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Background Dysfunction in blood vessel dynamics may contribute to changes in muscle measures. Therefore, we examined associations of vascular health measures with grip strength and gait speed in adults from the Framingham Heart Study. Methods The cross-sectional study (1998–2001) included participants with 1 measure of grip strength (kg, dynamometer) or gait speed (4-m walk, m/s) and at least 1 measure of aortic stiffness (carotid–femoral pulse wave velocity, brachial pulse pressure, and brachial flow pulsatility index) or brachial artery structure and function (resting flow velocity, resting brachial artery diameter, flow-mediated dilation %, hyperemic brachial blood flow velocity, and mean arterial pressure [MAP]) assessed by tonometry and brachial artery ultrasound. The longitudinal study included participants with ≥1 follow-up measurement of gait speed or grip strength. Multivariable linear regression estimated the association of 1 standard deviation (SD) higher level of each vascular measure with annualized percent change in grip strength and gait speed, adjusting for covariates. Results In cross-sectional analyses (n = 2 498, age 61 ± 10 years; 56% women), higher resting brachial artery diameter (β ± standard error [ SE ] per 1 SD : 0.59 ± 0.24, p =.01) and MAP (β ± SE : 0.39 ± 0.17, p =.02) were associated with higher grip strength. Higher brachial pulse pressure (β ± SE : −0.02 ± 0.01, p =.07) was marginally associated with slower gait speed. In longitudinal analyses (n = 2 157), higher brachial pulse pressure (β ± SE : −0.19 ± 0.07, p =.005), was associated with slowing of gait speed but not with grip strength. Conclusions Higher brachial artery pulse pressure (measure of aortic stiffness) was associated with loss of physical function over ~11 years, although we found no evidence that microvascular function contributed to the relation. [ABSTRACT FROM AUTHOR]

Background: Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow.Methods: Summary of workshop proceedings from the 2018-2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging.Results: Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals.Conclusions: Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span. [ABSTRACT FROM AUTHOR]

Background: Frailty is a risk factor for cardiovascular disease (CVD). Underlying mechanisms to explain the connection between frailty and CVD are unclear. We sought to examine the association between frailty and arterial stiffness, a precursor of hypertension and CVD.Methods: We conducted a cross-sectional analysis of community-dwelling Framingham Heart Study Offspring and Omni participants ≥60 years of age examined in 2005-2008. Frailty was defined primarily according to the Fried physical phenotype definition, which identifies nonfrail, prefrail, and frail individuals. Arterial stiffness was assessed using carotid-femoral pulse wave velocity (CFPWV). Generalized linear regression was used to examine the association between frailty level and CFPWV (modeled as -1000/CFPWV in msec/m, then transformed back to the original scale, m/s), adjusted for age, sex, cohort, mean arterial pressure, heart rate, height, and smoking.Results: Of 2,171 participants (55% women, 91% white), 45% were prefrail and 7% were frail. Mean ages were 67, 70, and 73 years, and adjusted CFPWV least squares means were 10.0 (95% CI, 9.9-10.1), 10.3 (10.2-10.5), and 10.5 m/s (10.1-11.0); p = .0002 for nonfrail, prefrail, and frail groups, respectively. Results were similar using the Rockwood cumulative deficit model of frailty, and in a sensitivity analysis adjusting for prevalent coronary heart disease and diabetes.Conclusions: Prefrailty and frailty were associated with higher arterial stiffness in a cohort of community-dwelling older adults. Arterial stiffness may help explain the relationship between frailty and CVD. [ABSTRACT FROM AUTHOR]

Background: Biologic age may better reflect an individual's rate of aging than chronologic age.Methods: We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at 1 second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (∆age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.0st Array.Results: Our discovery sample included 2,163 participants from the Framingham Offspring cohort (mean age 67 ± 9 years, 55% women). A total of 481 genes were significantly associated with ∆age (p < 2.8 × 10-6). Among them, 415 genes were validated (p < .05/481 = 1.0 × 10-4) in 2,946 participants from the Framingham Third Generation cohort (mean age 46 ± 9 years, 53% women). Many of the significant genes were involved in the ubiquitin-mediated proteolysis pathway. The replication in 414 Rotterdam Study participants (mean age 59 ± 8, 52% women) found 104 of 415 validated genes reached nominal significance (p < .05).Conclusion: We identified and validated 415 genes associated with ∆age in a community-based cohort. Future functional characterization of the biologic age-related gene network may identify targets to test for interventions to delay aging in older adults. [ABSTRACT FROM AUTHOR]

