Effect of caloric restriction on aging biomarkers, frailty, and multimorbidity in older adults

/Abstract Obesity is associated with poor quality of life and reduced lifespan and healthspan – the period of time free of multiple chronic diseases and disability. Given that over one-third of older adults are obese, identifying effective therapies that prevent obesity-related declines in healthspan and lifespan in older adults are urgently needed. Clinical trials by our group and others show that caloric restriction improves physical and metabolic function over the short-term in older adults with obesity. However, the long-term benefits of caloric restriction in this population remain controversial and weight loss is often not recommended because of uncertainty of whether the benefits outweigh the risks (e.g., loss of muscle mass and bone). The field of geroscience aims to address biological aging by targeting the fundamental biology shared by the aging process to prevent or delay common age-related chronic diseases in hopes of extending healthspan and lifespan. Caloric restriction is one such intervention known to alter aging biology to extend healthspan and lifespan in multiple species, including non-human primates; however, the effects of caloric restriction in extending healthspan and lifespan in humans remains unknown. The overall goals of the proposed study are to determine if short-term caloric restriction in older adults with obesity affects biomarkers of biological aging and whether these biomarkers of biological aging are correlated with healthspan. We will determine the effects of randomization to caloric restriction on a consensus derived blood-based biomarker index (Il-6, TNFαR1, GDF-15, cystatin C, CRP, and insulin; primary aim) and multimorbidity and deficit accumulation frailty indices (secondary aim) an average of 10 years after the completion of a caloric restriction intervention. Our primary hypothesis is that randomization to caloric restriction will result in improved biomarkers of biological aging compared to a control condition in older adults with obesity and this improvement will be reflected in better healthspan. We will leverage biospecimens and data from 5 NIH-supported randomized controlled trials conducted under the auspices of the Wake Forest Pepper Center that enrolled older adults (mean age at randomization, 67.3 years) with overweight or obesity (BMI≥27 kg/m2) and randomized them to caloric restriction (n=520) or no caloric restriction (n=446) from 2005 to 2014 to conduct an individual participant-level meta-analysis with sufficient sample size to definitively evaluate the effect of caloric restriction on biological aging. We will also explore the effects of randomization to caloric restriction on cellular senescence and proteomic biomarkers and the underlying molecular mechanisms of caloric restriction, as well as the associations between cellular senescence and proteomic biomarkers on multimorbidity and a deficit accumulation frailty index. The proposed study builds on the Wake Forest’s Pepper Center’s collaborative research focus in geriatric obesity treatment to answer compelling and clinically important questions regarding the efficacy of caloric restriction to slow biological aging and increase healthspan in older adults with obesity in an efficient and cost-effective manner. Project Number: 1RF1AG095175-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Denise Houston | Institution: WAKE FOREST UNIVERSITY HEALTH SCIENCES, WINSTON-SALEM, NC | Award Amount: $3,157,326 | Activity Code: RF1 | Study Section: Aging, Injury, Musculoskeletal, and Rheumatologic Disorders Study Section[AIMR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366484