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Background The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity. Methods The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age = 76.4, 56.5% women, and 85.9% non-Hispanic White) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95% CI]) for the likelihood of greater multimorbidity (4 levels: 0 conditions, N  = 332; 1 condition, N  = 299; 2 conditions, N  = 98; or 3+ conditions, N  = 35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions. Results Lower oxidative phosphorylation supported by fatty acids and/or complex I- and II-linked carbohydrates (eg, Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (POR = 1.32 [1.13, 1.54]) and separately with diabetes mellitus (OR = 1.62 [1.26, 2.09]), depressive symptoms (OR = 1.45 [1.04, 2.00]) and possibly chronic kidney disease (OR = 1.57 [0.98, 2.52]) but not significantly with other conditions (eg, cardiac arrhythmia, chronic obstructive pulmonary disease). Conclusions Lower muscle mitochondrial bioenergetic capacities were associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and are more strongly related to some conditions than others. [ABSTRACT FROM AUTHOR]

Background How magnetic resonance (MR) derived thigh muscle volume and deuterated creatine dilution derived muscle mass (D3Cr muscle mass) differentially relate to strength, fitness, and other functions in older adults—and whether associations vary by sex—is not known. Methods Men (N  = 345) and women (N  = 482) aged ≥70 years from the Study of Muscle, Mobility, and Aging completed leg extension strength (1-repetition max) and cardiopulmonary exercise testing to assess fitness (VO2peak). Correlations and adjusted regression models stratified by sex were used to assess the association between muscle size measures, study outcomes, and sex interactions. Results D3Cr muscle mass and MR thigh muscle volume were correlated (men: r  = 0.62, women: r  = 0.51, p  < .001). Each standard deviation (SD) decrement in D3Cr muscle mass was associated with lower 1-repetition max strength (−14 kg men, −4 kg women, p  < .001 for both; p -interaction = .003) and lower VO2peak (−79 mL/min men, −30 mL/min women, p  < .001 for both, p -interaction:.016). Each SD decrement in MR thigh muscle volume was also associated with lower strength (−32 kg men, −20 kg women, p  < .001 for both; p -interaction = .139) and lower VO2peak (−217 mL/min men, −111 mL/min women, p  < .001 for both, p -interaction = .010). There were associations, though less consistent, between muscle size or mass with physical performance and function; associations varied by sex. Conclusions Less muscle—measured by either D3Cr muscle mass or MR thigh muscle volume—was associated with lower strength and fitness. Varied associations by sex and assessment method suggest consideration be given to which measurement to use in future studies. [ABSTRACT FROM AUTHOR]

Background The effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community-dwelling older adults both overall, and in relation, to sociodemographic characteristics. Methods We examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (N  = 820, age = 76.4 years, 58.2% women) participating in the Study of Muscle, Mobility, and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance. Results Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR versus men (all p  < .05). Total activity (56%) and time of activity (20%) accounted for most of the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (p  < .001). Compared to the latest decile of acrophase, those in the earliest and midrange categories had more total activity (p  = .02). Being in a married-like relationship and a more stable financial situation were associated with stronger rhythms; higher education was associated with less rhythm strength (all p  < .05). Conclusions Older age was associated with dampened circadian behavior; behaviors were sexually dimorphic. Some sociodemographic characteristics were associated with circadian behavior. We identified a behavioral phenotype characterized by early time of day of peak activity, high rhythmic amplitude, and more total activity. [ABSTRACT FROM AUTHOR]

Background Gut dysbiosis has been linked to frailty, but its association with early mobility decline is unclear. Methods First, we determined the cross-sectional associations between walking speed and the gut microbiome in 740 older men (84 ± 4 years) from the MrOS cohort with available stool samples and 400 m walking speed measured in 2014–2016. Then, we analyzed the retrospective longitudinal associations between changes in 6 m walking speed (from 2005–2006 to 2014–2016, calculated by simple linear equation) and gut microbiome composition among participants with available data (702/740). We determined gut microbiome composition by 16S sequencing and examined diversity, taxa abundance, and performed network analysis to identify differences in the gut microbiome network of fast versus slow walkers. Results Faster 400 m walking speed (m/s) was associated with greater microbiome α-diversity (R  = 0.11; p  = .004). The association between a slower decline in 6 m walking speed and higher α-diversity (R  = 0.07; p  = .054) approached borderline significance. Faster walking speed and less decline in walking speed were associated with a higher abundance of genus-level bacteria that produce short-chain fatty acids, and possess anti-inflammatory properties, including Paraprevotella , Fusicatenibacter , and Alistipes , after adjusting for potential covariates (p  < .05). The gut microbiome networks of participants in the first versus last quartile of walking speed (≤0.9 vs ≥1.2 m/s) exhibited distinct characteristics, including different centrality measures (p  < .05). Conclusions Our findings suggest a possible relationship between gut microbiome diversity and mobility function, as indicated by the associations between faster walking speed and less decline in walking speed over 10 years with higher gut microbiome diversity in older men. [ABSTRACT FROM AUTHOR]

Background Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. Methods In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70–94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy for the maximal rate of adenosine triphosphate recovery (ATPmax) after an acute bout of exercise, and ex vivo by High-Resolution Respirometry for the maximal rate of complex I and II supported oxygen consumption (MaxOXPHOS) in permeabilized muscle fibers from the vastus lateralis. Results At least 1 fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400-m walk gait speed (1.0 ± 0.2 vs 1.1 ± 0.2, p <.001), reported fewer alcoholic drinks per week in the past year (2.4 ± 4.3 vs 2.8 ± 4.4, p =.054), and took a significantly greater number of medication in the 30 days before their baseline visit (5.6 ± 4.4 vs 4.2 ± 3.4, p <.05). A history of falls was reported in 63% of individuals who experienced recurrent falls in the first year of the study compared to 22.8% who experienced 1 or fewer falls. MaxOXPHOS was significantly lower in those who reported recurrent falls (p =.008) compared to those with 1 or fewer falls, but there was no significant difference in ATPmax (p =.369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (risk ratio = 1.33, 95% confidence interval = 1.02–1.73, p =.033). However, covariates accounted for the increased risk. Conclusions Mitochondrial energetics were largely unrelated to fall risk in older adults when accounting for variables, suggesting that the complex etiology of falls may not be related to a single "hallmark of aging" biological pathway. [ABSTRACT FROM AUTHOR]

The age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70–94 years). A Short Physical Performance Battery (SPPB) score ≤8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (eg, Maximal Complex I&II OXPHOS: Women = 55.06 ± 15.95; Men = 65.80 ± 19.74; p  < .001) and in individuals with mobility impairment compared to those without (eg, Maximal Complex I&II OXPHOS in women: SPPB ≥ 9 = 56.59 ± 16.22; SPPB ≤ 8 = 47.37 ± 11.85; p  < .001). Muscle energetics were negatively associated with age only in men (eg, Maximal ETS capacity: R  = −0.15, p  = .02; age/sex interaction, p  = .04), resulting in muscle energetics measures that were significantly lower in women than men in the 70–79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70–79 age group (70–79 age group, odds ratio [OR]age-adjusted = 1.78, 95% confidence interval [CI] = 1.03, 3.08, p  = .038; 80+ age group, ORage-adjusted = 1.05, 95% CI = 0.52, 2.15, p  = .89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment. [ABSTRACT FROM AUTHOR]

