disease. Such a correlation would suggest that impaired cerebrovascular function occurs before overt neurodegenerative disease. A total of 187 subjects (age 64–67 years) of the Metropolit Danish Male Birth Cohort participated in the study. ΔCBF Vis.Act was measured using arterial spin labelling (ASL) MRI. ΔCBF Vis.Act correlated positively with cognitive performance in: Global cognition ( p = 0.046), paired associative memory ( p = 0.025), spatial recognition ( p = 0.026), planning ( p = 0.016), simple processing speed ( p < 0.01), and with highly significant correlations with current intelligence ( p < 10 −5 ), and more complex processing speed ( p < 10 −3 ), the latter two explaining approximately 11–13% of the variance. Reduced ΔCBF Vis.Act was independent of brain atrophy. Our findings suggest that inhibited cerebrovascular response to neuronal activation is an early deficit in the ageing brain and associated with subclinical cognitive deficits. Cerebrovascular dysfunction could be an early sign of a trajectory pointing towards the development of neurodegenerative disease. Future efforts should elucidate if maintenance of a healthy cerebrovascular function can protect against the development of dementia.

Association of cerebral microvascular dysfunction and white matter injury in Alzheimer’s disease - Zsolt Bagi; Christopher D. Kroenke; Katie Anne Fopiano; Yanna Tian; Jessica A. Filosa; Larry S. Sherman; Eric B. Larson; C. Dirk Keene; Kiera Degener O’Brien; Philip A. Adeniyi; Stephen A. Back (GeroScience, 2022)

Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice - Jonathan A. Zegarra-Valdivia; Jansen Fernandes; Maria Estrella Fernandez de Sevilla; Angel Trueba-Saiz; Jaime Pignatelli; Kentaro Suda; Laura Martinez-Rachadell; Ana Maria Fernandez; Julio Esparza; Miguel Vega; Angel Nuñez; Ignacio Torres Aleman (GeroScience, 2022)

Alteration in peritoneal cells with the chemokine CX3CL1 reverses age-associated impairment of recognition memory - Yoshinori Takei; Yoko Amagase; Keiko Iida; Tomohiro Sagawa; Ai Goto; Ryuichi Kambayashi; Hiroko Izumi-Nakaseko; Akio Matsumoto; Shinichi Kawai; Atsushi Sugiyama; Tatsuyuki Takada; Akira Hirasawa (GeroScience, 2022)

Glucose metabolism patterns: A potential index to characterize brain ageing and predict high conversion risk into cognitive impairment - Jiehui Jiang; Can Sheng; Guanqun Chen; Chunhua Liu; Shichen Jin; Lanlan Li; Xueyan Jiang; Ying Han; Michael W. Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; et al. (GeroScience, 2022)

Cognitive control, interference inhibition, and ordering of information during working memory in younger and older healthy adults - Mina Mirjalili; Reza Zomorrodi; Zafiris J. Daskalakis; Sean L. Hill; Sanjeev Kumar; Daniel M. Blumberger; Corinne E. Fischer; Alastair J. Flint; Nathan Herrmann; Krista L. Lanctôt; Linda Mah; Benoit H. Mulsant; et al. (GeroScience, 2022)

Single-cell transcriptomics identifies premature aging features of TERC-deficient mouse brain and bone marrow - Chunying Yang; Yidan Pang; Yigang Huang; Fang Ye; Xiaoyi Chen; Youshui Gao; Changqing Zhang; Lufeng Yao; Junjie Gao (GeroScience, 2022)

CYB5R3 overexpression preserves skeletal muscle mitochondria and autophagic signaling in aged transgenic mice - Sara López-Bellón; Sandra Rodríguez-López; José A. González-Reyes; M. Isabel Burón; Rafael de Cabo; José M. Villalba (GeroScience, 2022)
Cytochrome b 5 reductase 3 (CYB5R3) overexpression activates respiratory metabolism and exerts prolongevity effects in transgenic mice, mimicking some of the salutary effects of calorie restriction. The aim of our study was to understand how CYB5R3 overexpression targets key pathways that modulate the rate of aging in skeletal muscle, a postmitotic tissue with a greater contribution to resting energy expenditure. Mitochondrial function, autophagy and mitophagy markers were evaluated in mouse hind limb skeletal muscles from young-adult (7 months old) and old (24 months old) males of wild-type and CYB5R3-overexpressing genotypes. Ultrastructure of subsarcolemmal and intermyofibrillar mitochondria was studied by electron microscopy in red gastrocnemius. CYB5R3, which was efficiently overexpressed and targeted to skeletal muscle mitochondria regardless of age, increased the abundance of complexes I, II, and IV in old mice and prevented the age-related decrease of complexes I, III, IV, and V and the mitofusin MFN-2. ATP was significantly decreased by aging, which was prevented by CYB5R3 overexpression. Coenzyme Q and the mitochondrial biogenesis markers TFAM and NRF-1 were also significantly diminished by aging, but CYB5R3 overexpression did not protect against these declines. Both aging and CYB5R3 overexpression upregulated SIRT3 and the mitochondrial fission markers FIS1 and DRP-1, although with different outcomes on mitochondrial ultrastructure: old wild-type mice exhibited mitochondrial fragmentation whereas CYB5R3 overexpression increased mitochondrial size in old transgenic mice concomitant with an improvement of autophagic recycling. Interventions aimed at stimulating CYB5R3 could represent a valuable strategy to counteract the deleterious effects of aging in skeletal muscle. Graphical abstract

Longitudinal associations between blood lysophosphatidylcholines and skeletal muscle mitochondrial function - Qu Tian; Brendan A. Mitchell; Marta Zampino; Luigi Ferrucci (GeroScience, 2022)
Lysophosphatidylcholines (LPCs) are phospholipids critical in the synthesis of cardiolipin, an essential component of mitochondrial membranes. Lower plasma LPCs have been cross-sectionally associated with lower skeletal muscle mitochondrial function, but whether lower LPCs and their decline over time are longitudinally associated with an accelerated decline of mitochondria function is unknown. We analyzed data from 184 participants in the Baltimore Longitudinal Study of Aging (mean age: 74.5 years, 57% women, 25% black) who had repeated measures of plasma LPCs (16:0, 16:1, 17:0, 18:0, 18:1, 18:2, 20:3, 20:4, 24:0, and 28:1) by liquid chromatography-tandem mass spectrometry and repeated measures of skeletal muscle oxidative capacity ( k PCr ) assessed by 31 P magnetic resonance spectroscopy over an average of 2.4 years. Rates of change in k PCr and each LPC were first estimated using simple linear regression. In multivariable linear regression models adjusted for baseline demographics and PCr % depletion, lower baseline LPC 16:1 and faster rates of decline in LPC 16:1 and 18:1 were significantly associated with a faster rate of decline in k PCr ( B = − 0.169, 95% CI: − 0.328, − 0.010, p = 0.038; B = 0.209, 95% CI: 0.065, 0.352, p = 0.005; B = 0.156, 95% CI: 0.011, 0.301, p = 0.035, respectively). Rates of change in other LPCs were not significantly associated with change in k PCr (all p > 0.05). Lower baseline concentrations and faster decline in selected plasma lysophosphatidylcholines over time are associated with faster decline in skeletal muscle mitochondrial function. Strategies to prevent the decline of plasma LPCs at an early stage may slow down mitochondrial function decline and impairment during aging.

A fly GWAS for purine metabolites identifies human FAM214 homolog medusa, which acts in a conserved manner to enhance hyperuricemia-driven pathologies by modulating purine metabolism and the inflammatory response - Tyler A. U. Hilsabeck; Ru Liu-Bryan; Tracy Guo; Kenneth A. Wilson; Neelanjan Bose; Daniel Raftery; Jennifer N. Beck; Sven Lang; Kelly Jin; Christopher S. Nelson; Tal Oron; Marshall Stoller; et al. (GeroScience, 2022)

Glycolytic and Oxidative Phosphorylation Defects Precede the Development of Senescence in Primary Human Brain Microvascular Endothelial Cells - Siva S. V. P. Sakamuri; Venkata N. Sure; Lahari Kolli; Ning Liu; Wesley R. Evans; Jared A. Sperling; David W. Busija; Xiaoying Wang; Sarah H. Lindsey; Walter L. Murfee; Ricardo Mostany; Prasad V. G. Katakam (GeroScience, 2022)

Integrative epigenomic and transcriptomic analyses reveal metabolic switching by intermittent fasting in brain - Gavin Yong-Quan Ng; Dominic Paul Lee Kok Sheng; Han-Gyu Bae; Sung Wook Kang; David Yang-Wei Fann; Jinsu Park; Joonki Kim; Asfa Alli-Shaik; Jeongmi Lee; Eunae Kim; Sunyoung Park; Jeung-Whan Han; et al. (GeroScience, 2022)

Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies - Charlotte Graham; Rhoda Stefanatos; Angeline E. H. Yek; Ruth V. Spriggs; Samantha H. Y. Loh; Alejandro Huerta Uribe; Tong Zhang; L. Miguel Martins; Oliver D. K. Maddocks; Filippo Scialo; Alberto Sanz (GeroScience, 2022)
Mitochondrial reactive oxygen species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) through respiratory complex I generates high levels of mtROS. Suppression of ROS production via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We find that in old fruit flies, ROS-RET is abolished when electron flux is decreased and that their mitochondria produce consistently high levels of mtROS. Finally, we demonstrate that in young flies, limiting electron exit, but not entry, from the ETC phenocopies mtROS generation observed in old individuals. Our results elucidate the mechanism by which ROS signalling is lost during ageing.

Aging-associated changes in motor function are ovarian somatic tissue-dependent, but germ cell and estradiol independent in post-reproductive female mice exposed to young ovarian tissue - Tracy L. Habermehl; Kaden B. Underwood; Kevin D. Welch; Steven P. Gawrys; Kate C. Parkinson; Augusto Schneider; Michal M. Masternak; Jeffrey B. Mason (GeroScience, 2022)

Senolytic treatment rescues blunted muscle hypertrophy in old mice - Cory M. Dungan; Vandre C. Figueiredo; Yuan Wen; Georgia L. VonLehmden; Christopher J. Zdunek; Nicholas T. Thomas; C. Brooks Mobley; Kevin A. Murach; Camille R. Brightwell; Douglas E. Long; Christopher S. Fry; Philip A. Kern; et al. (GeroScience, 2022)
With aging, skeletal muscle plasticity is attenuated in response to exercise. Here, we report that senescent cells, identified using senescence-associated β-galactosidase (SA β-Gal) activity and p21 immunohistochemistry, are very infrequent in resting muscle, but emerge approximately 2 weeks after a bout of resistance exercise in humans. We hypothesized that these cells contribute to blunted hypertrophic potential in old age. Using synergist ablation-induced mechanical overload (MOV) of the plantaris muscle to model resistance training in adult (5–6-month) and old (23–24-month) male C57BL/6 J mice, we found increased senescent cells in both age groups during hypertrophy. Consistent with the human data, there were negligible senescent cells in plantaris muscle from adult and old sham controls, but old mice had significantly more senescent cells 7 and 14 days following MOV relative to young. Old mice had blunted whole-muscle hypertrophy when compared to adult mice, along with smaller muscle fibers, specifically glycolytic type 2x + 2b fibers. To ablate senescent cells using a hit-and-run approach, old mice were treated with vehicle or a senolytic cocktail consisting of 5 mg/kg dasatinib and 50 mg/kg quercetin (D + Q) on days 7 and 10 during 14 days of MOV; control mice underwent sham surgery with or without senolytic treatment. Old mice given D + Q had larger muscles and muscle fibers after 14 days of MOV, fewer senescent cells when compared to vehicle-treated old mice, and changes in the expression of genes (i.e., Igf1 , Ddit4 , Mmp14 ) that are associated with hypertrophic growth. Our data collectively show that senescent cells emerge in human and mouse skeletal muscle following a hypertrophic stimulus and that D + Q improves muscle growth in old mice.

