Implications of metabolism on multi-systems healthy aging across the lifespan.

Aging is increasingly thought to involve dysregulation of metabolism in multiple organ systems that culminate in decreased functional capacity and morbidity. Here, we seek to understand complex interactions among metabolism, aging, and systems-wide phenotypes across the lifespan. Among 2469 adults (mean age 74.7 years; 38% Black) in the Health, Aging and Body Composition study we identified metabolic cross-sectionally correlates across 20 multi-dimensional aging-related phenotypes spanning seven domains. We used LASSO-PCA and bioinformatic techniques to summarize metabolome-phenome relationships and derive metabolic scores, which were subsequently linked to healthy aging, mortality, and incident outcomes (cardiovascular disease, disability, dementia, and cancer) over 9 years. To clarify the relationship of metabolism in early adulthood to aging, we tested association of these metabolic scores with aging phenotypes/outcomes in 2320 participants (mean age 32.1, 44% Black) of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We observed significant overlap in metabolic correlates across the seven aging domains, specifying pathways of mitochondrial/cellular energetics, host-commensal metabolism, inflammation, and oxidative stress. Across four metabolic scores (body composition, mental-physical performance, muscle strength, and physical activity), we found strong associations with healthy aging and incident outcomes, robust to adjustment for risk factors. Metabolic scores for participants four decades younger in CARDIA were related to incident cardiovascular, metabolic, and neurocognitive performance, as well as long-term cardiovascular disease and mortality over three decades. Conserved metabolic states are strongly related to domain-specific aging and outcomes over the life-course relevant to energetics, host-commensal interactions, and mechanisms of innate immunity.

Metabolomic characterization of vigor to frailty among community-dwelling older Black and White men and women.

Older women and Black individuals are more likely to experience frailty. A metabolomic characterization of frailty may help inform more effective interventions aimed at improving health, reducing disparities, and preventing frailty with aging. We sought to identify metabolites and pathways associated with vigor to frailty and determine whether associations differed by sex and/or race among n = 2189 older Black and White men and women from the Health, Aging, and Body Composition (Health ABC) study. Fasting plasma metabolites were measured using liquid chromatography-mass spectrometry. Vigor to frailty was based on weight change, physical activity, gait speed, grip strength, and usual energy. We used linear regression of a single metabolite on vigor to frailty, adjusting for age, sex, race, study site, and multiple comparisons using a Bonferroni correction. Among 500 metabolites, 113 were associated with vigor to frailty (p < 0.0001). Associations between metabolites and vigor to frailty did not differ significantly by race and/or sex. Lower amino acids, glycerophospholipids, sphingolipids, and dehydroepiandrosterone sulfate and higher acylcarnitines, fatty acids, amino acid derivatives, organic acids, carbohydrates, citric acid cycle metabolites, and trimethylamine oxide were associated with frailer scores. Pathway analyses identified the citric acid cycle as containing more frailty-associated metabolites than expected by chance (p = 0.00005). Calories and protein intake did not differ by vigor to frailty. Frailer Health ABC participants may have lower utilization of energy pathways, potentially as a result of less demand and less efficient utilization of similar amounts of nutrients when compared to more vigorous participants.

Proteomic architecture of frailty across the spectrum of cardiovascular disease.

While frailty is a prominent risk factor in an aging population, the underlying biology of frailty is incompletely described. Here, we integrate 979 circulating proteins across a wide range of physiologies with 12 measures of frailty in a prospective discovery cohort of 809 individuals with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation. Our aim was to characterize the proteomic architecture of frailty in a highly susceptible population and study its relation to clinical outcome and systems-wide phenotypes to define potential novel, clinically relevant frailty biology. Proteomic signatures (specifically of physical function) were related to post-intervention outcome in AS, specifying pathways of innate immunity, cell growth/senescence, fibrosis/metabolism, and a host of proteins not widely described in human aging. In published cohorts, the "frailty proteome" displayed heterogeneous trajectories across age (20-100 years, age only explaining a small fraction of variance) and were associated with cardiac and non-cardiac phenotypes and outcomes across two broad validation cohorts (N > 35,000) over ≈2-3 decades. These findings suggest the importance of precision biomarkers of underlying multi-organ health status in age-related morbidity and frailty.

A metabolomic signature of the APOE2 allele.