Background A goal of gerontology is to discover phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that are strongly associated with mortality could be used to define such a phenotype. However, the relation of such an index with multiple chronic conditions warrants further exploration. Methods A biomarker index (BI) was constructed in the Cardiovascular Health Study (N  = 3 197), with a mean age of 74 years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, interleukin-6, amino-terminal pro-B-type natriuretic peptide, cystatin-C, C-reactive protein, tumor necrosis factor-alpha soluble receptor 1, fasting insulin, and fasting glucose, and was built based on their relationships with mortality. Cox proportional hazards models predicting a composite of death and chronic disease involving cardiovascular disease, dementia, and cancer were calculated with 6 years of follow-up. Results The hazard ratio (HR, 95% CI) for the composite outcome of death or chronic disease per category of BI was 1.65 (1.52, 1.80) and 1.75 (1.58, 1.94) in women and men, respectively. The HR (95% CI) per 5 years of age was 1.57 (1.48, 1.67) and 1.55 (1.44, 1.67) in women and men, respectively. Moreover, BI could attenuate the effect of age on the composite outcome by 16.7% and 22.0% in women and men, respectively. Conclusions Biomarker index was significantly and independently associated with a composite outcome of death and chronic disease, and attenuated the effect of age. The BI that is composed of plasma biomarkers may be a practical intermediate phenotype for interventions aiming to modify the course of aging. [ABSTRACT FROM AUTHOR]

Background Frailty can occur in older adults without disability or multimorbidity. Current methods focus on the most frail, but poorly discriminate among those "not frail." Methods The Study of Muscle, Mobility, and Aging (SOMMA) included 879 adults aged 70 years and older without mobility disability. We operationalized frailty domains using: peak oxygen consumption (endurance), digit symbol substitution test (speed), leg power (strength), perceived fatigability, D3 creatine dilution (sarcopenia), and accelerometry (sedentary behavior) to construct a frailty score of 0–12 summing tertiles (0–2) of each component. We used linear or logistic regression with and without adjustment for confounders to examine associations with age, reported, and performance function. Results The SOMMA frailty score distribution was broad and strongly associated with age (r  = 0.33, p  < .0001). Each point was associated with a 30%–50% higher odds of having reported difficulty with activities of daily living or mobility. After grouping the total score (0–3, 4–7, and 8–12) those in the highest group were 9–31 times more likely to have functional limitation, and at least 8 times more likely to have poorer function after full adjustment. Higher scores identified those less likely to report ease of walking or higher physical activity. Peak oxygen consumption, leg power, fatigability, and digit symbol score contributed most to these associations. Conclusions The SOMMA frailty score characterizes frailty as a continuum from frail to vigorous with assessments that are amenable to change. Associations with age and function suggest utility for distinguishing a wide range of vigor and vulnerability in relatively well-functioning older adults. [ABSTRACT FROM AUTHOR]

Background Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8. Methods We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography–tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and FSTL-3 by immunoassay, in 2 longitudinal cohorts of older adults. Results In 2 599 participants (age 75.2 ± 4.3) followed for 10.8 ± 5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks, and lower kidney function. Conclusions Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-β superfamily pathways as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background The Pittsburgh Performance Fatigability Index (PPFI) quantifies the percent decline in cadence using accelerometry during standardized walking tasks. Although PPFI has shown strong correlations with physical performance, the developmental sample was relatively homogenous and small, necessitating further validation. Methods Participants from the Study of Muscle, Mobility and Aging (N  = 805, age = 76.4 ± 5.0 years, 58% women, 85% White) wore an ActiGraph GT9X on the nondominant wrist during usual-paced 400 m walk. Tri-axial accelerations were analyzed to compute PPFI (higher score = greater fatigability). To evaluate construct and discriminant validity, Spearman correlations (r s) between PPFI and gait speed, Short Physical Performance Battery (SPPB), chair stand speed, leg peak power, VO2peak, perceived fatigability, and mood were examined. Sex-specific PPFI cut-points that optimally discriminated gait speed using classification and regression tree were then generated. Their discriminate power in relation to aforementioned physical performance were further evaluated. Results Median PPFI score was 1.4% (25th–75th percentile range: 0%–21.7%), higher among women than men (p  < .001). PPFI score was moderate-to-strongly correlated with gait speed (r s = −0.75), SPPB score (r s = −0.38), chair stand speed (r s = −0.36), leg peak power (r s = −0.34) and VO2peak (r s = −0.40), and less strongly with perceived fatigability (r s = 0.28–0.29), all p  < .001. PPFI score was not correlated with mood (| r s| < 0.08). Sex-specific PPFI cut-points (no performance fatigability: PPFI = 0%; mild performance fatigability: 0% < PPFI < 3.5% [women], 0% < PPFI < 5.4% [men]; moderate-to-severe performance fatigability: PPFI ≥ 3.5% [women], PPFI ≥ 5.4% [men]) discriminated physical performance (all p  < .001), adjusted for demographics and smoking status. Conclusion Our work underscores the utility of PPFI as a valid measure to quantify performance fatigability in future longitudinal epidemiologic studies and clinical/pharmaceutical trials. [ABSTRACT FROM AUTHOR]

Background The Health, Aging, and Body Composition Study is a longitudinal cohort study that started just over 25 years ago. This ground-breaking study tested specific hypotheses about the importance of weight, body composition, and weight-related health conditions for incident functional limitation in older adults. Methods Narrative review with analysis of ancillary studies, career awards, publications, and citations. Results Key findings of the study demonstrated the importance of body composition as a whole, both fat and lean mass, in the disablement pathway. The quality of the muscle in terms of its strength and its composition was found to be a critical feature in defining sarcopenia. Dietary patterns and especially protein intake, social factors, and cognition were found to be critical elements for functional limitation and disability. The study is highly cited and its assessments have been widely adopted in both observational studies and clinical trials. Its impact continues as a platform for collaboration and career development. Conclusions The Health ABC provides a knowledge base for the prevention of disability and promotion of mobility in older adults. [ABSTRACT FROM AUTHOR]

Background The Study of Muscle, Mobility and Aging (SOMMA) aims to understand the biological basis of many facets of human aging, with a focus on mobility decline, by creating a unique platform of data, tissues, and images. Methods The multidisciplinary SOMMA team includes 2 clinical centers (University of Pittsburgh and Wake Forest University), a biorepository (Translational Research Institute at Advent Health), and the San Francisco Coordinating Center (California Pacific Medical Center Research Institute). Enrollees were age ≥70 years, able to walk ≥0.6 m/s (4 m); able to complete 400 m walk, free of life-threatening disease, and had no contraindications to magnetic resonance or tissue collection. Participants are followed with 6-month phone contacts and annual in-person exams. At baseline, SOMMA collected biospecimens (muscle and adipose tissue, blood, urine, fecal samples); a variety of questionnaires; physical and cognitive assessments; whole-body imaging (magnetic resonance and computed tomography); accelerometry; and cardiopulmonary exercise testing. Primary outcomes include change in walking speed, change in fitness, and objective mobility disability (able to walk 400 m in 15 minutes and change in 400 m speed). Incident events, including hospitalizations, cancer diagnoses, fractures, and mortality are collected and centrally adjudicated by study physicians. Results SOMMA exceeded its goals by enrolling 879 participants, despite being slowed by the COVID-19 pandemic: 59.2% women; mean age 76.3 ± 5.0 years (range 70–94); mean walking speed 1.04 ± 0.20 m/s; 15.8% identify as other than Non-Hispanic White. Over 97% had data for key measurements. Conclusions SOMMA will provide the foundation for discoveries in the biology of human aging and mobility. [ABSTRACT FROM AUTHOR]

Background Studies using heterochronic parabiosis discovered that circulating factors mediate brain aging in animal models. Methods We assessed growth differentiation factors (GDF)-11 and GDF-8 using mass spectrometry and inhibitors follistatin and follistatin-like protein-3 (FSTL-3) with ELISA in the Cardiovascular Health Study (CHS; N = 1 506) and the Health, Aging and Body Composition (Health ABC) Study (N = 1 237). CLL-11 and beta-2 microglobulin (β2M) were measured with ELISA in a subset of 400 individuals in Health ABC. Associations were assessed with cognitive function, brain magnetic resonance imaging (MRI) findings (CHS only), and incident dementia using correlations, linear regression, and Cox proportional hazards models. Results In CHS, levels of GDF-11, GDF-8, and follistatin were not correlated cross-sectionally with the 3MSE or DSST, brain MRI findings of white matter hyperintensity, atrophy, or small infarcts, nor were they associated with incident dementia. FSTL-3 was modestly correlated with poorer cognitive function, greater white matter hyperintensities, and atrophy on MRI, as well as with incident dementia with an adjusted hazard ratio (HR) of 1.72 (95% CI = 1.13, 2.61) per doubling of FSTL-3. FSTL-3 was not associated with cognition or dementia in Health ABC, but GDF-8 was associated with both. The adjusted HR for incident dementia was 1.50 (95% CI = 1.07, 2.10) per doubling of GDF-8. Conclusions Total GDF-11 level was not related to cognition or dementia in older adults. Associations of GDF-8 with cognitive outcomes in Health ABC were not expected, but consistent with animal models. Associations of FSTL-3 with cognition, brain abnormalities, and incident dementia in CHS implicate TGFβ superfamily inhibition in the pathogenesis of dementia. [ABSTRACT FROM AUTHOR]

