Skeletal muscle is a crucial facilitator of many of the effects of exercise on metabolic health. Intrinsic myocellular mechanisms, exercise-induced myokine secretion, and crosstalk between multiple organ systems contribute to the maintenance of energy homeostasis, cardiovascular health, strength, cognition, and quality of life. Investigating the molecular underpinnings of the skeletal muscle response to exercise from multiple perspectives, including the genetic, physiological, and environmental factors leading to metabolic dysfunction, has advanced our understanding of disease risk and helped identify avenues for the prevention and treatment of metabolic disorders and chronic diseases. The National Institutes of Health-funded Boston Area Nutrition Obesity Research Center, in partnership with the Harvard Medical School Division of Nutrition, hosted its 26th Annual Symposium, Muscle Movement and Metabolism: Exercise and Skeletal Muscle as Mediators of Health," in June of 2025. Speakers presented novel research and unique perspectives on exercise and skeletal muscle as key determinants of health. This manuscript synthesizes the symposium's major themes: 1) physiological and molecular mechanisms of exercise, 2) clinical implications of physical inactivity and reduced muscle function, and 3) individual variability and personalized medicine. By bridging mechanistic and clinical insights with principles of personalized medicine, the symposium provided key insights into the current landscape of treatments for metabolic diseases and evidence-based strategies for disease prevention.

BACKGROUND:Aging is accompanied by reduced muscle protein synthesis and increased circulating acid, both of which contribute to declines in muscle health. OBJECTIVES:To determine the effects of whey protein (WP) and alkali (potassium bicarbonate, KHCO3) supplementation on muscle performance and mass in healthy older adults. METHODS:In this randomized, 2 × 2 factorial, placebo-controlled study, healthy adults aged ≥65 years were assigned to either WP (1.5 g/kg/d) plus KHCO3 (81 mmol/d), WP plus placebo-KHCO3, placebo-WP plus KHCO3, or double placebo. Double leg press muscle power (primary outcome), physical performance, lean mass by dual energy x-ray absorptiometry, muscle mass by D3-creatine dilution, and serum insulin-like growth factor 1 (IGF-1) were measured at baseline and 24 weeks. Primary analyses estimated main effects of WP compared with placebo-WP and KHCO3 compared with placebo-KHCO3 using factorial comparisons "at-the-margins," following CONSORT/SPIRIT recommendations for factorial trials. Between-group differences in the 24-wk outcomes were estimated using analysis of covariance adjusted for baseline value, age, and sex. RESULTS:In the intention-to-treat sample (n = 128), 47.7% were female, mean ± SD age was 74 ± 6 y, and baseline protein intake was 0.85 ± 0.30 g/kg/d. Neither WP nor KHCO3 affected muscle power compared with their respective placebo {WP to placebo-WP difference 4.7 watts [95% confidence interval (CI): -21.1,30.5; P = 0.72]; KHCO3 to placebo-KHCO3 difference -13.6 watts [95% CI: -39.6, 12.4; P = 0.30]}. No group differences were noted in physical performance or muscle mass. However, 24-wk mean IGF-1 level was higher in the WP and KHCO3 groups compared with their respective placebo [WP to placebo-WP difference 14.2 ng/mL (95% CI: 7.5, 21.0; P < 0.01); KHCO3 to placebo-KHCO3 difference 7.2 ng/mL (95% CI: 0.4, 13.9; P = 0.04)]. CONCLUSIONS:In healthy free-living older adults reporting a protein intake at the current recommended daily allowance, neither increasing protein to 1.5 g/kg/d with WP nor adding a KHCO3 supplement for 24 wk improved measures of muscle power, physical performance, or muscle mass despite achieving higher circulating IGF-1 levels. CLINICAL TRIAL REGISTRY NUMBER:This trial was registered as NCT04048616 at https://clinicaltrials.gov/study/NCT04048616?term=ceglia&rank=1.