The Combined Oral Stable Isotope Assessment of Muscle (COSIAM) reveals D-3 creatine derived muscle mass as a standout cross-sectional biomarker of muscle physiology vitality in older age - Jessica Cegielski; Matthew S. Brook; Bethan E. Phillips; Catherine Boereboom; Amanda Gates; John F. R. Gladman; Kenneth Smith; Daniel J. Wilkinson; Philip J. Atherton (GeroScience, 2022)
Validated diagnostics of skeletal muscle vitality could benefit clinical and basic science in terms of mechanistic insights and in determining the efficacy of interventions, e.g. exercise/pharmaceuticals/nutrients. We recently developed a Combined Oral Assessment of Muscle (COSIAM) that can be used to simultaneously quantify whole-body muscle mass (WBMM), muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Here, we aimed to establish, in a cross-sectional fashion, links between COSIAM parameters and established aspects of muscle function. We recruited 37 healthy older adults (male (M):female (F) (21/16); 72 ± 5 y)) into a 3-day trial. Subjects consumed D 3 -creatine (D 3 -Cr dilution to assess WBMM), D 2 O (MPS by incorporation of alanine) and D 3 -3-methylhistidine (D 3 -MH dilution to assess MPB). A biopsy at day 3 was used to determine MPS, and blood/urine samples were collected to determine D 3 -Cr/D 3 -MH dilution for WBMM and MPB. Physiological measures of muscle mass (e.g. DXA/ultrasound) and function (e.g. handgrip strength, maximum voluntary contraction (MVC), one-repetition maximum (1-RM)) were ascertained. A stepwise linear regression approach was used to address links between facets of COSIAM (MPS, MPB, WBMM) and muscle physiology. Despite expected differences in muscle mass, there were no significant differences in MPS or MPB between sexes. WBMM as measured using D 3 -Cr positively correlated with DXA-derived lean body mass (LBM) and appendicular LBM (ABLM). Stepwise linear regression was used to assess which combination of MPS, MPB, D 3 -Cr and absolute synthesis rate (ASR) best predicted physiological measures of muscle health in these older adults. D 3 -Cr WBMM alone was the best predictor of handgrip, 1RM and MVC, and outperformed more traditional measures of muscle mass by DXA. The COSIAM approach substantiates D 3 -Cr as a robust biomarker of multiple muscle physiology health biomarkers. Future work using COSIAM should focus upon how and which parameters it can inform upon in relation to disease progression and the efficacy of interventions.

Immune phenotype of the CD4+ T cells in the aged lymphoid organs and lacrimal glands - Claudia M. Trujillo-Vargas; Kelsey E. Mauk; Humberto Hernandez; Rodrigo G. de Souza; Zhiyuan Yu; Jeremias G. Galletti; Jana Dietrich; Friedrich Paulsen; Cintia S. de Paiva (GeroScience, 2022)

Senescent macrophages in the human adipose tissue as a source of inflammaging - Giulia Matacchione; Jessica Perugini; Eleonora Di Mercurio; Jacopo Sabbatinelli; Francesco Prattichizzo; Martina Senzacqua; Gianluca Storci; Christian Dani; Giovanni Lezoche; Mario Guerrieri; Antonio Giordano; Massimiliano Bonafè; et al. (GeroScience, 2022)
Obesity is a major risk factor for type 2 diabetes and a trigger of chronic and systemic inflammation. Recent evidence suggests that an increased burden of senescent cells (SCs) in the adipose tissue of obese/diabetic animal models might underlie such pro-inflammatory phenotype. However, the role of macrophages as candidate SCs, their phenotype, the distribution of SCs among fat depots, and clinical relevance are debated. The senescence marker β-galactosidase and the macrophage marker CD68 were scored in visceral (vWAT) and subcutaneous (scWAT) adipose tissue from obese patients ( n =17) undergoing bariatric surgery and control patients ( n =4) subjected to cholecystectomy. A correlation was made between the number of SCs and BMI, serum insulin, and the insulin resistance (IR) index HOMA. The monocyte cell line (THP-1) was cultured in vitro in high glucose milieu (60 mM D-glucose) and subsequently co-cultured with human adipocytes (hMADS) to investigate the reciprocal inflammatory activation. In obese patients, a significantly higher number of SCs was observed in vWAT compared to scWAT; about 70% of these cells expressed the macrophage marker CD68; and the number of SCs in vWAT, but not in scWAT, positively correlated with BMI, HOMA-IR, and insulin. THP-1 cultured in vitro in high glucose milieu acquired a senescent-like phenotype (HgSMs), characterized by a polarization toward a mixed M1/M2-like secretory phenotype. Co-culturing HgSMs with hMADS elicited pro-inflammatory cytokine expression in both cell types, and defective insulin signaling in hMADS. In morbid obesity, expansion of visceral adipose depots involves an increased burden of macrophages with senescent-like phenotype that may promote a pro-inflammatory profile and impair insulin signaling in adipocytes, supporting a framework where senescent macrophages fuel obesity-induced systemic inflammation and possibly contribute to the development of IR.

Phosphorylation-dependent proteome of Marcks in ependyma during aging and behavioral homeostasis in the mouse forebrain - Nagendran Muthusamy; Taufika I. Williams; Ryan O’Toole; Jon J. Brudvig; Kenneth B. Adler; Jill M. Weimer; David C. Muddiman; H. Troy Ghashghaei (GeroScience, 2022)

Effects of task prioritization on a postural-motor task in early-stage Parkinson’s disease: EEG connectivity and clinical implication - Cheng-Ya Huang; Liang-Chi Chen; Ruey-Meei Wu; Ing-Shiou Hwang (GeroScience, 2022)

Age-dependent frequency of unconventional T cells in a healthy adult Caucasian population: a combinational study of invariant natural killer T cells, γδ T cells, and mucosa-associated invariant T cells - Parvind Singh; Marianna Szaraz-Szeles; Zoltan Mezei; Sandor Barath; Zsuzsanna Hevessy (GeroScience, 2022)
Unconventional T cells show distinct and unique features during antigen recognition as well as other immune responses. Their decrease in frequency is associated with various autoimmune disorders, allergy, inflammation, and cancer. The landscape frequency of the unconventional T cells altogether (iNKT, γδ T, and MAIT) is largely unestablished leading to various challenges affecting diagnosis and research in this field. In this study, we have established the age group–wise frequency of iNKT, γδ T, and MAIT cells altogether on a total of 203 healthy adult samples of the Caucasian population. The results revealed that iNKT cells were 0.095%, γδ T cells were 2.175%, and MAIT cells were 2.99% of the total T cell population. γδ and MAIT cell frequency is higher in younger age groups than elderly; however, there is no statistically significant difference in the frequency of iNKT cells. Furthermore, γδ and MAIT cells were negatively correlating with age, supporting immunosenescence, unlike iNKT cells. Our finding could be used for further age-wise investigation of various pathological conditions such as cancer and their prognosis, autoimmune diseases and their pathogenicity.

Cardiac troponin T and autoimmunity in skeletal muscle aging - Tan Zhang; Xin Feng; Juan Dong; Zherong Xu; Bo Feng; Karen M. Haas; Peggy M. Cawthon; Kristen M. Beavers; Barbara Nicklas; Stephen Kritchevsky (GeroScience, 2022)

Handgrip strength and risk of cognitive outcomes: new prospective study and meta-analysis of 16 observational cohort studies - Setor K. Kunutsor; Nzechukwu M. Isiozor; Ari Voutilainen; Jari A. Laukkanen (GeroScience, 2022)
Handgrip strength (HGS), a measure of muscular strength, might be a risk indicator for cognitive functioning, but the evidence is not consistent. Using a new prospective study and meta-analysis of published observational cohort studies, we aimed to evaluate the prospective associations of HGS with poor cognitive outcomes including cognitive impairment, dementia and Alzheimer’s disease (AD). Handgrip strength, measured using a Martin-Balloon-Vigorimeter, was assessed at baseline in a population-based sample of 852 men and women with good cognitive function in the Kuopio Ischemic Heart Disease cohort. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for cognitive outcomes. Relevant published studies were sought in MEDLINE, Embase and Web of Science from inception until October 2021 and pooled using random effects meta-analysis. During a median follow-up of 16.6 years, 229 dementia cases were recorded. Comparing extreme tertiles of HGS, the multivariable adjusted HR (95% CI) for dementia, AD and vascular dementia was 0.77 (0.55–1.07), 0.75 (0.52–1.10) and 0.49 (0.16–1.48), respectively. In a meta-analysis of 16 population-based prospective cohort studies (including the current study) comprising 180,920 participants, the pooled multivariable adjusted relative risks (95% CIs) comparing the top vs bottom thirds of HGS levels were as follows: 0.58 (0.52–0.65) for cognitive impairment; 0.37 (0.07–1.85) for cognitive decline; 0.73 (0.62–0.86) for dementia; 0.68 (0.53–0.87) for AD; and 0.48 (0.32–0.73) for vascular dementia. GRADE quality of evidence ranged from low to very low. Meta-analysis of aggregate prospective data suggests that HGS may be a risk indicator for poor cognitive outcomes such as cognitive impairment, dementia and AD. Systematic review registration: PROSPERO 2021: CRD42021237750.