Background Myostatin, a cytokine produced by skeletal muscle, may influence Alzheimer's disease (AD) pathogenesis, but sparse evidence exists in humans. We assessed the association between circulating levels of myostatin at Year 1 and plasma levels of β-amyloid 42/40 at Year 2, a marker of AD pathology, in a biracial cohort of older adults. Methods We studied 403 community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from Memphis, Tennessee, and Pittsburgh, PA. Mean age was 73.8 ± 3 years; 54% were female; and 52% were Black. Serum myostatin levels were measured at Year 1, plasma β-amyloid 42/40 levels in Year 2 (higher ratio indicating lower amyloid load). Multivariable linear regression analyses tested the association of serum myostatin with plasma levels of β-amyloid 42/40 adjusted for computed-tomography-derived thigh muscle cross-sectional area, demographics, APOe4 allele, and risk factors for dementia. We tested for 2-way.interactions between myostatin and race or sex; results were stratified by race and sex. Results In multivariable models, myostatin was positively associated with plasma levels of β-amyloid 42/40 (standardized regression coefficient: 0.145, p =.004). Results were significant for white men and women (0.279, p =.009, and 0.221, p =.035, respectively) but not for Black men or women; interactions by race and gender were not statistically significant. Conclusions Higher serum myostatin was associated with lower amyloid burden, independently of APOe4 alleles, muscle area and other established risk factors for dementia. The role of myostatin in AD pathogenesis and the influence of race should be further investigated. [ABSTRACT FROM AUTHOR]

Background Based on studies from animal models, growth differentiation factor-11 (GDF-11) may have rejuvenating effects in humans. GDF-11 has high sequence homology with GDF-8 (also known as myostatin); follistatin and follistatin-like protein-3 (FSTL-3) are inhibitory proteins of both GDF-8 and GDF-11. Methods Using highly specific liquid chromatography with tandem mass spectrometry assays for GDF-11 and GDF-8 and immunoassays for follistatin and FSTL-3, we quantified the association of these factors with muscle size, strength, and physical performance in 2 prospective cohort studies of community-dwelling older adults (Health, Aging, and Body Composition study [Health ABC] and Cardiovascular Health Study [CHS]). Results GDF-8 levels were positively associated with thigh muscle cross-sectional area and density in Health ABC (data not available in CHS). GDF-8 levels were positively associated with lean mass (a surrogate of muscle mass) in Health ABC but not CHS, and grip strength in CHS but not Health ABC. FSTL-3 (and perhaps follistatin) was negatively associated with lean mass and had variable associations with other variables. In contrast, GDF-11 was not significantly associated with strength or performance. Conclusions GDF-8 and its binding proteins, follistatin and FSTL-3, may constitute a counterregulatory system (chalones) to restrain age-related loss of muscle mass and strength. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness is largely understudied.Methods: In the Study of Muscle, Mobility, and Aging (SOMMA), we collected vastus lateralis biopsies from older adults (n=879,70-94 years,59.2% women). Maximal state 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2 peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta-coefficients expressed per 1 SD increment in the independent variable.Results: Max OXPHOS was associated with leg power for both women (β=0.12Watts/kg,p<0.001) and men (β=0.11Watts/kg,p<0.050). ATPmax was associated with leg power for men (β=0.09Watts/kg p<0.05) but was not significant for women (β=0.03Watts/kg,p=0.11). Max OXPHOS and ATPmax were associated with VO2 peak in women and men (Max OXPHOS, βwomen=1.03mL/kg/min, βmen=1.32 mL/kg/min; ATPmax βwomen=0.87mL/kg/min, βmen=1.50mL/kg/min;all p<0.001).Conclusions: Higher muscle mitochondrial energetics measures were associated with both better cardiorespiratory fitness and greater leg power in older adults. Muscle mitochondrial energetics explained a greater degree of variance in VO2 peak compared to leg power. [ABSTRACT FROM AUTHOR]

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 We sought to determine the associations between individual nonesterified fatty acids (NEFAs) and disability and mobility limitation. Methods We studied 1 734 participants in the Cardiovascular Health Study (CHS), an ongoing population-based cohort study of community-living older American adults. We measured 35 individual NEFA species in fasting serum samples obtained at the 1996–1997 clinic visit. Using yearly assessments of activities of daily living and self-reported mobility, we identified participants with incident disability or mobility limitation during 15 years of follow-up. Cox proportional hazards regression models were used to determine the associations between per SD increment in the individual NEFAs and incident disability and mobility limitations with adjustment for potential confounding factors. Results Higher concentrations of total and a broad range of individual NEFA species were associated with risk of disability and mobility limitation (disability: HR per SD of total NEFA [ SD  = 174.70] = 1.11, 95% CI = 1.04–1.18, p  = .001; mobility limitation: HR per SD of total NEFA = 1.09, 95% CI = 1.02–1.16, p  = .01). Among individual saturated NEFAs (SFAs), myristic (14:0) and palmitic (16:0) acids were significantly associated with higher risk of both disability and mobility limitations, but longer-chain FAs were not. Most individual monounsaturated (MUFA), n-6 polyunsaturated fatty acids (PUFAs), and trans FAs were positively significantly associated with higher risks of both disability and mobility limitation. In contrast, most n-3 PUFA species were not associated with disability or mobility limitation. Conclusions Higher risks of disability and mobility limitation were observed for proinflammatory intermediate-chain SFAs, MUFAs, n-6 PUFAs, and trans FAs. Our findings indicated no significant association for anti-inflammatory n-3 PUFAs. [ABSTRACT FROM AUTHOR]

Functional impairment and disability become increasingly common with aging. As more people are reaching old age, the number of people needing care will rise, creating a crisis of need for care. Population studies and clinical trials have demonstrated the importance of the detection of early loss of strength and walking speed in predicting disability and in designing interventions to prevent functional decline. There is a large societal burden linked to age-related disorders. Physical activity is to date the only intervention that has prevented disability in a long-term clinical trial, but is difficult to sustain. Novel interventions are needed to maintain function in late life. [ABSTRACT FROM AUTHOR]

Background Several candidate molecules that may have application in treating physical limitations associated with aging and chronic diseases are in development. Challenges in the framing of indications, eligibility criteria, and endpoints and the lack of regulatory guidance have hindered the development of function-promoting therapies. Methods Experts from academia, pharmaceutical industry, National Institutes of Health (NIH), and Food and Drug Administration (FDA) discussed optimization of trial design including the framing of indications, eligibility criteria, and endpoints. Results Mobility disability associated with aging and chronic diseases is an attractive indication because it is recognized by geriatricians as a common condition associated with adverse outcomes, and it can be ascertained reliably. Other conditions associated with functional limitation in older adults include hospitalization for acute illnesses, cancer cachexia, and fall injuries. Efforts are underway to harmonize definitions of sarcopenia and frailty. Eligibility criteria should reconcile the goals of selecting participants with the condition and ensuring generalizability and ease of recruitment. An accurate measure of muscle mass (eg, D3 creatine dilution) could be a good biomarker in early-phase trials. Performance-based and patient-reported measures of physical function are needed to demonstrate whether treatment improves how a person lives, functions, or feels. Multicomponent functional training that integrates training in balance, stability, strength, and functional tasks with cognitive and behavioral strategies may be needed to translate drug-induced muscle mass gains into functional improvements. Conclusions Collaborations among academic investigators, NIH, FDA, pharmaceutical industry, patients, and professional societies are needed to conduct well-designed trials of function-promoting pharmacological agents with and without multicomponent functional training. [ABSTRACT FROM AUTHOR]

