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People who have a balanced diet and engage in more physical activity live longer, healthier lives. This study aimed to test the hypothesis that these associations reflect a slowing of biological processes of aging. We analyzed data from 42 625 participants (aged 20–84 years, 51% female participants) from the National Health and Nutrition Examination Surveys (NHANES), 1999–2018. We calculated adherence to a Mediterranean diet (MeDi) and level of leisure time physical activity (LTPA) using standard methods. We measured biological aging by applying the PhenoAge algorithm, developed using clinical and mortality data from NHANES-III (1988–94), to clinical chemistries measured from a blood draw at the time of the survey. We tested the associations of diet and physical activity measures with biological aging, explored synergies between these health behaviors, and tested heterogeneity in their associations across strata of age, sex, and body mass index. Participants who adhered to the MeDi and who did more LTPA had younger biological ages compared with those who had less-healthy lifestyles (high vs low MeDi tertiles: β = 0.14 standard deviation [ SD ] [95% confidence interval {CI}: −0.18, −0.11]; high vs sedentary LTPA, β = 0.12 SD [−0.15, −0.09]), in models controlled for demographic and socioeconomic characteristics. Healthy diet and regular physical activity were independently associated with lower clinically defined biological aging, regardless of age, sex, and BMI category. [ABSTRACT FROM AUTHOR]

Impaired rest–activity circadian rhythm has been associated with increased risk for morbidity and mortality. Animals with mutations in clock genes display accelerated aging and shortened life span. Whether impaired rest–activity circadian rhythm is also associated with processes of aging in humans has not been explored. We analyzed accelerometry and physiological data from 7 539 adults participating in the 2011–2014 waves of the U.S. National Health and Nutrition Examination Surveys. We used accelerometry data to compute rest–activity rhythm measurements. We used physiological data to compute measurements of biological aging according to 3 published algorithms: Klemera–Doubal method (KDM) Biological Age, PhenoAge, and homeostatic dysregulation (HD). In the models adjusting multiple covariates, participants with higher relative amplitude (RA) and interdaily stability (IS) and lower intradaily variability (IV) exhibited less advanced biological aging indexed by KDM and PhenoAge (effect sizes for 1-quantile increase in these rest–activity measurements ranged from 0.54 to 0.57 "years" for RA, 0.24 to 0.28 "years" for IS, and 0.24 to 0.35 "years" for IV, p s <.001). Similar finding was observed for biological aging indexed by HD, but the significance was limited to RA with 1-quantile increase in RA associated with 0.09 log units decrease in HD (p <.001). The results indicate that blunted rest–activity circadian rhythm is associated with accelerated aging in the general population, suggesting that interventions aiming at enhancing circadian rhythm may be a novel approach for the extension of a healthy life span. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) increases healthy life span and is accompanied by slowing or reversal of aging-associated DNA methylation (DNAm) changes in animal models. In the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIETM) human trial, we evaluated associations of CR and changes in whole-blood DNAm. CALERIETM randomized 220 healthy, nonobese adults in a 2:1 allocation to 2 years of CR or ad libitum (AL) diet. The average CR in the treatment group through 24 months of follow-up was 12%. Whole blood (baseline, 12, and 24 months) DNAm profiles were measured. Epigenome-wide association study (EWAS) analysis tested CR-induced changes from baseline to 12 and 24 months in the n  = 197 participants with available DNAm data. CR treatment was not associated with epigenome-wide significant (false discovery rate [FDR] < 0.05) DNAm changes at the individual-CpG-site level. Secondary analysis of sets of CpG sites identified in published EWAS revealed that CR induced DNAm changes opposite to those associated with higher body mass index and cigarette smoking (p  < .003 at 12- and 24-month follow-ups). In contrast, CR altered DNAm at chronological-age-associated CpG sites in the direction of older age (p  < .003 at 12- and 24-month follow-ups). Although individual CpG site DNAm changes in response to CR were not identified, analyses of sets CpGs identified in prior EWAS revealed CR-induced changes to blood DNAm. Altered CpG sets were enriched for insulin production, glucose tolerance, inflammation, and DNA-binding and DNA-regulation pathways, several of which are known to be modified by CR. DNAm changes may contribute to CR effects on aging. [ABSTRACT FROM AUTHOR]