17α-estradiol does not adversely affect sperm parameters or fertility in male mice: implications for reproduction-longevity trade-offs - José V. V. Isola; Gabriel B. Veiga; Camila R. C. de Brito; Joao A. Alvarado-Rincón; Driele N. Garcia; Bianka M. Zanini; Jéssica D. Hense; Arnaldo D. Vieira; Michael Garratt; Bernardo G. Gasperin; Augusto Schneider; Michael B. Stout (GeroScience, 2022)

Correction to: Cannabinoid receptor 2 activation alleviates diabetes-induced cardiac dysfunction, inflammation, oxidative stress, and fibrosis - Mohanraj Rajesh; Partha Mukhopadhyay; Sándor Bátkai; Muhammad Arif; Zoltán V. Varga; Csaba Mátyás; Janos Paloczi; Andrea Lehocki; György Haskó; Pal Pacher (GeroScience, 2022)

From 1901 to 2022, how far are we from truly understanding the pathogenesis of age-related dementia? - Xing Fang; Jin Zhang; Richard J. Roman; Fan Fan (GeroScience, 2022)

A retrotransposon storm marks clinical phenoconversion to late-onset Alzheimer’s disease - Fabio Macciardi; Maria Giulia Bacalini; Ricardo Miramontes; Alessio Boattini; Cristian Taccioli; Giorgia Modenini; Rond Malhas; Laura Anderlucci; Yuriy Gusev; Thomas J. Gross; Robert M. Padilla; Massimo S. Fiandaca; et al. (GeroScience, 2022)
Recent reports have suggested that the reactivation of otherwise transcriptionally silent transposable elements (TEs) might induce brain degeneration, either by dysregulating the expression of genes and pathways implicated in cognitive decline and dementia or through the induction of immune-mediated neuroinflammation resulting in the elimination of neural and glial cells. In the work we present here, we test the hypothesis that differentially expressed TEs in blood could be used as biomarkers of cognitive decline and development of AD. To this aim, we used a sample of aging subjects (age > 70) that developed late-onset Alzheimer’s disease (LOAD) over a relatively short period of time (12–48 months), for which blood was available before and after their pheno conversion, and a group of cognitive stable subjects as controls. We applied our developed and validated customized pipeline that allows the identification, characterization, and quantification of the differentially expressed (DE) TEs before and after the onset of manifest LOAD, through analyses of RNA-Seq data. We compared the level of DE TEs within more than 600,000 TE-mapping RNA transcripts from 25 individuals, whose specimens we obtained before and after their phenotypic conversion ( pheno conversion) to LOAD, and discovered that 1790 TE transcripts showed significant expression differences between these two timepoints (logFC ± 1.5, logCMP > 5.3, nominal p value < 0.01). These DE transcripts mapped both over- and under-expressed TE elements. Occurring before the clinical pheno conversion, this TE storm features significant increases in DE transcripts of LINEs, LTRs, and SVAs, while those for SINEs are significantly depleted. These dysregulations end with signs of manifest LOAD. This set of highly DE transcripts generates a TE transcriptional profile that accurately discriminates the before and after pheno conversion states of these subjects. Our findings suggest that a storm of DE TEs occurs before pheno conversion from normal cognition to manifest LOAD in risk individuals compared to controls, and may provide useful blood-based biomarkers for heralding such a clinical transition, also suggesting that TEs can indeed participate in the complex process of neurodegeneration.

Telomere length and epigenetic clocks as markers of cellular aging: a comparative study - Emily E. Pearce; Rotana Alsaggaf; Shilpa Katta; Casey Dagnall; Geraldine Aubert; Belynda D. Hicks; Stephen R. Spellman; Sharon A. Savage; Steve Horvath; Shahinaz M. Gadalla (GeroScience, 2022)

Vitamin D supplementation is associated with slower epigenetic aging - Valentin Max Vetter; Yasmine Sommerer; Christian Humberto Kalies; Dominik Spira; Lars Bertram; Ilja Demuth (GeroScience, 2022)
Adverse effects of low vitamin D level on mortality and morbidity are controversially discussed. Especially older people are at risk for vitamin D deficiency and therefore exposed to its potentially harmful consequences. A way of measuring differences in the biological age is through DNA methylation age (DNAm age) and its deviation from chronological age, DNAm age acceleration (DNAmAA). We previously reported on an association between vitamin D deficiency and higher 7-CpG DNAmAA in participants of the Berlin Aging Study II (BASE-II). In this study, we employ a quasi-interventional study design to assess the relationship between DNAmAA of five epigenetic clocks and vitamin D supplementation. Longitudinal data were available for 1,036 participants of BASE-II that were reexamined on average 7.4 years later in the GendAge study (mean age at follow-up: 75.6 years, SD = 3.8 years, age range: 64.9–94.1 years, 51.9% female). DNAmAA was estimated with the 7-CpG clock, Horvath’s clock, Hannum’s clock, PhenoAge, and GrimAge. Methylation data were obtained through methylation-sensitive single nucleotide primer extension (MS-SNuPE) or Illumina’s Infinium “MethylationEPIC” array. Vitamin D–deficient participants who chose to start vitamin D supplementation after baseline examination showed a 2.6-year lower 7-CpG DNAmAA ( p = 0.011) and 1.3-year lower Horvath DNAmAA ( p = 0.042) compared to untreated and vitamin D–deficient participants. DNAmAA did not statistically differ between participants with successfully treated vitamin D deficiency and healthy controls ( p > 0.16). Therefore, we conclude that intake of vitamin D supplement is associated with lower DNAmAA in participants with vitamin D deficiency.

Favipiravir for the treatment of COVID-19 in elderly patients—what do we know after 2 years of COVID-19? - Henrietta Papp; Zsófia Lanszki; György M. Keserű; Ferenc Jakab (GeroScience, 2022)
Since the appearance of coronavirus disease 2019 (COVID-19), numerous studies have been conducted to find effective therapeutics. Favipiravir (FVP) is one of the repurposed drugs which has been authorized in a few countries on an emergency basis to treat COVID-19. Elderly individuals especially 65 years or older are more prone to develop severe illness. We aim to provide a short summary of the current knowledge of the antiviral efficacy of favipiravir with respect to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected elderly patients. We found that it is rather controversial whether favipiravir is effective against SARS-CoV-2 infection. Data regarding patients 65 years or older is not sufficient to support or reject the usage of favipiravir for COVD-19 treatment. Further studies would be advisable to elicit the efficiency of favipiravir in elderly COVID-19 patients.

Persistent viral RNA shedding of SARS-CoV-2 is associated with delirium incidence and six-month mortality in hospitalized COVID-19 patients - Ayush Batra; Jeffrey R. Clark; Anthony K. Kang; Sareen Ali; Tulsi R. Patel; Nathan A. Shlobin; Steven C. Hoffman; Patrick H. Lim; Zachary S. Orban; Lavanya Visvabharathy; Edith L. Graham; David P. Sullivan; et al. (GeroScience, 2022)

Perceived social isolation is correlated with brain structure and cognitive trajectory in Alzheimer’s disease - Ye Zhang; Yasuko Tatewaki; Yingxu Liu; Naoki Tomita; Tatsuo Nagasaka; Michiho Muranaka; Shuzo Yamamoto; Yumi Takano; Taizen Nakase; Tatsushi Mutoh; Yasuyuki Taki (GeroScience, 2022)

Role of inflammatory markers in the diagnosis of vascular contributions to cognitive impairment and dementia: a systematic review and meta-analysis - Carlo Custodero; Alessandro Ciavarella; Francesco Panza; Davide Gnocchi; Gennaro M. Lenato; Juhan Lee; Antonio Mazzocca; Carlo Sabbà; Vincenzo Solfrizzi (GeroScience, 2022)
Vascular contribution to cognitive impairment and dementia (VCID) is a clinical label encompassing a wide range of cognitive disorders progressing from mild to major vascular cognitive impairment (VCI), which is also defined as vascular dementia (VaD). VaD diagnosis is mainly based on clinical and imaging findings. Earlier biomarkers are needed to identify subjects at risk to develop mild VCI and VaD. In the present meta-analysis, we comprehensively evaluated the role of inflammatory biomarkers in differential diagnosis between VaD and Alzheimer’s disease (AD), and assessed their prognostic value on predicting VaD incidence. We collected literature until January 31, 2021, assessing three inflammatory markers [interleukin(IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α] from blood or cerebrospinal fluid (CSF) samples. Thirteen cross-sectional and seven prospective studies were included. Blood IL-6 levels were cross-sectionally significantly higher in people with VaD compared to AD patients (SMD: 0.40, 95% CI: 0.18 to 0.62) with low heterogeneity ( I 2 : 41%, p = 0.13). Higher IL-6 levels were also associated to higher risk of incident VaD (relative risk: 1.28, 95% CI: 1.03 to 1.59, I 2 : 0%). IL-6 in CSF was significantly higher in people with VaD compared to healthy subjects (SMD: 0.77, 95% CI: 0.17 to 1.37, I 2 : 70%), and not compared to AD patients, but due to limited evidence and high inconsistency across studies, we could not draw definite conclusion. Higher blood IL-6 levels might represent a useful biomarker able to differentiate people with VaD from those with AD and might be correlated with higher risk of future VaD.

Elevated α-synuclein and NfL levels in tear fluids and decreased retinal microvascular densities in patients with Parkinson’s disease - Chao-Wen Lin; Tzu-Ting Lai; Szu-Ju Chen; Chin-Hsien Lin (GeroScience, 2022)

Once-daily feeding is associated with better health in companion dogs: results from the Dog Aging Project - Emily E. Bray; Zihan Zheng; M. Katherine Tolbert; Brianah M. McCoy; Joshua M. Akey; Brooke Benton; Elhanan Borenstein; Marta G. Castelhano; Amanda E. Coleman; Kate E. Creevy; Kyle Crowder; Matthew D. Dunbar; et al. (GeroScience, 2022)

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation - Maria E. C. Bruno; Sujata Mukherjee; Whitney L. Powell; Stephanie F. Mori; Franklyn K. Wallace; Beverly K. Balasuriya; Leon C. Su; Arnold J. Stromberg; Donald A. Cohen; Marlene E. Starr (GeroScience, 2022)
Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44 hi CD62L low CD69 + ) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

Obesity as a premature aging phenotype — implications for sarcopenic obesity - Emily Nunan; Carson L. Wright; Oluwayemisi A. Semola; Madhan Subramanian; Priya Balasubramanian; Pamela C. Lovern; Ibra S. Fancher; Joshua T. Butcher (GeroScience, 2022)
Obesity and aging have both seen dramatic increases in prevalence throughout society. This review seeks to highlight common pathologies that present with obesity, along with the underlying risk factors, that have remarkable similarity to what is observed in the aged. These include skeletal muscle dysfunction (loss of quantity and quality), significant increases in adiposity, systemic alterations to autonomic dysfunction, reduction in nitric oxide bioavailability, increases in oxidant stress and inflammation, dysregulation of glucose homeostasis, and mitochondrial dysfunction. This review is organized by the aforementioned indices and succinctly highlights literature that demonstrates similarities between the aged and obese phenotypes in both human and animal models. As aging is an inevitability and obesity prevalence is unlikely to significantly decrease in the near future, these two phenotypes will ultimately combine as a multidimensional syndrome (a pathology termed sarcopenic obesity). Whether the pre-mature aging indices accompanying obesity are additive or synergistic upon entering aging is not yet well defined, but the goal of this review is to illustrate the potential consequences of a double aged phenotype in sarcopenic obesity. Clinically, the modifiable risk factors could be targeted specifically in obesity to allow for increased health span in the aged and sarcopenic obese populations.