Background: Few studies have examined the association of neighborhood environment and mortality among community-dwelling older populations. Geographic Information Systems-based measures of neighborhood physical environment may provide new insights on the health effects of the social and built environment.Method: We studied 4 379 community-dwelling older adults in the United States aged 65 years and older from the Cardiovascular Health Study. Principal component analysis was used to identify neighborhood components from 48 variables assessing facilities and establishments, demographic composition, socioeconomic status, and economic prosperity. We used a Cox model to evaluate the association of neighborhood components with 5-year mortality. Age, sex, race, education, income, marital status, body mass index, smoking status, disability, coronary heart disease, and diabetes were included as covariates. We also examined the interactions between neighborhood components and sex and race (Black vs White or other).Results: We identified 5 neighborhood components, representing facilities and resources, immigrant communities, community-level economic deprivation, resident-level socioeconomic status, and residents' age. Communities' economic deprivation and residents' socioeconomic status were significantly associated with 5-year mortality. We did not find interactions between sex or race and any of the 5 neighborhood components. The results were similar in a sensitivity analysis where we used 10-year mortality as the outcome.Conclusions: We found that communities' economic status but not facilities in communities was associated with mortality among older adults. These findings revealed the importance and benefits living in a socioeconomically advantaged neighborhood could have on health among older residents with different demographic backgrounds. [ABSTRACT FROM AUTHOR]

Background: Frailty is associated with chronic inflammation, which may be modified by aspirin. The purpose of this study was to determine whether low-dose aspirin reduces incident frailty in healthy older adult participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial.Methods: In the United States and Australia, 19 114 community-dwelling individuals aged ≥70 and older (U.S. minorities ≥65 years) and free of overt cardiovascular disease, persistent physical disability, and dementia were enrolled in ASPREE, a double-blind, placebo-controlled trial of 100-mg daily aspirin versus placebo. Frailty, a prespecified study end point, was defined according to a modified Fried frailty definition (Fried frailty) and the frailty index based on the deficit accumulation model (frailty index). Competing risk Cox proportional hazard models were used to compare time to incident frailty by aspirin versus placebo. Sensitivity analysis was conducted to include frailty data with and without imputation of missing data.Results: Over a median 4.7 years, 2 252 participants developed incident Fried frailty, and 4 451 had incident frailty according to the frailty index. Compared with placebo, aspirin treatment did not alter the risk of incident frailty (Fried frailty hazard ratio [HR]: 1.04, 95% confidence interval [CI] 0.96-1.13; frailty index HR: 1.03, 95% CI 0.97-1.09). The proportion of individuals classified as frail, and the trajectory in continuous frailty scores over time, were not different between the aspirin and placebo treatment groups. The results were consistent across a series of subgroups.Conclusions: Low-dose aspirin use in healthy older adults when initiated in older ages does not reduce risk of incident frailty or the trajectory of frailty. [ABSTRACT FROM AUTHOR]

Background and Objectives The high prevalence of overweight or obesity in older adults is a public health concern because obesity affects health, including the risk of mobility disability. Research Design and Methods The Mobility and Vitality Lifestyle Program, delivered by community health workers (CHWs), enrolled 303 community-dwelling adults to assess the impact of a 32-session behavioral weight management intervention. Participants completed the program at 26 sites led by 22 CHWs. Participation was limited to people aged 60–75 who had a body mass index (BMI) of 27–45 kg/m2. The primary outcome was the performance on the Short Physical Performance Battery (SPPB) over 12 months. Results Participants were aged 67.7 (SD 4.1) and mostly female (87%); 22.7% were racial minorities. The mean (SD) BMI at baseline was 34.7 (4.7). Participants attended a median of 24 of 32 sessions; 240 (80.3%) completed the 9- or 13-month outcome assessment. Median weight loss in the sample was 5% of baseline body weight. SPPB total scores improved by +0.31 units (p <.006), gait speed by +0.04 m/s (p <.0001), and time to complete chair stands by −0.95 s (p <.0001). Weight loss of at least 5% was associated with a gain of +0.73 in SPPB scores. Increases in activity (by self-report or device) were not independently associated with SPPB outcomes but did reduce the effect of weight loss. Discussion and Implications Promoting weight management in a community group setting may be an effective strategy for reducing the risk of disability in older adults. [ABSTRACT FROM AUTHOR]

Background: Perceived physical fatigability is highly prevalent in older adults and associated with mobility decline and other health consequences. We examined the prognostic value of perceived physical fatigability as an independent predictor of risk of death among older adults.Methods: Participants (N = 2 906), mean age 73.5 [SD, 10.4] years, 54.2% women, 99.7% white enrolled in the Long Life Family Study, were assessed at Visit 2 (2014-2017) with 2.7 [SD, 1.0] years follow-up. The Pittsburgh Fatigability Scale (PFS), a 10-item, self-administered validated questionnaire (score range 0-50, higher = greater fatigability) measured perceived physical fatigability at Visit 2. Deaths post-Visit 2 through December 31, 2019 were identified by family members notifying field centers, reporting during another family member's annual phone follow-up, an obituary, or Civil Registration System (Denmark). We censored all other participants at their last contact. Cox proportional hazard models predicted mortality by fatigability severity, adjusted for family relatedness and other covariates.Results: Age-adjusted PFS Physical scores were higher for those who died (19.1 [SE, 0.8]) compared with alive (12.2, [SE, 0.4]) overall, as well as across age strata (p < .001), except for those 60-69 years (p = .79). Participants with the most severe fatigability (PFS Physical scores ≥ 25) were over twice as likely to die (hazard ratio, 2.33 [95% CI, 1.65-3.28]) compared with those who had less severe fatigability (PFS Physical scores < 25) after adjustment.Conclusions: Our work underscores the utility of the PFS as a novel patient-reported prognostic indicator of phenotypic aging that captures both overt and underlying disease burden that predicts death. [ABSTRACT FROM AUTHOR]

Frailty is a state of heightened vulnerability and susceptibility to physiologic stressors that increases with age. It has shown increasing utility in predicting a range of adverse health outcomes. Here, we characterize a 67-item deficit-accumulation frailty index (FI) in 19 110 community-dwelling individuals in the ASPirin in Reducing Events in the Elderly clinical trial. Participants aged 65-98 years were recruited from the United States and Australia and were without diagnosed dementia and cardiovascular disease, and major physical disability. The median FI score was .10 (interquartile range: .07-.14) at baseline, and the prevalence of frailty (FI > .21) increased from 8.1% to 17.4% after 6 years. FI was positively associated with age, and women had significantly higher scores than men at all ages. The FI was negatively correlated with gait speed (r = -.31) and grip strength (r = -.46), and strongly associated with a modified Fried's frailty phenotype (p < .0001, for all comparisons). Frailty was associated with the primary composite outcome capturing independent life lived free of major disability and dementia, and increased the rate of persistent physical disability (hazard ratio: 21.3, 95% confidence interval: 15.6-28.9). It added significantly to the predictive capacity of these outcomes above age, sex, and ethnicity alone. The FI is thus a useful biomarker of aging even among relatively healthy older individuals and provides important information about an individual's vulnerability to and risk of disease. [ABSTRACT FROM AUTHOR]