The Physiology Of the WEight Reduced State (POWERS) study is a multi-center NIH-funded clinical trial designed to determine the physiological basis for variability in weight loss maintenance among adults with obesity following participation in a behavioral weight loss program. Two hundred and five healthy adults, aged 25–<60 years, with body mass index 30–<40 kg/m2 complete up to four serial assessments (before weight loss; after ≥7% weight loss; and four and 12 months later). This report, one in a five-part series on the POWERS study design, provides the rationale for and description of behavioral measures. Standardized laboratory meals are used to measure energy intake and eating-related behaviors. Behavioral and neurocognitive factors related to eating (e.g., food-choice decision making, taste preferences, reward, self-control) are assessed via computer-based tasks and self-report questionnaires. Functional and structural neuroimaging augment the behavioral assessments by identifying underlying neural circuitry. Psychological factors related to weight regulation (e.g., self-monitoring, stigma, self-efficacy) are assessed via self-report questionnaires. Free-living physical activity and sleep are measured via accelerometry, polysomnography and self-report questionnaires. We will evaluate how changes, integrated values and patterns in these predictors and components of energy intake and energy expenditure contribute to individual variability in weight change during the 12 months following weight loss. We anticipate that extensive phenotyping using sophisticated eating behavior paradigms and assessments of critical components of energy expenditure before and after weight loss will lead to improved predictions of successful weight loss maintenance. This, in turn, will inform more effective treatments for long-term sustained weight loss.

BACKGROUND:Sarcopenia is a progressive muscle disorder that may lead to mobility disability. No pharmaceutical interventions are currently available, and treatment relies on physical exercise and nutrition. The aim of SARA-INT was to investigate whether BIO101 (20-hydroxyecdysone), an activator of the MAS receptor, is safe and improves muscle function and physical performance of community dwelling older sarcopenic patients. METHODS:SARA-INT was a randomised three-arm interventional study (BIO101 175 mg bid /350 mg bid/placebo) with a planned 6-month treatment (up to 9 months in 50 subjects). Eligibility criteria for sarcopenia were meeting FNIH criteria for sarcopenia and Short Physical Performance Battery (SPPB) score ≤ 8/12 in men and women aged ≥ 65 years. Primary endpoint was the change from baseline (CFB) in gait speed (GS) measured by 400-m walking test (400MWT), secondary endpoints being CFB in other physical performance tests. RESULTS:A total of 233 participants were randomised (mean age 75.5 ± 7.12; 54.3% female), of whom 232 and 156 were included in the full analysis set (FAS) and per-protocol (PP) populations, respectively. Due to COVID-19 pandemic, 55% of on-site end-of-treatment efficacy assessments were lost, reducing the studies' power. In the primary analysis (mix of 6/9 months), BIO101 350 mg bid treatment after 6/9 months was associated with an improvement in the 400MWT of 0.07 m/s versus placebo in the FAS population (not significant) and of 0.09 m/s in the PP population (p = 0.008). BIO101 350 mg bid treatment effect on the 400MWT GS was also observed in pre-defined subpopulations at higher risk of mobility disability (0.0474 m/s for slow walkers, 0.0521 m/s for obese and 0.0662 m/s for chair stand sub-score ≤ 2 from SPPB in the FAS population), with a trend for a dose response. BIO101 showed a good safety profile at both doses (number of subjects with related treatment emergent adverse events (TEAEs) of 13 (16.0%), 10 (13.3%) and 10 (13.5%) in the placebo, 175 mg and 350 mg BIO101 groups, respectively). CONCLUSIONS:After 6 to 9 months of treatment, BIO101 350 mg bid showed strong trends consistent with a clinically relevant effect on the 400MWT GS, close to the minimal clinically important difference (MCID) in sarcopenia (0.1 m/s). This was also shown in predefined subpopulations at higher risk of mobility disability. BIO101 showed a good safety profile. Taken together, efficacy and safety data of this Phase 2 trial encourage us to pursue further development of BIO101 for the treatment of sarcopenia.