Imaging subtle leaks in the blood–brain barrier in the aging human brain: potential pitfalls, challenges, and possible solutions - Axel Montagne; Samuel R. Barnes; Daniel A. Nation; Kassandra Kisler; Arthur W. Toga; Berislav V. Zlokovic (GeroScience, 2022)

Stringent public health measures during COVID-19 across ischemic stroke care systems: the potential impact of patient perceptions on health care-seeking behaviors - Calin I. Prodan; Ayush Batra; Zoltan Ungvari; Eric M. Liotta (GeroScience, 2022)

The pathophysiology of chronic subdural hematoma revisited: emphasis on aging processes as key factor - Ralf Weigel; Lothar Schilling; Joachim K. Krauss (GeroScience, 2022)

Senolytic treatment reverses obesity-mediated senescent cell accumulation in the ovary - Jéssica D. Hense; Driele N. Garcia; José V. Isola; Joao A. Alvarado-Rincón; Bianka M. Zanini; Juliane B. Prosczek; Michael B. Stout; Jeffrey B. Mason; Patrick T. Walsh; Miguel A. Brieño-Enríquez; Ines Schadock; Carlos C. Barros; et al. (GeroScience, 2022)

Cannabinoid receptor 2 activation alleviates diabetes-induced cardiac dysfunction, inflammation, oxidative stress, and fibrosis - Mohanraj Rajesh; Partha Mukhopadhyay; Sándor Bátkai; Muhammad Arif; Zoltán V. Varga; Csaba Mátyás; Janos Paloczi; Andrea Lehocki; György Haskó; Pal Pacher (GeroScience, 2022)

Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice - Rodney M. Ritzel; Yun Li; Zhuofan Lei; Jordan Carter; Junyun He; Harry M. C. Choi; Niaz Khan; Hui Li; Samantha Allen; Marta M. Lipinski; Alan I. Faden; Junfang Wu (GeroScience, 2022)
Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking. The present study sought to identify potential inflammatory mechanisms underlying age-related outcomes late after TBI. Controlled cortical impact was used to induce moderate TBI in young and old male C57BL/6 mice. At 12 weeks post-injury, aged mice exhibited higher mortality, poorer functional outcomes, larger lesion volumes, and increased microglial activation. Transcriptomic analysis identified age- and TBI-specific gene changes consistent with a disease-associated microglial signature in the chronically injured brain, including those involved with complement, phagocytosis, and autophagy pathways. Dysregulation of phagocytic and autophagic function in microglia was accompanied by increased neuroinflammation in old mice. As proof-of-principle that these pathways have functional importance, we administered an autophagic enhancer, trehalose, in drinking water continuously for 8 weeks after TBI. Old mice treated with trehalose showed enhanced functional recovery and reduced microglial activation late after TBI compared to the sucrose control group. Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients.

Epigenetic clock and methylation studies in marsupials: opossums, Tasmanian devils, kangaroos, and wallabies - Steve Horvath; Amin Haghani; Joseph A. Zoller; Ken Raj; Ishani Sinha; Todd R. Robeck; Pete Black; Aidan Couzens; Clive Lau; Meghety Manoyan; Yadiamaris Aviles Ruiz; Annais Talbott; et al. (GeroScience, 2022)
The opossum ( Monodelphis domestica ), with its sequenced genome, ease of laboratory care and experimental manipulation, and unique biology, is the most used laboratory marsupial. Using the mammalian methylation array, we generated DNA methylation data from n = 100 opossum samples from the ear, liver, and tail. We contrasted postnatal development and later aging effects in the opossum methylome with those in mouse ( Mus musculus , C57BL/6 J strain) and other marsupial species such as Tasmanian devil, kangaroos, and wallabies. While the opossum methylome is similar to that of mouse during postnatal development, it is distinct from that shared by other mammals when it comes to the age-related gain of methylation at target sites of polycomb repressive complex 2. Our immunohistochemical staining results provide additional support for the hypothesis that PRC2 activity increases with later aging in mouse tissues but remains constant in opossum tissues. We present several epigenetic clocks for opossums that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (opossum and human). Two dual-species human-opossum pan-tissue clocks accurately measure chronological age and relative age, respectively. The human-opossum epigenetic clocks are expected to provide a significant boost to the attractiveness of opossum as a biological model. Additional epigenetic clocks for Tasmanian devil, red kangaroos and other species of the genus Macropus may aid species conservation efforts.

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume - Lidija Milicic; Michael Vacher; Tenielle Porter; Vincent Doré; Samantha C. Burnham; Pierrick Bourgeat; Rosita Shishegar; James Doecke; Nicola J. Armstrong; Rick Tankard; Paul Maruff; Colin L. Masters; et al. (GeroScience, 2022)
The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.

Cannabidiol induces autophagy and improves neuronal health associated with SIRT1 mediated longevity - Zhizhen Wang; Peng Zheng; Xi Chen; Yuanyi Xie; Katrina Weston-Green; Nadia Solowij; Yee Lian Chew; Xu-Feng Huang (GeroScience, 2022)
Autophagy is a catabolic process to eliminate defective cellular molecules via lysosome-mediated degradation. Dysfunctional autophagy is associated with accelerated aging, whereas stimulation of autophagy could have potent anti-aging effects. We report that cannabidiol (CBD), a natural compound from Cannabis sativa , extends lifespan and rescues age-associated physiological declines in C. elegans . CBD promoted autophagic flux in nerve-ring neurons visualized by a tandem-tagged LGG-1 reporter during aging in C. elegans . Similarly, CBD activated autophagic flux in hippocampal and SH-SY5Y neurons. Furthermore, CBD-mediated lifespan extension was dependent on autophagy genes ( bec-1 , vps-34 , and sqst-1 ) confirmed by RNAi knockdown experiments. C. elegans neurons have previously been shown to accumulate aberrant morphologies, such as beading and blebbing, with increasing age. Interestingly, CBD treatment slowed the development of these features in anterior and posterior touch receptor neurons (TRN) during aging. RNAi knockdown experiments indicated that CBD-mediated age-associated morphological changes in TRNs require bec-1 and sqst-1 , not vps-34 . Further investigation demonstrated that CBD-induced lifespan extension and increased neuronal health require sir-2.1 /SIRT1. These findings collectively indicate the anti-aging benefits of CBD treatment, in both in vitro and in vivo models, and its potential to improve neuronal health and longevity.

Diabetic patients treated with metformin during early stages of Alzheimer’s disease show a better integral performance: data from ADNI study - Carlos Pomilio; Nicolás González Pérez; Ismael Calandri; Lucía Crivelli; Ricardo Allegri; Gustavo Sevlever; Flavia Saravia (GeroScience, 2022)

Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults - Wan-Hsuan Lu; Kelly Virecoulon Giudici; John E. Morley; Sophie Guyonnet; Angelo Parini; Geetika Aggarwal; Andrew D. Nguyen; Yan Li; Randall J. Bateman; Bruno Vellas; Philipe de Souto Barreto; Bruno Vellas; et al. (GeroScience, 2022)

SGLT2 inhibition attenuates arterial dysfunction and decreases vascular F-actin content and expression of proteins associated with oxidative stress in aged mice - Rogerio N. Soares; Francisco I. Ramirez-Perez; Francisco J. Cabral-Amador; Mariana Morales-Quinones; Christopher A. Foote; Thaysa Ghiarone; Neekun Sharma; Gavin Power; James A. Smith; R. Scott Rector; Luis A. Martinez-Lemus; Jaume Padilla; et al. (GeroScience, 2022)
Aging of the vasculature is characterized by endothelial dysfunction and arterial stiffening, two key events in the pathogenesis of cardiovascular disease (CVD). Treatment with sodium glucose transporter 2 (SGLT2) inhibitors is now known to decrease cardiovascular morbidity and mortality in type 2 diabetes. However, whether SGLT2 inhibition attenuates vascular aging is unknown. We first confirmed in a cohort of adult subjects that aging is associated with impaired endothelial function and increased arterial stiffness and that these two variables are inversely correlated. Next, we investigated whether SGLT2 inhibition with empagliflozin (Empa) ameliorates endothelial dysfunction and reduces arterial stiffness in aged mice with confirmed vascular dysfunction. Specifically, we assessed mesenteric artery endothelial function and stiffness (via flow-mediated dilation and pressure myography mechanical responses, respectively) and aortic stiffness (in vivo via pulse wave velocity and ex vivo via atomic force microscopy) in Empa-treated (14 mg/kg/day for 6 weeks) and control 80-week-old C57BL/6 J male mice. We report that Empa-treated mice exhibited improved mesenteric endothelial function compared with control, in parallel with reduced mesenteric artery and aortic stiffness. Additionally, Empa-treated mice had greater vascular endothelial nitric oxide synthase activation, lower phosphorylated cofilin, and filamentous actin content, with downregulation of pathways involved in production of reactive oxygen species. Our findings demonstrate that Empa improves endothelial function and reduces arterial stiffness in a preclinical model of aging, making SGLT2 inhibition a potential therapeutic alternative to reduce the progression of CVD in older individuals. Graphical abstract

Prediction of disability-free survival in healthy older people - Johannes Tobias Neumann; Le T. P. Thao; Anne M. Murray; Emily Callander; Prudence R. Carr; Mark R. Nelson; Rory Wolfe; Robyn L. Woods; Christopher M. Reid; Raj C. Shah; Anne B. Newman; Jeff D. Williamson; et al. (GeroScience, 2022)
Prolonging survival in good health is a fundamental societal goal. However, the leading determinants of disability-free survival in healthy older people have not been well established. Data from ASPREE, a bi-national placebo-controlled trial of aspirin with 4.7 years median follow-up, was analysed. At enrolment, participants were healthy and without prior cardiovascular events, dementia or persistent physical disability. Disability-free survival outcome was defined as absence of dementia, persistent disability or death. Selection of potential predictors from amongst 25 biomedical, psychosocial and lifestyle variables including recognized geriatric risk factors, utilizing a machine-learning approach. Separate models were developed for men and women. The selected predictors were evaluated in a multivariable Cox proportional hazards model and validated internally by bootstrapping. We included 19,114 Australian and US participants aged ≥65 years (median 74 years, IQR 71.6–77.7). Common predictors of a worse prognosis in both sexes included higher age, lower Modified Mini-Mental State Examination score, lower gait speed, lower grip strength and abnormal (low or elevated) body mass index. Additional risk factors for men included current smoking, and abnormal eGFR. In women, diabetes and depression were additional predictors. The biased-corrected areas under the receiver operating characteristic curves for the final prognostic models at 5 years were 0.72 for men and 0.75 for women. Final models showed good calibration between the observed and predicted risks. We developed a prediction model in which age, cognitive function and gait speed were the strongest predictors of disability-free survival in healthy older people. Trial registration Clinicaltrials.gov (NCT01038583)

Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment - Jeremy A. Whitson; Richard Johnson; Lu Wang; Theo K. Bammler; Shin-Ichiro Imai; Huiliang Zhang; Jeanne Fredrickson; Elena Latorre-Esteves; Alessandro Bitto; Michael J. MacCoss; Peter S. Rabinovitch (GeroScience, 2022)

HIV, pathology and epigenetic age acceleration in different human tissues - Steve Horvath; David T. S. Lin; Michael S. Kobor; Joseph A. Zoller; Jonathan W. Said; Susan Morgello; Elyse Singer; William H. Yong; Beth D. Jamieson; Andrew J. Levine (GeroScience, 2022)
Epigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlate with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals. We used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen and pituitary gland) from 133 clinically characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history. Epigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multiorgan impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that amyotrophic lateral sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues. Blood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.