Background: Elevated interleukine-6 (IL-6) and C-reactive protein (CRP) are associated with aging-related reductions in physical function, but little is known about their independent and combined relationships with major mobility disability (MMD), defined as the self-reported inability to walk a quarter mile.Methods: We estimated the absolute and relative effect of elevated baseline IL-6, CRP, and their combination on self-reported MMD risk among older adults (≥68 years; 59% female) with slow gait speed (<1.0 m/s). Participants were MMD-free at baseline. IL-6 and CRP were assessed using a central laboratory. The study combined a cohort of community-dwelling high-functioning older adults (Health ABC) with 2 trials of low-functioning adults at risk of MMD (LIFE-P, LIFE). Analyses utilized Poisson regression for absolute MMD incidence and proportional hazards models for relative risk.Results: We found higher MMD risk per unit increase in log IL-6 (hazard ratio [HR] = 1.26; 95% confidence interval [95% CI] 1.13-1.41). IL-6 meeting predetermined threshold considered to be high (>2.5 pg/mL) was similarly associated with higher risk of MMD (HR = 1.31; 95% CI 1.12-1.54). Elevated CRP (CRP >3.0 mg/L) was also associated with increased MMD risk (HR = 1.38; 95% CI 1.10-1.74). The CRP effect was more pronounced among participants with elevated IL-6 (HR = 1.62; 95% CI 1.12-2.33) compared to lower IL-6 levels (HR = 1.19; 95% CI 0.85-1.66).Conclusions: High baseline IL-6 and CRP were associated with an increased risk of MMD among older adults with slow gait speed. A combined biomarker model suggests CRP was associated with MMD when IL-6 was elevated. [ABSTRACT FROM AUTHOR]

Background: Body composition assessment by computed tomography (CT) predicts health outcomes in diverse populations. However, its performance in predicting mortality has not been directly compared to dual-energy X-ray absorptiometry (DXA). Additionally, the association between different body compartments and mortality, acknowledging the compositional nature of the human body, is not well studied. Compositional data analysis, which is applied to multivariate proportion-type data set, may help to account for the interrelationships of body compartments by constructing log ratios of components. Here, we determined the associations of baseline CT-based measures of mid-thigh cross-sectional areas versus DXA measures of body composition with all-cause mortality in the Health ABC cohort, using both traditional (individual body compartments) and compositional data analysis (using ratios of body compartments) approaches.Methods: The Health ABC study assessed body composition in 2911 older adults in 1996-1997. We investigated the individual and ratios of (by compositional analysis) body compartments assessed by DXA (lean, fat, and bone masses) and CT (muscle, subcutaneous fat area, intermuscular fat, and bone) on mortality, using Cox proportional hazard models.Results: Lower baseline muscle area by CT (hazard ratio [HR]men = 0.56; 95% confidence interval [95% CI]: 0.48-0.67, HRwomen = 0.60; 95% CI: 0.48-0.74) and fat mass by DXA (HRmen = 0.48; 95% CI: 0.24-0.95) were predictors of mortality in traditional Cox regression analysis. Consistently, compositional data analysis revealed that lower muscle area versus IMF, muscle area versus bone area, and lower fat mass versus lean mass were associated with higher mortality in both sexes.Conclusion: Both CT measure of muscle area and DXA fat mass (either individually or relative to other body compartments) were strong predictors of mortality in both sexes in a community research setting. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular events, dementia, and cancer can contribute to physical disability with activities of daily living (ADL). It is unclear whether low-dose aspirin reduces this burden in aging populations. In a secondary analysis, we now examine aspirin's effects on incident and persistent ADL disability within a primary prevention aspirin trial in community-dwelling older adults.Methods: The ASPREE (ASPirin in Reducing Events in the Elderly) trial of daily 100 mg aspirin versus placebo recruited 19 114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the United States. Six basic ADLs were assessed every 6 months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after 6 months. Proportional hazards modeling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk.Results: Over a median of 4.7 years, incident ADL disability was similar in those receiving aspirin (776/9525) and placebo (787/9589) with walking, bathing, dressing, and transferring the most commonly reported. Only 24% of incident ADL disability progressed to persistent. Persistent ADL disability was lower in the aspirin group (4.3 vs 5.3 events/1000 py; hazard ratio [HR] = 0.81, 95% confidence interval [CI]: 0.66-1.00), with bathing and dressing the most common ADL disabilities in both groups. Following persistent ADL disability, there were more deaths in the aspirin group (24 vs 12).Discussion: Low-dose aspirin in initially healthy older people did not reduce the risk of incident ADL disability, although there was evidence of reduced persistent ADL disability. [ABSTRACT FROM AUTHOR]

Background: Cut-points to define slow walking speed have largely been derived from expert opinion.Methods: Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.Results: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.Conclusions: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without. [ABSTRACT FROM AUTHOR]

Background: Advances in computational algorithms and the availability of large datasets with clinically relevant characteristics provide an opportunity to develop machine learning prediction models to aid in diagnosis, prognosis, and treatment of older adults. Some studies have employed machine learning methods for prediction modeling, but skepticism of these methods remains due to lack of reproducibility and difficulty in understanding the complex algorithms that underlie models. We aim to provide an overview of two common machine learning methods: decision tree and random forest. We focus on these methods because they provide a high degree of interpretability.Method: We discuss the underlying algorithms of decision tree and random forest methods and present a tutorial for developing prediction models for serious fall injury using data from the Lifestyle Interventions and Independence for Elders (LIFE) study.Results: Decision tree is a machine learning method that produces a model resembling a flow chart. Random forest consists of a collection of many decision trees whose results are aggregated. In the tutorial example, we discuss evaluation metrics and interpretation for these models. Illustrated using data from the LIFE study, prediction models for serious fall injury were moderate at best (area under the receiver operating curve of 0.54 for decision tree and 0.66 for random forest).Conclusions: Machine learning methods offer an alternative to traditional approaches for modeling outcomes in aging, but their use should be justified and output should be carefully described. Models should be assessed by clinical experts to ensure compatibility with clinical practice. [ABSTRACT FROM AUTHOR]

Background: Many traditional cardiovascular risk factors do not predict survival to very old age. Studies have shown associations of estimated glomerular filtration rate (eGFR) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with cardiovascular disease and mortality in older populations. This study aimed to evaluate the associations of the level and change in eGFR and NT-pro-BNP with longevity to age 90 years.Method: The population included participants (n = 3,645) in the Cardiovascular Health Study, aged between 67 and 75 at baseline. The main exposures were eGFR, calculated with the Berlin Initiative Study (BIS) 2 equation, and NT-pro-BNP, and the main outcome was survival to age 90. Mixed models were used to estimate level and change of the main exposures.Results: There was an association between baseline level and change of both eGFR and NT-pro-BNP and survival to 90, and this association persisted after adjustment for covariates. Each 10 mL/min/1.73 m2 higher eGFR level was associated with an adjusted odds ratio (OR) of 1.23 (95% CI: 1.13, 1.34) of survival to 90, and a 0.5 mL/min/1.73 m2 slower decline in eGFR was associated with an OR of 1.51 (95% CI: 1.31, 1.74). A twofold higher level of NT-pro-BNP level had an adjusted OR of 0.67 (95% CI: 0.61, 0.73), and a 1.05-fold increase per year in NT-pro-BNP had an OR of 0.53 (95% CI: 0.43, 0.65) for survival to age 90.Conclusion: eGFR and NT-pro-BNP appear to be important risk factors for longevity to age 90. [ABSTRACT FROM AUTHOR]

Background: Frailty is more prevalent among black versus white older Americans. We previously identified 37 metabolites associated with the vigor to frailty spectrum using the Scale of Aging Vigor in Epidemiology (SAVE) among older black men from the Health, Aging, and Body Composition (Health ABC) study. Here, we sought to develop a metabolite composite score based on the 37 SAVE-associated metabolites and determine whether the composite score predicts mortality and whether it attenuates the association between frailty and mortality among older black men.Methods: Plasma metabolites were measured using liquid chromatography-mass spectrometry. Most of the 37 metabolites were organic acids/derivatives or lipids. Metabolites were ranked into tertiles: tertiles associated with more vigorous SAVE scores were scored 0, mid-tertiles were scored 1, and tertiles associated with frailer SAVE scores were scored 2. Composite scores were the sum of metabolite tertile scores. We examined mortality associations using Cox regression. Percent attenuation estimated the extent to which metabolites attenuated the association between frailty and mortality.Results: One standard deviation frailer SAVE was associated with 30% higher mortality, adjusting for age and site (p = .0002); this association was attenuated by 56% after additionally adjusting for the metabolite composite score. In this model, one standard deviation higher metabolite composite score was associated with 46% higher mortality (p < .0001). Metabolite composite scores also predicted mortality (p = .045) in a validation sample of 120 older adults (40% men, 90% white).Conclusion: These metabolites may provide a deeper characterization of the higher mortality that is associated with frailty among older adults. [ABSTRACT FROM AUTHOR]