Obesity accelerates the onset and progression of age-related conditions. In preclinical models, obesity drives cellular senescence, a cell fate that compromises tissue health and function, in part through a robust and diverse secretome. In humans, components of the secretome have been used as senescence biomarkers that are predictive of age-related disease, disability, and mortality. Here, using biospecimens and clinical data from two large and independent cohorts of older adults, we tested the hypothesis that the circulating concentrations of senescence biomarkers are influenced by body mass index. After adjusting for age, sex, and race, we observed significant increases in activin A, Fas, MDC, PAI1, PARC, TNFR1, and VEGFA, and a significant decrease in RAGE, from normal weight, to overweight, to obesity body mass index categories by linear regression in both cohorts (all p < .05). These results highlight the influence of body mass index on circulating concentrations of senescence biomarkers.

OBJECTIVES:Cellular senescence, characterized by a marked and multifactorial senescence-associated secretory phenotype (SASP), is a potential unifying mechanism of aging and chronic disease. Most studies of the SASP have focused on frailty and other functional outcomes. Senescent cells have been detected in the brains of patients with Alzheimer's disease, but few studies have examined associations between plasma SASP markers and cognition. The objective of this study was to examine the cross-sectional and longitudinal associations between plasma SASP markers and mild cognitive impairment among older adults at high risk of mobility disability. DESIGN:The Lifestyle Interventions for Elders (LIFE) study was a randomized controlled trial of a group-based physical activity program compared to a "successful aging" health education program to assess effects on major mobility disability that was conducted from February 2010 to December 2013. SETTING:Recruitment occurred at eight centers in the United States. PARTICIPANTS:We included 1,373 participants enrolled in the study with baseline measures of 27 biomarkers of cellular senescence and adjudication of mild cognitive impairment (MCI) and dementia at baseline and 24-month follow-up. At baseline, participants were aged 70-80, sedentary, and at high risk of mobility disability. MEASUREMENTS:A neuropsychological assessment was administered at baseline and 24 months post-randomization. At both timepoints, a clinical adjudication committee determined whether individuals had a diagnosis of cognitively normal, MCI, or dementia; individuals with dementia at baseline were excluded. The concentrations of 26 of the 27 plasma proteins identified as components of the SASP were measured with commercially available Luminex xMAP multiplex magnetic bead-based immunoassays analyzed on the MAGPIX System while 1 protein (Activin A) was measured using an enzyme-linked immunosorbent assay. RESULTS:Logistic regression models were used to examine the associations of each senescence biomarker, in quartiles, with baseline or incident MCI. Models stratified by clinical site and adjusted for intervention assignment, age, gender, race, and education. Among 1,373 participants, 117 (8.5%) were diagnosed with MCI at baseline. Increasing quartiles of myeloperoxidase (MPO) was associated with higher odds of MCI compared to quartile 1 (Q2: OR = 1.34, 95% CI: 0.74-2.45; Q3: OR = 1.43, 95% CI: 0.80-2.59; Q4: OR = 1.79, 95% CI: 1.02-3.22). Additionally, matrix metalloproteinase 1 (MMP1) quartiles 2-4 had lower odds of MCI compared to quartile 1 (Q2: OR = 0.61, 95% CI: 0.35-1.02; Q3: OR = 0.58, 95% CI: 0.33-0.98; Q4: OR = 0.64, 95% CI: 0.37-1.08). Of the 1,256 cognitively unimpaired participants at baseline, 141 (11.2%) were diagnosed with incident MCI or dementia at the 24-month follow-up. Compared to quartile 1, increasing baseline quartiles of MPO (Q2: OR = 1.10, 95% CI: 0.63-1.92; Q3: OR = 1.36, 95% CI: 0.80-2.33; Q4: OR = 1.92, 95% CI: 1.16-3.25) and matrix metalloproteinase 7 (MMP7, Q2: OR = 0.88, 95% CI: 0.47-1.62; Q3: OR = 1.46, 95% CI: 0.85-2.55; Q4: OR = 2.14, 95% CI: 1.28-3.65) were associated with increased odds of MCI or dementia at 24 months. CONCLUSIONS:Among older adults at high risk of mobility disability, high plasma MPO was cross-sectionally and, along with MMP7, longitudinally associated with increased odds of MCI and dementia. In contrast, high MMP1 was cross-sectionally associated with reduced odds of MCI.