Background: Socioeconomic disadvantage is a well-established predictor of morbidity and mortality, and is thought to accelerate the aging process. This study examined associations between life-course socioeconomic conditions and the Pace of Aging, a longitudinal measure of age-related physiological decline.Methods: Data were drawn from a Swiss population-based cohort of individuals originally recruited between 2003 and 2006, and followed up for 11 years (2 834 women, 2 475 men aged 35-75 years [mean 52]). Pace of Aging was measured using 3 repeated assessments of 12 biomarkers reflecting multiple body systems. Analysis tested associations of socioeconomic conditions with physiological status at baseline and with the Pace of Aging.Results: Participants with more life-course socioeconomic disadvantage were physiologically older at baseline and experienced faster Pace of Aging. Effect sizes (β) for associations of childhood socioeconomic disadvantage with baseline physiological status ranged from 0.1 to 0.2; for adulthood socioeconomic disadvantage, effect sizes ranged from 0.2 to 0.3. Effect sizes were smaller for associations with the Pace of Aging (<0.05 for childhood disadvantage, 0.05-0.1 for adulthood disadvantage). Those who experienced disadvantaged socioeconomic conditions from childhood to adulthood aged 10% faster over the 11 years of follow-up as compared with those who experienced consistently advantaged socioeconomic conditions. Covariate adjustment for health behaviors attenuated associations, but most remained statistically significant.Conclusions: Socioeconomic inequalities contribute to a faster Pace of Aging, partly through differences in health behaviors. Intervention to slow aging in at-risk individuals is needed by midlife, before etiology of aging-related diseases become established. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of some metabolic factors increases the risk of dementia. It remains unclear if overall metabolic dysregulation, or only certain components, contribute to cognitive aging and if these associations are sex specific.Methods: Data from the 2006-2016 waves of the Health and Retirement Study (HRS) was used to analyze 7 103 participants aged 65 and older at baseline (58% women). We created a metabolic-dysregulation risk score (MDRS) composed of blood pressure/hypertension status, glycosylated hemoglobin (HbA1c)/diabetes status, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and waist circumference, and assessed cognitive trajectories from repeated measures of the HRS-Telephone Interview for Cognitive Status (HRS-TICS) over 10 years of follow-up. Linear mixed-effects models estimated associations between MDRS or individual metabolic factors (biomarkers) with mean and change in HRS-TICS scores and assessed sex-modification of these associations.Results: Participants with higher MDRSs had lower mean HRS-TICS scores, but there were no statistically significant differences in rate of decline. Sex stratification showed this association was present for women only. MDRS biomarkers revealed heterogeneity in the strength and direction of associations with HRS-TICS. Lower HRS-TICS levels were associated with hypertension, higher HbA1c/diabetes, and lower HDL-C and TC, whereas faster rate of cognitive decline was associated with hypertension, higher HbA1c/diabetes, and higher TC. Participants with higher HbA1c/diabetes presented worse cognitive trajectories. Sex differences indicated that women with higher HbA1c/diabetes to have lower HRS-TICS levels, whereas hypertensive males presented better cognitive trajectory.Conclusions: Our results demonstrate that metabolic dysregulation is more strongly associated with cognition in women compared with men, though sex differences vary by individual biomarker. [ABSTRACT FROM AUTHOR]

