Omega-3 Slows Aging at the DNA Level, Vitamin D and Exercise Boost the Effect

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Feb 4 2025

New research shows that omega-3 fatty acids can slow biological aging at the molecular level, with vitamin D and exercise enhancing the effect—offering a promising strategy for healthier aging.

Research letter: Individual and additive effects of vitamin D, omega-3 and exercise on DNA methylation clocks of biological aging in older adults from the DO-HEALTH trial. Image Credit: evrymmnt / Shutterstock

In a recent study published in the journal Nature Aging, researchers used DNA methylation (DNAm) clocks to determine the individual and combined effects of vitamin D supplementation, omega-3 fatty acids, and a simple home exercise program (SHEP) on biological aging.

Background

Did you know that by 2050, the number of people aged 65 and older will double, reaching over 1.5 billion? With an aging population, chronic diseases such as heart disease, diabetes, and cognitive decline are increasing, creating a growing burden on healthcare systems. But what if aging itself could be slowed down? Scientists have turned to DNAm clocks (molecular markers of biological age) to explore how lifestyle factors influence the rate of aging.

Observational studies suggest that vitamin D supplementation, omega-3 fatty acids, and regular exercise may help slow biological aging, but rigorous clinical trials are needed. Understanding how these interventions work at the molecular level could lead to strategies that promote healthier aging. Despite promising early evidence, most prior studies were observational or small-scale trials, and their results were inconsistent. Large-scale trials evaluating these interventions in combination remain limited, making further research essential.

About the Study

This study was conducted as part of the Vitamin D, Omega-3, and Home Exercise-Healthy Aging and Longevity Trial (DO-HEALTH), a multicenter randomized controlled trial designed to evaluate the effects of vitamin D supplementation (2,000 International Units (IU) per day), omega-3 fatty acids (1 gram (g) per day), and a SHEP on aging biomarkers in older adults. The subset analyzed included 777 participants who provided DNAm data at baseline and after three years. Participants were generally healthy, aged 70 and older, and lived independently.

Participants were randomized into eight treatment arms in a 2×2×2 factorial design to assess individual and combined effects. Blood samples were collected at baseline and annually for three years. DNA was extracted and analyzed for methylation patterns using the Infinium MethylationEPIC array to quantify changes in four key DNAm clocks: PhenoAge, GrimAge, GrimAge2, and DunedinPACE, which specifically measures the rate of aging rather than biological age itself.

The statistical analysis focused on changes in biological aging measures over three years, comparing treatment and control groups using analysis of covariance (ANCOVA). Covariates included chronological age, sex, baseline body mass index (BMI), history of falls, and study site. Standardized effect sizes were computed to assess the extent of aging deceleration in response to interventions. Ethical approval was obtained, and all participants provided informed consent.

Study Results

Over the three years, omega-3 fatty acid supplementation significantly reduced age-acceleration values in three of the four DNAm clocks. Specifically, reductions were observed in PhenoAge, GrimAge2, and DunedinPACE, with standardized effect sizes ranging from -0.16 to -0.32 units, translating to a biological age reduction of 2.9 to 3.8 months.

Vitamin D supplementation and the SHEP did not exhibit significant independent effects on the clocks. However, in the case of PhenoAge, there was an additive effect when omega-3 fatty acids were combined with either vitamin D supplementation or exercise, and the strongest reductions were seen when all three interventions were used together. The combination showed standardized reductions ranging from -0.24 to -0.32 units.

Further analysis of epigenetic biomarkers linked to metabolic health revealed that omega-3 fatty acid supplementation significantly influenced DNAm levels of proteins associated with aging and inflammation, including plasminogen activator inhibitor-1 (PAI-1), leptin, and tissue inhibitor metalloproteinase-1 (TIMP-1). In addition, when all three interventions were combined, cumulative benefits were observed in additional biomarkers such as β2-microglobulin (B2M) and growth differentiation factor 15 (GDF-15), indicating a broader potential impact on metabolic aging.

Subgroup analyses indicated that omega-3 fatty acid supplementation had a stronger effect in individuals with higher baseline vitamin D levels and in those with initially lower omega-3 blood levels. Women and individuals with lower baseline polyunsaturated fatty acid levels exhibited greater biological age deceleration, suggesting the potential personalized benefits of these interventions.

When comparing DO-HEALTH findings to those from other aging studies, such as the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) trial on caloric restriction, the observed effects on DunedinPACE were smaller (approximately a 1% reduction in the pace of aging), but the impact on PhenoAge and GrimAge2 was more pronounced.

Conclusions

To summarize, this study provides evidence that omega-3 fatty acid supplementation alone and in combination with vitamin D supplementation and the SHEP can modestly slow biological aging, particularly as measured by PhenoAge, GrimAge2, and DunedinPACE. The findings suggest that something as simple as adding omega-3 fatty acids to daily routines, alongside exercise and vitamin D, could help older adults stay healthier for longer—though the long-term clinical implications remain uncertain.

While the reductions in biological aging were relatively small, even minor decelerations could translate into meaningful health benefits over longer periods. However, researchers caution that the study population was relatively healthy and active, which may limit how widely these findings apply to less active or more frail older adults. The additive effects suggest that combined interventions may be more effective in promoting healthy aging.