Background: Stiffening arteries, a risk factor of cognitive impairment, leads to increased pulse pressure (PP, difference between systolic and diastolic blood pressure). PP directly relates to bone metabolism by microvascular perfusion and mechanotransduction. We hypothesized that PP may mediate the known association between performance on episodic memory and bone health. Methods: Participants in the Study of Muscle, Mobility and Aging (SOMMA) study were > 70 years, able to complete a 400-meter walk at baseline, and free of advanced chronic disease. At the baseline SOMMA visit, participants completed a California Verbal Learning Test II short form (CVLT-II), a test of episodic memory. The SOMMA-Bone Study at the Pittsburgh site measured bone structure/microarchitecture using High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) at the distal radius and tibia after the 12-month SOMMA visit (N= 327; aged 76.2± 4.6 years; 60.5% women; 87.2% White). Total BMD (Tt.BMD, mg HA/cm 3 ), total area (Tt.Ar, mm 2 ), and failure load (F.ult, N) from micro-finite element analysis (µFEA) measurements were estimated and standardized by sex. A causal mediation analysis method was used to examine if PP mediated the association of CVLT-II performance and HR-pQCT measurements in women using the mediation package in R, adjusting for relevant confounders. To estimate the indirect (Average Causal Mediation Effect, ACME) and direct (Average Direct Effect, ADE) effects, we used nonparametric bootstrapping with 5000 simulations, assuming no unmeasured confounding. Results: There was no association between episodic memory and bone parameters in men. Of the women in SOMMA-Bone (n=198, 76.2 ± 4.7 years, 83.8% White), mean PP was 59.1±13.8 mmHg. Better performance on the immediate (but not short or long) recall was associated with higher F.ult in the tibia. Better performance on short and long recall tests (but not immediate) were associated with higher Tt. BMD (Table 1). At the radius, better performance on the long recall test was associated with lower Tt.Ar only. In all models, PP was not a significant mediator. Conclusions: In associations between better episodic memory and better skeletal parameters, there was no evidence of mediation through PP. This suggests that cognitive and skeletal health may share underlying biological mechanisms independent of PP in older women. Serum proteomic analysis is underway to identify the biology of this relationship.

Dopamine (DA) in the central nervous system is considered a master regulator of mobility performance and vigor, but its mechanistic relationship with skeletal muscle energetics is unclear. We tested the cross-sectional association of striatal DA and skeletal muscle mitochondrial function in 146 older adults participating in the Study of Muscle, Mobility and Aging (75.4 years old, 54% women). Striatal DA was measured using (+)-a-[11C] dihydrotetrabenazine (DTBZ) PET imaging for the limbic, sensorimotor, and executive control subregions. Mitochondrial capacity to produce ATP (ATPmax, mM ATP/s) was measured in vivo using 31P magnetic resonance spectroscopy after repeated voluntary muscle contractions. Ex-vivo respirometry assays from biopsies of resting muscle captured complementary aspects of mitochondrial function under optimal conditions. In multivariable linear regression models, [11C]DTBZ in the limbic striatum, but not other subregions, was positively associated with greater ATPmax in vivo, independent of demographics, muscle volume, leg power, white matter hyperintensities, gray matter atrophy, moderate-to-vigorous physical activity and diabetes (β = 0.275, standard error 0.108, p=0.019). [11C]DTBZ was not associated with the ex-vivo mitochondrial respiration markers (p>0.2). The role of striatal limbic DA and the energetic capacity of skeletal muscles should be further investigated in older adults.

