Importance Studying how to prevent or delay not just 1 disease but multiple chronic conditions is of great importance for public health; however, few interventions have demonstrated success during long-term follow-up. Objective To examine the association of lifestyle or metformin compared with placebo on long-term multimorbidity in adults with prediabetes. Design, Setting, and Participants Observational follow-up cohort study of a randomized clinical trial conducted at 27 sites in the United States from June 1, 1996, to December 31, 2021. From June 1, 1996, through May 28, 1999, 3234 adults at high risk of diabetes enrolled in the 3-year Diabetes Prevention Program (DPP). They were subsequently enrolled in the DPP Outcomes Study (DPPOS). Of this cohort, Centers for Medicare & Medicaid Services (CMS) morbidity data were available through 2021 for 1173 participants who provided consent. Data were analyzed from June 5, 2024, to November 7, 2025. Exposures Participants in DPP were randomly assigned to intensive lifestyle intervention, metformin, or placebo. During DPPOS, medications were unmasked with discontinuation of placebo; metformin was continued. Group booster classes were offered to the lifestyle group semiannually and all participants were offered lifestyle classes quarterly until 2014. Main Outcomes and Measures The primary outcome was multimorbidity (presence of ≥2 of 15 prevalent conditions, defined in CMS’ Chronic Condition Data Warehouse and adapted for Medicare Advantage encounters). Cox proportional hazard models were applied to estimate associations between randomized treatment groups and time to development of outcomes. Results Of the 1173 participants (median age, 74 years [IQR, 70-80]; 795 [68%] were female), 997 (85%) experienced greater than or equal to 2 conditions (median, 5 [IQR, 3-7]) by the end of follow-up (316 of 385 [82%], 327 of 385 [85%], and 350 of 403 [87%], respectively, among lifestyle, metformin, and placebo groups). The risk of multimorbidity was lower among lifestyle compared with placebo participants (hazard ratio [HR], 0.79; 95% CI, 0.68-0.93) after adjustment for relevant covariates. There was no difference between participants in the metformin and placebo groups (HR, 0.91; 95% CI, 0.78-1.07). These relationships persisted when diabetes was excluded from the multimorbidity definition. When restricted to dyads of the costliest conditions, the association with lifestyle vs placebo yielded an HR of 0.57 (95% CI, 0.38-0.85). Conclusions and Relevance Among adults with prediabetes at baseline, lifestyle intervention, but not metformin, was associated with a lower burden of multimorbidity. Lifestyle programs may persistently lower the development of chronic conditions. Trial Registration ClinicalTrials.gov Identifier: DPP, NCT00004992 ; DPPOS, NCT00038727

Introduction and Objective: Look AHEAD, a randomized trial initiated in 2001 comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE) in 5145 individuals with overweight/obesity and type 2 diabetes, found no significant differences in all-cause mortality during 10 yrs of intervention nor at 17 yrs of follow-up. The cohort has been followed continuously since the close of the trial in an observational study. Throughout this period, cumulative weight loss has been significantly greater in ILI than in DSE. Since effects of ILI may take many years to emerge, we pursued an intense mortality search, yielding 500 new deaths, and conducted an intent-to-treat analysis comparing mortality in ILI to DSE for a maximum of 23 yrs. Methods: The cohort of 5145 initially included adults aged 45-76 yrs, 59% female, 37% from underrepresented groups, and 14% with prior cardiovascular disease. Primary outcome for the current analysis was all-cause mortality from randomization to 23 yrs. Other outcomes included interactions by pre-specified subgroups. Analyses used proportional hazards regression and likelihood ratio tests. Results: A total of 1661 deaths were recorded (800 in ILI and 861 in DSE) across 80,725 person-yrs. The incidence of all-cause mortality was reduced in ILI relative to DSE (hazard ratio [HR] 0.89 [95% CI 0.81, 0.98]). There were no significant interactions between treatment and prespecified subgroups of age, sex, and cardiovascular disease history. However, race/ethnicity interacted with treatment (p = 0.01) yielding HRs for participants identifying as Hispanic 0.54 (CI 0.39, 0.74), Caucasian 0.94 (CI 0.84, 1.05), and African American 0.96 (CI 0.75, 1.23). Conclusion: ILI focused on weight loss modestly reduced long-term mortality risk in persons with diabetes and obesity/overweight, which appears to be driven by a strong reduction in mortality among participants of Hispanic ethnicity. L.E. Wagenknecht: None. J.K. Evans: None. H. Chen: None. D.K. Houston: None. C. Semelka: None. T.D. Beckner: None. P.J. Huckfeldt: None. M.E. Salive: None. S.B. Kritchevsky: None. H.P. Hazuda: None. D.M. Reboussin: None. R.R. Wing: None. M. Espeland: Consultant; Nestlé Health Science. Other Relationship; AnnovisBio, Acumen. National Institute of Aging (U01AG073697)

