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OBJECTIVEThe aim of this study was to describe cross-sectional and longitudinal associations between glycated hemoglobin (HbA1c) levels and strategies to control type 2 diabetes with baseline levels and 8-year changes in a deficit accumulation frailty index (FI), a commonly used marker of biological aging.RESEARCH DESIGN AND METHODSWe conducted exploratory analyses from 4,169 participants, aged 45–76 years, who were followed in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, pooling data across intervention groups. We related baseline and 8-year levels of HbA1c with FI scores using analyses of variance and covariance. Associations between 8-year changes in FI and the use of diabetes medication classes and weight changes were assessed with control for HbA1c levels. Inverse probability weighting was used to assess bias associated with differential follow-up.RESULTSBaseline and average HbA1c levels over time of 5% were independently associated with slower increases in frailty.CONCLUSIONSLower HbA1c levels among individuals with diabetes are associated with slower biological aging as captured by a deficit accumulation FI. Strategies to control diabetes through weight loss or metformin use may also slow aging.

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.

OBJECTIVE: The aim of this study was to describe cross-sectional and longitudinal associations between glycated hemoglobin (HbA1c) levels and strategies to control type 2 diabetes with baseline levels and 8-year changes in a deficit accumulation frailty index (FI), a commonly used marker of biological aging. RESEARCH DESIGN AND METHODS: We conducted exploratory analyses from 4,169 participants, ages 45-76, who were followed in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, pooling data across intervention groups. We related baseline and 8-year levels of HbA1c with FI scores using analyses of variance and covariance. Associations between 8-year changes in FI and the use of diabetes medication classes and weight changes were assessed with control for HbA1c levels. Inverse probability weighting was used to assess bias associated with differential follow-up. RESULTS: Baseline and average HbA1c levels over time of >8%, were associated with less increase in FI scores over 8 years (both p<0.002). After adjustment for HbA1c, use of metformin and weight loss >5% were independently associated with slower increases in frailty. CONCLUSIONS: Lower HbA1c levels among individuals with diabetes are associated with slower biological aging as captured by a deficit accumulation FI. Strategies to control diabetes through weight loss or metformin use may also slow aging.

For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets.

Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer’s disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.

Background Indices of multimorbidity and deficit accumulation (ie, frailty indices) have been proposed as markers of biological aging. If true, changes in these indices over time should predict downstream changes in cognition and physical function, and mortality. Methods We examined associations that 8-year changes in (i) a multimorbidity index comprised of 9 chronic diseases and (ii) a frailty index (FI) based on deficit accumulation in functional, behavioral, and clinical characteristics had with subsequent measures of cognitive and physical function over 10 years. We drew data from 3 842 participants in the Action for Health in Diabetes clinical trial. They were aged 45–76 years at baseline and at risk for accelerated biological aging due to overweight/obesity and type 2 diabetes mellitus. Results A total of 1 501 (39%) of the cohort had 8-year increases of 1 among the 9 diseases tracked in the multimorbidity index and 868 (23%) had increases of ≥2. Those with greatest increases in multimorbidity tended to be older individuals, males, and non-Hispanic Whites. Greater FI increases tended to occur among individuals who were older, non-Hispanic White, heavier, and who had more baseline morbidities. Changes in multimorbidity and FI were moderately correlated (r = 0.26; p < .001). Increases in both multimorbidity and FI were associated with subsequently poorer composite cognitive function and 400-m walk speed and increased risk for death (all p < .001). Conclusions Accelerated biological aging, as captured by multimorbidity and frailty indices, predicts subsequent reduced function and mortality. Whether intensive lifestyle interventions generally targeting multimorbidity and FI reduce risks for downstream outcomes remains to be seen. Clinical Trials Registration Number: NCT00017953

Background: Identification of factors that may help to preserve cognitive function in late life could elucidate mechanisms and facilitate interventions to improve the lives of millions of people. However, the large number of potential factors associated with cognitive function poses an analytical challenge. Objective: We used data from the longitudinal Women’s Health Initiative Memory Study (WHIMS) and machine learning to investigate 50 demographic, biomedical, behavioral, social, and psychological predictors of preserved cognitive function in later life. Methods: Participants in WHIMS and two consecutive follow up studies who were at least 80 years old and had at least one cognitive assessment following their 80th birthday were classified as cognitively preserved. Preserved cognitive function was defined as having a score ≥39 on the most recent administration of the modified Telephone Interview for Cognitive Status (TICSm) and a mean score across all assessments ≥39. Cognitively impaired participants were those adjudicated by experts to have probable dementia or at least two adjudications of mild cognitive impairment within the 14 years of follow-up and a last TICSm score