Objective:. In a randomized, embedded, multifactorial, adaptive platform (REMAP) trial, we hypothesized that perioperative metformin would improve postoperative time alive and out of the hospital, defined by 90-day hospital-free days (HFD-90), among nondiabetic aged adults. Background:. As our population ages, patients are increasingly frail requiring an emphasis on treatments to counteract their diminished resilience, especially following the stress of surgery. Growing literature supports metformin as an antiaging and anti-inflammatory therapy with beneficial effects extending into the perioperative period. Methods:. At-risk adults (≥60 years) scheduled for elective surgical interventions were randomized to placebo (N = √3) or metformin (N = 1:1:1; 500 mg:1000 mg:1500 mg) for short (7–28 days), intermediate (29–90 days), or long (>90 days) preoperative durations. An adaptive sample size of (N = 1000–2500) would identify at least a 15% improvement in HFD-90 for >1 metformin doses. Using intention-to-treat analysis, Bayesian ordinal logistic regression compared HFD-90 and frequentist logistic regression compared 90-day reoperation and readmission. Results:. Before trial closure, we randomized 302 (N = 106 placebo, N = 196 metformin [N = 64, 500 mg; N = 66, 1000 mg; and N = 66, 1500 mg]) patients without differences in baseline demographics (age 68 ± 6 years, 45% females, and 92% White race) or interventions (spine [29%], general [38%], colorectal [13%], and other [20%]). The odds of HFD-90 did not significantly differ between all doses and duration of metformin or placebo. There were no differences in the odds of reintervention (OR = 1.1 [95% CI, 0.6–2.0]) or readmission (OR = 1.5 [95% CI, 0.7–2.8]). Conclusions:. Pretreatment with metformin did not improve postoperative outcomes in this REMAP trial, although trial enrollment was markedly limited by the COVID-19 pandemic and is underpowered.

Unintentional weight loss in older populations is linked to greater mortality and morbidity risks. This study aims to understand the metabolic mechanisms of unintentional weight loss and their relationship with body composition changes in older adults. We investigated plasma metabolite associations with weight and body composition changes over 5 years in 1335 participants (mean age 73.4 years at Year 1, 51

BACKGROUND:As individuals age, their ability to cope with and recover from health challenges becomes vital for maintaining independence and quality of life. This study aims to develop a multivariate phenotype of physical resilience based on individual recovery dynamics before and after a physical stressor. METHODS:This prospective observational study included 104 individuals aged ≥60 who underwent elective total knee replacement (TKR) for degenerative joint disease between December 2, 2019 and January 4, 2023. A multivariate resilience phenotype was derived from physical function assessments over 12 months after TKR using the Short Physical Performance Battery, the Pittsburgh Fatigability Scale Physical Subscale, the Knee Injury and Osteoarthritis Outcome Quality of Life Score, and the 36-Item Short Form Health Survey Physical Component Score. Validation was performed using markers (ie, frailty and self-reported health) and determinants (eg, the Charlson Comorbidity Index (CCI)) of recovery potential. RESULTS:Distinct resilience profiles were identified across the 4 measures, showing varied baseline levels and/or change rates over 12 months. By combining and analyzing resilience profiles across measures, 2 distinct groups emerged: 33.7% were classified as nonresilient and 66.4% as resilient. The nonresilient group had a higher prevalence of frailty (37.1% vs 10.1%, p < .01), poor or fair self-reported health (48.6% vs 5.8%, p < .01), and moderate or severe comorbidity burden (CCI > 2; 28.6% vs 10.1%, p = .03). CONCLUSIONS:Recovery trajectories after TKR revealed varying resilience levels that could not be fully explained by baseline health status. Understanding individual resilience can enhance patient care by promoting recovery and overall well-being.

Identifying mechanisms that compensate for slow gait speed in older adults is crucial. Dopaminergic neurotransmission curbs deleterious associations of cerebrovascular disease with gait, but whether it compensates for peripheral systemic risk factors (PSRF) for gait slowing has not been studied. In this cross-sectional study of community-dwelling older adults, we examined the relationship between nigrostriatal dopaminergic terminal integrity and gait speed in individuals with and without ≥ 1 PSRF for gait slowing: obesity, joint pain, or reduced muscle strength. The primary outcome was gait speed cost (%GSC) on transition from even to uneven surface. Participants underwent dopaminergic imaging with dihydrotetrabenazine [11C]DTBZ positron emission tomography. Among 197 individuals, (mean (SD) age 74.92 (4.53) years; 61.93 % female; 90.86 % White), 130 (65.99 %) had ≥ 1 PSRF. Relationship between posterior putamen [11C]DTBZ binding and %GSC was modified by PSRF; in those with ≥ 1 PSRF (but not in those with no PSRF), posterior putamen [11C]DTBZ binding was associated with %GSC (β = 0.198, p = 0.03) independent of potential confounders. This cross-sectional study indicates that higher striatal dopaminergic neurotransmission may compensate for the effects of PSRF on gait slowing.

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart in silico. Additionally, novel ASAT-secreted proteins such as NID2 and APOA4 were implicated in mediating ASAT crosstalk with skeletal muscle and brain in silico. Our framework provides insights into ASAT-driven tissue crosstalk underlying physical and cognitive performance in older adults and offers a valuable resource for understanding the role of ASAT in human aging.