ObjectivesType 2 diabetes (T2D) and prediabetes are associated with poor walking endurance, a marker of physical function. We aimed to examine the long-term effects of metformin or intensive lifestyle intervention in adults at high risk of T2D on their 6-min walk test (6MWT) performance.MethodsParticipants were randomized in the 3-year Diabetes Prevention Program (DPP) to one of the three groups: lifestyle intervention, metformin, or placebo, and were subsequently followed in the DPP Outcomes Study. A 6MWT was conducted 20 years after randomization. Associations between DPP interventions and 6MWT completion (achieving a distance ≥200 m) were assessed using logistic regression. Among the test completers, differences in distance walked (6MWD) were evaluated using multivariable linear regression. Additional variables of interest included concomitant measures of body mass index (BMI) and grip strength along with mean measures of HbA1c and self-reported physical activity (PA).ResultsData on 1830 participants were analyzed. The interventions were not associated with test completion or the 6MWD among test completers (362, 364, and 360 m in the lifestyle, metformin, and placebo groups, respectively, p = 0.8). Age, education, grip strength, and PA were each significantly associated with the 6MWT completion and the 6MWD after adjustment. Grip strength, PA, and education were positively associated with the 6MWD, while age, BMI, and HbA1c were negatively associated with the 6MWD.ConclusionWe confirmed that the 6MWT is related to other measures of physical ability such as PA and grip strength in persons at risk for and with T2D, suggesting potential long-term benefits of maintaining a healthy lifestyle. However, we did not observe a sustained effect of the original randomized interventions.Clinical trial registrationhttp://www.clinicaltrials.gov/ct/show/NCT00004992, identifier DPP NCT00004992; http://www.clinicaltrials.gov/ct/show/NCT00038727, identifier DPPOS NCT00038727

Abstract Multimorbidity, or the accumulation of multiple chronic diseases, is an important clinical issue in aging and is associated with geriatric syndromes, physical and cognitive function declines, increased health care costs, and poorer health-related quality of life. This study aims to better understand multimorbidity occurrence and accumulation over the postintervention period (2013-2019) of Look AHEAD, which randomized 5145 individuals aged 45-76 in 2001-2004 with type 2 diabetes and overweight/obesity to an intensive lifestyle intervention (ILI) or a control arm receiving diabetes support and education (DSE). The ILI was previously found to reduce weight, improve diabetes control, and reduce diabetes complications. The ILI was also associated with relative improvements in self-reported multimorbidity during the intervention period. We included 2940 participants consenting to linkage of their trial data with Medicare data, focusing on participant years with Medicare fee-for-service coverage during the postintervention period. We identified conditions from the list developed by the “Department of Health and Human Services Initiative on 21 Multiple Chronic Conditions (MCC)”. We estimated ILI versus control differences in numbers of conditions using linear models that control for baseline demographic and clinical characteristics and study site. We found similar levels of multimorbidity for the ILI and DSE groups (4.21 versus 4.31, p=0.41). This result suggests that the positive impacts of the ILI on diabetes control did not translate to long-term reductions in multimorbidity.

ABSTRACT Charting the Path to Health in Midlife and Beyond: The Biology and Practice of Wellness was a Translational Science Symposium held on Tuesday, September 21, 2021. Foundational psychosocial and behavioral approaches to promote healthy aging and strategies to disseminate this information were discussed. The following synopsis documents the conversation, describes the state of the science, and outlines a path forward for clinical practice. Wellness, in its broadest sense, prioritizes an orientation toward health, and an embrace of behaviors that will promote it. It involves a journey to improve and maintain physical and mental health and overall well-being to fully engage and live one's best life. It is more about recognizing and optimizing what one can do than what one cannot do and emphasizes the individual's agency over changing what they are able to change. Wellness is therefore not a passive state but rather an active goal to be sought continually. When viewed in this fashion, wellness is accessible to all. The conference addressed multiple aspects of wellness and embraced this philosophy throughout.

