Alongside calorie restriction, exercise represents the gold standard of proof for an intervention to slow degenerative aging. Sadly the research community has demonstrated all too few approaches that can robustly improve on exercise and physical fitness in the matter of aging, and none of those yet have compelling human data to support the extensive animal studies. Rapamycin and senolytics spring to mind as those with the greatest amount of data. Partial epigenetic reprogramming is also interesting but still too new to have gathered a very large body of animal work, despite the vast funding devoted to it in recent years. Thus pharmacological mimicry of the response to exercise continues to interest researchers, and programs in this part of the field continue to emerge.
Global declines in physical activity have contributed to an acceleration in immune aging, characterized by systemic inflammation (inflammaging) and impaired immune regulation (immunosenescence). This narrative review provides an overview of the evidence in both preclinical and clinical models supporting exercise as a critical intervention to counteract immune aging and its related diseases.
Regular physical activity modulates systemic inflammation, reduces neutrophil extracellular trap (NET) formation, and promotes favorable shifts in immune cell populations, including T cell and natural killer (NK) cell subsets. Exercise interventions have been associated not only with maintaining immune health but also in mitigating autoimmune disease progression, improving metabolic regulation, enhancing tumor immune surveillance, and reducing neuroinflammation. Emerging studies highlight the role of exercise in promoting vascular normalization within the tumor microenvironment, alleviating tumor hypoxia and acidosis, and restoring T and NK cell function.
In the elderly, appropriately prescribed multimodal exercise regimens may lower infection risk without clear evidence of immunodepression, supporting exercise as a potentially safe and effective strategy for immune rejuvenation. Furthermore, novel mechanistic insights, including the modulation of NET burden, IGF-1 signaling, kynurenine metabolism, and microbiome composition, suggest that exercise influences key biological pathways underlying age-related immune decline. While exercise offers broad clinical benefits, future research should prioritize mechanistic studies to optimize exercise prescriptions and inform the development of exercise-mimetic therapeutics.
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