ABSTRACT Background The Sarcopenia and Quality of Life (SarQoL) questionnaire is recognized as the only disease‐specific patient‐reported outcome measure (PROM) for assessing sarcopenia‐related HRQoL. This systematic review and meta‐analysis aimed to provide a quantitative summary of all evidence reported on the reliability, validity, responsiveness and floor/ceiling effects of SarQoL in older adults. Methods Following PRISMA‐COSMIN guidelines, a systematic search for studies evaluating the psychometric properties of SarQoL (i.e., reliability, validity, responsiveness and floor and ceiling effects) in older people was conducted on MEDLINE (via OVID), PsycINFO, Scopus and EMBASE. Studies published between 2013 and November 2024 using a consensual definition of sarcopenia were included. Study selection and data extraction were made by two independent reviewers. A random‐effects model meta‐analysis was applied. PROSPERO registration: CRD42024546880. Results From 411 studies identified by the search strategy, 25 fulfilled the inclusion criteria, including 4585 community‐dwelling individuals, of which 1311 were diagnosed as sarcopenic. SarQoL demonstrated high reliability (pooled Cronbach's alpha values consistently exceeding 0.80) and excellent test–retest reliability (pooled ICC = 0.98). Construct validity was confirmed with strong convergent correlations (pooled r > 0.54) with related dimensions of generic SF‐36 and EQ‐5D and weaker divergent correlations (pooled r < 0.47). Responsiveness, evaluated in two studies using different methodologies, supported the ability of SarQoL to detect meaningful changes in HRQoL. The certainty of evidence was rated as high for reliability, validity and responsiveness. Conclusion This meta‐analysis consolidates a decade of evidence and confirms the strong psychometric properties of SarQoL, with a high level of evidence.

The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force convened in March 2024 to address patient-reported outcomes measures (PROMs) in the field of sarcopenia. PROMs are crucial to enhance healthcare services at both individual and societal levels. PROMs complement objective outcome measures by capturing insights that patients are best suited to judge. In recent years, there has been an increase in the recognition of PROMs’ importance within clinical trials by pharmaceutical industries and regulatory agencies. Consequently, it has become imperative to develop valid and reliable tools tailored to capture various aspects of patient's experience and health status. This report aims to present the state-of-the-art available and validated PROMs for sarcopenia that can be used within clinical settings by various stakeholders, and to highlight several research gaps and barriers that need to be addressed to expedite and improve the use of these outcome measures within the context of clinical trials.

Background: Chronic inflammation contributes to functional decline in older adults, yet interventions targeting inflammatory pathways have shown inconsistent results. Metabolomics offers a promising approach to identify biological heterogeneity and uncover molecular signatures underlying differential functional trajectories. Objective: Our objective was to examine whether untargeted serum metabolomics can identify metabolic signatures associated with baseline physical function, functional trajectories, and treatment response in older adults with chronic inflammation participating in the ENRGISE trial. Methods: We performed untargeted metabolomic profiling on serum samples (n = 731) collected at baseline, 6, and 12 months from participants (mean age ≥ 70) enrolled in the ENRGISE pilot randomized trial. Participants were randomized to losartan, omega-3 supplementation, both, or placebo. Functional measures included grip strength and 400 m gait speed. Group-based trajectory modeling classified participants into functional trajectories over 12 months. Partial least squares-discriminant analysis (PLS-DA) and pathway enrichment (mummichog algorithm) were used to identify differentially abundant metabolites and perturbed pathways. Results: Baseline metabolomic profiles differed by physical function status. Participants with low grip strength showed enrichment in vitamin A metabolism pathways, while slower gait speed was associated with higher levels of prostaglandin and eicosanoid metabolites. Baseline metabolic profiles distinguished individuals who later declined versus improved in functional performance. Omega-3 supplementation, but not losartan, induced distinct changes in lipid-related pathways, including fatty acid activation, omega-3 metabolism, and prostaglandin biosynthesis, indicating that individuals responded to these interventions metabolically despite null clinical outcomes. Conclusions: Serum metabolomic signatures were associated with baseline physical function, predicted functional trajectories, and revealed pharmacologic activity of omega-3 supplementation. These findings support the use of metabolomics to uncover biological heterogeneity and inform precision geroscience strategies in aging populations.

