The legacy of colonialism and commercial tobacco-caused social inequities.

Aging is a process that involves the cross-talk of genetic, environmental, and lifestyle factors. Among lifestyle factors, physical activity (PA) has been shown to delay the onset of age-related diseases and improve overall health span [,]. Mechanistically, PA exerts its benefits by reducing chronic inflammation [], oxidative stress [], and cellular senescence []—key drivers of aging. DNA methylation (DNAm), an epigenetic modification that influences gene expression, has recently emerged as a powerful biomarker of biological aging []. DNAm biomarkers, including phenotypic age (PhenoAge) [] and GrimAge [], have been developed as predictors of biological aging, providing more accurate measures than chronological age. PhenoAge, in particular, is associated with various health outcomes such as all-cause mortality, cardiovascular disease, and cognitive decline, making it a critical measure of aging-related morbidity []. These markers capture the cumulative effects of environmental and lifestyle factors on the epigenome, offering a method for assessing biological aging. Currently, evidence from both objectively measured physical activity using accelerometers and self-reported physical activity assessed through questionnaires shows a consistent relationship: engagement of physical activity may be associated with a lower PhenoAge [, , ]. Our previous investigation also found that PA may influence DNAm patterns linked to aging [, , ]. Despite advances in epigenetic research, the association between PA and these aging markers remains underexplored, particularly in diverse populations. Several studies have reported inverse associations between PA and DNAm of individual age-related genes like TP53, IL-6, NF-κB, and CXCL8 [,], suggesting that PA may contribute to slowing biological aging. However, comprehensive analyses that account for a range of covariates, such as gender, BMI, and socioeconomic status, are limited []. Moreover, whether PA influences the broader DNAm-predicted aging markers across different demographic groups, and how this relationship varies with factors such as gender or body weight, requires further investigation. β2-microglobulin (β2M) is the soluble light chain of major histocompatibility complex class I (MHC-I) molecules [,], with elevated levels detected in the plasma and cerebrospinal fluid of aged mice and older adults []. Compared to β-amyloid, which is widely recognized for its pivotal role in aging and the pathogenesis of Alzheimer’s disease [,], β2M appears to be emerging as a novel biomarker in the context of aging and cognitive decline. Recent evidence suggests that β2M may represent a distinct and complementary mechanism underlying age-related neurodegeneration [,]. Unlike β-amyloid, which aggregates into plaques, β2M is a soluble protein linked to immune and inflammatory processes, with elevated levels observed in aging and certain neurodegenerative conditions []. Moreover, elevated circulating levels of β2M are associated with inflammation, immune dysfunction, and age-related decline in physical function [,]. However, whether β2M acts as a mediator of PA’s effects on PhenoAge remains unclear, warranting further investigation.