Epidemiologic studies have consistently demonstrated inverse associations between cancer and dementia. One hypothesis is that differential attrition bias leads to an apparent inverse association. Another hypothesis posits that cancer and dementia result from opposite extremes of shared biological mechanisms, where dysregulation in one direction promotes cancer risk, and dysregulation in the opposite direction promotes dementia risk. Such a shared mechanism would produce unmeasured confounding. To assess attrition bias, we used data from n = 2,153 participants in the Health, Aging and Body Composition Study who had neither a history of cancer (self-report) nor dementia (dementia medications or Modified Mini-Mental <78) at baseline to examine whether time-varying cancer history was associated with subsequent incident dementia using cause-specific discrete-time Cox models with and without inverse-probability weighting (IPW) for drop-out and death. To assess possible shared biological mechanisms, we used data from a subset of 1,674 participants with baseline plasma metabolomics characterized. We fit IPW cause-specific Cox models with and without adjustment for the top 20 metabolites jointly associated with cancer and dementia. Cancer history was inversely associated with dementia (Hazard Ratio[HR]=0.648; 95%Confidence Interval[CI]=0.441-0.951), which remained when using IPW (HR = 0.650; 95%CI=0.440-0.960). Among participants in the metabolomics subset, cancer history was inversely associated with dementia (HR = 0.620, 95%CI=0.391-0.982), but the association was slightly attenuated and lost statistical significance after adjustment for metabolites (HR = 0.669; 95%CI=0.420-1.065). Findings suggest that the inverse association between cancer and dementia is not explained by attrition bias, but may be partially explained by shared biological mechanisms (unmeasured confounding). Multi-omic replication studies are needed.

Background: Walking ability is important for the quality of life of older adults. A self-reported walking ability index (WAI) covering the difficulty and ease of walking captures a broader spectrum of walking ability in healthy older persons. Methods: Using metabolomics in the Health, Aging and Body Composition study, we identified Year 2 metabolites cross-sectionally and longitudinally related to WAI (0–9, higher scores indicate better walking ability) using probabilistic index models and multinomial logistic models, respectively. Results: Among 2334 participants (mean age 74.6 years, 51% women, 37% Black), 27% scored 0–5, 36% scored 6–8, and 37% scored 9 at Year 2. Over 4 years, 52% maintained a stable WAI, 6% improved, while 42% declined (22% 1–2 points and 20% >2 points decline). We identified 81 metabolites significantly associated with both poorer concurrent WAI and faster decline, including higher acylcarnitine species, shorter-chain saturated diglycerides and triglycerides, and TCA cycle intermediates (cis-aconitic, fumaric, and malic acids), and lower phospholipids levels. Eighteen additional metabolites were only associated with faster WAI decline: higher short-chain saturated triglycerides and energy metabolism markers (ATP/ADP/AMP) and lower margaric acid and glycine levels. Notably, those with improved WAI, despite poorer baseline WAI and lifestyles, showed more favorable metabolic profiles than others. Conclusions: Metabolites linked to the TCA cycle and energy metabolism, as well as inflammation and protein catabolism, were related to mobility function. Some metabolites might be particularly important for the early detection of older adults at risk of mobility decline. Metabolic profiles may also help identify older individuals (i.e., with improving WAI) with greater metabolic resilience to lifestyle risk factors and health conditions.

PURPOSE:It is recognized that disruptions in circadian behavior, such as with shift work or jet lag, are associated with diminished health. This known relationship implies that people with stronger indices of circadian behavior will exhibit improved physiology. To address the association between rhythmic activity behavior and physiology, we proposed that metrics indicative of "more rhythmic" rest-activity patterns would be associated with better cardiorespiratory fitness and walking energetics in a cohort of older adults. METHODS:Using baseline data from the Study of Muscle, Mobility and Aging ( N = 799, age: 76 ± 5 yr, 58% female), we quantified metrics describing rhythmic aspects of rest-activity behavior (amplitude, robustness, time of peak activity, others) from continuous wrist-worn accelerometry. We used linear models to examine cross-sectional associations between rhythmic metrics with V̇O 2peak and walking energetics (cost-capacity ratio at slow and preferred walking speeds) adjusted for age, sex, race, height, health conditions, and other factors. RESULTS:Metrics that reflect more rhythmic behavior were associated with V̇O 2peak (higher amplitude: Q1: 18.4 vs Q4: 22.0 mL·kg -1 ·min -1 ; P -trend < 0.001) higher pseudo- F statistic/robustness (Q1: 19.2 vs Q4: 21.3 mL·kg -1 ·min -1 ; P -trend < 0.001), and earlier time of peak activity (Q1 (earliest): 20.9 vs Q4 (latest): 19.2 mL·kg -1 ·min -1 ; P -trend < 0.001). Similar trends were observed with lower cost-capacity ratio at preferred and slow walking speeds (amplitude, pseudo- F statistic, acrophase: P -trend < 0.001 for all). CONCLUSIONS:More rhythmic activity behavior and earlier time of peak activity were associated with better cardiorespiratory fitness and walking energetics. These findings support the framework that rhythmic activity supports healthy physiology. Further investigations are warranted to determine if declines in rhythmicity of human behavior are predictive of disease.