Obesity is a multifactorial disease caused by physiological and environmental factors. Adults who have obesity are at increased risk for several additional chronic and infectious diseases, resulting in reduced life expectancy, compared to those with lower body mass indices. Weight loss (WL) has several clinical benefits to reducing these risks. However, among those who intentionally lose weight, it is common for some, or all, of the lost weight to be regained. There is evidence that changes affecting energy intake or expenditure, including metabolic adaptations in the weight-reduced state, work against maintaining WL. The Physiology Of the WEight Reduced State consortium (POWERS) designed a study to describe behavioral and metabolic adaptations to the weight reduced state and to examine their contributions to weight variability following WL. This is accomplished by quantifying physiological, psychosocial, behavioral and other factors before and after a behavioral intervention that induces WL. The primary goal of POWERS is to identify factors that explain the variability in weight change following intentional weight loss. This multi-center project includes a POWERS-designed WL intervention implemented at two clinical centers for 205 enrolled participants. Those losing at least 7% of their pre-intervention weight and attaining weight stability are followed in a 1-year observational phase that includes sequential physiological and behavioral phenotyping. It is anticipated that 70% of those enrolled in the WL program will enter the observational phase of the study and that 100 will complete the study. The primary outcome is weight change during the observational period with primary independent variables measuring energy intake and energy expenditure. Detailed endophenotypes of energy intake and energy expenditure are assessed using a combination of biospecimens, neuroimaging, objective measures (e.g., doubly labeled water, calorimetry, accelerometry, polysomnography), self-report questionnaires, and interviews to address their contributions to weight change variability up to 1 year following WL.

Aging is associated with a progressive change of body composition characterized by muscle mass decline and accumulation of adipose tissue that can lead to sarcopenia and obesity, respectively. The prevalence of sarcopenia is poorly known given the different parameters and thresholds in proposed definitions. The combination of obesity (defined as a percentage of body fat mass of > 25