With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR < 10%. The group includes 10 glycerolipids and 4 glycerophospholipids that were all higher in E2 carriers compared to E3, with fold change ranging from 1.08 to 1.25. The organic acid 6-hydroxyindole sulfate, previously linked to changes in gut microbiome that were reflective of healthy aging and longevity, was also higher in E2 carriers compared to E3 carriers. Three sterol lipids and one sphingolipid species were significantly lower in carriers of the E2 genotype group. For some of these metabolites, the effect of the E2 genotype opposed the age effect. No metabolites reached a statistically significant association with the E4 group. This work confirms and expands previous results connecting the APOE gene to lipid regulation and suggests new links between the e2 allele, lipid metabolism, aging, and the gut-brain axis.

Oxylipins Associated with D3-Creatine Muscle Mass/Weight and Physical Performance among Community-Dwelling Older Men.

Poor physical function is highly prevalent with aging, and strongly associated with D3-creatine muscle mass/weight. Using metabolomics, we previously identified several triglycerides consisting mostly of polyunsaturated fatty acids that were higher in older adults with good mobility. Here, we sought to further investigate polyunsaturated fatty-acid-related metabolites, i.e., oxylipins, and their associations with D3-creatine muscle mass/weight, gait speed, grip strength, and the Short Physical Performance Battery among 463 older men from the Osteoporotic Fractures in Men Study (MrOS). Oxylipins were measured in fasting serum using liquid chromatography-mass spectrometry. Muscle mass was estimated using D3-creatine dilution and adjusted for body size. We used linear regression to determine oxylipins associated with D3-creatine muscle mass/weight and physical performance, while adjusting for age, education, physical activity, Western dietary pattern, fish oil supplementation, and multiple comparisons. Among 42 oxylipins, none were associated with grip strength and 3 were associated with the Short Physical Performance Battery. In contrast, 18 and 17 oxylipins were associated with D3-creatine muscle mass/weight and gait speed, respectively. A subset of associations between oxylipins and gait speed were partially attenuated by D3-creatine muscle mass/weight. Higher levels of fatty acid alcohol and ketone oxylipins tended to be most strongly associated with gait speed and D3-creatine muscle mass/weight, potentially reflecting anti-inflammatory activity from these select oxylipins in MrOS older men.

Replacing sedentary time with light activity was associated with less adiposity across several depots in African ancestry men.

OBJECTIVE: The aim of this study was to determine whether displacement of sedentary time with activity was cross-sectionally associated with less adiposity among Black Caribbean men in the Tobago Health Study. METHODS: Objectively assessed activity was categorized as sedentary (< 1.5 metabolic equivalents; METs), light (≥ 1.5 to < 3.0 METs), or moderate-to-vigorous (≥ 3.0 METs) using the SenseWear Pro armband. Computed tomography scans of the chest, abdomen, liver, and thigh were used to assess subcutaneous and ectopic adipose tissue. The isotemporal substitution framework paired with linear regression was used to examine associations between activity and adiposity adjusting for age, height, total awake time, and multiple comparisons. RESULTS: On average, participants (n = 271) were 63 years old with 11.2 h/d of sedentary behavior, 4.5 h/d of light activity, and 54 min/d of moderate-to-vigorous activity. Replacing sedentary time with light activity was cross-sectionally associated with lower volume and higher density of abdominal and thigh subcutaneous adiposity, visceral adiposity, abdominal and thigh intermuscular adiposity, and pericardial adiposity and higher liver attenuation (p values ≤ 0.0001). CONCLUSIONS: Displacement of sedentary time with light activity was associated with less adiposity among this Black Caribbean cohort. Interventions focused on increasing light activity may be easier to maintain than higher intensity interventions and thus may be more successful at reducing adiposity.

Using lipid profiling to better characterize metabolic differences in apolipoprotein E (APOE) genotype among community-dwelling older Black men.

Apolipoprotein E (APOE) allelic variation is associated with differences in overall circulating lipids and risks of major health outcomes. Lipid profiling provides the opportunity for a more detailed description of lipids that differ by APOE, to potentially inform therapeutic targets for mitigating higher morbidity and mortality associated with certain APOE genotypes. Here, we sought to identify lipids, lipid-like molecules, and important mediators of fatty acid metabolism that differ by APOE among 278 Black men ages 70-81. Using liquid chromatography-mass spectrometry methods, 222 plasma metabolites classified as lipids, lipid-like molecules, or essential in fatty acid metabolism were detected. We applied principal factor analyses to calculate a factor score for each main lipid category. APOE was categorized as ε4 carriers (n = 83; ε3ε4 or ε4ε4), ε2 carriers (n = 58; ε2ε3 or ε2ε2), or ε3 homozygotes (n = 137; ε3ε3). Using analysis of variance, the monoacylglycerol factor, cholesterol ester factor, the factor for triacylglycerols that consist mostly of polyunsaturated fatty acids, sphingosine, and free carnitine significantly differed by APOE (p < 0.05, false discovery rate < 0.30). The monoacylglycerol factor, cholesterol ester factor, and sphingosine were lower, whereas the factor for triacylglycerols that consisted mostly of polyunsaturated fatty acids was higher among ε2 carriers than remaining participants. Free carnitine was lower among ε4 carriers than ε3 homozygotes. Lower monoacylglycerols and cholesteryl esters and higher triacylglycerols that consist mostly of polyunsaturated fatty acids may be protective metabolic characteristics of APOE ε2 carriers, whereas lower carnitine may reflect altered mitochondrial functioning among ε4 carriers in this cohort of older Black men.

