National Institute on Aging's 50th anniversary: Advancing aging research and the health and well-being of older adults.

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.

National Institute on Aging Workshop: Repurposing Drugs or Dietary Supplements for Their Senolytic or Senomorphic Effects: Considerations for Clinical Trials.

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.

Report: NIA Workshop on Measures of Physiologic Resiliencies in Human Aging.

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.

A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity.

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.

Advances in geroscience: impact on healthspan and chronic disease.

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.

The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men.

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.

Skeletal muscle function deficit: a new terminology to embrace the evolving concepts of sarcopenia and age-related muscle dysfunction.

BACKGROUND: Concerns remain as to the best terminology to embrace sarcopenia's 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. METHODS: Review of literature on the evolving conceptualization of sarcopenia since its early definition in 1989 and concerns with terminology. RESULTS: 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 sarcopenia's 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. CONCLUSIONS: 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.

Exceptional memory performance in the Long Life Family Study.

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 (ß = 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.

Approaches for quantifying energy intake and %calorie restriction during calorie restriction interventions in humans: the multicenter CALERIE study.

Calorie restriction (CR) is a component of most weight loss interventions and a potential strategy to slow aging. Accurate determination of energy intake and %CR is critical when interpreting the results of CR interventions; this is most accurately achieved using the doubly labeled water method to quantify total energy expenditure (TEE). However, the costs and analytical requirements of this method preclude its repeated use in many clinical trials. Our aims were to determine 1) the optimal TEE assessment time points for quantifying average energy intake and %CR during long-term CR interventions and 2) the optimal approach for quantifying short-term changes in body energy stores to determine energy intake and %CR during 2-wk DLW periods. Adults randomized to a CR intervention in the multicenter CALERIE study underwent measurements of TEE by doubly labeled water and body composition at baseline and months 1, 3, and 6. Average %CR achieved during the intervention was 24.9 ± 8.7%, which was computed using an approach that included four TEE assessment time points (i.e., TEE(baseline, months 1, 3, and 6)) plus the 6-mo change in body composition. Approaches that included fewer TEE assessments yielded %CR values of 23.4 ± 9.0 (TEE(baseline,) months 3 and 6), 25.0 ± 8.7 (TEE(baseline,) months 1 and 6), and 20.9 ± 7.1% (TEE(baseline, month 6)); the latter approach differed significantly from approach 1 (P < 0.001). TEE declined 9.6 ± 9.9% within 2-4 wk of CR beginning and then stabilized. Regression of daily home weights provided the most reliable estimate of short-term change in energy stores. In summary, optimal quantification of energy intake and %CR during weight loss necessitates a TEE measurement within the first month of CR to capture the rapid reduction in TEE.

The Lifestyle Interventions and Independence for Elders Study: design and methods.

BACKGROUND: As the number of older adults in the United States rises, maintaining functional independence among older Americans has emerged as a major clinical and public health priority. Older people who lose mobility are less likely to remain in the community; demonstrate higher rates of morbidity, mortality, and hospitalizations; and experience a poorer quality of life. Several studies have shown that regular physical activity improves functional limitations and intermediate functional outcomes, but definitive evidence showing that major mobility disability can be prevented is lacking. A Phase 3 randomized controlled trial is needed to fill this evidence gap. METHODS: The Lifestyle Interventions and Independence for Elders (LIFE) Study is a Phase 3 multicenter randomized controlled trial designed to compare a supervised moderate-intensity physical activity program with a successful aging health education program in 1,600 sedentary older persons followed for an average of 2.7 years. RESULTS: LIFE's primary outcome is major mobility disability, defined as the inability to walk 400 m. Secondary outcomes include cognitive function, serious fall injuries, persistent mobility disability, the combined outcome of major mobility disability or death, disability in activities of daily living, and cost-effectiveness. CONCLUSIONS: Results of this study are expected to have important public health implications for the large and growing population of older sedentary men and women.

Do gender, disability, and morbidity affect aging rate in the LLFS? Application of indices of cumulative deficits.