Intermediate endpoints are needed to evaluate the effect of interventions targeting the biology of aging in clinical trials. A working group identified five blood-based biomarkers that may serve such a purpose as an integrated index. We evaluated the responsiveness of the panel to caloric restriction or aerobic exercise in the context of a randomized clinical trial conducted in patients with heart failure with preserved ejection fraction (HFpEF) with obese phenotype who were predominantly female. Obese HFpEF is highly prevalent in women, and is a geriatric syndrome whose disease pathology is driven by non-cardiac factors and shared drivers of aging. We measured serum Interleukin-6, TNF-α-receptor-I, growth differentiating factor-15, cystatin C, and N-terminal pro-b-type natriuretic peptide at baseline and after 20 weeks in older participants with stable obese HFpEF participating in a randomized, controlled, 2 × 2 factorial trial of caloric restriction and/or aerobic exercise. We calculated a composite biomarker index, summing baseline quintile scores for each biomarker, and analyzed the effect of the interventions on the index and individual biomarkers and their associations with changes in physical performance. This post hoc analysis included 88 randomized participants (71 women [81%]). The mean ± SD age was 66.6 ± 5.3 years, and body mass index (BMI) was 39.3 ± 6.3 kg/m(2). Using mixed models, mean values of the biomarker index improved over 20 weeks with caloric restriction (− 0.82 [Formula: see text] 0.58 points, p = 0.05), but not with exercise (− 0.28 [Formula: see text] 0.59 points, p = [Formula: see text] ), with no evidence of an interaction effect of CR [Formula: see text] EX [Formula: see text] time (p = 0.80) with adjustment for age, gender, and BMI. At baseline, the biomarker index was inversely correlated with 6-min walk distance, scores on the short physical performance battery, treadmill test peak workload and exercise time to exhaustion (all [Formula: see text] (s) = between − 0.21 and − 0.24). A reduction in the biomarker index was also associated with increased 4-m usual walk speed ([Formula: see text] (s) = − 0.31). Among older patients with chronic obese HFpEF, caloric restriction improved a biomarker index designed to reflect biological aging. Moreover, the index was associated with physical performance and exercise tolerance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00509-9.

Sarcopenia is a universal characteristic of the aging process and is often accompanied by increases in whole-body adiposity. These changes in body composition have important clinical implications, given that loss of muscle and gain of fat mass are both significantly and independently associated with declining physical performance as well as an increased risk for disability, hospitalizations, and mortality in older individuals. This increased fat mass is not exclusively stored in adipose depots but may become deposited in non-adipose tissues, such as skeletal muscle, when the oxidative capacity of the adipose tissue itself is exceeded. The redistributed adipose tissue is thought to exert detrimental local effects on the muscle environment given the close proximity. Thus, sarcopenia observed with aging may be better defined in the context of loss of muscle quality rather than loss of muscle quantity per se. In this perspective, we briefly review the age-related physiological changes in cellularity, secretory profiles, and inflammatory status of adipose tissue which drive lipotoxicity (spillover) of skeletal muscle and then provide evidence of how this may affect specific fiber type contractility. We focus on biological contributors (cellular machinery) to contractility for which there is some evidence of vulnerability to lipid stress distinguishing between fiber types.

Accelerated biological aging is associated with decreased physical capability and cognitive functioning, which are associated with increased risk of morbidity and mortality.We investigated associations between epigenetic age acceleration (EAA), a biomarker associated with aging, and healthy longevity among older women.This cohort study was a secondary analysis of participants in the Women's Health Initiative (WHI) who were eligible to survive to age 90 years by September 30, 2020. Participants were located in multiple centers. This study was restricted to women with genome-wide DNA methylation data, generated from baseline blood samples within 3 WHI ancillary studies. Median (IQR) follow-up times from baseline were 21.6 (19.6-22.9) years and 21.4 (19.8-22.7) years for women who survived to age 90 years with and without intact mobility, respectively, and 13.2 (8.8-16.7) for women who did not survive to age 90 years. Data were analyzed from December 2020 to July 2021.EAA was estimated using 4 established "clocks": Horvath pantissue, Hannum, Pheno, and Grim.Using multinomial logistic regression, odds ratios (ORs) and 95% CIs were estimated for 3 healthy longevity outcomes for each clock: survival to age 90 years with intact mobility, survival to age 90 years without intact mobility, and no survival to age 90 years.Among 1813 women, there were 464 women (mean [SD] age at baseline, 71.6 [3.5] years) who survived to age 90 years with intact mobility and cognitive functioning, 420 women (mean [SD] age at baseline, 71.3 [3.2] years) who survived to age 90 years without intact mobility and cognitive functioning, and 929 women (mean [SD] age at baseline, 70.2 [3.4] years) who did not survive to age 90 years. Women who survived to age 90 years with intact mobility and cognitive function were healthier at baseline compared with women who survived without those outcomes or who did not survive to age 90 years (eg, 143 women [30.8%] vs 101 women [24.0%] and 202 women [21.7%] with 0 chronic conditions). The odds of surviving to age 90 years with intact mobility were lower for every 1 SD increase in EAA compared with those who did not survive to age 90 years as measured by AgeAccelHorvath (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AgeAccelHannum (OR, 0.67; 95% CI, 0.56-0.80; P .001), AgeAccelPheno (OR, 0.60; 95% CI, 0.51-0.72; P .001), and AgeAccelGrim (OR, 0.68; 95% CI, 0.55-0.84; P .001). ORs were similar for women who survived to age 90 years with intact mobility and cognitive function (eg, AgeAccelHorvath: OR per 1 SD increase in EAA, 0.83; 95% CI, 0.71-0.98; P = .03) compared with women who did not survive to age 90 years.These findings suggest that EAA may be a valid biomarker associated with healthy longevity among older women and may be used for risk stratification and risk estimation of future functional and cognitive aging. Outcomes suggest that future studies may focus on the potential for public health interventions to counteract EAA and its association with poor health outcomes to lower disease burden while increasing longevity.