Background: We tested the association of biologic age (BA) measures constructed from different types of biomarkers with mortality and disease in a community-based sample.Methods: In Framingham Offspring participants at Exams 7 (1998-2001, mean age 62 ± 10) and 8 (2005-2008, mean age 67 ± 9), we used the Klemera-Doubal method to estimate clinical BA and inflammatory BA and computed the difference (∆age) between BA and CA. Clinical ∆age was computed at Exam 2 (1979-1983, mean age 45 ± 10). At Exam 8, we computed measures of intrinsic and extrinsic epigenetic age. Participants were followed through 2014 for outcomes. Cox proportional hazards models tested the association of each BA estimate with each outcome adjusting for covariates.Results: Sample sizes ranged from 2532 to 3417 participants. In multivariable models, each 1-year increase in clinical ∆age at Exam 2 (hazard ratio [HR] = 1.04-1.06, p < 2 × 10-16) and clinical ∆age and inflammatory ∆age at Exam 7 significantly increased the hazards of mortality and incident cardiovascular disease (HR = 1.01-1.05, p < 2 × 10-7), whereas inflammatory ∆age increased the hazards of cancer (HR = 1.01, p < .05). At Exam 8, increased clinical ∆age, inflammatory ∆age, and extrinsic epigenetic age all significantly increased the hazard of mortality (HR = 1.03-1.05, all p < .05); clinical ∆age and inflammatory ∆age increased cardiovascular disease risk (HR = 1.04-1.05, all p < .01); and clinical ∆age increased cancer risk (HR = 1.03, p < .01) when all three BA measures were included in the model. Intrinsic epigenetic age was not significantly associated with any outcome.Conclusions: Our findings suggest BA measures may be complementary in predicting risk for mortality and age-related disease. [ABSTRACT FROM AUTHOR]

Background: Having longer lived parents has been shown to be an important predictor of health trajectories and life span. As such, parental life span is an important phenotype that may uncover genes that affect longevity.Methods: A genome-wide association study of parental life span in participants of European and African ancestry from the Health and Retirement Study was conducted.Results: A genome-wide significant association was observed for rs35715456 (log10BF = 6.3) on chromosome 18 for the dichotomous trait of having at least one long-lived parent versus not having any long-lived parent. This association was not replicated in an independent sample from the InCHIANTI and Framingham Heart Study. The most significant association among single nucleotide polymorphisms in longevity candidate genes (APOE, MINIPP1, FOXO3, EBF1, CAMKIV, and OTOL1) was observed in the EBF1 gene region (rs17056207, p = .0002).Conclusions: A promising genetic signal for parental life span was identified but was not replicated in independent samples. [ABSTRACT FROM AUTHOR]

Background: Self-rated health is a commonly used global indicator of health status. Few studies have examined the association of self-rated health and mobility with estrone and estradiol in men. Accordingly, we determined the cross-sectional, incident, and mediating relations between circulating estrone and estradiol levels with self-rated health, mobility limitation, and physical performance in community-dwelling men.Methods: The cross-sectional sample included 1,148 men, who attended Framingham Offspring Study Examinations 7 and 8. Estrone and estradiol levels were measured using liquid chromatography tandem mass spectrometry at Examination 7. Self-reported mobility limitation and self-rated health were assessed at Examinations 7 and 8. Additionally, short physical performance battery, usual walking speed, and grip strength were assessed at Examination 7.Results: In incident analysis, estradiol levels at Examination 7 were associated with increased odds of fair or poor self-rated health at Examination 8, after adjusting for age, body mass index, comorbidities, and testosterone levels; in an individual with 50% greater estradiol than other, the odds of reporting "fair or poor" self-rated health increased by 1.78 (95% confidence interval: 1.25-2.55; p = .001). Neither estrone nor estradiol levels were associated with any physical performance measure at baseline.Conclusions: Higher circulating levels of estradiol are associated with increased risk of incident fair/poor self-rated health in community-dwelling men. The mechanisms by which circulating levels of estradiol are related to self-rated health in men need further investigation. [ABSTRACT FROM AUTHOR]

Objective: The study objective was to describe self-reported advance care planning, health care preferences, use of advance directives, and health perceptions in a very elderly community-dwelling sample.Methods: We interviewed surviving participants of the original cohort of the Framingham Heart Study who were cognitively intact and attended a routine research examination between February 2004 and October 2005. Participants were queried about discussions about end-of-life care, preferences for care, documentation of advance directives, and health perceptions.Results: Among 220 community-dwelling respondents, 67% were women with a mean age of 88 years (range 84-100 years). Overall, 69% discussed their wishes for medical care at the end of life with someone, but only 17% discussed their wishes with a physician or health care provider. Two thirds had a health care proxy, 55% had a living will, and 41% had both. Most (80%) respondents preferred comfort care over life-extending care, and 71% preferred to die at home; however, substantially fewer respondents said they would rather die than receive specific life-prolonging interventions (chronic ventilator [63%] or feeding tube [64%]). Many were willing to endure distressing health states, with fewer than half indicating that they would rather die than live out their life in a great deal of pain (46%) or be confused and/or forgetful (45%) all of the time.Conclusions: Although the vast majority of very elderly community-dwellers in this sample appear to prefer comfort measures at the end of life, many said they were willing to endure specific life-prolonging interventions and distressing health states to avoid death. Our results highlight the need for physicians to better understand patients' preferences and goals of care to help them make informed decisions at the end of life. [ABSTRACT FROM AUTHOR]

