The National Institute on Aging (NIA), part of the National Institutes of Health (NIH), was founded in 1974 to support and conduct research on aging and the health and well-being of older adults. Fifty years ago, the concept of studying aging generated much skepticism. Early NIA-funded research findings helped establish the great value of aging research and provided the foundation for significant science advances that have improved our understanding of the aging process, diseases and conditions associated with aging, and the effects of health inequities, as well as the need to promote healthy aging lifestyles. Today, we celebrate the many important contributions to aging research made possible by NIA, as well as opportunities to continue to make meaningful progress. NIA emphasizes that the broad aging research community must continue to increase and expand our collective efforts to recruit and train a diverse next generation of aging researchers.

Observational evidence suggests that higher physical activity is associated with slower kidney function decline; however, to our knowledge, no large trial has evaluated whether activity and exercise can ameliorate kidney function decline in older adults.To evaluate whether a moderate-intensity exercise intervention can affect the rate of estimated glomerular filtration rate per cystatin C (eGFRCysC) change in older adults.This ancillary analysis of the Lifestyle Interventions and Independence For Elders randomized clinical trial enrolled 1199 community-dwelling, sedentary adults aged 70 to 89 years with mobility limitations and available blood specimens. The original trial was conducted across 8 academic centers in the US from February 2010 through December 2013. Data for this study were analyzed from March 29, 2021, to February 28, 2022.Structured, 2-year, partially supervised, moderate-intensity physical activity and exercise (strength, flexibility) intervention compared with a health education control intervention with 2-year follow-up. Physical activity was measured by step count and minutes of moderate-intensity activity using accelerometers.The primary outcome was change in eGFRCysC. Rapid eGFRCysC decline was defined by the high tertile threshold of 6.7%/y.Among the 1199 participants in the analysis, the mean (SD) age was 78.9 (5.2) years, and 800 (66.7%) were women. At baseline, the 2 groups were well balanced by age, comorbidity, and baseline eGFRCysC. The physical activity and exercise intervention resulted in statistically significantly lower decline in eGFRCysC over 2 years compared with the health education arm (mean difference, 0.96 mL/min/1.73 m2; 95% CI, 0.02-1.91 mL/min/1.73 m2) and lower odds of rapid eGFRCysC decline (odds ratio, 0.79; 95% CI, 0.65-0.97).Results of this ancillary analysis of a randomized clinical trial showed that when compared with health education, a physical activity and exercise intervention slowed the rate of decline in eGFRCysC among community-dwelling sedentary older adults. Clinicians should consider targeted recommendation of physical activity and moderate-intensity exercise for older adults as a treatment to slow decline in eGFRCysC.ClinicalTrials.gov Identifier: NCT01072500.

Abstract The Long Life Family Study (LLFS), funded by the National Institute on Aging, is an international collaborative study of the genetics and familial components of exceptional longevity and healthy aging. We phenotyped 4,953 individuals from 539 two-generational families (1,727 proband; 3,226 offspring) at baseline (2006-2009). A second visit (2014-2017) was conducted for 2,904 (478 proband; 2,426 offspring) participants. The longitudinal, comprehensive in-person visits measured domains of healthy aging, including physical performance, cognition, and blood markers. Extensive genetic analyses were performed using the baseline blood draw, including genotyping with the Illumina 2.5M Human Omni array, linkage analyses with the families, whole genome sequencing using the TopMED protocol, and metabolomic assays. Collectively, this symposium will present novel findings that examined differences in end of life events and cause of death between non-exceptional and exceptional long-lived women, elucidate potential rare variants associated with exceptional longevity, and examine new potential metabolomics pathways involved in gait speed and cardiovascular disease. Specifically, Dr. Galvin will share results from three Danish nationwide studies (including LLFS) on different end of life events in long-lived female siblings. Then, Dr. Gurinovich will share findings on new uncommon variants associated with extreme longevity. Next, Dr. Kuipers will discuss associations between lipid metabolomics and vascular health. Lastly, Dr. Santanasto will discuss lipid metabolomics associated with lower odds of slow gait speed. Dr. Evan Hadley, NIA, will be the discussant and will share insights and propose future directions for LLFS.

BACKGROUND:Cell senescence is implicated in numerous age-related conditions. Drugs and nutritional supplements developed for a variety of purposes kill senescent cells (senolytics) or suppress their secretions (senomorphics). There is interest in repurposing such drugs to treat or prevent age-related diseases. To date, only small-scale preliminary trials have been conducted.METHOD:At a workshop convened by the National Institute on Aging in August 2019, academic, industry, and government scientists reviewed issues for phase II trials of potentially repurposable drugs, or dietary supplements, to assess benefits and risks of their senolytic (killing senescent cells) or senomorphic (altering senescent cells' phenotypes) effects in treating or preventing age-related conditions.RESULTS:Participants reviewed mechanisms and effects of cellular senescence, senolytics, and senomorphics of several classes and their potential role in treating or preventing disease, modulators of the senescence-associated secretory phenotype, needs for senescence markers, data and specimen resources, infrastructure for planning trials, and potential effects on outcomes in older patients with multimorbidity and polypharmacy.CONCLUSIONS:Participants noted the importance of considering potential effects of candidate drugs on multiple aging outcomes. It is important to assess drugs' specificity for killing senescent cells and the balance between senolytic and cytotoxic effects. Markers of specific senescent cell types are needed to assess intervention responses. There are potential interactions with coexisting diseases and their treatments in older persons. Standardized measures could enhance comparisons and pooling of data. Additional characterization of human cell senescent phenotypes is needed for developing better and more specific senolytics and senomorphics.