12009 Background: Innovative strategies to facilitate rapid frailty screening are critically needed to enhance personalized oncology care among vulnerable older patients. An electronic frailty index (eFI) holds promise as a passive measure of frailty. The eFI was initially designed for primary care. The objective of this study was to establish feasibility, estimate prevalence of frailty, and evaluate the predictive value of the eFI for overall survival (OS) among older adults with cancer planned to receive chemotherapy. Methods: Consecutive patients (N = 509) aged 65+ with newly diagnosed lung, colorectal or breast cancer treated with chemotherapy were identified from our cancer registry between 2017 and 2020. Calculation of the eFI requires at least two ambulatory visits over a 2-year period and utilizes demographic information, vital signs, smoking status, ICD-10 diagnosis codes, select outpatient laboratory measurements, and functional information (if available from Medicare Annual Wellness Visits) during the 2 years prior to diagnosis. Frailty status is categorized as fit (eFI ≤0.10), pre-frail (0.10 < eFI≤0.21), and frail (eFI > 0.21) based on the proportion of deficits present over the total number evaluated (score range 0-1). Non-calculable scores indicate insufficient historical primary care data within two years prior to cancer diagnosis. OS was estimated by eFI category using Kaplan Meier curves and compared using log rank testing. Cox proportional hazards models evaluated the adjusted association between eFI categories and mortality. Results: The cohort included 509 adults (median age 72.2 yrs, 55% female, 83.5% white, 13.4% black, 45.8% stage 4) with lung (N = 312), colorectal (N = 111) and breast (N = 86) cancer. Distribution of eFI categories at diagnosis were fit (25.9%), pre-frail (41.1%), frail (17.3 %) and not calculable (15.7%). The proportion of patients categorized as “fit” differed by disease type (19.9% lung, 30.6% colorectal, 41.9% breast, p < 0.0001). In univariate analyses, eFI frailty category was associated with OS (median OS for fit, pre-frail, frail and not calculable were > 54, 25, 19 and 10 months respectively, p < 0.0001.). Adjusting for age, gender, race, stage, and cancer type, the hazard of death was higher for pre-frail (Hazard Ratio, [HR] 1.7, 95% Confidence Interval [CI] 1.2-2.4), frail (HR 2.3, 95% CI 1.5-3.4) and not calculable eFI categories (HR 2.8, 95% CI 1.8-4.2) compared to fit patients. Conclusions: Calculating an EHR embedded eFI at the time of diagnosis among older adults treated with chemotherapy was feasible and identified nearly one-fifth of patients as frail. eFI-defined frailty status was associated with survival, with poorer survival among the most frail supporting eFI validity. The eFI is a promising scalable tool to efficiently conduct frailty screening in oncology clinical practice.

Dual declines in gait speed and cognitive performance are associated with increased risk of developing dementia. Characterizing the patterns of such impairments therefore is paramount to distinguishing healthy from pathological aging. Nonhuman primates such as vervet/African green monkeys (Chlorocebus aethiops sabaeus) are important models of human neurocognitive aging, yet the trajectory of dual decline has not been characterized. We therefore (1) assessed whether cognitive and physical performance (i.e., gait speed) are lower in older aged animals; (2) explored the relationship between performance in a novel task of executive function (Wake Forest Maze Task—WFMT) and a well-established assessment of working memory (delayed response task—DR task); and (3) examined the association between baseline gait speed with executive function and working memory at 1-year follow-up. We found (1) physical and cognitive declines with age; (2) strong agreement between performance in the novel WFMT and DR task; and (3) that slow gait is associated with poor cognitive performance in both domains. Our results suggest that older aged vervets exhibit a coordinated suite of traits consistent with human aging and that slow gait may be a biomarker of cognitive decline. This integrative approach provides evidence that gait speed and cognitive function differ across the lifespan in female vervet monkeys, which advances them as a model that could be used to dissect relationships between trajectories of dual decline over time. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00338-w.