Elevated skin senescence in young mice causes delayed wound healing - Rex Jeya Rajkumar Samdavid Thanapaul; Maria Shvedova; Grace Haeun Shin; Jack Crouch; Daniel S. Roh (GeroScience, 2022)

Humoral immune response after COVID-19 infection or BNT162b2 vaccine among older adults: evolution over time and protective thresholds - Maxence Meyer; Florentin Constancias; Claudia Worth; Anita Meyer; Marion Muller; Alexandre Boussuge; Georges Kaltenbach; Elise Schmitt; Saïd Chayer; Aurélie Velay; Thomas Vogel; Samira Fafi-Kremer; et al. (GeroScience, 2022)

Impact of medium-chain triglycerides on gait performance and brain metabolic network in healthy older adults: a double-blind, randomized controlled study - Tatsushi Mutoh; Keiko Kunitoki; Yasuko Tatewaki; Shuzo Yamamoto; Benjamin Thyreau; Izumi Matsudaira; Ryuta Kawashima; Yasuyuki Taki (GeroScience, 2022)

Analysis of complexity in the EEG activity of Parkinson’s disease patients by means of approximate entropy - Chiara Pappalettera; Francesca Miraglia; Maria Cotelli; Paolo Maria Rossini; Fabrizio Vecchio (GeroScience, 2022)

Correction to: Early dysfunction of functional connectivity in healthy elderly with subjective memory complaints - Ricardo Bajo; Nazareth P. Castellanos; Maria Eugenia López; José María Ruiz-Sanchez de Leon; Pedro Montejo; Mercedes Montenegro; Marcos Llanero; Pedro Gil; Raquel Yubero; Evgenia Baykova; Nuria Paul; Sara Aurtenetxe; et al. (GeroScience, 2022)

Correction to: Pterocarpus marsupium extract extends replicative lifespan in budding yeast - Mitchell B. Lee; Michael G. Kiflezghi; Mitsuhiro Tsuchiya; Brian Wasko; Daniel T. Carr; Priya A. Uppal; Katherine A. Grayden; Yordanos C. Elala; Tu Anh Nguyen; Jesse Wang; Priya Rastogi; Sunny Nguyen; et al. (GeroScience, 2022)

Early-life educational attainment, APOE ε4 alleles, and incident dementia risk in late life - Hao Ma; Tao Zhou; Xiang Li; Demetrius Maraganore; Yoriko Heianza; Lu Qi (GeroScience, 2022)

Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases - Miracle Ozzoude; Brenda Varriano; Derek Beaton; Joel Ramirez; Melissa F. Holmes; Christopher J. M. Scott; Fuqiang Gao; Kelly M. Sunderland; Paula McLaughlin; Jennifer Rabin; Maged Goubran; Donna Kwan; et al. (GeroScience, 2022)

Correction to: Targeting senescent retinal pigment epithelial cells facilitates retinal regeneration in mouse models of age-related macular degeneration - Jae-Byoung Chae; Hyoik Jang; Chanok Son; Chul-Woo Park; Huyeon Choi; Seongeon Jin; Ho-Yeon Lee; Hyungwoo Lee; Ja-Hyoung Ryu; Namshin Kim; Chaekyu Kim; Hyewon Chung (GeroScience, 2022)

Poly(A) RNA sequencing reveals age-related differences in the prefrontal cortex of dogs - Sára Sándor; Dávid Jónás; Kitti Tátrai; Kálmán Czeibert; Eniko Kubinyi (GeroScience, 2022)
Dogs may possess a unique translational potential to investigate neural aging and dementia because they are prone to age-related cognitive decline, including an Alzheimer’s disease–like pathological condition. Yet very little is known about the molecular mechanisms underlying canine cognitive decline. The goal of the current study was to explore the transcriptomic differences between young and old dogs’ frontal cortex, which is a brain region often affected by various forms of age-related dementia in humans. RNA isolates from the frontal cortical brain area of 13 pet dogs, which represented 7 different breeds and crossbreds, were analyzed. The dogs were euthanized for medical reasons, and their bodies had been donated by their owners for scientific purposes. The poly(A) tail RNA subfraction of the total transcriptome was targeted in the sequencing analysis. Cluster analyses, differential gene expression analyses, and gene ontology analyses were carried out to assess which genes and genetic regulatory mechanisms were mostly affected by aging. Age was the most prominent factor in the clustering of the animals, indicating the presence of distinct gene expression patterns related to aging in a genetically variable population. A total of 3436 genes were found to be differentially expressed between the age groups, many of which were linked to neural function, immune system, and protein synthesis. These findings are in accordance with previous human brain aging RNA sequencing studies. Some genes were found to behave more similarly to humans than to rodents, further supporting the applicability of dogs in translational aging research.

Higher white matter hyperintensity load adversely affects pre-post proximal cognitive training performance in healthy older adults - Emanuel M. Boutzoukas; Andrew O’Shea; Jessica N. Kraft; Cheshire Hardcastle; Nicole D. Evangelista; Hanna K. Hausman; Alejandro Albizu; Emily J. Van Etten; Pradyumna K. Bharadwaj; Samantha G. Smith; Hyun Song; Eric C. Porges; et al. (GeroScience, 2022)

Long-term exercise pre-training attenuates Alzheimer’s disease–related pathology in a transgenic rat model of Alzheimer’s disease - Luodan Yang; Chongyun Wu; Yong Li; Yan Dong; Celeste Yin-Chieh Wu; Reggie Hui-Chao Lee; Darrell W. Brann; Hung Wen Lin; Quanguang Zhang (GeroScience, 2022)

Lipidomic signatures from physically frail and robust older adults at hospital admission - Robinson Ramírez-Vélez; Nicolás Martínez-Velilla; María Correa-Rodríguez; Mikel L. Sáez de Asteasu; Fabricio Zambom-Ferraresi; Sara Palomino-Echeverria; Antonio García-Hermoso; Mikel Izquierdo (GeroScience, 2022)
Identifying serum biomarkers that can predict physical frailty in older adults would have tremendous clinical value for primary care, as this condition is inherently related to poor quality of life and premature mortality. We compared the serum lipid profile of physically frail and robust older adults to identify specific lipid biomarkers that could be used to assess physical frailty in older patients at hospital admission. Forty-three older adults (58.1% male), mean (range) age 86.4 (78–100 years) years, were classified as physically frail ( n = 18) or robust ( n = 25) based on scores from the Short Physical Performance Battery (≤ 6 points). Non-targeted metabolomic study by ultra-high performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis with later bioinformatics data analysis. Once the significantly different metabolites were identified, the KEGG database was used on them to establish which were the metabolic pathways mainly involved. Area under receiver-operating curve (AUROC) analysis was used to test the discriminatory ability of lipid biomarkers for frailty based on the Short Physical Performance Battery. We identified a panel of five metabolites including ceramides Cer (40:2), Cer (d18:1/20:0), Cer (d18:1/23:0), cholesterol, and phosphatidylcholine (PC) (14:0/20:4) that were significantly increased in physically frail older adults compared with robust older adults at hospital admission. The most interesting in the physically frail metabolome study found with the KEGG database were the metabolic pathways, vitamin digestion and absorption, AGE-RAGE signaling pathway in diabetic complications, and insulin resistance. In addition, Cer (40:2) (AUROC 0.747), Cer (d18:1/23:0) (AUROC 0.720), and cholesterol (AUROC 0.784) were identified as higher values of physically frail at hospital admission. The non-targeted metabolomic study can open a wide view of the physically frail features changes at the plasma level, which would be linked to the physical frailty phenotype at hospital admission. Also, we propose that metabolome analysis will have a suitable niche in personalized medicine for physically frail older adults.

High-velocity resistance training mitigates physiological and functional impairments in middle-aged and older adults with and without mobility-limitation - Gustavo Z. Schaun; Marcas M. Bamman; Luana S. Andrade; Gabriela B. David; Vitor L. Krüger; Eduardo F. Marins; Gabriela N. Nunes; Mariana S. Häfele; Graciele F. Mendes; Maria Laura B. Gomes; Paula C. Campelo; Stephanie S. Pinto; et al. (GeroScience, 2022)

A neuromuscular perspective of sarcopenia pathogenesis: deciphering the signaling pathways involved - Alexandra Moreira-Pais; Rita Ferreira; Paula A. Oliveira; José A. Duarte (GeroScience, 2022)

Inverse association between the anticholinergic burden and hippocampus volume in a population-based cohort across the entire adult age range - Ingo Kilimann; Diana Wucherer; Till Ittermann; Henry Völzke; Robin Bülow; Wolfgang Hoffmann; Hans Jörgen Grabe; Katharina Wittfeld; Stefan Johannes Teipel (GeroScience, 2022)
Many medications of different indications have a relevant anticholinergic activity. The anticholinergic burden of medication has been shown to have significant effects on the cognition and the risk for cognitive impairment and dementia particularly in older patients. So far, most of the studies used data from geriatric patients and the effect of the anticholinergic burden on brain structures is still unexplored. Our study aimed to analyze possible associations of hippocampus and cholinergic basal forebrain volumes as vulnerable brain structures for the development of dementia and the anticholinergic burden in a population-based cohort of non-demented participants spanning the adult age range from 21 to 80 years. We analyzed associations between medication-related anticholinergic burden and structural MRI volumes from participants ( n = 3087, 52.2% female) of the population-based “Study of Health in Pomerania” (SHIP). Anticholinergic burden was obtained from the current medication plan using the Anticholinergic Burden Scale (ACB). All analyses were adjusted for age, sex, education, and total intracranial volume. We found statistically significant associations between the ACB and the left and right hippocampus volume but not for the basal forebrain cholinergic system. Complementary voxel-based analysis across all participants revealed FWE-corrected ( p = < 0.05) clusters in the temporo-parietal regions reaching into frontal areas, showing reduced volumes with higher ACB scores. We identified an association between anticholinergic burden of medication on hippocampal volume suggesting a potential inverse effect of such medication. This association highlights the importance of a careful prescription of medication with anticholinergic activity at any adult age.