Associations Between Lipoprotein Subfractions and Area and Density of Abdominal Muscle and Intermuscular Adipose Tissue: The Multi-Ethnic Study of Atherosclerosis.

Skeletal muscle quantity and quality decrease with older age, which is partly attributed to ectopic fat infiltration and has negative metabolic consequences. To inform efforts to preserve skeletal muscle with aging, a better understanding of biologic correlates of quantity and quality of muscle and intermuscular adipose tissue (IMAT) is needed. We used targeted lipidomics of lipoprotein subfractions among 947 Multi-Ethnic Study of Atherosclerosis participants to provide a detailed metabolic characterization of area and density of abdominal muscle and IMAT. Serum lipoprotein subfractions were measured at the first visit using 1H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm2) and density (Hounsfield units) were estimated at visit 2 or 3 using computed tomography of the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, rectus abdominis) muscles. We identified lipoprotein subfractions associated with body composition using linear regression adjusting for demographics, lifestyle, and multiple comparisons. Among 105 lipoprotein subfractions, 24 were associated with total muscle area (absolute standardized regression coefficient range: 0.07-0.10, p-values ≤ 0.002), whereas none were associated with total muscle density. When examining muscle subgroups, 25 lipoprotein subfractions were associated with stabilization muscle area, with associations strongest among the obliques. For total IMAT area, there were 27 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.09-0.13, p-values ≤ 0.002). Specifically, 27 lipoprotein subfractions were associated with stabilization IMAT area, with associations strongest among the oblique and rectus abdominis muscles. For total IMAT density, there were 39 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.10-0.19, p-values ≤ 0.003). Specifically, 28 and 33 lipoprotein subfractions were associated with IMAT density of locomotion and stabilization (statistically driven by obliques) muscles, respectively. Higher VLDL (cholesterol, unesterified cholesterol, phospholipids, triglycerides, and apolipoprotein B) and lower HDL (cholesterol and unesterified cholesterol) were associated with higher muscle area, higher IMAT area, and lower IMAT density. Several associations between lipoprotein subfractions and abdominal muscle area and IMAT area and density were strongest among the stabilization muscles, particularly the obliques, illustrating the importance of examining muscle groups separately. Future work is needed to determine whether the observed associations indicate a lipoprotein profile contributing to worse skeletal muscle with fat infiltration.

Metabolic Markers Demonstrate the Heterogeneity of Myosteatosis in Community-Dwelling Older Black Men from the Health ABC Study.

Myosteatosis is a complex condition, associated with aging and diverse pathological conditions (e.g., diabetes), that contributes to mobility disability. Improved characterization of myosteatosis is required to develop targeted interventions to maintain muscle health in aging. We first determined the associations between plasma metabolites and intermuscular fat (IMF) in a cross-sectional analysis of 313 older Black men from Health ABC Study. Using partial correlation analysis, 34/350 metabolites were associated with IMF, the majority of which were lipids and organic acids. Next, we used Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), as an indicator of metabolic health to delineate the anthropometric, functional, and metabolic heterogeneity of myosteatosis in a case-control matching analysis. We categorized participants based on their IMF and HOMA-IR levels into: Low-IMF with Low- versus High-HOMA, as well as High-IMF with Low- versus High-HOMA. Among participants with similar levels of IMF, those who were metabolically unhealthy, i.e., with High HOMA-IR, had higher fat and lean mass, muscle strength, and had hyperglycemia, hypertriglyceridemia, hyperinsulinemia, and higher levels of plasma metabolites belonging to diacylglycerols, triacylglycerols, fatty acid and aminoacyl-tRNA biosynthesis pathways versus those with Low HOMA-IR. In summary, HOMA-IR delineates the heterogeneity of myosteatosis by distinguishing metabolically healthy versus unhealthy individuals.

A Metabolite Composite Score Attenuated a Substantial Portion of the Higher Mortality Risk Associated With Frailty Among Community-Dwelling Older Adults.