Our global population is aging, and this changing demographic portends unprecedented levels of chronic diseases and healthcare burden. In response, new efforts to extend human healthspan are underway, informed by the “geroscience hypothesis,” which holds that incidence of aging-related chronic disease can be prevented, delayed, or attenuated by therapeutically targeting fundamental biology shared by the aging process and common chronic diseases. The promise of geroscience is that interventions will be found that target biological aging processes, thereby delaying the onset of multiple chronic diseases simultaneously. A major geroscience accomplishment has been to frame a set of tightly interrelated cellular biologic processes that are altered with aging that could be targeted to extend lifespan and healthspan: macromolecular damage, metabolism, proteostasis, inflammation, adaptation to stress, epigenetics, cell senescence, stem cells/regeneration, and pleiotropic processes. One of these biologic processes, cellular senescence and its related senescence-associated secretory phenotype, is an underlying contributor to age-related loss of physiologic integrity and function. Thus, interventions that mitigate senescent cell burden, termed “senotherapeutics,” would be expected to improve function, chronic diseases, and geriatric syndromes. This chapter is intended as an in-depth summary of research evaluating the clinical potential of senotherapeutics, with a focus on current testing of preclinical and clinical drugs, and practical considerations on translation of experimental therapy of cellular senescence to humans.

We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.

Reliable biomarkers are needed to test the effectiveness of interventions intended to improve health and extend lifespan.

Background Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. Methods A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored. Findings Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p

Chronic psychosocial stress is associated with increased risk of many chronic diseases including type 2 diabetes mellitus. However, it is difficult to establish a causal relationship between stress and diabetes in human studies because stressors often are self-reported and may be distant in time from metabolic consequences. Macaques are useful models of the effects of chronic psychosocial stress on health and may develop obesity and diabetes similar to human beings. Thus, we studied the relationships between social subordination stress – a well-validated psychological stressor in macaques – and body composition and carbohydrate metabolism in socially housed, middle-aged female cynomolgus monkeys (Macaca fascicularis; n=42). Following an 8-week baseline phase, the monkeys were fed a Western diet for 36 months (about equivalent to 10 human years). Social status was determined based on the outcomes of agonistic interactions ([Formula: see text] observation hours/monkey). Phenotypes collected included plasma cortisol, body composition, circulating markers of glucose metabolism, activity levels, and heart rate variability measured as RMSSD (root of mean square of successive differences) and SDDN (standard deviation of beat to beat interval) after 1.5- and 3-years on diet. Mixed model analyses of variance revealed that aggression received, submissions sent, and cortisol were higher, and RMSSD and SDNN were lower in subordinates than dominants (social status: p 100 mg/dl) incidence was significantly higher in subordinates (23%) than dominants (0%) (Fisher’s exact test, p

α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans.We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q).We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence.Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials.This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.

Significant progress in defining the biology of aging, particularly in animal models, supports the geroscience hypothesis, which posits that by therapeutically targeting biological aging, the onset of multiple age-related diseases can be delayed "en suite". Geroscience investigators are preparing to test this hypothesis in humans for the first time. In this review, we describe development of large-scale clinical trials designed to determine if multiple age-related health conditions can be simultaneously alleviated with interventions targeting the underlying biology of aging. We describe the rationale and collaborative, consensus building approach used to design the first aging outcomes trial called Targeting Aging with Metformin (TAME). Through this case study, we outline features that could be more broadly extended to other geroscience-guided clinical trials, including a process for selecting biochemical and molecular markers of biologic age and we provide a perspective on the potential impact of clinical trials targeting aging.

Background Recent studies suggest curcumin is a promising nutraceutical for improving important clinical and physiological markers of healthy aging, including motor and cognitive function. Objective To determine if curcumin supplementation improves motor and cognitive function in healthy middle-aged and older adults. Methods 39 healthy men and postmenopausal women (45-74 yrs) were randomized to 12 weeks of placebo (n = 19) or curcumin supplementation (2000 mg/day Longvida®; n = 20) with motor and cognitive function assessed at week 0 and 12. Results Using measures of the NIH Toolbox and other standardized tests, there were no changes in muscle strength and rate of torque development, dexterity, fatigability, mobility, endurance, and balance between the placebo and curcumin groups after 12 weeks (all P > 0.05). Additionally, there were no changes after 12 weeks of placebo and curcumin supplementation in measures of fluid cognitive ability, a cognitive domain that declines with age, including processing speed, executive function, working memory, and episodic memory (all P > 0.3). There were marginal changes in language, a measure of crystallized cognitive ability that is stable with age, following the intervention, wherein reading decoding increased 3% in the curcumin group (post: 2428±35 vs. pre: 2357±34, P = 0.003), but was unchanged in the placebo group (post: 2334±39 vs. pre: 2364±40, P = 0.07). Conclusions Overall, 12 weeks of curcumin supplementation does not improve motor and cognitive functions in healthy middle-aged and older adults. It is possible that curcumin may enhance these functions in groups with greater baseline impairments than those studied here, including adults greater than 75 years of age and/or patients with clinical disorders.

