Questions regarding the relative importance of different mechanisms and dysfunctions to the progression of aging and eventual mortality are hard to answer definitively. Even given a straightforward class of therapies to target one specific mechanism of aging in isolation of all others, such as senolytics to clear lingering senescent cells, one still has to look at a lot of different studies, extrapolate from mice to humans, and the answer is fuzzy. The other sort of fuzzy answer comes from statistical techniques applied to large longitudinal human epidemiological data sets: compare humans who exhibited different levels of the mechanism in question, and see what happened to them over time. That is the approach taken here in the matter of the chronic inflammation as a driver of aging and age-related mortality. As you can see, the answer produced is a sizable range, arguably not all that informative.
Global population aging underscores the urgent need for biomarkers quantifying biological aging trajectories. While DNA methylation-derived pace of aging (DunedinPoAm) measures individual differences, its generalizability across diverse populations and mechanistic links to systemic inflammation remain underexplored. This study aimed to systematically examine the longitudinal associations between the DunedinPoAm and all-cause mortality in a multiethnic cohort, and to quantify the extent to which systemic inflammatory biomarkers mediate these associations using causal mediation analysis.
For this cohort study, information on a nationally representative cohort of 21,004 U.S. adults was extracted from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2002. Data were analyzed from 2,532 participants, with a mean follow-up duration of 18.5 ± 1.29 years. Higher DunedinPoAm quartiles exhibited graded mortality risks (Q4 vs. Q1: hazard ratio, HR = 2.50), which persisted after multivariable adjustment. Restricted cubic splines revealed a non-linear association, indicating the presence of threshold effects. Systemic inflammation mediated 2.33% to 23.5% of the mortality risk associated with DunedinPoAm, driven by CD4+ T cells, B cells, CRP and comprehensive inflammatory indices. A significant interaction with diabetes underscored metabolic dysregulation as a vulnerability factor.