Rationale: The dose-response relationship between secondhand smoke (SHS) exposure and respiratory health outcomes remains unclear, particularly in individuals with no history of cigarette smoking. We hypothesized that greater SHS exposure would be associated with increased respiratory symptoms and risk of hospitalization or death related to chronic lower respiratory diseases in a large, multi-ethnic, US general population-based sample of never-smoking adults. Methods: Data were pooled from two prospective NHLBI cohorts: Atherosclerosis Risk In Communities (ARIC) and the Multi-Ethnic Study of Atherosclerosis (MESA). Participants with a history of ≥100 lifetime cigarettes were excluded. Self-reported hours of SHS exposure per week over the past year was assessed by questionnaire and classified as SHS non-exposure (0 hours/week, referent category for all analyses) versus SHS exposure (>0 hours/week, sub-categorized into tertiles). Chronic cough and chronic phlegm were self-reported via questionnaire and dyspnea was assessed by the MRC scale. Administrative criteria were used to classify incident hospitalizations or deaths associated with COPD (ICD-9: 491, 492, 496; ICD-10: J44, J40-2, J43) and asthma (ICD-9: 493; ICD-10: J45-6). Logistic regression and Cox proportional hazards models were stratified by cohort and adjusted for sociodemographic factors, anthropometry, and comorbidities. Results: Among 8,474 participants (mean age 58±9 years, 68% female, 57% Non-Hispanic White, 26% Non-Hispanic Black, 9% Hispanic, 7% Asian), 4,629 (55%) reported SHS exposure (median SHS in tertile [T] 1, 1 hour/week; in T2, 5 hours/week; in T3, 30 hours/week). SHS exposure (vs non-exposure) was associated with greater odds of chronic cough (aOR:1.38; 95%CI:1.02-1.87), chronic phlegm (aOR:1.25; 95%CI:1.00-1.70), and MRC grade 2+ dyspnea (aOR:1.29; 95%CI:1.02-1.64). Over a median follow-up of 17 years, participants in T3 (vs non-exposure) had higher hazards of incident COPD-related events (aHR:1.48; 95%CI:1.13-1.96) but not asthma-related events (Figure). There was no significant effect modification by age, sex, race/ethnicity, education, or comorbidities. Conclusion: SHS exposure was associated with increased odds of chronic respiratory symptoms and a higher hazard of COPD-related events in adults with no history of cigarette smoking. These findings highlight the potential risks of SHS exposure for respiratory health and emphasize the need for public health measures to reduce SHS exposure.

Using multiple sources, we provide the conceptual justification and statistical support for a multimorbidity outcome associated with obesity-related conditions, which we term the Health Conditions Index (HCI). This index was designed to capture the health effects of multi-year studies of caloric restriction for older adults with BMIs in the overweight or obesity classification. We used a subset of participants in the Health, Aging and Body Composition Cohort Study to evaluate multiple aspects of the index and its components over 5 years of follow-up. The 937 participants in the subset had an average age of 73 years and a BMI of 30.7 kg/m2; 53% were female and 43% were Black; 80% were hypertensive and 14% had type 2 diabetes. Results demonstrated that the components of the index were consistently related to initial BMI and percent body fat on cohort entry, generally showed an increasing prevalence over the 5-year follow-up, and, as a composite index, exhibited an association between faster progression and higher initial levels of age, BMI, and percent body fat. Further, the initial HCI was associated with a statistically significant increase in the rate of mortality over 5 years of follow-up (hazard ratio = 1.22, 95% CI 1.04 to 1.44). By using outcomes like the HCI, clinical trials of caloric restriction in older adults may gain a better understanding of how intentional weight loss relates to future risk of multiple chronic conditions associated with aging.