It is unknown if consumption of a Western diet (WD; high-fat/sucrose), versus a non-WD (healthy diet), accelerates declines in physical function over the adult lifespan, and whether regular voluntary activity attenuates age- and WD-associated declines in function. Accordingly, we studied 4 cohorts of mice that consumed either normal chow [NC] or WD with or without access (sedentary, Sed) to voluntary wheel running [VWR] beginning at 3 mo of age. We assessed coordination, grip strength and endurance every 6 mo throughout life, and measured skeletal muscle mass and inflammation at 3 pre-determined ages (6-7, 13-14 and 19-20 mo). Age-related declines (% change 3-18 mo) in physical function were accelerated in WD-Sed versus NC-Sed (coordination: +47 ± 5%; grip strength: +18 ± 2%; endurance: +32 ± 5%; all p < 0.05). VWR attenuated declines in physical function within diet group (coordination: -31 ± 3% with WD-VWR; -18 ± 2% with NC-VWR; grip strength: -26 ± 2% with WD-VWR; -24 ± 2% with NC-VWR; endurance: -48 ± 4% with WD-VWR; -23 ± 6% with NC-VWR; all p < 0.05). Skeletal muscle mass loss and pro-inflammatory cytokine abundance were exacerbated by WD throughout life (mass: NC-Sed [-]7-28%, WD-Sed [-]17-40%; inflammation: NC-Sed [+]40-65%, WD-Sed [+]40-84%, all p < 0.05 versus NC-Sed), and attenuated by VWR (mass: NC-VWR, [-]0-10%, WD-VWR [-]0-10%; inflammation: NC-VWR [+]0-30%, WD-VWR [+]0-42%, all p < 0.05 versus diet-matched Sed group). Our results depict the temporal impairment of physical function over the lifespan in mice, acceleration of dysfunction with WD, the protective effects of voluntary exercise, and the potential associations with skeletal muscle mass and inflammation.

Objective Atherosclerosis developed during premenopausal years predicts postmenopausal atherosclerosis burden. Selective serotonin reuptake inhibitor (SSRI) antidepressants, recently approved for hot flushes, have been associated with increased ischemic stroke risk in several observational studies; however, effects on carotid artery atherosclerosis, a strong predictor of future vascular events, are unknown. Methods The effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on atherosclerosis in the carotid artery was assessed in a placebo-controlled, longitudinal, randomized study of premeonopausal depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n = 42). Physiologic and behavioral phenotypes were evaluated at baseline and after 18 months of oral sertraline (20 mg/kg, n = 21) or placebo (n = 21). Carotid artery atherosclerosis was measured post mortem via histomorphometry. Results Atherosclerosis extent in the right common carotid artery, on average, was 60% greater in sertraline-treated depressed monkeys compared with all other groups (P = 0.028). The results of linear regression analyses suggested that sertraline and depression effects on atherosclerosis were not mediated by their effects on behavioral and physiological risk factors. Conclusions These findings suggest that chronic SSRI treatment is associated with the progression of carotid artery atherosclerosis, which may increase the risk for future vascular events, particularly in depressed women. The underlying mechanism remains to be determined, but does not appear to be related to SSRI effects on traditional cardiovascular risk factors.

The NIA’s Butler-Williams Scholars Program and GSA’s Emerging Scholars and Professional Organization are united in providing career development opportunities for early career scholars in a manner that promotes leadership, diversity, and inclusivity. This provides a foundation to develop a network of next generation of scientists, clinicians, and policy makers capable of shaping health in aging. Among the chief concerns of our aging population are disparities in health associated with race/ethnicity, experience, sociocultural and socioeconomic factors, as well as access to and communications regarding health care. GSA’s early career professionals and alumni of the prestigious NIA Butler-Williams Scholars Program have tackled these issues directly and the scientific scholarship that results is astounding in its breadth and depth. Dr. Glenna Brewster (Butler-Williams class of 2018) will discuss new findings from a study of African American caregivers of persons living with dementia. Dr. Candace Brown, Ph.D. (Butler-Williams class of 2017), will present on overcoming social and environmental barriers to exercise among older adults. Dr. Joseph Saenz (Butler-Williams class of 2017), will present current work disparities in cognition function in the older Mexican population. The final speaker, Dr. Sarah Forrester (Butler-Williams class of 2019) will explore new perspectives on health equity in physiological dysregulation and aging. In sum, the featured talks by rising stars in aging research deepen our understanding of the influence of race, ethnicity, and overcoming barriers to understand ‘why aging matters’ across our diverse aging populations.

Aging-related illnesses are increasing and effective strategies to prevent and/or treat them are lacking. This is because of a poor understanding of therapeutic targets. Low-grade inflammation is often higher in older adults and remains a key risk factor of aging-related morbidities and mortalities. Emerging evidence indicates that abnormal (dysbiotic) gut microbiome and dysfunctional gut permeability (leaky gut) are linked with increased inflammation in older adults. However, currently available drugs do not treat aging-related microbiome dysbiosis and leaky gut, and little is known about the cellular and molecular processes that can be targeted to reduce leaky gut in older adults. Here, we demonstrated that metformin, a safe Food and Drug Administration-approved antidiabetic drug, decreased leaky gut and inflammation in high-fat diet-fed older obese mice, by beneficially modulating the gut microbiota. In addition, metformin increased goblet cell mass and mucin production in the obese older gut, thereby decreasing leaky gut and inflammation. Mechanistically, metformin increased the goblet cell differentiation markers by suppressing Wnt signaling. Our results suggest that metformin can be used as a regimen to prevent and treat aging-related leaky gut and inflammation, especially in obese individuals and people with western-style high-fat dietary lifestyle, by beneficially modulating gut microbiome/goblet cell/mucin biology.

