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Background <p>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 investigate potential causality between fish intake and healthspan markers.</p> Methods <p>Bidirectional Mendelian randomization was performed in the two-sample setting with publicly available GWAS summary statistics. GWAS data from the UK Biobank for oily fish consumption (<i>n</i> = 460,443) and fish oil supplementation (<i>n</i> = 461,384) were used as the primary exposures. First-generation epigenetic clocks Hannum age and intrinsic epigenetic age acceleration (IEAA), as well as second-generation clocks GrimAge and PhenoAge were collected from an independent dataset of individuals of European ancestry (<i>n</i> = [34,449–34,667]). Finally, data from the Integrative Epidemiology Unit database was used for serum proxies of lipidemia and systemic inflammation (<i>n</i> = [61,308–78,700]). Additional sensitivity analyses, such as reverse causation testing and the Cochran’s Q test were performed for exposure-outcome pairs where the inverse variance weighted (IVW) method was significant (<i>p</i>-value &lt; 0.05), and where the MR Egger method indicated an effect in the same direction as the IVW result.</p> Results <p>We report that oily fish consumption appears to decrease PhenoAge acceleration (<i>p</i> &lt; 0.0086), whereas fish oil supplementation appears to decrease GrimAge (<i>p</i> <InlineEquation ID="IEq1"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="40246_2025_756_Article_IEq1.gif" Format="GIF" Height="6" Rendition="HTML" Resolution="72" Type="Linedraw" Width="14" /> </InlineMediaObject> <EquationSource Format="TEX">\(=\)</EquationSource> <EquationSource Format="MATHML"><math> <mo>=</mo> </math></EquationSource> </InlineEquation> 0.037). Both omega-3 exposures modify the epigenetic clocks in the expected negative, or age-decelerating, direction. For the serum biomarkers, we find evidence that fish oil consumption leads to a reduction in triglycerides (<i>p</i> <InlineEquation ID="IEq2"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="40246_2025_756_Article_IEq1.gif" Format="GIF" Height="6" Rendition="HTML" Resolution="72" Type="Linedraw" Width="14" /> </InlineMediaObject> <EquationSource Format="TEX">\(=\)</EquationSource> <EquationSource Format="MATHML"><math> <mo>=</mo> </math></EquationSource> </InlineEquation> 0.004), although HDL and LDL were not significantly modified. Finally, we also detected a suggestive inverse relationship between oily fish consumption and hsCRP (<i>p</i> <InlineEquation ID="IEq3"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="40246_2025_756_Article_IEq1.gif" Format="GIF" Height="6" Rendition="HTML" Resolution="72" Type="Linedraw" Width="14" /> </InlineMediaObject> <EquationSource Format="TEX">\(=\)</EquationSource> <EquationSource Format="MATHML"><math> <mo>=</mo> </math></EquationSource> </InlineEquation> 0.064).</p> Conclusions <p>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 provided evidence further linking fish oil intake and lower triglyceride levels. These results, based on robust MR-based analyses, emphasize the effectiveness of dietary choices in modifying emerging measures of healthspan.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年5月24日

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  • Paul Fabian,
  • Gil Blander,
  • Renee Deehan,
  • Ali Torkamani,
  • Bartek Nogal

摘要

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 investigate potential causality between fish intake and healthspan markers.

Methods

Bidirectional Mendelian randomization was performed in the two-sample setting with publicly available GWAS summary statistics. GWAS data from the UK Biobank for oily fish consumption (n = 460,443) and fish oil supplementation (n = 461,384) were used as the primary exposures. First-generation epigenetic clocks Hannum age and intrinsic epigenetic age acceleration (IEAA), as well as second-generation clocks GrimAge and PhenoAge were collected from an independent dataset of individuals of European ancestry (n = [34,449–34,667]). Finally, data from the Integrative Epidemiology Unit database was used for serum proxies of lipidemia and systemic inflammation (n = [61,308–78,700]). Additional sensitivity analyses, such as reverse causation testing and the Cochran’s Q test were performed for exposure-outcome pairs where the inverse variance weighted (IVW) method was significant (p-value < 0.05), and where the MR Egger method indicated an effect in the same direction as the IVW result.

Results

We report that oily fish consumption appears to decrease PhenoAge acceleration (p < 0.0086), whereas fish oil supplementation appears to decrease GrimAge (p \(=\) = 0.037). Both omega-3 exposures modify the epigenetic clocks in the expected negative, or age-decelerating, direction. For the serum biomarkers, we find evidence that fish oil consumption leads to a reduction in triglycerides (p \(=\) = 0.004), although HDL and LDL were not significantly modified. Finally, we also detected a suggestive inverse relationship between oily fish consumption and hsCRP (p \(=\) = 0.064).

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 provided evidence further linking fish oil intake and lower triglyceride levels. These results, based on robust MR-based analyses, emphasize the effectiveness of dietary choices in modifying emerging measures of healthspan.