BACKGROUND:Peak oxygen consumption during exercise (VO2peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO2peak variation are not clear. Our objective is to understand the microRNA (miRNA) signatures that relate to VO2peak variation, which could provide insights to novel mechanisms that contribute to low VO2peak. METHODS:We used small RNA sequencing to analyze baseline, cross-sectional serum samples from 72 participants (70- to 91-year old). We analyzed samples from individuals with low or high VO2peak (N = 18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO2peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. RESULTS:We identified 1055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO2peak (P < .05). After P-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The Area Under the Curve for the five miRNAs ranged from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70% to 80% and 80% to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO2peak (P < .05) and miR-519a-3p remained significant based on adjusted P-values. CONCLUSIONS:We identified a miRNA signature of VO2peak in older individuals that might provide insights to novel mechanisms that drive low VO2peak. Future studies will validate the findings in a larger, longitudinal study cohort.

BACKGROUND AND OBJECTIVES:Parkinson disease (PD) pathology begins years before clinical diagnosis. Identifying individuals in this prodromal period is of high priority because they are candidates for clinical trials. Several characteristics of the PD prodrome have been described, but many are nonspecific. Among community-dwelling older adults unselected for PD risk, their relationship to objective measures of nigrostriatal dopaminergic nerve terminal density has not been studied in vivo. We determined prevalence of PD risk factors and prodromal signs/symptoms in community-dwelling older adults, examined their relationship with dopaminergic nerve terminal density, and explored prevalence and distribution of other possible prodromal features. METHODS:This was a cross-sectional observational study of community-dwelling older adults without diagnosed neurologic disorders in Southwestern Pennsylvania. Participants were assessed for 5 PD risk markers and ≤8 prodromal signs/symptoms, and underwent dopaminergic imaging with dihydrotetrabenazine ([11C](+)-α-DTBZ)-PET to assess nigrostriatal dopamine terminal density. Probability of prodromal PD based on Movement Disorders Society criteria was calculated. Possible prodromal PD (pPD) was defined as an estimated posterior probability for prodromal PD of >30%. The relationship between prodromal probability and age-adjusted and sex-adjusted [11C]DTBZ striatal binding was examined. RESULTS:A total of 231 participants were included, mean (SD) age 75.1 (4.5) years, 94 (40.7%) men. More than 1 prodromal sign/symptom was present in 131 (56.7%), with cognitive deficit being the most common. pPD was present in 18 (7.8%) of the sample. Compared with the not pPD group, the pPD group had lower mean age-adjusted and sex-adjusted predicted [11C]DTBZ posterior putamen binding (2.45 [0.119] vs 2.38 [0.150], p = 0.014) and greater left-right asymmetry (0.027 [0.006] vs 0.030 [0.007], p = 0.014). Hyposmia was significantly associated with lower posterior putamen binding compared with normosmia (β = -0.179, 95% CI -0.332 to -0.026, p = 0.022). DISCUSSION:Prodromal nonmotor and motor signs/symptoms of PD are common in community-dwelling older adults. Increased probability of prodromal PD is associated with decreased dopaminergic nerve terminal density of the posterior putamen that is also more asymmetric. Our findings support the use of composite measures of prodromal features to identify individuals at the population level who may be at risk for PD.

Individuals with isolated rapid eye movement sleep behavior disorder (iRBD) are at high risk of neurodegenerative parkinsonian disorders or dementia (NPD). Determining which characteristics predict greatest risk could improve clinical care. Our objectives were to utilize electronic health record data to apply prodromal Parkinson’s disease research diagnostic criteria to outpatients with iRBD and determine their utility for identifying patients with iRBD at high vs low risk for NPD diagnosis. This was a retrospective cohort study at a tertiary care center in western Pennsylvania. Diagnosis of iRBD was confirmed with expert manual chart review. Prodromal risk markers and signs and symptoms were determined with diagnostic codes. Multivariable Cox proportional hazards models examined a range of covariates as predictors of time to NPD diagnosis. Of 448 patients with iRBD, 82 (18.30

