BACKGROUND AND AIM: Low-grade inflammation (LGI) and metabolic dysfunction are tightly linked processes central to the onset and progression of complex diseases and aging. LGI acts both as a driver and a consequence of metabolic disturbances and represents a hallmark of "inflammaging", the chronic, systemic inflammatory state arising from sustained immune activation that characterizes aging and underlies many age-related pathologies. Targeting LGI through lifestyle changes, particularly diet, offers a promising approach for healthy aging. Epigenetic clocks have recently emerged as biomarkers of biological aging, capturing the cumulative effects of environmental and lifestyle factors, including diet. This study aims to assess whether the inflammatory potential of the diet influences epigenetic age acceleration (EAA), as measured by several next-generation epigenetic clocks, and whether this relationship is mediated by LGI.
METHODS: This study included 691 participants from the Lifelines-DEEP cohort. Habitual dietary intake was assessed using food frequency questionnaires to derive overall diet quality and the intake of pro- and anti-inflammatory dietary components. Circulating biomarkers of LGI were measured and combined into composite inflammatory scores alongside individual markers. EAA was estimated from blood DNA methylation data using next-generation principal component-based epigenetic clocks (PCPhenoAge and PCGrimAge) and the DunedinPACE clock, selected for their enhanced sensitivity to lifestyle-related exposures compared with traditional clocks. Multivariable regression models were applied to examine associations between dietary inflammatory profiles and EAA, and mediation analyses were conducted to evaluate the contribution of LGI to these relationships.
RESULTS: Overall diet quality was significantly associated with EAA, particularly when assessed using the PCGrimAge clock, which showed the strongest and most consistent associations among the analyzed clocks. PCGrimage EAA was further related specific food categories: consumption of high-energy beverages (HHB) and NOVA4 foods was positively associated with EAA, whereas intake of vegetables and tea showed inverse associations. Mediation analyses indicated that the link between overall diet quality and PCGrimage EAA involved both direct and indirect components. Specifically, the positive associations of HHB and NOVA4 foods with EAA were largely explained by higher LGI levels, whereas the inverse associations observed for beneficial food categories (i.e., NOVA1, vegetables, tea) reflected both direct effects and indirect effects mediated by lower LGI. For the other clocks, associations with dietary features were no longer significant after accounting for LGI mediation.
CONCLUSIONS: These findings support PCGrimAge as a particularly informative epigenetic clock for capturing nutritional influences on the epigenome, emphasizing that diet, inflammation, and epigenetic aging are interrelated yet distinct processes that should be jointly considered when assessing long-term health risk.