Aging, a universal and inevitable process, is characterized by a progressive accumulation of physiological alterations and functional decline over time, leading to increased vulnerability to diseases and ultimately mortality as age advances. Lifestyle factors, notably physical activity (PA) and exercise, significantly modulate aging phenotypes. Physical activity and exercise can prevent or ameliorate lifestyle-related diseases, extend health span, enhance physical function, and reduce the burden of non-communicable chronic diseases including cardiometabolic disease, cancer, musculoskeletal and neurological conditions, and chronic respiratory diseases as well as premature mortality.Physical activity influences the cellular and molecular drivers of biological aging, slowing aging rates—a foundational aspect of geroscience. Thus, PA serves both as preventive medicine and therapeutic agent in pathological states. Sub-optimal PA levels correlate with increased disease prevalence in aging populations. Structured exercise prescriptions should therefore be customized and monitored like any other medical treatment, considering the dose-response relationships and specific adaptations necessary for intended outcomes. Current guidelines recommend a multifaceted exercise regimen that includes aerobic, resistance, balance, and flexibility training through structured and incidental (integrated lifestyle) activities.Tailored exercise programs have proven effective in helping older adults maintain their functional capacities, extending their health span, and enhancing their quality of life. Particularly important are anabolic exercises, such as Progressive resistance training (PRT), which are indispensable for maintaining or improving functional capacity in older adults, particularly those with frailty, sarcopenia or osteoporosis, or those hospitalized or in residential aged care. Multicomponent exercise interventions that include cognitive tasks significantly enhance the hallmarks of frailty (low body mass, strength, mobility, PA level, and energy) and cognitive function, thus preventing falls and optimizing functional capacity during aging. Importantly, PA/exercise displays dose-response characteristics and varies between individuals, necessitating personalized modalities tailored to specific medical conditions. Precision in exercise prescriptions remains a significant area of further research, given the global impact of aging and broad effects of PA.Economic analyses underscore the cost benefits of exercise programs, justifying broader integration into health care for older adults. However, despite these benefits, exercise is far from fully integrated into medical practice for older people. Many healthcare professionals, including geriatricians, need more training to incorporate exercise directly into patient care, whether in settings including hospitals, outpatient clinics, or residential care. Education about the use of exercise as isolated or adjunctive treatment for geriatric syndromes and chronic diseases would do much to ease the problems of polypharmacy and widespread prescription of potentially inappropriate medications. This intersection of prescriptive practices and PA/exercise offers a promising approach to enhance the well-being of older adults. An integrated strategy that combines exercise prescriptions with pharmacotherapy would optimize the vitality and functional independence of older people whilst minimizing adverse drug reactions.This consensus provides the rationale for the integration of PA into health promotion, disease prevention, and management strategies for older adults. Guidelines are included for specific modalities and dosages of exercise with proven efficacy in randomized controlled trials. Descriptions of the beneficial physiological changes, attenuation of aging phenotypes, and role of exercise in chronic disease and disability management in older adults are provided. The use of exercise in cardiometabolic disease, cancer, musculoskeletal conditions, frailty, sarcopenia, and neuropsychological health is emphasized. Recommendations to bridge existing knowledge and implementation gaps and fully integrate PA into the mainstream of geriatric care are provided. Particular attention is paid to the need for personalized medicine as it applies to exercise and geroscience, given the inter-individual variability in adaptation to exercise demonstrated in older adult cohorts. Overall, this consensus provides a foundation for applying and extending the current knowledge base of exercise as medicine for an aging population to optimize health span and quality of life.

Gait speed and grip strength are widely used measures of physical function in older adults and are predictive of disability, hospitalization, and mortality. However, there is a limited understanding of the long-term trajectories of these measures and which older adults are at the highest risk of functional decline. We used data from the National Health and Aging Trends Study (NHATS) to identify subgroups of community-dwelling older adults with distinct 10-year trajectories in gait speed and grip strength and to examine the baseline factors associated with these patterns. The sample included 4961 adults aged 65 years and older who completed gait speed and grip strength assessments in 2011 and at least one subsequent wave between 2013 and 2021. Using latent class growth analysis, we identified three trajectories for each measure: worsening, stable, and improving. More than one-third of participants were in the worsening group for at least one measure. In multinomial logistic regression models, lower income, Medicaid coverage, cognitive impairment, and multiple chronic conditions were associated with membership in worsening trajectory groups. These findings highlight the heterogeneity of physical aging and the importance of the early identification of older adults who may benefit from targeted interventions to maintain function and independence over time.

With the increasing number of elderly individuals worldwide, the prevalence of age-related loss of muscle mass, referred to as sarcopenia, is expected to increase. Sarcopenia is a relatively new recognized syndrome, which is thought to affect 13% individuals worldwide, and the significant efforts made by different groups have advanced our understanding of the diagnosis, treatment, and natural history of this condition. However, the challenge is now to standardize its measurement and diagnosis to facilitate research in this area and a greater understanding of this condition and its management between clinicians and researchers. The Global Leadership Initiative on Sarcopenia (GLIS) is at the forefront of an international effort to produce standardized definition of sarcopenia. Setting a definition for sarcopenia entails several considerations and trade-offs. In this critical review, we have addressed key challenges driving the process of standardizing the definition, while delving into future avenues in sarcopenia research. Establishing a clear consensus on the working definition of sarcopenia is essential not only for advancing research in this field but also for assessing the prognostic implications of diagnosing sarcopenia and determining the most suitable treatment for affected patients.