Abstract Dr. Hadley will discuss research priorities for the Division of Geriatrics and Clinical Gerontology. Dr. Hadley will also be available for small group discussion.

Abstract Five NIH-funded studies, the Long Life Family Study (LLFS, U19), the Longevity Consortium (LC, U19), Longevity Genomics (U24), and Protective Omics Profiles in Centenarians (UH2) work together to triangulate on mechanisms of extreme longevity and healthy aging with the ultimate goal of discovering predictors and targetable pathways. Linkage analyses by LLFS identified extremely strong genetic linkage peaks for cross-sectional as well as longitudinal trajectory rates-of-change phenotypes. Deep sequencing suggests these peaks are driven by rare, protective variants in selected pedigrees. In cross-species studies (UH2, LC), genomics, metabolomics and proteomics are used to exploit many-fold variances in natural life spans to discover protective mechanisms that explain some of these differences. Proteome analysis reveal several longevity-related proteins such as Cip1/p21, FOXO3, TOP2A, AKT1, RICTOR, INSR and SIRT6 harboring post translational modification sites that preferentially appear in short- versus long-lived species. The U24 effort developed a tool using genetically-mediated gene expression to prioritize genes for longevity translational efforts. We found that BLOC1S1 was associated with longevity and protection from atrial fibrillation and hearing loss without being associated with adverse events. This novel target is undergoing functional characterization. A proteomic assay (4,131 proteins, Somascan) annotated by genome-wide association study results in a total of 1,797 centenarians and 3,685 controls divided into independent discovery and replication sets, discovered significant and replicated over-expression (thus, pro-longevity) of BIRC2 and under-expression of APOB in carriers of the APOE ɛ-2 allele. A novel protein signature of rs2184061 (CDKN2a/CDKN2B in chromosome 9) was also associated with slower aging.

Abstract Dr. Hadley will review accomplishments of the Division of Geriatrics and Clinical Gerontology and make projections for the future.

Abstract The Longevity Consortium (LC), a NIA-Cooperative project, is an integrated multi-disciplinary effort with cutting edge bioinformatic, systems biology and chemoinformatics approaches exploiting multiple omics data generated from multiple well-phenotyped aging cohorts, Study of Osteoporotic Fractures, MrOS (fractures in men), Cardiovascular Health Study, the Long Life Family Study and the Centenarian Project to discover pharmacologically targetable protective pathways that promote healthy aging. Omics studies of mice treated with candidate drugs and of multiple species with varying life spans further informs the LC efforts. We describe the integration of the above efforts and the LC goals as well as opportunities for interested investigators to access shared results as well as opportunity funds for pilot projects. Early successes are described in 4 presentations: (1) A genome-wide association study including 1317 centenarians discovered 8 new loci in chromosomes 3, 6, 7, 9, 10, 14 and 15. The list includes new serum pQTLs that suggest a new biological mechanism involved in extreme longevity. (2) Novel, high-throughput discovery-proteomics of serum from 2,473 MrOs participants identified 25 proteins, mostly found in inflammatory pathways, associated with living beyond the 90th percentile birth-cohort survival. (3) A biological age estimation algorithm utilizing multi-omics assays significantly differentiated between 3,558 wellness program participants and controls. (4) Mediation analyses were used to test causal relationships between many candidate aging-modulating drugs and compounds, expression levels of gene and protein variants (eQTLs and pQTLs) and aging and longevity phenotypes. This high throughput method shows promise as a means of discovering candidate drugs for healthy aging.

This pilot work examined associations of brain grey matter volumes (GMV) with perceived fatigability in older adults to elucidate disablement mechanisms. A subsample (n = 29; age = 77.2 +/- 5.5; 86% female) of participants from the Lifestyle Interventions and Independence for Elders (LIFE) Study was utilized to quantify GMV for regions of interest in the basal ganglia and limbic system normalized to intracranial volume. The Pittsburgh Fatigability Scale measured physical and mental fatigability (score 0-50; higher physical fatigability >= 15; higher mental fatigability >= 13). We used an exploratory alpha level of p < 0.1. Nineteen (66%) participants had higher physical fatigability, 19 (66%) had higher mental fatigability, of these, 17 (57%) had both. Right hippocampal volumes/ICV were smaller in participants with higher verses lower physical fatigability (0.261 +/- 0.039 vs. 0.273 +/- 0.022, p = 0.07); associations were similar for right putamen and bilateral thalamus. Higher mental fatigability was associated with smaller right hippocampus, thalamus, and posterior cingulum and bilateral amygdala. Higher fatigability in older adults may be associated with smaller volumes of the basal ganglia and limbic system, indicating mechanisms for further exploration.

