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.

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.

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.

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.

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.

Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults.

Evolving definitions of frailty, and improved understanding of molecular and physiological declines in multiple systems that may increase vulnerability in frail, older adults has encouraged investigators from many disciplines to contribute to this emerging field of research. This article reports on the results of the 2004 American Geriatrics Society/National Institute on Aging conference on a Research Agenda on Frailty in Older Adults, which brought together a diverse group of clinical and basic scientists to encourage further investigation in this area. This conference was primarily focused on physical and physiological aspects of frailty. Although social and psychological aspects of frailty are critically important and merit future research, these topics were largely beyond the scope of this meeting. Included in this article are sections on the evolving conceptualization and definitions of frailty; physiological underpinnings of frailty, including the potential contributions of inflammatory, endocrine, skeletal muscle, and neurologic system changes; potential molecular and genetic contributors; proposed animal models; and integrative, system biology approaches that may help to facilitate future frailty research. In addition, several specific recommendations as to future directions were developed from suggestions put forth by participants, including recommendations on definition and phenotype development, methodological development to perform clinical studies of individual-system and multiple-system vulnerability to stressors, development of animal and cellular models, application of population-based studies to frailty research, and the development of large collaborative networks in which populations and resources can be shared. This meeting and subsequent article were not meant to be a comprehensive review of frailty research; instead, they were and are meant to provide a more-targeted research agenda-setting process.

Effects of a physical activity intervention on measures of physical performance: Results of the lifestyle interventions and independence for Elders Pilot (LIFE-P) study.

BACKGROUND: The Short Physical Performance Battery (SPPB), which includes walking, balance, and chair stands tests, independently predicts mobility disability and activities of daily living disability. To date, however, there is no definitive evidence from randomized controlled trials that SPPB scores can be improved. Our objective was to assess the effect of a comprehensive physical activity (PA) intervention on the SPPB and other physical performance measures. METHODS: A total of 424 sedentary persons at risk for disability (ages 70-89 years) were randomized to a moderate-intensity PA intervention or a successful aging (SA) health education intervention and were followed for an average of 1.2 years. RESULTS: The mean baseline SPPB score on a scale of 0-12, with 12 corresponding to highest performance, was 7.5. At 6 and 12 months, the PA versus SA group adjusted SPPB (+/- standard error) scores were 8.7 +/- 0.1 versus 8.0 +/- 0.1, and 8.5 +/- 0.1 versus 7.9 +/- 0.2, respectively (p < .001). The 400-meter walking speed was also significantly improved in the PA group. The PA group had a lower incidence of major mobility disability defined as incapacity to complete a 400-meter walk (hazard ratio = 0.71, 95% confidence interval = 0.44-1.20). CONCLUSIONS: A structured PA intervention improved the SPPB score and other measures of physical performance. An intervention that improves the SPPB performance may also offer benefit on more distal health outcomes, such as mobility disability.

Exceptional survival in human populations: National Institute on Aging perspectives and programs.

Identifying the factors that contribute to long and healthy life can lead to improved interventions that can help delay or prevent the onset of major aging-related diseases and disabilities and increase the time that older persons spend in good health. Studies on longevity and other exceptional survival outcomes can contribute to this knowledge. The National Institute on Aging (NIA) supports a considerable amount of basic, behavioral, demographic, epidemiologic, and clinical research on these topics, including a large research program on longevity assurance genes, primarily in laboratory animals, and in biodemographic aspects of longevity in humans and other species. This article describes NIA's activities regarding one important aspect of research on longevity and related phenotypes: exceptional survival phenotypes in humans, including exceptional longevity, health span, and active life expectancy.

The lifestyle interventions and independence for elders (LIFE) pilot study: design and methods.

The LIFE study is a multicenter pilot for a proposed full scale, two-arm randomized controlled trial that will contrast the effect of a physical activity intervention with a successful aging education program on the occurrence of incident major mobility disability (the inability to complete a 400 m walk) or death in at-risk sedentary older adults. Four hundred older adults from 4 clinical sites will be recruited for this purpose. All participants will be followed for at least 1-year; however, we will continue to follow all participants until the final randomized individual has reached the 1-year mark. This will enable us to acquire additional information about maintenance. Additional outcomes will include lower extremity physical performance as well as gait speed over 4 m and 400 m. These latter measures will provide data on the efficacy of the intervention on intermediate endpoints linked to the primary outcome of interest. The goals of the pilot study are to (a) estimate the sample size needed for a full scale trial, (b) examine the consistency of the effects of the physical activity intervention on several continuous measures of physical function, (c) assess the feasibility of recruitment, (d) evaluate study adherence and retention, (d) evaluate the efficacy of a stepped care approach for managing intercurrent illness in this at-risk population, and (e) develop a comprehensive system for monitoring and ensuring participant safety. Other goals of this pilot phase include assessments of health-related quality of life and cost-effectiveness.

From bedside to bench: research agenda for frailty.

The American Geriatrics Society sponsored a working conference in January 2004, funded by the National Institute on Aging, to establish the state of the art in frailty research and to set a research agenda for the future. The invited participants included senior basic biologists, epidemiologists, geneticists, and clinical investigators who study aging-related issues. This article summarizes the central theoretical observations on frailty and research needs and opportunities presented and discussed at this conference, and lays out an agenda for future research on frailty.

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.

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.

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.

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.

The future of aging therapies.

Advances in understanding aging processes and their consequences are leading to the development of therapies to slow or reverse adverse changes formerly considered to be "normal" aging and processes that underlie multiple age-related conditions. Estimating the effectiveness of candidate aging therapies, whose effects on human aging may require many years to determine, is a particular challenge. Strategies for identifying candidate interventions can be developed through multiple approaches, including the screening of molecular targets and pathways in vitro and in animal models, informed as well by evidence from human genetic and epidemiologic data. A number of recently established programs and networks can serve as resources for such research. For all these research approaches, from in vitro molecular studies to clinical trials, contributions of cell and molecular biology are crucial and offer the prospect of therapeutic advances that address fundamental biological processes as well as the clinically important challenges of aging.