Causal impact of genetically-determined fish and fish oil intake on epigenetic age acceleration and related serum markers

Abstract

Background: The interplay between diet and healthspan is a topic of great interest in biomedical research. Toward this end, consumption of marine omega-3 fatty acids is of particular significance, as reports suggest that diets focused on seafood can prolong the disease-free portion of the human lifespan. Fish consumption has also been linked to reduced biological aging as measured by epigenetic clocks, but there is no conclusive evidence of a causal relationship. Moreover, fish oils reduce triglycerides, and may affect other lipid profiles, as well as systemic inflammation. To investigate further, we used two-sample Mendelian randomization to infer causality between fish intake and healthspan markers. Methods: We perform bidirectional Mendelian randomization in the two-sample setting using publicly available GWAS summary statistics repositories. Usingoily fish consumption and fish oil supplementation as the primary exposures, we attempt to elucidate the causal landscape of these interventions on first- and second-generation epigenetic clocks as well as serum proxies of lipidemia and systemic inflammation. Results: We report that oily fish consumption appears to causally modify PhenoAge (p < 0.0074), whereas it begins to approach causality with respect to GrimAge (p = 0.097). However, fish oil supplements do exhibit a causal relationship with GrimAge (p = 0.037). Both omega-3 exposures modify the epigenetic clocks in the expected negative, or age-decelerating, direction. We also confirm the causal relationship between fish oil consumption and triglyceride reduction (p = 0.004), though HDL and LDL were not significantly modified. Finally, we also detect suggestive causality between oily fish consumption and reduced hsCRP (p = 0.062). Conclusions: Our analysis shows that consuming fish oil, whether through whole food or as a supplement, can have a rejuvenating impact as measured by PhenoAge and GrimAge acceleration. We have also confirmed the causal link between fish oil intake and lower triglyceride levels. These results, based on robust MR-based analyses, emphasize the effectiveness of dietary choices in influencing healthspan.