BACKGROUND/OBJECTIVES:Resilience, the ability to resist or recover from adverse effects of a stressor, is of widespread interest in social, psychologic, biologic, and medical research and particularly salient as the capacity to respond to stressors becomes diminished with aging. To date, research on human resilience responses to and factors influencing these responses has been limited. METHODS:The National Institute on Aging convened a workshop in August 2015 on needs for research to improve measures to predict and assess resilience in human aging. Effects of aging-related factors in impairing homeostatic responses were developed from examples illustrating multiple determinants of clinical resilience outcomes. Research directions were identified by workshop participants. RESULTS:Research needs identified included expanded uses of clinical data and specimens in predicting or assessing resilience, and contributions from epidemiological studies in identifying long-term predictors. Better measures, including simulation tests, are needed to assess resilience and its determinants. Mechanistic studies should include exploration of influences of biologic aging processes on human resiliencies. Important resource and infrastructure needs include consensus phenotype definitions of specific resiliencies, capacity to link epidemiological and clinical resilience data, sensor technology to capture responses to stressors, better laboratory animal models of human resiliencies, and new analytic methods to understand the effects of multiple determinants of stress responses. CONCLUSIONS:Extending the focus of care and research to improving the capacity to respond to stressors could benefit older adults in promoting a healthier life span.

BACKGROUND Caloric restriction (CR), energy intake reduced below ad libitum (AL) intake, increases life span in many species. The implications for humans can be clarified by randomized controlled trials of CR. METHODS To determine CR's feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21-51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change ("RMR residual") and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures. RESULTS Body mass index averaged 25.1 (range: 21.9-28.0 kg/m(2)). Eighty-two percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7±0.7 %CR (mean ± standard error) and maintained 10.4±0.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months (p = .04) but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at M12 and M24 (p < .001), while tumor necrosis factor-α decreased significantly more only at M24 (p = .02). CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life. CONCLUSIONS Sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.

Population aging is unprecedented, without parallel in human history, and the 21st century will witness even more rapid aging than did the century just past. Improvements in public health and medicine are having a profound effect on population demographics worldwide. By 2017, there will be more people over the age of 65 than under age 5, and by 2050, two billion of the estimated nine billion people on Earth will be older than 60 (http://unfpa.org/ageingreport/). Although we can reasonably expect to live longer today than past generations did, the age-related disease burden we will have to confront has not changed. With the proportion of older people among the global population being now higher than at any time in history and still expanding, maintaining health into old age (or healthspan) has become a new and urgent frontier for modern medicine. Geroscience is a cross-disciplinary field focused on understanding the relationships between the processes of aging and age-related chronic diseases. On October 30-31, 2013, the trans-National Institutes of Health GeroScience Interest Group hosted a Summit to promote collaborations between the aging and chronic disease research communities with the goal of developing innovative strategies to improve healthspan and reduce the burden of chronic disease.

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results.

Concerns remain as to the best terminology to embrace sarcopenias evolving conceptualization. Many of these concerns stem from the fact that age-related decrements in muscle performance associated with physical impairment are only partially explained by decreases in muscle mass and that other pathophysiologic factors contribute to age-related impairments in muscle performance.Review of literature on the evolving conceptualization of sarcopenia since its early definition in 1989 and concerns with terminology.Early definitions of sarcopenia were based solely on muscle mass in relationship to the range of muscle within a reference population. Subsequent definitions added performance criteria to muscle mass alone. The Foundation for the National Institutes of Health Sarcopenia Project identified criteria for clinically relevant low muscle strength (weakness) and low lean mass. Progress on the sarcopenias evolving definitions has not been accompanied by recommendations on specific terminologies that address the lack of sufficient specificity from the use of an anatomic term to define a functional condition with numerous now known nonanatomic contributory factors. Skeletal Muscle Function Deficit is a broader construct that accommodates a set of diagnoses that includes both sarcopenia and other age-related muscle dysfunctions.Skeletal Muscle Function Deficit is proposed as a new terminology to embrace the evolving conceptualization of sarcopenia and other age-related muscle dysfunctions. It comprises a variety of contributory etiologies and has the potential to provide a framework for developing diagnostic categories that are useful for both clinical practice and research.

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.

Research to understand variability at the highest end of the cognitive performance distribution has been scarce. Our aim was to define a cognitive endophenotype based on exceptional episodic memory (EM) performance and to investigate familial aggregation of EM in families from the Long Life Family Study (LLFS). Using a sample of 1911 nondemented offspring of long-lived probands, we created a quantitative phenotype, EM (memory z ≥ 1.5), and classified LLFS families as EM and non-EM families based on the number of EM offspring. We then assessed differences in memory performance between LLFS relatives in the parental generation of EM families and those in non-EM families using multivariate analysis adjusted for APOE Apolipoprotein E genotype. LLFS relatives in the proband generation from EM families showed better EM performance than those from non-EM families (β = 0.74, standard error = 0.19, p = 1.4 × 10(-4)). We demonstrated that there is a familial correlation of the EM endophenotype, suggesting that genetic variants might influence memory performance in long-lived families.