Background: Loneliness and social isolation are emerging public health challenges for aging populations.Methods: We followed N = 11 302 U.S. Health and Retirement Study participants aged 50-95 from 2006 to 2014 to measure persistence of experiences of loneliness and exposure to social isolation. We tested associations of longitudinal loneliness and social isolation phenotypes with disability, morbidity, mortality, and biological aging through 2018.Results: During follow-up, 18% of older adults met criteria for loneliness, with 6% meeting criteria at 2 or more follow-up assessments. For social isolation, these fractions were 21% and 8%. Health and Retirement Study participants who experienced loneliness and were exposed to social isolation were at increased risk for disease, disability, and mortality. Those experiencing persistent loneliness were at a 57% increased hazard of mortality compared to those who never experienced loneliness. For social isolation, the increase was 28%. Effect sizes were somewhat larger for counts of prevalent activity limitations and somewhat smaller for counts of prevalent chronic diseases. Covariate adjustment for socioeconomic and psychological risks attenuated but did not fully explain associations. Older adults who experienced loneliness and were exposed to social isolation also exhibited physiological indications of advanced biological aging (Cohen's d for persistent loneliness and social isolation = 0.26 and 0.21, respectively). For loneliness, but not social isolation, persistence was associated with increased risk.Conclusions: Deficits in social connectedness prevalent in a national sample of U.S. older adults were associated with morbidity, disability, and mortality and with more advanced biological aging. Bolstering social connectedness to interrupt experiences of loneliness may promote healthy aging. [ABSTRACT FROM AUTHOR]

Many studies have shown that estimates of biological age (BA) can predict health-related outcomes in older adults. Often, researchers employ multiple measures belonging to a variety of biological/physiological systems, and assess the validity of BA estimates by how well they approximate chronological age (CA). However, it is not clear whether this is the best approach for judging a BA estimate, or whether certain groups of measures are more informative to this end. Using data from the Canadian Longitudinal Study on Aging, we composed panels of biological measures based on the physiological systems/domains they belong to (blood, organ function, physical/cognitive performance), and also composed a panel of measures that optimized the association of BA with CA. We then compared BA estimates for each according to their association with CA and health-related outcomes, including frailty, multimorbidity, chronic condition domains, disability, and health care utilization. Although BA estimated using all 40 measures (r = 0.74) or our age-optimized panel (r = 0.77) most closely approximated CA, the strength of associations to health-related outcomes was comparable or weaker than that of our panel composed only of physical performance measures (CA r = 0.59). All BA estimates were significantly associated to the outcomes considered, with exception to the neurological and musculoskeletal disease domains, and only varied slightly by sex. In summary, while the approximation of CA is important to consider when estimating BA, the strength of associations to prospective outcomes may be of greater importance. Hence, the context in which BA is estimated should be influenced by an investigator's specific research goals. [ABSTRACT FROM AUTHOR]

Quantification of biological aging is of interest in gerontology as a means to surveil aging rates in the population and to evaluate the effects of interventions to increase healthy life span. Analysis of proposed methods to quantify biological aging has focused on samples of midlife or mixed-age adults in the West. Research is needed to test whether quantifications of biological aging can differentiate aging rates among older adults and if quantifications of biological aging developed in Western samples can differentiate aging rates in non-Western populations. We conducted analysis of Klemera-Doubal method (KDM) Biological Age and homeostatic dysregulation measures of biological aging developed in the U.S. NHANES and tested in a sample of older Taiwanese adults in the Social Environment and Biomarkers of Aging Study. We conducted analysis of physical and cognitive function and mortality, comparing quantifications of biological aging to a biomarker index based on norms within our analysis sample and to participants' ratings of their own health. Results showed that quantifications of biological aging (a) predicted differences in physical and cognitive function and in mortality risk among Taiwanese older adults and (b) performed as well as a traditional biomarker index and participant self-rated health for prediction of these outcomes. [ABSTRACT FROM AUTHOR]