The interplay between adipose tissue and skeletal muscle and the impact on mobility and aging remain enigmatic. The progressive decline in mobility promoted by aging has been previously attributed to the loss of skeletal mass and function and more recently linked to changes in body fat composition and quantity. Regardless of body size, visceral and intermuscular adipose depots increase with aging and are associated with adverse health outcomes. However, the quality of adipose tissue, in particular abdominal subcutaneous as it is the largest depot, likely plays a significant role in aging outcomes, such as mobility decline, though its communication with other tissues such as skeletal muscle. In this review, we discuss the age-associated development of a pro-inflammatory profile, cellular senescence, and metabolic inflexibility in abdominal subcutaneous adipose tissue. Collectively, these facets of adipose tissue quality influence its secretory profile and crosstalk with skeletal muscle and likely contribute to the development of muscle atrophy and disability. Therefore, the identification of the key structural and functional components of adipose tissue quality—including necrosis, senescence, inflammation, self-renewal, metabolic flexibility—and adipose tissue-secreted proteins that influence mobility via direct effects on skeletal muscle are necessary to prevent morbidity/mortality in the aging population.

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age.

a major goal of graduate education is the development of students as “stewards of the discipline,” scholars who can create and preserve knowledge and responsibly translate it through writing, teaching, and practical applications ([5][1]). These qualities are consistent with the American

Life extension is no longer considered sufficient evidence of delayed aging in research animals. It must also be demonstrated that a broad swathe of health indicators have been extended. During a retreat of the Geroscience Network, a consortium of basic and clinical aging researchers, potential measures of mouse health were considered for their potential as easily standardized, highly informative metrics. Major health domains considered were neuromuscular, cognitive, cardiovascular, metabolic, and inflammatory functions as well as body composition and energetics and a multitude of assays interrogating these domains. A particularly sensitive metric of health is the ability to respond to, and recover, from stress. Therefore, the Network also considered stresses of human relevance that could be implemented in mouse models to assess frailty and resilience. Mouse models already exist for responses to forced immobility, cancer chemotherapy, infectious diseases, dietary challenges, and surgical stress, and it was felt that these could be employed to determine whether putative senescence-retarding interventions increased and extended organismal robustness. The Network discussed challenges in modeling age-related human chronic diseases and concluded that more attention needs to be paid to developing disease models with later age of onset, models of co- and multimorbidity, diversifying the strains and sexes commonly used in aging research, and considering additional species.

Aging is the leading risk factor for many chronic diseases. Through traditional approaches to drug development and treatment focus on treating one disease at a time, the geroscience hypothesis posits that by targeting fundamental aging processes one could alleviate multiple age-related diseases. Now several geroscience-guided interventions are at the point of entering human clinical trials. To accelerate testing of this important hypothesis, an interdisciplinary Translational Geroscience Network (TGN; R33 AG061456) has recently been established. The TGN is a new national resource of aging research centers committed to working together toward complementary, small-scale, proof-of-concept “use case” clinical studies. One such pilot will be highlighted: a translational trial of senolytics, or drugs targeting the biological aging process cellular senescence in patients with idiopathic pulmonary fibrosis. The promise of geroscience provides another reason “why age matters”: by studying the basic biology of aging, we may open novel therapeutic opportunities for challenging age-related diseases.

Older adults are suffering from several aging-related illnesses including cognitive decline and effective strategies to prevent and/or treat them are lacking, because of a poor understanding of therapeutic targets. Low-grade inflammation is a key risk factor of aging-related morbidities and mortalities, and it is often higher in older adults. Although, precise reasons for increased inflammation remain unknown, however, emerging evidence indicates that abnormal (dysbiotic) gut microbiome and dysfunctional gut permeability (leaky gut) are linked with increased inflammation in older adults. However, no drugs are available to treat aging-related microbiome dysbiosis and leaky gut, and little is known about the cellular and molecular processes that can be targeted to reduce leaky gut in older adults. Here, we demonstrated that metformin, a safe FDA approved antidiabetic drug, decreased leaky gut and inflammation in older obese mice, by beneficially modulating the gut microbiota. In addition, metformin increased goblet cell mass and mucin production in the older gut, thereby decreasing leaky gut and inflammation. Mechanistically, metformin increased the goblet cell differentiation markers by suppressing Wnt signaling. Our results suggest that metformin can prevent and treat aging-related leaky gut and inflammation, by beneficially modulating gut microbiome/goblet cell/mucin biology.