Background: Age-related deposition of fat in skeletal muscle is associated with functional limitations. Skeletal muscle fat may be present in people with preserved muscle mass or accompanied by muscle wasting. However, it is not clear if the association between muscle fat deposition and physical performance is moderated by muscle mass.Objective: To determine whether the association between midthigh intermuscular fat and physical performance is moderated by muscle area.Methods: We performed a cross-sectional analysis of the Health, Aging, and, Body Composition (ABC) study data collected in 2002-2003 (n = 1897, women: 52.2%). Midthigh muscle cross-sectional area (by computed tomography) and physical performance measures were compared across quartiles of intermuscular fat absolute area. Moderation analysis was performed to determine the conditional effect of intermuscular fat on physical performance as a function of muscle area. Conditional effects were evaluated at three levels of muscle area (mean and ± 1 standard deviation [SD]; 213.2 ± 53.2 cm2).Results: Simple slope analysis showed that the negative association between intermuscular fat area (cm2) and leg strength (N·m) was of greater magnitude (beta coefficient [b], 95% confidence interval [CI] = -0.288 [-0.427, -0.148]) in participants with greater muscle area (ie, 1 SD above the mean) compared to those with lower muscle area (ie, at mean [b = -0.12 {-0.248, 0.008}] or 1 SD below the mean [b = 0.048 {-0.122, 0.217}]). Similarly, the negative association of intermuscular fat with 400-m walk speed (m/s) and chair stand (seconds) was greater in those with higher muscle areas (p < .001) compared to those with lower muscle areas.Conclusions: The association between higher intermuscular fat area and impaired physical function in aging is moderated by muscle area. [ABSTRACT FROM AUTHOR]

Background: Low walking ability is highly prevalent with advancing age and predicts major health outcomes. Metabolomics may help to better characterize differences in walking ability among older adults, providing insight into potentially altered molecular processes underlying age-related decline in functioning. We sought to identify metabolites and metabolic pathways associated with high versus low walking ability among 120 participants ages 79-95 from the CHS All Stars study.Methods: Using a nested case-control design, 60 randomly selected participants with low walking ability were matched one-to-one on age, gender, race, and fasting time with 60 participants with high walking ability. High versus low walking ability was defined as being in the best versus worst tertiles for both gait speed (≥0.9 vs <0.7 m/s) and the Walking Ability Index (7-9 vs 0-1). Using liquid chromatography-mass spectrometry, 569 metabolites were identified in overnight-fasting plasma.Results: Ninety-six metabolites were associated with walking ability, where 24% were triacylglycerols. Triacylglycerols that were higher among those with high walking ability consisted mostly of polyunsaturated fatty acids, whereas triacylglycerols that were lower among those with high walking ability consisted mostly of saturated or monounsaturated fatty acids. Body composition partly explained associations between some metabolites and walking ability. Proline and arginine metabolism was a top pathway associated with walking ability.Conclusion: These results may partly reflect pathways of modifiable risk factors, including excess dietary lipids and lack of physical activity, contributing to obesity and further alterations in metabolic pathways that lead to age-related decline in walking ability in this older adult cohort. [ABSTRACT FROM AUTHOR]

Background: The population age 90 years and older is the fastest growing segment of the U.S. population. Only recently is it possible to study the factors that portend survival to this age. Methods: Among participants of the Cardiovascular Health Study, we studied the association of repeated measures of cardiovascular risk factors measured over 15–23 years of follow-up and not only survival to 90 years of age, but also healthy aging outcomes among the population who reached age 90. We included participants aged 67–75 years at baseline (n = 3,613/5,888) to control for birth cohort effects, and followed participants until death or age 90 (median follow-up = 14.7 years). Results: Higher systolic blood pressure was associated with a lower likelihood of survival to age 90, although this association was attenuated at older ages (p-value for interaction <.001) and crossed the null for measurements taken in participants’ 80’s. Higher levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and body mass index (BMI) were associated with greater longevity. Among the survivors to age 90, those with worse cardiovascular profile (high blood pressure, LDL cholesterol, glucose, and BMI; low HDL cholesterol) had lower likelihood of remaining free of cardiovascular disease, cognitive impairment, and disability. Conclusion: In summary, we observed paradoxical associations between some cardiovascular risk factors and survival to old age; whereas, among those who survive to very old age, these risk factors were associated with higher risk of adverse health outcomes. [ABSTRACT FROM AUTHOR]

Background: The concept of resilience has gained increasing attention in aging research; however, current literature lacks consensus on how to measure resilience. We constructed a novel resilience measure based on the degree of mismatch between persons' frailty level and disease burden and examined its predictive validity. We also sought to explore the physiological correlates of resilience.Methods: Participants were 2,457 older adults from the Health, Aging, and Body Composition Study. We constructed the resilience measure as the residual taken from the linear model regressing frailty on age, sex, race/ethnicity, 14 diseases, self-reported health, and number of medications. Participants were classified into three groups-adapters, expected agers, and premature frailers-based on residuals (less than, within, or above one standard deviation of the mean). Validation outcomes included years of able life (YAL), years of healthy life (YHL), years of healthy and able life (YHAL), disability, hospitalization, and survival.Results: The average YHAL was 5.1, 7.7, and 9.1 years among premature frailers, expected agers, and adapters, respectively. Compared with premature frailers and expected agers, adapters had significantly lower rates of disability, hospitalization, and mortality and higher proportion surviving to 90 years. The likelihood of surviving to 90 years was 20.4%, 30.6%, and 39.7% among premature frailers, expected agers, and adapters.Conclusions: We developed and validated a novel approach for quantifying and classifying physical resilience in a cohort of well-functioning white and black older adults. Persons with high physical resilience level had longer healthy life span and lower rates of adverse outcomes. [ABSTRACT FROM AUTHOR]

Background: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition.Methods: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut points, and preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia.Results: The SDOC assembled data from eight epidemiological cohorts consisting of 18,831 participants, clinical populations from 10 randomized trials and observational studies, and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength divided by body mass index was identified as discriminators of risk for mobility disability (walking speed <0.8 m/s), whereas dual-energy X-ray absorptiometry-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability, and instrumental activities of daily living disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert Panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature.Conclusions: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength-absolute or adjusted for body mass index-is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, race, and comorbidities. [ABSTRACT FROM AUTHOR]

Background: The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this article was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation.Methods: We examined 7-year change in physical (free of activities of daily living difficulty), cognitive (Mini-Mental State Examination score ≥ 24), and overall independence (physically/cognitively independent) in adults aged 90.3 ± 6.3 from LLFS's oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics, and physical and cognitive performance tasks and were determined using generalized estimating equations (α: p < .05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication.Results: At baseline (n = 1442), 67.3%, 83.8%, and 79.7% were overall, physically, and cognitively independent, respectively. After 7 years, 66% died, 7.5% were lost to follow-up, and the prevalence of overall independence decreased to 59.1% in survivors (-8.2%, 95% confidence interval: -14.1%, 2.2%). Of those with baseline independence, 156/226 (69.0%) remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery score and lung function, smaller waist circumference, and lower soluble receptor for advanced glycation end-product levels (p < .05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p < .05).Conclusions: The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms. [ABSTRACT FROM AUTHOR]

