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Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFα, were significantly lowered in CD3 + T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise., (© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Dr. Mark Mattson has had a highly productive and impactful tenure as a neuroscientist at the Intramural Research Program of the National Institute on Aging. He has made notable contributions to understanding the mechanisms by which energetic stress, imparted by behaviors such as physical activity and periods of fasting, promotes rejuvenation and resilience within brain regions critical for learning and memory. In honor of Dr. Mattson's work, this manuscript will highlight the fascinating mechanisms by which endurance exercise training conveys beneficial effects upon the structure and function of the nervous system; that is, by mediating the synthesis and secretion of factors that directly support brain homeostasis, including brain-derived neurotrophic factor, FNDC5/irisin, ketone bodies, growth factors, cathepsin B, serotonin, and 4-hydroxynonenal. The molecular and cellular effects of these factors are discussed herein. In the face of population aging and an overwhelming surge in the prevalence of Alzheimer's disease and related disorders, Dr. Mattson's work as a champion and role model for physically active lifestyles is more important than ever., (Copyright © 2020 Elsevier B.V. All rights reserved.)