Older adults experience a higher prevalence of multiple chronic conditions (MCCs). Establishing the presence and pattern of MCCs in individuals or populations is important for healthcare delivery, research, and policy. This report describes four emerging approaches and discusses their potential applications for enhancing assessment, treatment, and policy for the aging population. The National Institutes of Health convened a 2-day panel workshop of experts in 2018. Four emerging models were identified by the panel, including classification and regression tree (CART), qualifying comorbidity sets (QCS), the multimorbidity index (MMI), and the application of omics to network medicine. Future research into models of multiple chronic condition assessment may improve understanding of the epidemiology, diagnosis, and treatment of older persons.

BACKGROUND:Multimorbidity, the co-occurrence of 2 or more chronic diseases, is more common than having a single chronic disease, especially among persons age 65 years and older. The routine measurement of multimorbidity can facilitate a better understanding of potential causes and interactions and promote more effective treatment and improved outcomes. OBJECTIVES:To present a multimorbidity research framework and identify gaps in the research literature related to multimorbidity. DESIGN:In preparation for an expert panel workshop convened in September 2018, planning committee members reviewed the literature and developed a guiding framework that informed the selection of topics and speakers. RESULTS:The framework, grounded in a patient-centered approach, incorporates the concept of concordant and discordant comorbidity, and includes potential causes, interactions, and outcomes. This work informed workshop presentations and discussion related to identifying and selecting the best available multimorbidity instruments and determining future research needs. CONCLUSIONS:Multimorbidity research can be advanced by addressing gaps in study design and target populations, and by increasing attention to universal outcome measurement.

With aging, most older adults are at risk of having more than two diseases, conventionally defined as multimorbidity. We determined body organ disease number (BODN) as a new multimorbidity index. We measured the degree to which each disease level, from mild to severe, predicts longitudinal BODN uncoupled from chronological age. We determined Body Clock using global disease levels burden from all systems predicting longitudinal BODN for each individual, which is a proxy of the personalized rate of biological aging. Change in Body Clock predicts late-life age-related outcomes and can be used for geriatric clinics and clinical trials for precision medicine.

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

Whereas the burgeoning population of older adults is intrinsically vulnerable to cardiovascular disease, the utility of many management precepts that were validated in younger adults is often unclear. Whereas biomarker- and imaging-based tests are a major part of cardiovascular disease care, basic assumptions about their use and efficacy cannot be simply extrapolated to many older adults. Biology, physiology, and body composition change with aging, with important influences on cardiovascular disease testing procedures and their interpretation. Furthermore, clinical priorities of older adults are more heterogeneous, potentially undercutting the utility of testing data that are collected. The American College of Cardiology and the National Institutes on Aging, in collaboration with the American Geriatrics Society, convened, at the American College of Cardiology Heart House, a 2-day multidisciplinary workshop, "Diagnostic Testing in Older Adults with Cardiovascular Disease," to address these issues. This review summarizes key concepts, clinical limitations, and important opportunities for research.

Dr. Arti Hurria was an outstanding physician, geriatrician and oncologist specializing in the care of older adults with cancer, whose exemplary career was tragically cut short in 2018 at the age of 48. She trained in geriatrics and then oncology, ultimately serving as Chief Fellow at Memorial Sloan-Kettering Cancer Center (MSKCC), a program of 50 medical oncology fellows at the time. Dr. Hurria first came to the attention of the National Institute on Aging (NIA) as a member of the 2005 class of the Paul B. Beeson Award, NIA's premier career development award (K23) for future leaders in the field of aging research. Her project, submitted by the MSKCC, was entitled “Can Geriatric Assessment Predict Oncology Outcomes?” It was a meticulous and exceptionally well-written application, which initiated steps toward overcoming a long-standing under-representation of geriatrics within the field of oncology. The MSKCC chief identified Dr. Hurria as the institution's only dually-trained geriatrician and oncologist. She was identified even then as a rising star who would have an enormous impact on patients, trainees and the field. She moved the grant with her to City of Hope in 2006, and it ultimately was one of the most productive Beeson awards, accounting for 47 peer-reviewed articles up through its completion in 2011. Her most impactful paper in 2011 [ [1] Hurria A. Togawa K. Mohile S.G. et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011; 29: 3457-3465 Crossref PubMed Scopus (1179) Google Scholar ] examined the utility of the geriatric assessment to predict chemotherapy toxicity, and led to important national scale implementation.