BACKGROUND Despite readily available treatments, control of blood pressure (BP) with population aging remains suboptimal. Further, there are gaps in the understanding of the management of high BP in the aged. We explored antihypertensive treatment and control among elderly hypertensive participants free from overt cardiovascular disease (CVD), and identified factors related to both "untreated" and "treated but uncontrolled" high BP. METHODS We analyzed baseline data from 19,114 individuals aged ≥65 years enrolled from Australia and United States (US) in the ASPirin in Reducing Events in the Elderly study. Hypertension was defined as an average systolic/diastolic BP ≥140/90 mm Hg and/or the use of any BP lowering medication. "Controlled hypertension" was defined if participants were receiving antihypertensive medication and BP <140 and 90 mm Hg. Descriptive analyses were used to summarize hypertension control rates; logistic regression was used to investigate relationships with treatment and BP control. RESULTS Overall, 74% (14,213/19,114) of participants were hypertensive; and of these 29% (4,151/14,213) were untreated. Among those treated participants, 53% (5,330/10,062) had BP ≥140/90 mm Hg. Participants who were untreated were more likely to be men, have higher educational status, and be in good physical health, and less likely to have significant comorbidities. The factors related to "treated but uncontrolled" BP included older age, male, Black race (vs. White), using antihypertensive monotherapy (vs. multiple) and residing in Australia (vs. US). CONCLUSIONS High levels of "untreated" and "treated but uncontrolled" BP occur in healthy elderly people without CVD, suggesting there are opportunities for better BP control in the primary prevention of CVD in this population. CLINICAL TRIALS REGISTRATION NCT01038583. [ABSTRACT FROM AUTHOR]

Background: To evaluate the discordance in frailty classification between the frailty index (FI) and the physical frailty phenotype (PFP) and identify factors discriminating those with discordant frailty classification from each other and from those for whom the assessments agree.Methods: A prospective observational study of older adults aged 65 and older selected from Medicare eligibility lists in four U.S. communities (n = 5,362). The PFP was measured by the Cardiovascular Health Study PFP. Participants meeting three or more of the five criteria were deemed frail. The FI was calculated as the proportion of deficits in an a priori selected set of 48 measures, and participants were classified as frail if FI is greater than 0.35.Results: The prevalence of frailty was 7.0% by the PFP and 8.3% by the FI. Of the 730 deemed frail by either instrument, only 12% were in agreement, whereas 39% were classified as frail by the PFP, but not the FI, and 48% were classified as frail by the FI, but not the PFP. Participants aged 65-72 years or with greater disease burden were most likely to be characterized as being FI-frail, but not PFP-frail. The associations of frailty with age and mortality were stronger when frailty was measured by the PFP rather than the FI.Conclusions: Despite comparable frailty prevalence between the PFP and the FI, there was substantial discordance in individual-level classification, with highest agreement existing only in the most vulnerable subset. These findings suggest that there are clinically important contexts in which the PFP and the FI cannot be used interchangeably. [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]

Heterogeneous exposure associations (HEAs) can be defined as differences in the association of an exposure with an outcome among subgroups that differ by a set of characteristics. In this article, we intend to foster discussion of HEAs in the epidemiologic literature and present a variant of the random forest algorithm that can be used to identify HEAs. We demonstrate the use of this algorithm in the setting of the association between systolic blood pressure and death in older adults. The training set included pooled data from the baseline examination of the Cardiovascular Health Study (1989–1993), the Health, Aging, and Body Composition Study (1997–1998), and the Sacramento Area Latino Study on Aging (1998–1999). The test set included data from the National Health and Nutrition Examination Survey (1999–2002). The hazard ratios ranged from 1.25 (95% confidence interval: 1.13, 1.37) per 10-mm Hg increase in systolic blood pressure among men aged ≤67 years with diastolic blood pressure greater than 80 mm Hg to 1.00 (95% confidence interval: 0.96, 1.03) among women with creatinine concentration ≤0.7 mg/dL and a history of hypertension. HEAs have the potential to improve our understanding of disease mechanisms in diverse populations and guide the design of randomized controlled trials to control exposures in heterogeneous populations. [ABSTRACT FROM AUTHOR]

Background: The movement profile of older adults with compromised function is unknown, as is the relationship between these profiles and the development of major mobility disability (MMD)-a critical clinical outcome. We first describe the dimensions of movement in older adults with compromised function and then examine whether these dimensions predict the onset of MMD.Methods: Older adults at risk for MMD (N = 1,022, mean age = 78.7 years) were randomized to receive a structured physical activity intervention or health education control. We assessed MMD in 6-month intervals (average follow-up of 2.2 years until incident MMD), with activity assessed at baseline, 6-, 12- and 24-month follow-up via accelerometry.Results: A principal components analysis of 11 accelerometer-derived metrics yielded three components representing lifestyle movement (LM), extended bouts of moderate-to-vigorous physical activity (MVPA), and stationary body posture. LM accounted for the greatest proportion of variance in movement (53%). Within health education, both baseline LM (HR = 0.74; 95% CI 0.62 to 0.88) and moderate-to-vigorous physical activity (HR = 0.69; 95% CI 0.54 to 0.87) were associated with MMD, whereas only LM was associated with MMD within physical activity (HR = 0.74; 95% CI 0.61 to 0.89). There were similar nonlinear relationships present for LM in both physical activity and health education (p < .04), whereby risk for MMD was lower among individuals with higher levels of LM.Conclusions: Both LM and moderate-to-vigorous physical activity should be central in treatment regimens for older adults at risk for MMD.Trial Registration: clinicaltrials.gov Identifier NCT01072500. [ABSTRACT FROM AUTHOR]

Background: Low-grade chronic inflammation, characterized by elevations in plasma Interleukin-6 (IL-6), is an independent risk factor of impaired mobility in older persons. Angiotensin receptor blockers and omega-3 polyunsaturated fatty acids (ω-3) may reduce IL-6 and may potentially improve physical function. To assess the main effects of the angiotensin receptor blocker losartan and ω-3 as fish oil on IL-6 and 400 m walking speed, we conducted the ENRGISE Pilot multicenter randomized clinical trial.Methods: The ENRGISE Pilot enrolled participants between April 2016 and June 2017, who participated for 12 months. Participants were aged ≥70 years with mobility impairment, had IL-6 between 2.5 and 30 pg/mL, and were able to walk 400 m at baseline. Participants were randomized in three strata 2 × 2 factorial to: (i) losartan 50-100 mg/d or placebo (n = 43), (ii) fish oil 1,400-2,800 mg/d or placebo (n = 180), and (iii) with both (n = 66).Results: Two hundred eighty-nine participants were randomized (mean age 78.3 years, 47.4% women, 17.0% black). There was no effect of losartan (difference of means = -0.065 ± 0.116 [SE], 95% confidence interval [CI]: -0.293-0.163, p = .58) or fish oil (-0.020 ± 0.077, 95% CI: -0.171-0.132, p = .80) on the log of IL-6. Similarly, there was no effect of losartan (-0.025 ± 0.026, 95% CI: -0.076-0.026, p = .34) or fish oil (0.010 ± 0.017, 95% CI: -0.025-0.044, p = .58) on walking speed (m/s).Conclusions: These results do not support the use of these interventions to prevent mobility loss in older adults at risk of disability with low-grade chronic inflammation.Registration: Clinicaltrials.gov NCT02676466. [ABSTRACT FROM AUTHOR]

Background: Hospitalization-associated functional decline is a common problem for older adults, but it is unclear how hospitalizations affect physical performance measures such as gait speed. We sought to determine hospitalization-associated change in gait speed and likelihood of new limitations in mobility and activities of daily living (ADLs).Methods: We used longitudinal data over 5 years from the Health, Aging and Body Composition Study, a prospective cohort of black and white community-dwelling men and women, aged 70-79 years, who had no limitations in mobility (difficulty walking 1/4 mile or climbing 10 steps) or ADLs (transferring, bathing, dressing, and eating) at baseline. Gait speed, and new self-reported limitations in mobility and ADLs were assessed annually. Selected participants (n = 2,963) had no limitations at the beginning of each 1-year interval. Hospitalizations were self-reported every 6 months and verified with medical record data. Generalized estimating equations were used to examine hospitalization-associated change in gait speed and odds of new limitations over each 1-year interval. Fully adjusted models included demographics, hospitalization within the past year, health conditions, symptoms, body mass index, and health-related behaviors.Results: In fully adjusted models, any hospitalization was associated with decrease in gait speed (-0.04 m/s; 95% confidence interval [CI]: -0.05 to -0.03) and higher odds of new limitations in mobility or ADLs (odds ratio = 1.97, 95% CI: 1.70-2.28), and separately with increased odds of new mobility limitation (odds ratio = 2.22, 95% CI: 1.90-2.60) and new ADL limitations (odds ratio = 1.84, 95% CI: 1.53-2.21). Multiple hospitalizations within a year were associated with gait speed decline (-0.06 m/s; 95% CI: -0.08 to -0.04) and greater odds of new limitations in mobility or ADLs (odds ratio = 2.96, 95% CI: 2.23-3.95).Conclusions: Functionally independent older adults experienced hospitalization-associated declines in gait speed and new limitations in mobility and ADLs. [ABSTRACT FROM AUTHOR]