Background: The healthy aging index (HAI) was developed as a marker of health in multiple systems that can identify individuals who age most successfully.Methods: We calculated an HAI in 934 Framingham Offspring Study participants aged 60 or older at baseline. Heart rate and C-reactive protein (CRP) were added in modified versions of the HAI. Cox proportional hazard models were used to quantify the association of the HAI with mortality, cardiovascular disease (CVD), and cancer. We used fully conditional specification to multiply impute missing values for HAI components, increasing the sample size by 44%.Results: Over 10 years of follow-up, there were 138 deaths, 103 incident cases of CVD, and 138 incident cases of cancer. In models adjusted for age, sex, and behavioral risk factors, the HAI was associated with mortality (hazard ratio [HR] per unit of HAI 1.24, 95% confidence interval [CI] 1.13-1.36) and with CVD (HR 1.27, 95% CI 1.13-1.42), but not with cancer (HR 1.01, 95% CI 0.91-1.11) in observed (non-missing) data. In multivariable models further adjusting for prevalent diseases, results were slightly attenuated. When including heart rate and CRP, a modified HAI gave stronger associations. Results with imputed data are similar to results from complete case analyses.Conclusions: In our large community-based sample, the HAI is a strong predictor of mortality and CVD. Other factors that are strongly associated with mortality, such as heart rate and CRP can improve the ability of the HAI to identify the healthiest older adults. [ABSTRACT FROM AUTHOR]

At the 67th Gerontological Society of America Annual Meeting, a preconference workshop was convened to discuss the challenges of accurately assessing physical activity in older populations. The advent of wearable technology (eg, accelerometers) to monitor physical activity has created unprecedented opportunities to observe, quantify, and define physical activity in the real-world setting. These devices enable researchers to better understand the associations of physical activity with aging, and subsequent health outcomes. However, a consensus on proper methodological use of these devices in older populations has not been established. To date, much of the validation research regarding device type, placement, and data interpretation has been performed in younger, healthier populations, and translation of these methods to older populations remains problematic. A better understanding of these devices, their measurement properties, and the data generated is imperative to furthering our understanding of daily physical activity, its effects on the aging process, and vice versa. The purpose of this article is to provide an overview of the highlights of the preconference workshop, including properties of the different types of accelerometers, the methodological challenges of employing accelerometers in older study populations, a brief summary of ongoing aging-related research projects that utilize different types of accelerometers, and recommendations for future research directions. [ABSTRACT FROM AUTHOR]

Background: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.Methods: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.Results: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.Conclusions: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity. [ABSTRACT FROM AUTHOR]

Background. As creatinine-based estimates of renal function are inaccurate in older adults, an alternative is an estimated glomerular filtration rate (eGFRcys) based on cystatin C. We examined the prospective association between chronic kidney disease (CKDcys) as determined by eGFRcys with the primary outcome of incident mobility disability and the secondary outcome of change in gait speed. Methods. Framingham Offspring Study participants older than 60 years and free of mobility disability at baseline (1998–2001) were eligible. Baseline CKDcys was defined as eGFRcys less than 60 mL/min/1.73 m2. At follow-up (2005–2008), the outcomes of mobility disability, defined as self-reported inability to walk 1/2 mile and/or climb a flight of stairs, and gait speed were measured. Logistic and linear regression models were adjusted for age, sex, body mass index, smoking, diabetes, C reactive protein, and physical activity. Results. Of 1,226 participants, 230 (19%) had CKDcys at baseline. After a mean follow-up of 6.6 years, 185 (15%) developed mobility disability. Of those with CKDcys, 60 (26%) developed mobility disability. Those with CKDcys had greater odds of mobility disability in the age- and sex-adjusted (odds ratio [OR] 1.91, 95% CI 1.32, 2.75) and fully adjusted (OR 1.55, 95% CI 1.05, 2.31) models compared with those without CKDcys. In fully adjusted models, participants with CKDcys had greater gait speed declines than those without CKDcys (β = 0.07 [SE 0.02], p = .0022). Conclusion. CKDcys was associated with higher odds of incident mobility disability and greater decline in gait speed, highlighting the loss of physical independence in elders with CKD. [ABSTRACT FROM PUBLISHER]