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.

Circulating Procollagen Type III N-Terminal Peptide and Physical Function in Adults from the Long Life Family Study.

BACKGROUND: Circulating levels of procollagen type III N-terminal peptide (P3NP) may reflect increased fibrosis of skeletal muscle and other tissues with aging. Herein, we tested if P3NP was associated with baseline and 7-year change in physical function. METHOD: Participants (n = 400) were from the Long Life Family Study, a study of exceptional familial longevity. Plasma P3NP concentration was measured using a sandwich enzyme-linked immunosorbent assay (inter-assay coefficient of variation <5.5%). At baseline and 7-year follow-up visits, physical function was measured using the Short Physical Performance Battery (SPPB score 0-12), which consists of gait speed, balance, and chair-rise tests. Grip strength was measured using a handheld dynamometer. The association between log-transformed P3NP and physical function was examined using generalized estimating equations adjusted for familial relatedness, age, sex, height, weight, lifestyle characteristics, liver function, kidney function, lung function, and chronic disease prevalence. RESULTS: Participants were aged 73.1 ± 15.2 years (range: 39-104), 54% female, had body mass index of 26.6 ± 4.3 kg/m2, and gait speeds of 1.0 ± 0.3 m/s. One standard deviation higher log-transformed P3NP was related to worse baseline SPPB score (ß = -0.9points), gait speed (ß = -0.05m/s), chair-rises per-second (ß = -0.46chair-rises/10 seconds), and grip strength (ß = -2.0kg; all p < .001). Higher P3NP was also associated with greater declines in gait speed (ß = -1.41, p < .001) and transitioning to being unable to perform chair-rises (ß = 0.41, p < .001) after 7 years. CONCLUSION: Plasma P3NP may be a strong, novel biomarker of current and future physical function. Future research is needed to extend our findings to other cohorts and determine mechanisms underlying these associations.

Metabolites Associated with Walking Ability Among the Oldest Old from the CHS All Stars Study.

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.

Prevalence, Incidence, and Risk Factors for Overall, Physical, and Cognitive Independence Among Those From Exceptionally Long-Lived Families: The Long Life Family Study.

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.

Quantifying and Classifying Physical Resilience Among Older Adults: The Health, Aging, and Body Composition Study.

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.

Heterogeneity of healthy aging: comparing long-lived families across five healthy aging phenotypes of blood pressure, memory, pulmonary function, grip strength, and metabolism.

Five healthy aging phenotypes were developed in the Long Life Family Study to uncover longevity pathways and determine if healthy aging across multiple systems clustered in a subset of long-lived families. Using blood pressure, memory, pulmonary function, grip strength, and metabolic measures (body mass index, waist circumference and fasting levels of glucose, insulin, triglycerides, lipids, and inflammatory markers), offspring were ranked according to relative health using gender-, age-, and relevant confounder-adjusted z-scores. Based on our prior work, families met a healthy aging phenotype if ≥ 2 and ≥ 50% of their offspring were exceptionally healthy for that respective phenotype. Among 426 families, only two families met criteria for three healthy aging phenotypes and none met criteria for four or more healthy aging phenotypes. Using Spearman correlation, the proportion of offspring within families with exceptionally healthy pulmonary function was correlated with the proportion of offspring within families with exceptional strength (r = 0.19, p = 0.002). The proportion of offspring within families meeting the healthy blood pressure and metabolic phenotypes were also correlated (r = 0.14, p = 0.006), and more families were classified as meeting healthy blood pressure and metabolic phenotypes (Kappa = 0.10, p = 0.02), as well as the healthy pulmonary and blood pressure phenotypes than expected by chance (Kappa = 0.09, p = 0.03). Other phenotypes were weakly correlated (|r| ≤ 0.07) with low pairwise agreement (Kappa ≤ 0.06). Among these families selected for familial longevity, correspondence between healthy aging phenotypes was weak, supporting the heterogeneous nature of longevity and suggesting biological underpinnings of each individual phenotype should be examined separately to determine their shared and unique determinants.

Metabolites Associated with Vigor to Frailty Among Community-Dwelling Older Black Men.