We used an approach of cumulative deficits to evaluate the rate of aging in 4954 participants of the Long-Life Family Study (LLFS) recruited in the U.S. (Boston, New York, and Pittsburgh) and Denmark. We used an array of 85 health-related deficits covering major health dimensions including depression, cognition, morbidity, physical performance, and disability to construct several deficit indices (DIs) with overlapping and complementary sets of deficits to test robustness of the estimates. Our study shows that the DIs robustly characterize accelerated rates of aging irrespective of specific of deficits. When a wider spectrum of health dimensions is considered these rates are better approximated by quadratic law. Exponential rates are more characteristic for more severe health dimensions. The aging rates are the same for males and females. Individuals who contracted major diseases and those who were free of them exhibited the same aging rates as characterized by the DI constructed using mild deficits. Unlike health, disability can qualitatively alter the aging patterns of the LLFS participants. We report on systemic differences in health among the LLFS centenarians residing in New York and Boston. This study highlights importance of aggregated approaches to better understand systemic mechanisms of health deterioration in long-living individuals.

Health and function of participants in the Long Life Family Study: A comparison with other cohorts.

Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.

Design and conduct of the CALERIE study: comprehensive assessment of the long-term effects of reducing intake of energy.

BACKGROUND: In a robust and consistent manner, sustained caloric restriction (CR) has been shown to retard the aging process in a variety of animal species. Nonhuman primate studies suggest that CR may have similar effects in longer-lived species. The CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy) research program is the first systematic investigation of CR in nonobese human beings. In the phase 2 study, it is hypothesized that 2 years of sustained CR, involving a 25% reduction of ad libitum energy intake, results in beneficial effects similar to those observed in animal studies. This article presents the design and implementation of this study. METHODS: The study is a multicenter, parallel-group, randomized controlled trial. A sample of 225 participants (22.0 ≤ body mass index [BMI] < 28.0 kg/m(2)) is being enrolled with 2:1 allocation to CR. RESULTS: An intensive dietary and behavioral intervention was developed to achieve 25% CR and sustain it over the 2 years. Adherence is monitored using a doubly labeled water technique. Primary outcomes are resting metabolic rate and core temperature, and are assessed at baseline and at 6-month intervals. Secondary outcomes address oxyradical formation, cardiovascular risk markers, insulin sensitivity and secretion, immune function, neuroendocrine function, quality of life and cognitive function. Biologic materials are stored in a central repository. CONCLUSIONS: An intricate protocol has been developed to conduct this study. Procedures have been implemented to safeguard the integrity of the data and the conclusions drawn. The results will provide insight into the detrimental changes associated with the human aging process and how CR mitigates these effects.

Toward an integrated research agenda for critical illness in aging.

Aging brings an increased predisposition to critical illness. Patients older than 65 years of age account for approximately half of all intensive care unit (ICU) admissions in the United States, a proportion that is expected to increase considerably with the aging of the population. Emerging research suggests that elderly survivors of intensive care suffer significant long-term sequelae, including accelerated age-related functional decline. Existing evidence-based interventions are frequently underused and their efficacy untested in older subjects. Improving ICU outcomes in the elderly will require not only better methods for translating sound science into improved ICU practice but also an enhanced understanding of the underlying molecular, physiological, and pathophysiological interactions of critical illness with the aging process itself. Yet, significant barriers to research for critical illness in aging exist. We review the state of knowledge and identify gaps in knowledge, research opportunities, and barriers to research, with the goal of promoting an integrated research agenda for critical illness in aging.

"Predicting" parental longevity from offspring endophenotypes: data from the Long Life Family Study (LLFS).