Background: The Enabling Reduction of Low-grade Inflammation in Seniors (ENRGISE) Pilot Study is a multicenter randomized clinical trial examining the feasibility of testing whether omega-3 fish oil (ω-3) and the angiotensin receptor blocker losartan alone or in combination can reduce inflammation and improve walking speed in older adults with mobility impairment. We describe recruitment methods and results.Methods: Eligible participants were 70 years and older, had elevated interleukin-6 levels (2.5-30 pg/mL) and mobility impairment.Results: Of those who responded to recruitment, 83% responded to mailings. A total of 5,424 telephone screens were completed; of these, 2,011 (37.1%) were eligible for further screening. The most common reasons for ineligibility at the telephone screens were lack of mobility impairment or use of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (n=1.789). Of the 1,305 initial screening visits, 1,087 participants had slow gait speed (<1 m/s). Of these, 701 (64%) had elevated interleukin-6 and were eligible for second screening visits. Of the 582 second screening visits, 335 (57.6%) were eligible to be randomized. A total of 289 participants (96% of goal) were randomized: 180 in the ω-3 stratum (240% of goal); 43 in the losartan (57% of goal), and 66 in the combination (44% of goal). The telephone screen and first screening visit to randomization ratio was 19 to 1 and 4.5 to 1, respectively. The estimated cost of recruitment per randomized participant was $1,782.Conclusion: Recruitment for ω-3 exceeded goals, but goals for the losartan and combination strata were not met due to the high proportion of participants taking angiotensin receptor blockers or angiotensin-converting enzyme inhibitors. [ABSTRACT FROM AUTHOR]

Background: Baseline scores on a Healthy Aging Index (HAI), including five key physiologic domains, strongly predict health outcomes. This study aimed to characterize 9-year changes in a HAI and explore their relationship to subsequent mortality.Methods: Data are from the Health, Aging, and Body Composition study of well-functioning adults aged 70-79 years. A HAI, which ranges from 0 to 10, was constructed at years 1 and 10 of the study including systolic blood pressure, forced expiratory volume, digit symbol substitution test, cystatin C, and fasting glucose. The relationships between the HAI at years 1 and 10 and the change between years and subsequent mortality until year 17 were estimated from Cox proportional hazards models.Results: Two thousand two hundred sixty-four participants had complete data on a HAI at year 1, of these 1,122 had complete data at year 10. HAI scores tended to increase (i.e. get worse) over 9-year follow-up, from (mean [SD]) 4.3 (2.1) to 5.7 (2.1); mean within-person change 1.5 (1.6). After multivariable adjustment, HAI score was related to mortality from year 1 (hazard ratio [95% confidence interval] = 1.17 [1.13-1.21] per unit) and year 10 (1.20 [1.14-1.27] per unit). The change between years was also related to mortality (1.08 [1.02-1.15] per unit change).Conclusions: HAI scores tended to increase with advancing age and stratified mortality rates among participants remaining at year 10. The HAI may prove useful to understand changes in health with aging. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease (CKD) is associated with poor mobility. Peripheral nerve function alterations play a significant role in low mobility. We tested the hypothesis that early CKD is associated with altered sensory, motor and autonomic nerve function. Methods Participants in the Health, Aging and Body Composition cohort who had kidney function measures in Year 3 (1999–2000) and nerve function measurements at Year 4 (2000–01) were analyzed (n  = 2290). Sensory (vibration threshold, monofilament insensitivity to light and standard touch), motor [compound motor action potentials (CMAPs), nerve conduction velocities (NCVs)] and autonomic (heart rate response and recovery after a 400-m walk test) nerve function as well as participant characteristics were compared across cystatin C- and creatinine-based estimated glomerular filtration rate categorized as ≤60 (CKD) or >60 mL/min/1.73 m2 (non-CKD). The association between CKD and nerve function was examined with logistic regression adjusted for covariates. Results Participants with CKD (n  = 476) were older (77 ± 3 versus 75 ± 3 years; P < 0.05) and had a higher prevalence of diabetes (20.6% versus 13.1%; P < 0.001). CKD was associated with higher odds for vibration detection threshold {odds ratio [OR] 1.7 [95% confidence interval (CI) 1.1–2.7]} and light touch insensitivity [OR 1.4 (95% CI 1.1–1.7)]. CMAPs and NCVs were not significantly different between CKD and non-CKD patients. In adjusted analyses, participants with CKD had higher odds of an abnormal heart rate response [OR 1.6 (95% CI 1.1–2.2)] and poor heart rate recovery [OR 1.5 (95% CI 1.1–2.0)]. Conclusions CKD is associated with changes in sensory and autonomic nerve function, even after adjustment for demographics and comorbidities, including diabetes. Longitudinal studies in CKD are needed to determine the contribution of nerve impairments to clinically important outcomes. [ABSTRACT FROM AUTHOR]

Background: To determine if adiponectin levels are associated with weight loss, low muscle mass, and physical functioning among the elderly and to determine independent associations with incident disability and death.Methods: Included were 3,044 participants from the Health, Aging and Body Composition Study, who had whole-body dual energy absorptiometry performed to evaluate appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2), computed tomography measures of thigh muscle density, weight histories, estimates of physical functioning, and adiponectin levels at enrollment. Associations between adiponectin levels and body composition, weight loss, and physical functioning were assessed in multivariable linear regression models. Associations between adiponectin and incident disability and mortality were assessed in mediation analyses, adjusting for other factors.Results: Greater adiponectin at baseline was independently associated with low FMI Z-score, lower waist circumference, low ALMI Z-score, low muscle density, a history of weight loss, and poor physical functioning (all p < .05). Greater adiponectin levels (per SD) were associated with incident disability [HR: 1.14 (1.08, 1.20), p < .001] and greater mortality [HR: 1.17 (1.10, 1.25), p < .001] in models adjusting for demographic factors, adiposity, and comorbid conditions. The association was completely attenuated and no longer significant (all p > 0.05) when adjusting for body composition, muscle density, weight loss, and physical functioning at baseline.Conclusions: Greater serum adiponectin levels are associated with historical weight loss, low skeletal muscle mass, low muscle density, and poor physical functioning. High adiponectin is associated with a greater risk of incident disability and death, but not independently of these factors. [ABSTRACT FROM AUTHOR]

The US population aged 90 years or more is growing rapidly, and there are limited data on their health. The Cardiovascular Health Study is a prospective study of black and white adults aged ≥65 years recruited in 2 waves (1989–1990 and 1992–1993) from Medicare eligibility lists in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. We created a synthetic cohort of the 1,889 participants who had reached age 90 years at baseline or during follow-up through July 16, 2015. Participants entered the cohort at 90 years of age, and we evaluated their changes in health after age 90 years (median duration of follow-up, 3 years (interquartile range, 1.3–5)). Measures of health included cardiovascular events, cognitive function, depressive symptoms, prescription medications, self-rated health, and functional status. The mortality rate was high: 19.0 per 100 person-years (95% confidence interval : 17.8, 20.3) in women and 20.9 per 100 person-years (95% confidence interval: 19.2, 22.8) in men. Cognitive function and all measures of functional status declined with age; these changes were similar by sex. When we isolated period effects, we found that medication use increased over time. These estimates can help inform future research and can help health-care systems meet the needs of this growing population. [ABSTRACT FROM AUTHOR]