Rationale: Chronic lung diseases are associated with increased risk of mortality due to coronary heart disease (CHD). Nonetheless, the population attributable fraction (PAF) of lung function impairment relative to other established cardiovascular risk factors is unclear. Objectives: To evaluate the PAF of low lung function for CHD mortality Methods: We harmonized and pooled lung function and clinical data across eight U.S. general population cohorts. Impaired lung function was defined as forced expiratory volume in 1 second (FEV1) and/or forced vital capacity ≤ 95% predicted on baseline spirometry. The association between CHD mortality and risk factors was assessed using cause-specific proportional hazards and Fine-Gray proportional subdistribution hazard models, treating non-CHD mortality as a competing risk. Models were adjusted for lung function as well as age, sex, race/ethnicity, educational attainment, body mass index, smoking status, pack-years of smoking, diabetes mellitus, high-density lipoprotein, and high low-density lipoprotein (≥130 mg/dl). PAF was calculated as the relative change in the average absolute risk of 10-year CHD mortality by elimination of lung function lower than 95% predicted. Results: Among 35,143 participants, 1,844 of 13,174 (14.0%) deaths were due to CHD. Compared with percentage predicted FEV1 (FEV1pp) > 95%, the subdistribution adjusted hazard ratio for low FEV1pp was 1.30 (95% confidence interval, 1.18-1.44). The PAF for FEV1pp ≤ 95% was 12%, ranking low FEV1 third on the list of PAF for CHD mortality, after hypertension and diabetes. Low FEV1pp ranked second in the subgroup of active smokers (PAF 14%), after hypertension. Conclusions: Low lung function, even in the range considered clinically normal, ranks high on the list of attributable risk factors for CHD mortality and should be considered in cardiovascular risk stratification.

Fatigability, a phenotype of poor energy regulation, is associated with lower physical activity in older adults, but independent associations with sedentary behavior are unknown. We examined whether sedentary behavior was associated with fatigability using cross-sectional data from the Study of Muscle, Mobility and Aging. Mean sedentary time, sedentary bout length, and sedentary breaks/day were measured using 7-day waking hour data collected from a thigh-worn accelerometer. Fatigability was assessed using the Pittsburgh Fatigability Scale Physical subscale (PFS, score 0–50, higher = greater fatigability) and the Pittsburgh Performance Fatigability Index (PPFI), a percentage decline of observed cadence to maximal cadence from a wrist-worn accelerometer captured during a usual-paced 400 m walk (range 0–100%, higher = more performance deterioration). The participants (N = 663; 76.4 ± 5.1 years, 58% women, 54% high PFS, median PPFI 1.4%) were sedentary for 614.8 ± 111.7 min/day, with a mean 15.0 ± 5.5 min/day bout length and mean 46.1 ± 13.2 sedentary breaks/day. Higher total sedentary time was associated with greater PFS Physical score (β = 0.71, p = 0.0368), but this association was not independent of step count/day. After adjusting for step count/day, higher sedentary time was associated with lower PPFI score (β = −0.44, p = 0.0039). Sedentary bout length and breaks/day were not associated with perceived or performance fatigability. Future studies should aim to better understand the inter-relatedness of these behaviors.

Background Metabolic-inflammatory states are central to multiorgan mechanisms of aging, but precise functional biomarkers of physiological aging remain less clear. Methods In the Health, Aging and Body Composition study, we defined metabolomic profiles of the Healthy Aging Index (HAI), a composite of cardiovascular, lung, cognitive, metabolic, and renal function (0-10, with higher scores indicating poorer health) in a split set design from 2015 older participants (mean age 73.6 years; 50% women; 35% Black). We used standard regression to identify metabolomic correlates of Year 1 and Year 10 HAI, change in HAI over time, and mortality. A metabolite score of HAI was developed using LASSO regression. Results We identified 42 metabolites consistently associated with Year 1 and Year 10 HAI, as well as change in HAI: 13 lipids, 4 amino acids, and 4 metabolites of other classes were associated with worse and worsening HAI while 20 lipids and 1 amino acid was associated with better and improving HAI. Most of these associations were no longer significant after additionally adjusting for inflammation biomarkers. A higher metabolite score of Year 1 HAI was associated with greater HAI deterioration over time (hold-out “test” set beta 0.40 [0.15-0.65]) and higher mortality (hold-out “test” set hazard ratio: 1.43 [1.23-1.67]). Conclusions A multi-organ healthy aging phenotype was linked to lipid metabolites, suggesting potential pathways related to mitochondrial function, oxidative stress and inflammation. Metabolomics of HAI at older age were related to worsening health and mortality, suggesting potential links between metabolism and accelerated physiological aging.