While there is evidence that longevity runs in families, the study of long-lived families is complicated by the fact that longevity-related information is available only for the oldest old, many of whom may be deceased and unavailable for testing, and information on other living family members, primarily descendents, is censored. This situation requires a creative approach for analyzing determinants of longevity in families. There are likely biomarkers that predict an individual's longevity, suggesting the possibility that those biomarkers which are heritable may constitute valuable endophenotypes for exceptional survival. These endophenotypes could be studied in families to identify human longevity genes and elucidate possible mechanisms of their influence on longevity. In this paper, we analyze data collected in the Long Life Family Study (LLFS) investigating whether indicators of physiological state, cognitive functioning and health/well-being among offspring predict longevity in parents. Good predictors can be used as endophenotypes for exceptional survival. Our analyses revealed significant associations between cumulative indices describing physiological state, as well as a number of offspring phenotypes, and parental lifespan, supporting both their familial basis and relevance to longevity. We conclude that the study of endophenotypes within families is a valid approach to the genetics of human longevity.

A family longevity selection score: ranking sibships by their longevity, size, and availability for study.

Family studies of exceptional longevity can potentially identify genetic and other factors contributing to long life and healthy aging. Although such studies seek families that are exceptionally long lived, they also need living members who can provide DNA and phenotype information. On the basis of these considerations, the authors developed a metric to rank families for selection into a family study of longevity. Their measure, the family longevity selection score (FLoSS), is the sum of 2 components: 1) an estimated family longevity score built from birth-, gender-, and nation-specific cohort survival probabilities and 2) a bonus for older living siblings. The authors examined properties of FLoSS-based family rankings by using data from 3 ongoing studies: the New England Centenarian Study, the Framingham Heart Study, and screenees for the Long Life Family Study. FLoSS-based selection yields families with exceptional longevity, satisfactory sibship sizes and numbers of living siblings, and high ages. Parameters in the FLoSS formula can be tailored for studies of specific populations or age ranges or with different conditions. The first component of the FLoSS also provides a conceptually sound survival measure to characterize exceptional longevity in individuals or families in various types of studies and correlates well with later-observed longevity.

Prospects for life span extension.

Life expectancy has increased dramatically in the United States and in much of the world in recent years and decades. The factors underlying this increase are incompletely understood and are undoubtedly complex. A question that drives current research is whether life expectancy can be further extended using current knowledge of modifiable risk factors. A still more challenging research focus is on the possibility that life expectancy might be further increased through knowledge gained from studies of the basic biology of aging and its genetic and environmental modifiers.

Validation study of energy expenditure and intake during calorie restriction using doubly labeled water and changes in body composition.

BACKGROUND: Clinical trials involving calorie restriction (CR) require an assessment of adherence to a prescribed CR with the use of an objective measure of energy intake (EI). OBJECTIVE: The objective was to validate the use of energy expenditure (EE) measured by doubly labeled water (DLW), in conjunction with precise measures of body composition, to calculate an individual's EI during 30% CR. DESIGN: Ten participants underwent 30% CR for 3 wk. During the last week (7 d), 24-h EE was measured in a respiratory chamber and simultaneously by DLW (EEDLW). EI was calculated from 7-d EE measured by DLW and from changes in energy stores (ES) (weight and body composition). Calculated EI was then compared with the actual EI measured in the chamber by using the following equations: calculated EI (kcal/d) = EEDLW + DeltaES, where DeltaESFM/FFM (kcal/d) = (9.3 x DeltaFM, g/d) + (1.1 x DeltaFFM, g/d), FM is fat mass, and FFM is fat-free mass. RESULTS: We found close agreement (R = 0.88) between EE measured in the metabolic chamber and EEDLW during CR. Using the measured respiratory quotient, we found that the mean (+/-SD) EE(DLW) was 1934 +/- 377 kcal/d and EE measured in the metabolic chamber was 1906 +/- 327 kcal/d, ie, a 1.3 +/- 8.9% overestimation. EI calculated from EEDLW and from changes in ES was 8.7 +/- 36.7% higher than the actual EI provided during the chamber stay (1596 +/- 656 kcal/d). CONCLUSIONS: DLW methods can accurately estimate 24-h EE during CR. Although the mean difference between actual and calculated EIs for the group was small, we conclude that the interindividual variability was too large to provide an assessment of CR adherence on an individual basis.