Aging is associated with progressive declines in physical function. However, it is unknown if consumption of a western-style diet (WD; high-fat and sucrose, low fiber), compared with a non-WD (healthy diet), accelerates declines in physical function over the adult lifespan, and whether regular voluntary exercise attenuates age- and WD-associated declines in function. To determine this, we studied 4 cohorts of male C57BL/6 mice that consumed either normal chow [NC] or WD with or without access to voluntary running [VR] wheels beginning at 3 mo of age and assessed strength (grip strength normalized to body mass) and endurance (rota-rod distance) every 3 mo throughout life. WD decreased average lifespan by 30% (WD: 18.6±0.5 vs. NC: 26.7±0.8 mo); therefore, function was compared from 3-18 mo of age in all groups. Age-related declines (% change over 3-18 mo) in physical function were accelerated by WD (strength: WD -61.2±10.1%, NC -43.2±10.2%; endurance: WD -97.4±5.1%, NC -65.1±6.3%; all p

Significant progress in the biology of aging and animal models supports the geroscience hypothesis: by targeting biological aging the onset of age-related diseases can be delayed. Geroscience investigators will test this hypothesis in a multicenter clinical trial, to determine if interventions on biological aging processes can prevent accumulation of multiple age-related diseases and aging phenotypes in older adults. Prodigious activity is underway to develop markers of biological aging, but currently there is no aging biomarker consensus to support geroscience-guided clinical trial outcomes. We convened an expert committee to establish a framework for selection of blood-based biomarkers, emphasizing: feasibility/reliability; aging relevance; ability to predict clinical trial outcomes; and responsiveness to intervention. We applied this framework and identified a short-list of blood-based biomarkers with potential use in multicenter trials on aging. We review progress on efforts to test these candidate biomarkers of aging and development of biomarkers strategy for geroscience-guided clinical trials.

Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction and arterial stiffening with aging. Supplementation with sodium nitrite, a precursor of NO, ameliorates age-related vascular endothelial dysfunction and arterial stiffness in mice, but effects on humans, including the metabolic pathways altered, are unknown. The purpose of this study was to determine the safety, feasibility, and efficacy of oral sodium nitrite supplementation for improving vascular function in middle-aged and older adults and to identify related circulating metabolites. Ten weeks of sodium nitrite (80 or 160 mg/day, capsules, TheraVasc; randomized, placebo control, double blind) increased plasma nitrite acutely (5- to 15-fold, P < 0.001 vs. placebo) and chronically ( P < 0.10) and was well tolerated without symptomatic hypotension or clinically relevant elevations in blood methemoglobin. Endothelial function, measured by brachial artery flow-mediated dilation, increased 45-60% vs. baseline ( P < 0.10) without changes in body mass or blood lipids. Measures of carotid artery elasticity (ultrasound and applanation tonometry) improved (decreased β-stiffness index, increased cross-sectional compliance, P < 0.05) without changes in brachial or carotid artery blood pressure. Aortic pulse wave velocity was unchanged. Nitrite-induced changes in vascular measures were significantly related to 11 plasma metabolites identified by untargeted analysis. Baseline abundance of multiple metabolites, including glycerophospholipids and fatty acyls, predicted vascular changes with nitrite. This study provides evidence that sodium nitrite supplementation is well tolerated, increases plasma nitrite concentrations, improves endothelial function, and lessens carotid artery stiffening in middle-aged and older adults, perhaps by altering multiple metabolic pathways, thereby warranting a larger clinical trial.

Most nations of the world are undergoing rapid and dramatic population ageing, which presents great socio-economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population ageing has been 'compression of morbidity' and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological ageing research, 'geroscience', is focused on healthspan extension. Superimposed on this background are new attitudes and demand for 'optimal longevity' - living long, but with good health and quality of life. A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with ageing, which causes functional limitations (e.g. reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan centre on slowing the fundamental biological processes of ageing such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global ageing. Effective strategies should delay, reduce in magnitude or abolish reductions in function with ageing (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention). Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first-line function-preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel 'nutraceutical' compounds, serving as potential complementary approaches. Future research efforts should focus on defining the temporal patterns of functional declines with ageing, identifying the underlying mechanisms and modulatory factors involved, and establishing the most effective lifestyle practices and pharmacological options for maintaining function. Continuing development of effective behavioural approaches for enhancing adherence to healthy ageing practices in diverse populations, and ongoing analysis of the socio-economic costs and benefits of healthspan extension will be important supporting goals. To meet the demands created by rapid population ageing, a new emphasis in physiological geroscience is needed, which will require the collaborative, interdisciplinary efforts of investigators working throughout the translational research continuum from basic science to public health.

BACKGROUND: Ample evidence implicates cellular senescence as a contributor to frailty and functional decline in rodents, but considerable effort remains to translate these findings to human aging. METHODS: We quantified senescence biomarker p16(INK4a)-expressing cells in thigh adipose tissue obtained from older women previously enrolled in a 5-month resistance training intervention, with or without caloric restriction (RT ± CR, n = 11 baseline, 8 pre–post-intervention pairs). Women in this subsample were older (72.9 ± 3.4 y) and overweight/obese (body mass index: 30.6 ± 2.4 kg/m(2)). p16(INK4a)+ cells were identified from 12 to 20 random visual fields/sample at 20× magnification (immunohistochemical, nuclear staining) and were present in all adipose samples. RESULTS: Cross-sectional associations were observed between p16(INK4a)+ cell burden and physical function, including grip strength (r = –0.74), 400-m walk time (r = 0.74), 4-m gait speed (r = –0.73), and self-perceived mobility (r = –0.78) (p ≤ .05). These relationships remained significant after independent adjustments for age and adiposity (p ≤ .05). p16(INK4a)+ cell abundance was lower following the intervention (pre: 5.47 ± 3.4%, post: 2.17 ± 1.1% count p16(INK4a)+ cells, p ≤ .05). CONCLUSIONS: These results provide proof-of-concept that p16(INK4a)+ cells in thigh adipose are associated with physical function, and may be sensitive to change with RT ± CR in overweight/obese older women.