Declining life expectancy and increasing all-cause mortality in the United States have been associated with unhealthy behaviors, socioecological factors, and preventable disease. A growing body of basic science, clinical research, and population health evidence points to the benefits of healthy behaviors, environments and policies to maintain health and prevent, treat, and reverse the root causes of common chronic diseases. Similarly, innovations in research methodologies, standards of evidence, emergence of unique study cohorts, and breakthroughs in data analytics and modeling create new possibilities for producing biomedical knowledge and clinical translation. To understand these advances and inform future directions research, The Lifestyle Medicine Research Summit was convened at the University of Pittsburgh on December 4–5, 2019. The Summit's goal was to review current status and define research priorities in the six core areas of lifestyle medicine: plant-predominant nutrition, physical activity, sleep, stress, addictive behaviors, and positive psychology/social connection. Forty invited subject matter experts (1) reviewed existing knowledge and gaps relating lifestyle behaviors to common chronic diseases, such as cardiovascular disease, diabetes, many cancers, inflammatory- and immune-related disorders and other conditions; and (2) discussed the potential for applying cutting-edge molecular, cellular, epigenetic and emerging science knowledge and computational methodologies, research designs, and study cohorts to accelerate clinical applications across all six domains of lifestyle medicine. Notably, federal health agencies, such as the Department of Defense and Veterans Administration have begun to adopt “whole-person health and performance” models that address these lifestyle and environmental root causes of chronic disease and associated morbidity, mortality, and cost. Recommendations strongly support leveraging emerging research methodologies, systems biology, and computational modeling in order to accelerate effective clinical and population solutions to improve health and reduce societal costs. New and alternative hierarchies of evidence are also be needed in order to assess the quality of evidence and develop evidence-based guidelines on lifestyle medicine. Children and underserved populations were identified as prioritized groups to study. The COVID-19 pandemic, which disproportionately impacts people with chronic diseases that are amenable to effective lifestyle medicine interventions, makes the Summit's findings and recommendations for future research particularly timely and relevant.

Nutrition plays an important role in health promotion and disease prevention and treatment across the lifespan. Physicians and other healthcare professionals are expected to counsel patients about nutrition, but recent surveys report minimal to no improvements in medical nutrition education in US medical schools. A workshop sponsored by the National Heart, Lung, and Blood Institute addressed this gap in knowledge by convening experts in clinical and academic health professional schools. Representatives from the National Board of Medical Examiners, the Accreditation Council for Graduate Medical Education, the Liaison Committee on Medical Education, and the American Society for Nutrition provided relevant presentations. Reported is an overview of lessons learned from nutrition education efforts in medical schools and health professional schools including interprofessional domains and competency-based nutrition education. Proposed is a framework for coordinating activities of various entities using a public-private partnership platform. Recommendations for nutrition research and accreditation are provided.

Multimorbidity occurs in adults of all ages, but the number and complexity of comorbid conditions commonly increase with advancing age such that cardiovascular disease (CVD) in older adults typically occurs in a context of multimorbidity. Current clinical practice and research mainly target single disease-specific care that does not embrace the complexities imposed by concurrent conditions. In this paper, emerging concepts regarding CVD in combination with multimorbidity are reviewed, including recommendations for incorporating multimorbidity into clinical decision making, critical knowledge gaps, and research priorities to optimize care of complex older patients.

Multimorbidity, defined as the co-occurrence of two or more chronic conditions, increases with age and may be found in approximately two-thirds of older adults in population studies, commonly including a variety of cardiovascular risk factors and chronic diseases. This article offers a research agenda for cardiovascular disease from a patient-centered multimorbidity perspective. Definitional issues remain for multimorbidity, along with high interest in understanding the inter-relationships between aging, diseases, treatments, and organ dysfunction in the development and progression of multimorbidity. Clinical trials, practice-based and population-based observational studies, and linkages of big data can play a role in improving health outcomes among persons with multimorbidity.

Aging is characterized by rising susceptibility to development of multiple chronic diseases and, therefore, represents the major risk factor for multimorbidity. From a gerontological perspective, the progressive accumulation of multiple diseases, which significantly accelerates at older ages, is a milestone for progressive loss of resilience and age-related multisystem homeostatic dysregulation. Because it is most likely that the same mechanisms that drive aging also drive multiple age-related chronic diseases, addressing those mechanisms may reduce the development of multimorbidity. According to this vision, studying multimorbidity may help to understand the biology of aging and, at the same time, understanding the underpinnings of aging may help to develop strategies to prevent or delay the burden of multimorbidity. As a consequence, we believe that it is time to build connections and dialogue between the clinical experience of general practitioners and geriatricians and the scientists who study aging, so as to stimulate innovative research projects to improve the management and the treatment of older patients with multiple morbidities.