Sarcopenia is the accelerated loss of skeletal muscle mass and function commonly, but not exclusively, associated with advancing age. It is observed across many species including humans in whom it can lead to decline in physical function and mobility as well as to increased risk of adverse outcomes including falls, fractures and premature mortality. Although prevalence estimates vary because sarcopenia has been defined in different ways, even using a conservative approach, the prevalence is between 5% and 10% in the general population. A life course framework has been proposed for understanding not only the occurrence of sarcopenia in later life but also influences operating at earlier life stages with potentially important implications for preventive strategies. Harnessing progress in understanding the hallmarks of ageing has been key to understanding sarcopenia pathophysiology. Considerable convergence in approaches to diagnosis of sarcopenia has occurred over the last 10 years, with a growing emphasis on the central importance of muscle strength. Resistance exercise is currently the mainstay of treatment; however, it is not suitable for all. Hence, adjunctive and alternative treatments to improve quality of life are needed. An internationally agreed approach to definition and diagnosis will enable a step change in the field and is likely to be available in the near future through the Global Leadership Initiative in Sarcopenia.

OBJECTIVES:Prior research suggested that loss of appetite (LOA) among adults with Medicare fee-for-service (FFS) insurance in the United States increased the risk of mortality within 1 year; those findings were not adjusted for risk factors and confounders. The objective of this study was to compare the risk of mortality among Medicare FFS beneficiaries with LOA to a control group without LOA while controlling or adjusting for age, comorbidities, body mass index (BMI), and weight loss. DESIGN:Retrospective and observational analysis of Medicare FFS health insurance claims data from October 1, 2015 to December 31, 2021. SETTING:Claims from all settings (e.g., hospital inpatient/outpatient, office, assisted living facility, skilled nursing facility, hospice, rehabilitation facility, home) were included in these analyses. PARTICIPANTS:The LOA group included all individuals aged 65-115 years with continuous Medicare FFS medical coverage (Parts A and/or B) for at least 12 months before a claim with ICD-10 diagnosis code "R63.0 Anorexia". The control group was drawn from individuals aged 65-115 years with continuous Medicare FFS coverage who did not have a diagnosis of R63.0. Individuals with LOA were matched 1:3 to those in the control group based on age, sex, and race/ethnicity. MEASUREMENTS:Mortality in the LOA group was compared to mortality in the control group using Kaplan-Meier and Cox regression analyses and stratified or adjusted in terms of Charlson Comorbidity Index (CCI), claims-based frailty index (CFI), BMI, and weight loss. RESULTS:The study population of 1,707,031 individuals with LOA and 5,121,093 controls without LOA was 61.7% female and 82.2% White. More individuals with LOA compared with the control group had a CCI score 5+ (52.4% vs. 19.4%), CFI score 5+ (31.6% vs. 6.4%), and BMI < 20 kg/m2 (11.2% vs. 2.1%). Median follow-up was 12 months (individuals with LOA) and 49 months (control group). In a matched population, the risk of mortality was significantly higher (unadjusted hazard ratio 4.40, 95% confidence interval 4.39-4.42) for individuals with LOA than the control group. Median survival time was 4 months (individuals with LOA) and 26 months (control group); differences in survival time remained when stratifying by CCI, BMI, and weight loss. CONCLUSION:Individuals with LOA had a substantially increased risk of death even after matching for age, sex, race/ethnicity, and adjusting for comorbidities. These findings highlight the burden of illness in older adults with LOA and the need for therapies.