Black versus white older Americans are more likely to experience frailty, a condition associated with adverse health outcomes. To reduce racial disparities in health, a complete understanding of the pathophysiology of frailty is needed. Metabolomics may further our understanding by characterizing differences in the body during a vigorous versus frail state. We sought to identify metabolites and biological pathways associated with vigor to frailty among 287 black men ages 70-81 from the Health, Aging, and Body Composition study. Using liquid chromatography-mass spectrometry, 350 metabolites were measured in overnight-fasting plasma. The Scale of Aging Vigor in Epidemiology (SAVE) measured vigor to frailty based on weight change, strength, energy, gait speed, and physical activity. Thirty-seven metabolites correlated with SAVE scores (p < 0.05), while adjusting for age and site. Fourteen metabolites remained significant after multiple comparisons adjustment (false discovery rate < 0.30). Lower values of tryptophan, methionine, tyrosine, asparagine, C14:0 sphingomyelin, and 1-methylnicotinamide, and higher values of glucoronate, N-carbamoyl-beta-alanine, isocitrate, creatinine, C4-OH carnitine, cystathionine, hydroxyphenylacetate, and putrescine were associated with frailer SAVE scores. Pathway analyses identified nitrogen metabolism, aminoacyl-tRNA biosynthesis, and the citric acid cycle. Future studies need to confirm these SAVE-associated metabolites and pathways that may indicate novel mechanisms involved in the frailty syndrome.

A novel healthy metabolic phenotype developed among a cohort of families enriched for longevity.

BACKGROUND: Long-lived individuals and their offspring have healthier metabolic characteristics than expected, such as more favorable levels of fasting glucose, insulin, and lipids than controls without longevity. Dysregulation in metabolic pathways has also shown to predict accelerated aging. Using information from the Long Life Family Study (LLFS), a multi-center study of two-generation families selected for exceptional longevity, we developed an indicator of healthy metabolism to determine whether metabolic health was more prevalent in a subset of LLFS families and whether it was heritable and associated with other metrics of healthy aging. METHODS: A Latent Profile Analysis was applied to age- and gender-adjusted z-scores of fasting levels of glucose, insulin, triglycerides, and high-density lipoprotein cholesterol, body mass index, waist circumference, interleukin-6, and C-reactive protein. Families were defined as meeting the healthy metabolic phenotype if ≥2 and ≥50% of their offspring were classified into a latent subgroup with a profile of healthier metabolic markers than expected given age and gender relative to all LLFS offspring. RESULTS: The log odds of being classified into the latent subgroup with a healthy profile of metabolic markers was heritable (h2 = 0.40, p < 0.001). Among 388 families, 39 (10%) met the healthy metabolic phenotype. Participants from these families had somewhat better cognition than those from remaining families. Proband-generation participants from families who met the healthy metabolic phenotype also had better pulmonary functioning and physical performance. CONCLUSIONS: The better cognition, pulmonary function, and physical performance among probands from families with the healthy metabolic phenotype may indicate that this subset of LLFS families have a more extreme longevity phenotype than other LLFS families since cognitive, physical, and pulmonary function are top mortality predictors for older adults. Future work is needed to determine if rare or protective alleles confer a healthy metabolic phenotype in this subset of LLFS families with exceptional metabolism.

Metabolite Profiles of Healthy Aging Index Are Associated With Cardiovascular Disease in African Americans: The Health, Aging, and Body Composition Study.

Background: Metabolic dysfunction is a hallmark of differential aging, specifically in African Americans. Investigation of systemic metabolic state, multiorgan aging, and long-term cardiovascular outcome in African Americans has not been reported. Methods: We studied 291 African American males in the Health, Aging, and Body Composition (Health ABC) study to identify circulating metabolites related to the Newman healthy aging index (HAI; a multiparametric score comprised of blood pressure, blood glucose, neurocognitive function, creatinine, and forced vital capacity). We examined the relationship of selected metabolites differential abundant at the extremes of HAI with long-term survival from cardiovascular mortality. Results: The median age was 73 years. We identified 19 metabolites differentially expressed in blood in 86 study participants at the extremes of HAI (HAI 0-3: N = 30 vs 8-10: N = 56). At a median follow-up of 10 years, 78 participants (27 per cent) died from cardiovascular causes. After adjustment for age, body mass index, presence of prevalent cardiovascular disease, creatinine, and HAI, six of these 19 metabolites were associated with long-term cardiovascular mortality. Although several metabolites had been previously reported in Caucasians (eg, isocitrate), we identified several metabolites with unreported association with cardiac disease. Metabolites associated with HAI and cardiac death in African Americans specified pathways relevant to nitric oxide, oxidative stress, mitochondrial function, urea cycle, and gut microbial metabolism. Conclusions: Metabolite profiling in African Americans identified known and novel metabolic pathways linked to HAI and cardiovascular death. Further investigation in larger patient cohorts is required to uncover race-based signatures of cardiovascular disease with aging.

Mortality in Relation to Changes in a Healthy Aging Index: The Health, Aging, and Body Composition Study.

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.