Quantification of biological aging has been proposed for population surveillance of age-related decline in system integrity and evaluation of geroprotective therapies. However, methods of quantifying biological aging have been little studied in geriatric populations. We analyzed three clinical-biomarker-algorithm methods to quantify biological aging. Klemera-Doubal method Biological Age and homeostatic dysregulation algorithms were parameterized from analysis of U.S. National Health and Nutrition Examination Surveys (NHANES) data (N = 36,207) based on published methods. Levine method Biological Age was adapted from published analysis of NHANES data. Algorithms were applied to biomarker data from the Duke Established Populations for Epidemiologic Studies of the Elderly (Duke-EPESE) cohort of older adults (N = 1,374, aged 71-102 years, 35% male, 52% African American). We tested associations of biological aging measures with participant reported Activities of daily living (ADL), instrumental activities of daily living (IADL) dependencies, and mortality. We evaluated the sensitivity of results to the demographic composition of reference samples and biomarker sets used to develop biological aging algorithms. African American and white Duke-EPESE participants with more advanced biological aging reported dependence in more ADLs and IADLs and were at increased risk of death over follow-up through 2017. Effect sizes were similar across algorithms, but were strongest for Levine method Biological Age (per-quintile increase in ADL incidence rate ratio = 1.25, 95% confidence interval [1.17-1.37], IADL incidence rate ratio = 1.23 [1.15-1.32], mortality hazard ratio = 1.12 [1.08-1.16]). Results were insensitive to demographic composition of reference samples, but modestly sensitive to the biomarker sets used to develop biological aging algorithms. Blood-chemistry-based quantifications of biological aging show promise for evaluating the effectiveness of interventions to extend healthy life span in older adults. [ABSTRACT FROM AUTHOR]

Biological aging measures have been proposed as proxies for extension of healthy life span in trials of geroprotective therapies that aim to slow aging. Several methods to measure biological aging show promise but it is not known if these methods are sensitive to changes caused by geroprotective therapy. We conducted analysis of two proposed methods to quantify biological aging using data from a recently concluded trial of an established geroprotector, caloric restriction. We obtained data from the National Institute on Aging CALERIE randomized trial through its public-access biobank (https://calerie.duke.edu/). The CALERIE trial randomized N = 220 nonobese adults to 25% caloric restriction (n = 145; 11.7% caloric restriction was achieved, on average) or to maintain current diet (n = 75) for 2 years. We analyzed biomarker data collected at baseline, 12-, and 24-month follow-up assessments. We applied published biomarker algorithms to these data to calculate two biological age measures, Klemera-Doubal Method Biological Age and homeostatic dysregulation. Intent-to-treat analysis using mixed-effects growth models of within-person change over time tested if caloric restriction slowed increase in measures of biological aging across follow-up. Analyses of both measures indicated caloric restriction slowed biological aging. Weight loss did not account for the observed effects. Results suggest future directions for testing of geroprotective therapies in humans. [ABSTRACT FROM AUTHOR]

Background: To prevent onset of age-related diseases and physical and cognitive decline, interventions to slow human aging and extend health span must eventually be applied to people while they are still young and healthy. Yet most human aging research examines older adults, many with chronic disease, and little is known about aging in healthy young humans.Method: This article explains how this knowledge gap is a barrier to extending health span and puts forward the case that geroscience should invest in researching the pace of aging in young adults. As one illustrative example, we describe an initial effort to study the pace of aging in a young-adult birth cohort by using repeated waves of biomarkers collected across the third and fourth decades to quantify the pace of coordinated physiological deterioration across multiple organ systems (eg, pulmonary, periodontal, cardiovascular, renal, hepatic, metabolic, and immune function).Results: Findings provided proof of principle that it is possible to quantify individual variation in the pace of aging in young adults still free of age-related diseases.Conclusions: This article articulates research needs to improve longitudinal measurement of the pace of aging in young people, to pinpoint factors that slow or speed the pace of aging, to compare pace of aging against genomic clocks, to explain slow-aging young adults, and to apply pace of aging in preventive clinical trials of antiaging therapies. This article puts forward a research agenda to fill the knowledge gap concerning lifelong causes of aging. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses articles in the issue on topics including impact of Vitamin-D on the health span; treatment of biological aging with vitamin D3 supplementation; and the human trials of therapies hypothesized to affect aging or aging-related processes.