Interaction of aging with lipoxygenase deficiency initiates hypersplenism, cardiac dysfunction, and profound leukocyte directed non-resolving inflammation - Vasundhara Kain; Yusuf Mat; Ganesh V. Halade (GeroScience, 2022)

Classical risk factors for primary coronary artery disease from an aging perspective through Mendelian Randomization - Swetta A. Jansen; Bas Huiskens; Stella Trompet; JWouter Jukema; Simon P. Mooijaart; Ko Willems van Dijk; Diana van Heemst; Raymond Noordam (GeroScience, 2022)

Circulating testosterone and dehydroepiandrosterone are associated with individual motor unit features in untrained and highly active older men - Yuxiao Guo; Jessica Piasecki; Agnieszka Swiecicka; Alex Ireland; Bethan E. Phillips; Philip J. Atherton; Daniel Stashuk; Martin K. Rutter; Jamie S. McPhee; Mathew Piasecki (GeroScience, 2022)
Long-term exercise training has been considered as an effective strategy to counteract age-related hormonal declines and minimise muscle atrophy. However, human data relating circulating hormone levels with motor nerve function are scant. The aims of the study were to explore associations between circulating sex hormone levels and motor unit (MU) characteristics in older men, including masters athletes competing in endurance and power events. Forty-three older men (mean ± SD age: 69.9 ± 4.6 years) were studied based on competitive status. The serum concentrations of dehydroepiandrosterone (DHEA), total testosterone (T) and estradiol were quantified using liquid chromatography mass spectrometry. Intramuscular electromyographic signals were recorded from vastus lateralis (VL) during 25% of maximum voluntary isometric contractions and processed to extract MU firing rate (FR), and motor unit potential (MUP) features. After adjusting for athletic status, MU FR was positively associated with DHEA levels ( p = 0.019). Higher testosterone and estradiol were associated with lower MUP complexity; these relationships remained significant after adjusting for athletic status ( p = 0.006 and p = 0.019, respectively). Circulating DHEA was positively associated with MU firing rate in these older men. Higher testosterone levels were associated with reduced MUP complexity, indicating reduced electrophysiological temporal dispersion, which is related to decreased differences in conduction times along axonal branches and/or MU fibres. Although evident in males only, this work highlights the potential of hormone administration as a therapeutic interventional strategy specifically targeting human motor units in older age.

Novel immortalization approach defers senescence of cultured canine adipose-derived mesenchymal stromal cells - Ana Stojiljković; Véronique Gaschen; Franck Forterre; Ulrich Rytz; Michael H. Stoffel; Jasmin Bluteau (GeroScience, 2022)

Untapped research opportunities in China: promising future avenues and potential concerns for aging companion animals - Jessica M. Hoffman; Shanshan Song; Katharina Brugger; Teresa G. Valencak (GeroScience, 2022)
Companion animals have recently been proposed as ideal translational models of human aging due to their shared susceptibility for certain diseases, similar environments, and sophisticated veterinary medicine diagnostics, all of which are not possible in rodent laboratory models. Here, we introduce and propose the study of companion animals in China as a largely untapped resource in academic and veterinary aging research. Pet ownership rates along with economic gains in the pet industry have skyrocketed over the last decade in China. Yet, the majority of research institutions still focus on agricultural animal research, not companion animals. In this perspective, we compare available pet ownership rates between the USA, the European Union, and China before focusing on the potential of companion animal aging research in China. In addition, we highlight some ethical considerations that must be addressed before large-scale companion animal aging research can be completed.

Omicron variant (B.1.1.529) of SARS-CoV-2: understanding mutations in the genome, S-glycoprotein, and antibody-binding regions - Manojit Bhattacharya; Ashish Ranjan Sharma; Kuldeep Dhama; Govindasamy Agoramoorthy; Chiranjib Chakraborty (GeroScience, 2022)

Proximal improvement and higher-order resting state network change after multidomain cognitive training intervention in healthy older adults - Cheshire Hardcastle; Hanna K. Hausman; Jessica N. Kraft; Alejandro Albizu; Andrew O’Shea; Emanuel M. Boutzoukas; Nicole D. Evangelista; Kailey Langer; Emily J. Van Etten; Pradyumna K. Bharadwaj; Hyun Song; Samantha G. Smith; et al. (GeroScience, 2022)

Brain cellular senescence in mouse models of Alzheimer’s disease - Angela O. Dorigatti; Ruben Riordan; Zhen Yu; Grace Ross; Rong Wang; Nadjalisse Reynolds-Lallement; Kathy Magnusson; Veronica Galvan; Viviana I. Perez (GeroScience, 2022)

Accelerated epigenetic aging and inflammatory/immunological profile (ipAGE) in patients with chronic kidney disease - Igor Yusipov; Elena Kondakova; Alena Kalyakulina; Mikhail Krivonosov; Nadezhda Lobanova; Maria Giulia Bacalini; Claudio Franceschi; Maria Vedunova; Mikhail Ivanchenko (GeroScience, 2022)

Examination of pituitary adenylate cyclase-activating polypeptide in Parkinson’s disease focusing on correlations with motor symptoms - Daniel Pham; Beata Polgar; Tunde Toth; Adel Jungling; Norbert Kovacs; Istvan Balas; Endre Pal; Dora Szabo; Balazs Daniel Fulop; Dora Reglodi; Zalan Szanto; Robert Herczeg; et al. (GeroScience, 2022)
The neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) have been shown in numerous in vitro and in vivo models of Parkinson’s disease (PD) supporting the theory that PACAP could have an important role in the pathomechanism of the disorder affecting mostly older patients. Earlier studies found changes in PACAP levels in neurological disorders; therefore, the aim of our study was to examine PACAP in plasma samples of PD patients. Peptide levels were measured with ELISA and correlated with clinical parameters, age, stage of the disorder based on the Hoehn and Yahr (HY) scale, subtype of the disease, treatment, and specific scores measuring motor and non-motor symptoms, such as movement disorder society-unified Parkinson’s disease rating scale (MDS-UPDRS), Epworth sleepiness scale (ESS), Parkinson’s disease sleep scale (PDSS-2), and Beck depression inventory (BDI). Our results showed significantly decreased PACAP levels in PD patients without deep brain stimulation (DBS) therapy and in akinetic-rigid subtype; additionally we also observed a further decrease in the HY stage 3 and 4. Elevated PACAP levels were found in patients with DBS. There were no significant correlations between PACAP level with MDS-UPDRS, type of pharmacological treatment, PDSS-2 sleepiness, or depression (BDI) scales, but we found increased PACAP level in patients with more severe sleepiness problems based on the ESS scale. Based on these results, we suggest that following the alterations of PACAP with other frequently used clinical biomarkers in PD patients might improve strategic planning of further therapeutic interventions and help to provide a clearer prognosis regarding the future perspective of the disease.

SARS-CoV-2 interacts with renin-angiotensin system: impact on the central nervous system in elderly patients - Jorge Quarleri; M. Victoria Delpino (GeroScience, 2022)

Selective brain regional changes in lipid profile with human aging - Natalia Mota-Martorell; Pol Andrés-Benito; Meritxell Martín-Gari; José Daniel Galo-Licona; Joaquim Sol; Anna Fernández-Bernal; Manuel Portero-Otín; Isidro Ferrer; Mariona Jove; Reinald Pamplona (GeroScience, 2022)
Fatty acids are key components in the structural diversity of lipids and play a strategic role in the functional properties of lipids which determine the integrity of neuronal and glial cell membranes, the generation of lipid signaling mediators, and the chemical reactivity of acyl chains. The present study analyzes using gas chromatography the fatty acid profiles of 13 regions of the human central nervous system in healthy individuals ranging from 40 to 80 years old. The outcomes suggest the existence of general traits in fatty acid composition such as an average chain length of 18 carbon atoms, high monounsaturated fatty acid content, and predominance in polyunsaturated fatty acids of those of series n-6 over series n-3 which are shared by all brain regions regardless of age. Our results also show a general sustained and relatively well-preserved lipid profile throughout the adult lifespan in most studied regions (olive, upper vermis, substantia nigra, thalamus, hippocampus, putamen, caudate, occipital cortex, parietal cortex, entorhinal cortex, and frontal cortex) with minor changes that are region-dependent. In contrast, of particular relevance is the involvement of the inferior temporal cortex and cingulate cortex. It is proposed that during normal human brain aging, the lipid profile is resistant to changes with age in most human brain regions to ensure cell survival and function, but some particular regions involved in specific memory domains are greatly affected.

A naturally hypersensitive porcine model may help understand the mechanism of COVID-19 mRNA vaccine-induced rare (pseudo) allergic reactions: complement activation as a possible contributing factor - László Dézsi; Tamás Mészáros; Gergely Kozma; Mária H-Velkei; Csaba Zs. Oláh; Miklós Szabó; Zsófia Patkó; Tamás Fülöp; Mark Hennies; Miklós Szebeni; Bálint András Barta; Béla Merkely; et al. (GeroScience, 2022)
A tiny fraction of people immunized with lipid nanoparticle (LNP)-enclosed mRNA (LNP-mRNA) vaccines develop allergic symptoms following their first or subsequent vaccinations, including anaphylaxis. These reactions resemble complement (C) activation-related pseudoallergy (CARPA) to i.v. administered liposomes, for which pigs provide a naturally oversensitive model. Using this model, we injected i.v. the human vaccination dose (HVD) of BNT162b2 (Comirnaty, CMT) or its 2-fold (2x) or 5-fold (5x) amounts and measured the hemodynamic changes and other parameters of CARPA. We observed in 6 of 14 pigs transient pulmonary hypertension along with thromboxane A2 release into the blood and other hemodynamic and blood cell changes, including hypertension, granulocytosis, lymphopenia, and thrombocytopenia. One pig injected with 5x CMT developed an anaphylactic shock requiring resuscitation, while a repeat dose failed to induce the reaction, implying tachyphylaxis. These typical CARPA symptoms could not be linked to animal age, sex, prior immune stimulation with zymosan, immunization of animals with Comirnaty i.v., or i.m. 2 weeks before the vaccine challenge, and anti-PEG IgM levels in Comirnaty-immunized pigs. Nevertheless, IgM binding to the whole vaccine, used as antigen in an ELISA, was significantly higher in reactive animals compared to non-reactive ones. Incubation of Comirnaty with pig serum in vitro showed significant elevations of C3a anaphylatoxin and sC5b-9, the C-terminal complex. These data raise the possibility that C activation plays a causal or contributing role in the rare HSRs to Comirnaty and other vaccines with similar side effects. Further studies are needed to uncover the factors controlling these vaccine reactions in pigs and to understand their translational value to humans.