Aging is a multifactorial longitudinal process involving complex interactions; an easily defined set of biomarkers does not exist. Nonetheless, biomarkers provide an important strategy for evaluating geroscience-guided interventions. We convened expert panels, and conducted comprehensive reviews to identify 229 candidate biomarkers of aging. We next derived a set of selection criteria to identify biomarkers that were: 1) reliably and objectively measured; feasible for multi-center trial; 2) relevant to aging; 3) consistently predictive of clinical and functional outcomes; 4) responsive to intervention. We were conservative and parsimonious in selection, and arrived 8 a priori lab-based biomarkers: inflammation and stress response (IL-6, TNFRII, CRP, GDF-15), kidney aging (cystatin-C), clot formation/fibrinolysis (tPA), insulin/IGF-1, and metformin levels. These efforts reveal the scarcity of sufficiently mechanistic biomarkers for multi-center clinical trials on aging, and the need for a biomarker strategy that combines a well-justified multi-system biomarker panel with integrated multi-omics and discovery platforms.

The NIA’s Butler-Williams Scholars Program and GSA’s Emerging Scholars and Professional Organization are united in providing career development opportunities for early career scholars in a manner that promotes leadership, diversity, and inclusivity. This provides a foundation to develop a network of next generation of scientists, clinicians, and policy makers capable of shaping health in aging. Among the chief concerns of our aging population are disparities in health associated with race/ethnicity, experience, environment, access to health care, and sociocultural and socioeconomic factors. GSA’s early career professionals and alumni of the prestigious NIA Butler-Williams Scholars Program have tackled these issues directly and the scientific scholarship that results is astounding in its breadth and depth. Dr. Vicki Johnson-Lawrence, Ph.D. (Butler-Williams class of 2014), will present on the interacting effects of education and race/ethnicity on multi-morbidity, highlighting lessons learned from the National Health Interview Study. Dr. Lauren Parker (Butler-Williams class of 2018) will review efforts to develop culturally competent content for recruitment of Hispanic and black/African American persons to NIA-supported dementia-caregiving studies. Dr. Ryon Cobb (Butler-Williams class of 2016) will discuss the impact of race/ethnicity on kidney function among older adults, with evidence from the Health and Retirement Study. The final speaker, Dr. Ana Quiñones (Butler-Williams class of 2012), will present on longitudinal tracking of multi-morbidity in racially/ethnically diverse older adults. In sum, the featured talks by rising stars in aging research deepen our understanding of the influence of race, ethnicity, and experience on health and chronic disease in diverse aging populations.

This ESPO Presidential Symposium features a multidisciplinary perspective and recent scientific advances made by early career researchers from each of the GSA scientific sections. They will provide examples of how their work is addressing ways to build and maintain networks in aging and gerontological workforce. These talks will span research on the age-associated transcriptional networks (Biological Sciences, Kulkarni), enhancing care for persons with dementia using a professional healthcare network (Health Sciences, Kovaleva), ways to maintain care networks in nursing home residents (Behavioral and Social Sciences, Kennedy), exploring the impact of social isolation in older adults on the Autism Spectrum (Social Research, Policy, and Practice, Waldron) and reflections on a project that linked aging education and student involvement within the aging network at the state level (Academy for Gerontology in Higher Education, Stephenson). These talks will demonstrate the diversity of aims, strategies, methodologies, and tools employed across disciplines. In addition, these early career researchers will share how they use networks in their own disciplines to advance their science with the goal of building an independent program of research. We will conclude with a discussion on ways to identify synergies across different fields and promote strategies for successful cross-discipline collaboration.

The geroscience hypothesis holds that targeting fundamental mechanisms of aging has the potential to prevent or reduce severity of multiple age-related diseases. Cellular senescence is a key mechanism that may be driving disease in human aging, including Idiopathic pulmonary fibrosis (IPF), a progressive, ultimately fatal, senescence-associated disease. Importantly, cellular senescence may be targeted therapeutically. Senolytic agents are drugs that selectively induce senescent cell apoptosis by transiently disabling anti-apoptotic pathways. Selective ablation of senescent cells using the senolytic drug combination dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered IPF mouse model. We conducted the first-in-human trial of senolytics in IPF patients, and our data indicate that short-term, intermittent administration of DQ may alleviate physical dysfunction that accompanies IPF in human aging, including clinically-meaningfully improvements in mobility (p