Background. Age trends in estradiol and estrone levels in men and how lifestyle factors, comorbid conditions, testosterone, and sex hormone–binding globulin affect these age trends remain poorly understood, and were examined in men of the Framingham Heart Study. Methods. Estrone and estradiol concentrations were measured in morning fasting samples using liquid chromatography tandem mass spectrometry in men of Framingham Offspring Generation. Free estradiol was calculated using a law of mass action equation. Results. There were 1,461 eligible men (mean age [±SD] 61.1±9.5 years and body mass index [BMI] 28.8±4.5kg/m2). Total estradiol and estrone were positively associated with age, but free estradiol was negatively associated with age. Age-related increase in total estrone was greater than that in total estradiol. Estrone was positively associated with smoking, BMI, and testosterone, and total and free estradiol with diabetes, BMI, testosterone, and comorbid conditions; additionally, free estradiol was associated negatively with smoking. Collectively, age, BMI, testosterone, and other health and behavioral factors explained only 18% of variance in estradiol, and 9% of variance in estrone levels. Men in the highest quintile of estrone levels had significantly higher age and BMI, and a higher prevalence of smoking, diabetes, and cardiovascular disease than others, whereas those in the highest quintile of estradiol had higher BMI than others. Conclusions. Total estrone and estradiol levels in men, measured using liquid chromatography tandem mass spectrometry, revealed significant age-related increases that were only partially accounted for by cross-sectional differences in BMI, diabetes status, and other comorbidities and health behaviors. Longitudinal studies are needed to confirm these findings. [ABSTRACT FROM PUBLISHER]

Background. Sarcopenia defined by lean mass has been inconsistently associated with disability in elders. Studies suggest that definitions should consider body size and additional influences of high fat mass (FM; sarcopenic-obesity). We examined sarcopenia accounting for body size, and sarcopenic-obesity, in relation to mobility limitations among 767 elderly men and women (mean age 79 years) from the Framingham Study. Methods. Whole-body dual-energy x-ray absorptiometry measured appendicular lean mass (ALM) and total FM in 1992–1995. Sarcopenia was defined in two ways: ALM/height squared (ALM/ht2) and ALM adjusted for height and FM (residuals). Sarcopenic-obesity categories (referent, obese, sarcopenic, and sarcopenic-obese) were defined by cross-classifying ALM/ht2 and obesity (% body fat: more than 30 for men and more than 40 for women). Mobility limitation was defined as self-reported inability to walk one-half mile, climb stairs, or perform heavy housework. Sex-specific logistic regression calculated odds ratios (OR) and 95% confidence intervals (CI) for mobility limitation, adjusting for covariates. Results. Sixteen percent of men and 30% of women had mobility limitation. Among men, both ALM/ht2 (OR = 6.3, 95% CI = 2.5–16.1) and residuals (OR = 4.6, 95% CI = 2.0–10.5) sarcopenia were associated with increased limitation. For sarcopenic-obesity, odds of limitation was higher in sarcopenic (OR = 6.1, 95% CI = 2.2–16.9) and sarcopenic-obese categories (OR = 3.5, 95% CI = 1.0–12.7) but suggested no synergistic effect. In women, only residuals sarcopenia was associated with higher odds of limitation (OR = 1.8, 95% CI = 1.2–2.9). Conclusions. Low lean mass is associated with mobility limitations after accounting for body size and fat, and lean and FM have independent effects on mobility in elders. These findings support previous reports that sarcopenia definitions should consider body size and fat. [ABSTRACT FROM PUBLISHER]

Genetic factors clearly contribute to exceptional longevity and healthy aging in humans, yet the identification of the underlying genes remains a challenge. Longevity is a complex phenotype with modest heritability. Age-related phenotypes with higher heritability may have greater success in gene discovery. Candidate gene and genome-wide association studies (GWAS) for longevity have had only limited success to date. The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium conducted a meta-analysis of GWAS data for longevity, defined as survival to age 90 years or older, that identified several interesting associations but none achieved genome-wide significance. A recent GWAS of longevity conducted in the Leiden Longevity Study identified the ApoE E4 isoform as deleterious to longevity that was confirmed in an independent GWAS of long-lived individuals of German descent. Notably, no other genetic loci for longevity have been identified in these GWAS. To examine the conserved genetic mechanisms between the mouse and humans for life span, we mapped the top Cohorts for Heart and Aging Research in Genomic Epidemiology GWAS associations for longevity to the mouse chromosomal map and noted that eight of the ten top human associations were located within a previously reported mouse life-span quantitative trait loci. This work suggests that the mouse and human may share mechanisms leading to aging and that the mouse model may help speed the understanding of how genes identified in humans affect the biology of aging. We expect these ongoing collaborations and the translational work with basic scientists to accelerate the identification of genes that delay aging and promote a healthy life span. [ABSTRACT FROM PUBLISHER]