New imaging tools for mouse models of osteoarthritis - S. Drevet; B. Favier; B. Lardy; G. Gavazzi; E. Brun (GeroScience, 2022)

Old blood from heterochronic parabionts accelerates vascular aging in young mice: transcriptomic signature of pathologic smooth muscle remodeling - Tamas Kiss; Ádám Nyúl-Tóth; Rafal Gulej; Stefano Tarantini; Tamas Csipo; Peter Mukli; Anna Ungvari; Priya Balasubramanian; Andriy Yabluchanskiy; Zoltan Benyo; Shannon M. Conley; Jonathan D. Wren; et al. (GeroScience, 2022)

Loss of aly/ALYREF suppresses toxicity in both tau and TDP-43 models of neurodegeneration - Rebecca L. Kow; Aristide H. Black; Aleen D. Saxton; Nicole F. Liachko; Brian C. Kraemer (GeroScience, 2022)

Distribution of 54 polygenic risk scores for common diseases in long lived individuals and their offspring - Sophia Gunn; Michael Wainberg; Zeyuan Song; Stacy Andersen; Robert Boudreau; Mary F. Feitosa; Qihua Tan; May E. Montasser; Jeffrey R. O’Connell; Nathan Stitziel; Nathan Price; Thomas Perls; et al. (GeroScience, 2022)

Naked mole-rats maintain cardiac function and body composition well into their fourth decade of life - Emine Can; Megan Smith; Bastiaan J. Boukens; Ruben Coronel; Rochelle Buffenstein; Johannes Riegler (GeroScience, 2022)
The prevalence of cardiovascular disease increases exponentially with age, highlighting the contribution of aging mechanisms to cardiac diseases. Although model organisms which share human disease pathologies can elucidate mechanisms driving disease, they do not provide us with innate examples how cardiac aging might be slowed or attenuated. The identification of animal models that preserve cardiac function throughout most of life offers an alternative approach to study mechanisms which might slow cardiac aging. One such species may be the naked mole-rat (NMR), a mouse-sized (40 g) rodent with extraordinary longevity (> 37 years), and constant mortality hazard over its four decades of life. We used a cross-sectional study design to measure a range of physiological parameters in NMRs between 2 and 34 years of age and compared these findings with those of mice aged between 3 months and 2.5 years. We observed a rapid decline in body fat content and bone mineral density in old mice, but no changes in NMRs. Similarly, rhythm disorders (premature atrial and ventricular complexes) occurred in aged mice but not in NMRs. Magnetic resonance and ultrasound imaging showed age-dependent increases in cardiac hypertrophy and diastolic dysfunction in mice which were absent in NMRs. Finally, cardiac stress tests showed an age-dependent decline in normalized cardiac output in mice, which was absent in NMRs. Unlike mice, that manifest several aspects of human cardiac aging, NMRs maintain cardiac function and reserve capacity throughout their long lives and may offer insights on how to delay or prevent cardiac aging.

Correction to: Primary neuron and astrocyte cultures from postnatal Callithrix jacchus: a non-human primate in vitro model for research in neuroscience, nervous system aging, and neurological diseases of aging - Angela O. Dorigatti; Stacy A. Hussong; Stephen F. Hernandez; Aubrey M. Sills; Adam B. Salmon; Veronica Galvan (GeroScience, 2022)

Strategies for handling missing data that improve Frailty Index estimation and predictive power: lessons from the NHANES dataset - Glen Pridham; Kenneth Rockwood; Andrew Rutenberg (GeroScience, 2022)

Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain - Tamas Kiss; Ádám Nyúl-Tóth; Jordan DelFavero; Priya Balasubramanian; Stefano Tarantini; Janet Faakye; Rafal Gulej; Chetan Ahire; Anna Ungvari; Andriy Yabluchanskiy; Graham Wiley; Lori Garman; et al. (GeroScience, 2022)

Evaluation of a blood-based geroscience biomarker index in a randomized trial of caloric restriction and exercise in older adults with heart failure with preserved ejection fraction - Jamie N. Justice; Nicholas M. Pajewski; Mark A. Espeland; Peter Brubaker; Denise K. Houston; Santica Marcovina; Barbara J. Nicklas; Stephen B. Kritchevsky; Dalane W. Kitzman (GeroScience, 2022)

Associations between sociodemographic factors, health spending, disease burden, and life expectancy of older adults (70 + years old) in 22 countries in the Western Pacific Region, 1995–2019: estimates from the Global Burden of Disease (GBD) Study 2019 - Alex Molassiotis; Stephen W. H. Kwok; Angela Y. M. Leung; Stefanos Tyrovolas (GeroScience, 2022)
The needs of the aging populations are putting increasing burden on healthcare particularly in the Western Pacific Region (WPR), which is the home of aging economies such as Hong Kong and Japan alongside rapid increases in older people in low- and middle-income countries (LMICs). However, little is known about the associations between sociodemographic factors, disease burden, and life expectancy in WPR. The current study conducted secondary analysis on the Global Burden of Disease (GBD) estimates of populations aged 70 years and older in WPR countries between 1995 and 2019. Correlation tests, linear mixed regressions and generalized additive mixture models were run to examine the associations of interest. Unsupervised machine learning was conducted to segment the data automatically, at cluster analysis. The sociodemographic development index was found an important factor to the disease burden in terms of Years Lived with Disability (YLD) rate and mortality rate among older adults. YLD rate and mortality rate of non-communicable diseases (NCDs) attributable to different risk groups were significant contributors to higher expectation of Lost Healthy Years (LHE) and shorter life expectancy respectively in the context of rising YLD rate, particularly in LMICs. Three clusters of countries with similar characteristics were identified. NCDs were the most significant contributors to shorter life expectancy within which the time living in poor health did not improve. Better management of NCDs in aging populations should be emphasized in all countries. The country clusters may help in a more regional strategic planning.

Premorbid aspirin use is not associated with lower mortality in older inpatients with SARS-CoV-2 pneumonia - Coralie Sullerot; Kevin Bouiller; Caroline Laborde; Marine Gilis; Amélie Fèvre; Arthur Hacquin; Patrick Manckoundia; Florence Hoefler; Messaline Bermejo; Aline Mendes; Christine Serratrice; Virginie Prendki; et al. (GeroScience, 2022)

Cerebral venous congestion exacerbates cerebral microhemorrhages in mice - Adam Nyul-Toth; Gabor A. Fulop; Stefano Tarantini; Tamas Kiss; Chetan Ahire; Janet A. Faakye; Anna Ungvari; Peter Toth; Attila Toth; Anna Csiszar; Zoltan Ungvari (GeroScience, 2022)

Modeling of nursing care-associated airborne transmission of SARS-CoV-2 in a real-world hospital setting - Attila Nagy; Alpár Horváth; Árpád Farkas; Péter Füri; Tamás Erdélyi; Balázs G. Madas; Aladár Czitrovszky; Béla Merkely; Attila Szabó; Zoltán Ungvári; Veronika Müller (GeroScience, 2022)
Respiratory transmission of SARS-CoV-2 from one older patient to another by airborne mechanisms in hospital and nursing home settings represents an important health challenge during the COVID-19 pandemic. However, the factors that influence the concentration of respiratory droplets and aerosols that potentially contribute to hospital- and nursing care-associated transmission of SARS-CoV-2 are not well understood. To assess the effect of health care professional (HCP) and patient activity on size and concentration of airborne particles, an optical particle counter was placed (for 24 h) in the head position of an empty bed in the hospital room of a patient admitted from the nursing home with confirmed COVID-19. The type and duration of the activity, as well as the number of HCPs providing patient care, were recorded. Concentration changes associated with specific activities were determined, and airway deposition modeling was performed using these data. Thirty-one activities were recorded, and six representative ones were selected for deposition modeling, including patient’s activities (coughing, movements, etc.), diagnostic and therapeutic interventions (e.g., diagnostic tests and drug administration), as well as nursing patient care (e.g., bedding and hygiene). The increase in particle concentration of all sizes was sensitive to the type of activity. Increases in supermicron particle concentration were associated with the number of HCPs ( r = 0.66; p < 0.05) and the duration of activity ( r = 0.82; p < 0.05), while submicron particles increased with all activities, mainly during the daytime. Based on simulations, the number of particles deposited in unit time was the highest in the acinar region, while deposition density rate (number/cm 2 /min) was the highest in the upper airways. In conclusion, even short periods of HCP-patient interaction and minimal patient activity in a hospital room or nursing home bedroom may significantly increase the concentration of submicron particles mainly depositing in the acinar regions, while mainly nursing activities increase the concentration of supermicron particles depositing in larger airways of the adjacent bed patient. Our data emphasize the need for effective interventions to limit hospital- and nursing care-associated transmission of SARS-CoV-2 and other respiratory pathogens (including viral pathogens, such as rhinoviruses, respiratory syncytial virus, influenza virus, parainfluenza virus and adenoviruses, and bacterial and fungal pathogens).

Retraction Note to: Omega-3 fatty acid levels in red blood cell membranes and physical decline over 3 years: longitudinal data from the MAPT study - Bertrand Fougère; Sabine Goisser; Christelle Cantet; Gaëlle Soriano; Sophie Guyonnet; Philipe De Souto Barreto; Matteo Cesari; Sandrine Andrieu; Bruno Vellas (GeroScience, 2022)

Cingulo-opercular and frontoparietal control network connectivity and executive functioning in older adults - Hanna K. Hausman; Cheshire Hardcastle; Alejandro Albizu; Jessica N. Kraft; Nicole D. Evangelista; Emanuel M. Boutzoukas; Kailey Langer; Andrew O’Shea; Emily J. Van Etten; Pradyumna K. Bharadwaj; Hyun Song; Samantha G. Smith; et al. (GeroScience, 2022)

Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer’s disease and longevity in an Italian population - Maria Giulia Bacalini; Flavia Palombo; Paolo Garagnani; Cristina Giuliani; Claudio Fiorini; Leonardo Caporali; Michelangelo Stanzani Maserati; Sabina Capellari; Martina Romagnoli; Sara De Fanti; Luisa Benussi; Giuliano Binetti; et al. (GeroScience, 2022)
Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.

The elderly at risk: aldosterone as modulator of the immune response to SARS-CoV-2 infection - Pasquale Campana; Maria Emiliana Palaia; Maddalena Conte; Teresa Cante; Laura Petraglia; Grazia Daniela Femminella; Valentina Parisi; Dario Leosco (GeroScience, 2022)

Correction to: Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels - Ryan Frankum; Tom S. O. Jameson; Bridget A. Knight; Francis B. Stephens; Benjamin T. Wall; Timothy A. Donlon; Trevor Torigoe; Bradley J. Willcox; D. Craig Willcox; Richard C. Allsopp; Lorna W. Harries (GeroScience, 2022)

Epigenetic clock and methylation studies in vervet monkeys - Anna J. Jasinska; Amin Haghani; Joseph A. Zoller; Caesar Z. Li; Adriana Arneson; Jason Ernst; Kylie Kavanagh; Matthew J. Jorgensen; Julie A. Mattison; Kevin Wojta; Oi-Wa Choi; Joseph DeYoung; et al. (GeroScience, 2022)
DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey ( Chlorocebus sabaeus ), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, we developed two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes that gain methylation with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for anti-aging studies in vervets.

