Study: “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”
Publisher: Nature Aging
Published date: February 2025
PubMed link to study: https://pubmed.ncbi.nlm.nih.gov/39900648/
Summary of the study
The study reports on a post hoc analysis conducted within the DO-HEALTH trial. This randomized, controlled study involved 777 healthy, active adults aged 70 years and older from Switzerland. The trial tested whether three interventions, daily vitamin D (2,000 IU), omega-3 fatty acids (1 g), and a home-based exercise program (30 minutes, three times per week), could slow biological aging over a three-year period.
Biological aging was assessed using several “epigenetic clocks,” which are algorithms that estimate a person’s biological age based on patterns of DNA methylation (DNAm). The study focused on advanced (second-generation) clocks, in this case being PhenoAge, GrimAge, and GrimAge2, and the third-generation clock DunedinPACE (which estimates the pace of aging).
The primary findings were:
- Omega-3 supplementation alone produced modest but statistically significant improvements on three out of the four clocks (PhenoAge, GrimAge2, and DunedinPACE). These changes corresponded to a reduction in biological aging of approximately 2.9–3.8 months over three years.
- Vitamin D and exercise alone did not show significant effects on the clocks.
- However, when combined with omega-3, there was evidence of additive benefits, particularly with the PhenoAge measure.
The study, therefore, suggests that targeted nutritional interventions, in particular omega-3 fatty acids, can impact molecular markers of aging, and that combining interventions may enhance these effects.
You can view the details of the DO-HEALTH trials via ClinicalTrials.gov identifier: NCT01745263
PoI Perspective
The findings from this study provides several important insights into the field of anti-aging research, particularly concerning the use of epigenetic clocks to monitor the effectiveness of anti-aging interventions.
The Specific Impact of Omega-3 Supplementation
One of the standout results is the observation that omega-3 supplementation alone slowed the progression of biological aging as measured by multiple epigenetic clocks.
Omega-3 fatty acids are widely recognized for their anti-inflammatory and cardioprotective properties. In the context of epigenetics, the study shows that omega-3s can influence DNA methylation patterns, which are subtle molecular modifications that accumulate with age and are associated with disease risk. This supports the idea that omega-3 fatty acids might slow cellular aging by modulating inflammation and other metabolic pathways.
Importantly, the study noted that individuals with lower baseline levels of omega-3 (as measured by blood DHA and EPA) experienced greater shifts in their epigenetic age. This finding aligns with the broader movement in personalized medicine, suggesting that baseline nutritional status might help identify those who would benefit most from supplementation. In the wider literature, similar conclusions have been drawn from smaller studies, but the DO-HEALTH trial strengthens the evidence by leveraging a randomized controlled design and multiple validated epigenetic biomarkers.
Additive Effects of Combining Interventions
While omega-3 alone had a measurable effect, the research also revealed that combining omega-3 with vitamin D and exercise yielded additive benefits on one of the clocks (PhenoAge).
This is a significant point because aging is a complex, multi-system process influenced by various lifestyle and nutritional factors. Vitamin D is known for its roles in bone health and immune function, and regular physical activity contributes to maintaining muscle mass and metabolic health. Their combined use with omega-3 suggests that interventions targeting multiple pathways may have a compounded benefit on slowing biological aging.
The notion of additive or synergistic effects is not new in anti-aging research, but this study provides molecular evidence, through the lens of DNA methylation, that a combined intervention can yield benefits greater than the sum of its parts. It supports findings from other studies, such as the CALERIE trial (which examined caloric restriction) and other lifestyle intervention studies, that emphasize the importance of multi-modal approaches to extend health span.
Broader Implications for Anti-Aging Research
Epigenetic clocks have rapidly gained attention as promising biomarkers that provide a quantifiable measure of biological aging beyond chronological age.
The use of second- and third-generation clocks (like PhenoAge, GrimAge2, and DunedinPACE) is particularly noteworthy because these clocks correlate more strongly with morbidity and mortality. Although, the effect sizes reported in this study are modest, on the order of a few months’ delay in biological aging, the cumulative impact over a longer period or across large populations could be significant. Even small decelerations in biological aging may translate into reduced risks for age-related chronic diseases, improved quality of life, and lower healthcare burdens.
It is also important to recognize the methodological strengths of the study. The factorial design allowed for the independent and combined evaluation of three interventions, and the rigorous collection and processing of blood samples ensured that technical variability was minimized. However, as the authors note, the study is limited by its relatively short time frame (three years) and the selection of a particularly healthy and active older population. Future studies with larger cohorts and longer follow-up periods will be critical to determine whether these epigenetic changes translate into longer-term clinical benefits.
Translational and Public Health Perspectives
From a translational perspective, the study’s findings support the geroscience hypothesis that interventions capable of modifying the fundamental processes of aging can have downstream effects on health outcomes such as frailty, cancer, and chronic disease.
Public health strategies that incorporate nutritional supplementation (e.g., omega-3 fatty acids) and exercise could be relatively low-cost approaches to promote healthy aging, particularly if targeted to individuals based on their baseline status.
Moreover, the integration of epigenetic biomarkers into clinical trials provides a valuable tool for rapidly assessing the efficacy of interventions aimed at decelerating aging. As our understanding of the mechanisms underlying these DNA methylation changes improves, it may become possible to develop even more precise interventions that target specific molecular pathways involved in aging.
Critical Perspective of the Study
Although the finds are of great interest there are several aspects of the study that merit a critical perspective.
- Healthy, Preselected Sample:
The analysis focused on a subgroup of Swiss participants from the DO-HEALTH trial who were generally healthier and more active than the broader older adult population. This pre-selection raises concerns about generalizability and the effects observed might differ in a more diverse or less healthy group. - Geographical and Lifestyle Factors:
The Swiss subgroup also had lower baseline omega-3 levels, potentially influenced by regional dietary habits. This means that the findings, particularly regarding omega-3 responsiveness, may not translate directly to populations with different nutritional baselines. - Adherence and Measurement of Exercise:
The exercise component was home-based and self-reported to some degree, which might introduce variability in adherence and intensity. This variability could dilute the measurable effects of the exercise intervention on the epigenetic clocks. - Post Hoc Analysis and Two Time Points:
The study is a post hoc analysis of a subset of the trial, and the DNAm measurements were taken only at baseline and at the 3-year follow-up. This limited number of time points can increase measurement error and may not capture the nuances of how biological aging progresses over time. - Duration of Follow-Up:
A three-year period is relatively short when considering the long-term nature of aging. While the study reports modest changes in epigenetic clocks, it remains uncertain whether these changes would lead to meaningful clinical outcomes over a longer period.
In Summary
The DO-HEALTH trial adds to the growing body of evidence that lifestyle and nutritional interventions, in particular omega-3 supplementation, can exert measurable effects on the molecular markers of aging. The study highlights the potential for additive benefits when combining interventions such as vitamin D supplementation and exercise with omega-3. While the changes observed are modest, they are consistent with the idea that even small shifts in the rate of biological aging can have meaningful health implications over time
Feel welcome to share your own thoughts on this research in the comment section below as well. I will be happy to discuss and learn more about how you see its potential in this field.