Mediation of the APOE associations with Alzheimer’s and coronary heart diseases through body mass index and lipids - Yury Loika; Fan Feng; Elena Loiko; Alexander M. Kulminski (GeroScience, 2022)

DNA damage-induced degradation of Sp1 promotes cellular senescence - Michelle L. Swift; Christian Sell; Jane Azizkhan-Clifford (GeroScience, 2022)
Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. Sp1 has been found to play a role in double strand break (DSB) repair, and a link between Sp1 and aging has also been established, where Sp1 protein, but not RNA, levels decrease with age. Interestingly, inhibition ATM reverses the age-related degradation of Sp1, suggesting that DNA damage signaling is involved in senescence-related degradation of Sp1. Proteasomal degradation of Sp1 in senescent cells is mediated via sumoylation, where sumoylation of Sp1 on lysine 16 is increased in senescent cells. Taking into consideration our previous findings that Sp1 is phosphorylated by ATM in response to DNA damage and that proteasomal degradation of Sp1 at DSBs is also mediated by its sumoylation and subsequent interaction with RNF4, we investigated the potential contribution of Sp1’s role as a DSB repair factor in mediating cellular senescence. We report here that Sp1 expression is decreased with a concomitant increase in senescence markers in response to DNA damage. Mutation of Sp1 at serine 101 to create an ATM phospho-null mutant, or mutation of lysine 16 to create a sumo-null mutant, prevents the sumoylation and subsequent proteasomal degradation of Sp1 and results in a decrease in senescence. Conversely, depletion of Sp1 or mutation of Sp1 to create an ATM phosphomimetic results in premature degradation of Sp1 and an increase in senescence markers. These data link a loss of genomic stability with senescence through the action of a DNA damage repair factor.

Obesity paradox in joint replacement for osteoarthritis — truth or paradox? - Setor K. Kunutsor; Michael R. Whitehouse; Ashley W. Blom (GeroScience, 2022)
Obesity is associated with an increased risk of cardiovascular disease (CVD) and other adverse health outcomes. In patients with pre-existing heart failure or coronary heart disease, obese individuals have a more favourable prognosis compared to individuals who are of normal weight. This paradoxical relationship between obesity and CVD has been termed the ‘obesity paradox’. This phenomenon has also been observed in patients with other cardiovascular conditions and diseases of the respiratory and renal systems. Taking into consideration the well-established relationship between osteoarthritis (OA) and CVD, emerging evidence shows that overweight and obese individuals undergoing total hip or knee replacement for OA have lower mortality risk compared with normal weight individuals, suggesting an obesity paradox. Factors proposed to explain the obesity paradox include the role of cardiorespiratory fitness (“fat but fit”), the increased amount of lean mass in obese people, additional adipose tissue serving as a metabolic reserve, biases such as reverse causation and confounding by smoking, and the co-existence of older age and specific comorbidities such as CVD. A wealth of evidence suggests that higher levels of fitness are accompanied by prolonged life expectancy across all levels of adiposity and that the increased mortality risk attributed to obesity can be attenuated with increased fitness. For patients about to have joint replacement, improving fitness levels through physical activities or exercises that are attractive and feasible, should be a priority if intentional weight loss is unlikely to be achieved.

Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels - Ryan Frankum; Tom S. O. Jameson; Bridget A. Knight; Francis B. Stephens; Benjamin T. Wall; Timothy A. Donlon; Trevor Torigoe; Bradley J. Willcox; D. Craig Willcox; Richard C. Allsopp; Lorna W. Harries (GeroScience, 2022)
The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5′ truncated FOXO3 isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes. FOXO3 isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length FOXO3 isoforms in peripheral blood and a decrease in truncated FOXO3 isoforms in skeletal muscle RNA. We suggest that the longevity effect of FOXO3 SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5′ truncated FOXO3 isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality.

Liver frailty and all-cause mortality in the older participants of the Salus in Apulia Study - Roberta Zupo; Fabio Castellana; Rossella Donghia; Luisa Lampignano; Vito Guerra; Giovanni De Pergola; Madia Lozupone; Ilaria Bortone; Sara De Nucci; Rossella Tatoli; Sarah Tirelli; Giancarlo Sborgia; et al. (GeroScience, 2022)

Lipid and metabolite correlation networks specific to clinical and biochemical covariate show differences associated with sexual dimorphism in a cohort of nonagenarians - Francesca Di Cesare; Leonardo Tenori; Gaia Meoni; Anna Maria Gori; Rossella Marcucci; Betti Giusti; Raffaele Molino-Lova; Claudio Macchi; Silvia Pancani; Claudio Luchinat; Edoardo Saccenti (GeroScience, 2022)
This study defines and estimates the metabolite-lipidic component association networks constructed from an array of 20 metabolites and 114 lipids identified and quantified via NMR spectroscopy in the serum of a cohort of 355 Italian nonagenarians and ultra-nonagenarian. Metabolite-lipid association networks were built for men and women and related to an array of 101 clinical and biochemical parameters, including the presence of diseases, bio-humoral parameters, familiarity diseases, drugs treatments, and risk factors. Different connectivity patterns were observed in lipids, branched chains amino acids, alanine, and ketone bodies, suggesting their association with the sex-related and sex-clinical condition-related intrinsic metabolic changes. Furthermore, our results demonstrate, using a holistic system biology approach, that the characterization of metabolic structures and their dynamic inter-connections is a promising tool to shed light on the dimorphic pathophysiological mechanisms of aging at the molecular level.

Lower human defensin 5 in elderly people compared to middle-aged is associated with differences in the intestinal microbiota composition: the DOSANCO Health Study - Yu Shimizu; Kiminori Nakamura; Mani Kikuchi; Shigekazu Ukawa; Koshi Nakamura; Emiko Okada; Akihiro Imae; Takafumi Nakagawa; Ryodai Yamamura; Akiko Tamakoshi; Tokiyoshi Ayabe (GeroScience, 2022)
Recently, aging is considered a risk factor for various diseases. Although changes in the intestinal microbiota along with aging are thought to associate with the increased disease risk, mechanisms that cause age-related transition of the intestinal microbiota remain unknown. This study aims to clarify relationships between the amount of human defensin 5 (HD5), a Paneth cell α-defensin, which is known to regulate the intestinal microbiota, and age-related differences of the intestinal microbiota composition. Fecal samples from 196 healthy Japanese (35 to 81 years old) were collected and measured HD5 concentration. HD5 concentration in the elderly group (age > 70 years old) was significantly lower than the middle-aged group (age ≤ 70 years old). Furthermore, individual age was negatively correlated with HD5 concentration ( r = − 0.307, p < 0.001). In β-diversity, the intestinal microbiota of the elderly showed a significantly different composition compared to the middle-aged. At the genus level, relative abundance of Collinsella , Alistipes , Peptococcaceae; unassigned, Lactobacillus , Lactococcus , Weissella , Christensenellaceae R-7 group , Megasphaera , and [Eubacterium] eligens group was significantly higher, and Lachnospiraceae; unassigned, Blautia , Anaerostipes , Fusicatenibacter , Dorea , and Faecalibacterium was significantly lower in the elderly compared to the middle-aged. In addition, HD5 concentration was negatively correlated with Alistipes , Peptococcaceae; unassigned, and Christensenellaceae R-7 group and positively correlated with Lachnospiraceae; unassigned and Dorea . These results provide novel insights into the immunosenescence of enteric innate immunity, indicating low HD5 is suggested to contribute to the age-related differences in the intestinal microbiota and may relate to increased risk of diseases in elderly people.

Dual effects of insulin resistance on mortality and function in non-diabetic older adults: findings from the Toledo Study of Healthy Aging - Leocadio Rodríguez-Mañas; Javier Angulo; José A. Carnicero; Mariam El Assar; Francisco J. García-García; Alan J. Sinclair (GeroScience, 2022)

Using lipid profiling to better characterize metabolic differences in apolipoprotein E (APOE) genotype among community-dwelling older Black men - Megan M. Marron; Steven C. Moore; Stacy G. Wendell; Robert M. Boudreau; Iva Miljkovic; Akira Sekikawa; Anne B. Newman (GeroScience, 2022)

A small-molecule Psora-4 acts as a caloric restriction mimetic to promote longevity in C. elegans - Tesfahun Dessale Admasu; Diogo Barardo; Li Fang Ng; Krishna Chaithanya Batchu; Amaury Cazenave-Gassiot; Markus R. Wenk; Jan Gruber (GeroScience, 2022)

Maternal stress programs a demasculinization of glutamatergic transmission in stress-related brain regions of aged rats - Remy Verhaeghe; Vance Gao; Sara Morley-Fletcher; Hammou Bouwalerh; Gilles Van Camp; Francesca Cisani; Ferdinando Nicoletti; Stefania Maccari (GeroScience, 2022)
Brain aging may be programmed by early-life stress. Aging affects males and females differently, but how perinatal stress (PRS) affects brain aging between sexes is unknown. We showed behavioral and neurobiological sex differences in non-stressed control rats that were strongly reduced or inverted in PRS rats. In particular, PRS decreased risk-taking behavior, spatial memory, exploratory behavior, and fine motor behavior in male aged rats. In contrast, female aged PRS rats displayed only increased risk-taking behavior and reduced exploratory behavior. PRS induced large reductions in the expression of glutamate receptors in the ventral and dorsal hippocampus and prefrontal cortex only in male rats. PRS also reduced the expression of synaptic vesicle-associated proteins, glucocorticoid receptors (GR), and mineralocorticoid receptors (MR) in the ventral hippocampus of aged male rats. In contrast, in female aged rats, PRS enhanced the expression of MRs and brain-derived neurotrophic factor (BDNF) in the ventral hippocampus and the expression of glial fibrillary acidic protein (GFAP) and BDNF in the prefrontal cortex. A common PRS effect in both sexes was a reduction in exploratory behavior and metabotropic glutamate (mGlu2/3) receptors in the ventral hippocampus and prefrontal cortex. A multidimensional analysis revealed that PRS induced a demasculinization profile in glutamate-related proteins in the ventral and dorsal hippocampus and prefrontal cortex, as well as a demasculinization profile of stress markers only in the dorsal hippocampus. In contrast, defeminization was observed only in the ventral hippocampus. Measurements of testosterone and 17-β-estradiol in the plasma and aromatase in the dorsal hippocampus were consistent with a demasculinizing action of PRS. These findings confirm that the brains of males and females differentially respond to PRS and aging suggesting that females might be more protected against early stress and age-related inflammation and neurodegeneration. Taken together, these results may contribute to understanding how early environmental factors shape vulnerability to brain aging in both sexes and may lay the groundwork for future studies aimed at identifying new treatment strategies to improve the quality of life of older individuals, which is of particular interest given that there is a high growth of aging in populations around the world.