Introduction
The DO-HEALTH trial investigated the impact of vitamin D, omega-3 fatty acid supplementation, and structured home exercise programs (SHEP) on biological aging using DNA methylation (DNAm) clocks. These clocks assess biological age based on epigenetic markers, helping researchers understand aging beyond chronological age. Previous observational studies suggested that these interventions may slow biological aging, but large-scale clinical trials were lacking. This study sought to determine whether these interventions, individually or in combination, influence epigenetic aging markers in older adults over a 3-year period.
Study Design and Methods
The study was a randomized controlled trial involving 777 participants (subset of 2,157 from the DO-HEALTH study) aged 70 years and older across multiple European countries. Participants were divided into different intervention groups receiving vitamin D (2,000 IU/day), omega-3 (1 g/day), and/or a structured home exercise program (SHEP) three times per week. The trial followed a 2×2×2 factorial design, meaning different combinations of interventions were tested. Blood samples were collected at baseline and after 3 years to assess DNAm measures of aging.
The researchers focused on four next-generation DNAm clocks:
- PhenoAge
- GrimAge
- GrimAge2
- DunedinPACE
These clocks are known for their strong association with morbidity, mortality, and lifestyle influences.
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Key Results
Omega-3 Slowed Biological Aging
- Omega-3 supplementation significantly reduced the aging acceleration rates of three of the four DNAm clocks:
- PhenoAge: Δ = -0.16 (95% CI: -0.02 to -0.30)
- GrimAge2: Δ = -0.32 (95% CI: -0.06 to -0.59)
- DunedinPACE: Δ = -0.17 (95% CI: -0.04 to -0.31)
- These results suggest omega-3 had a protective effect against biological aging.
Additive Effects of Interventions
- While vitamin D and SHEP alone did not significantly impact DNAm clocks, combining omega-3 with either vitamin D or SHEP produced additive benefits for PhenoAge (Δ ranging from -0.24 to -0.32).
- No additive effects were observed for GrimAge, GrimAge2, or DunedinPACE.
Impact on Plasma Protein Biomarkers
- The GrimAge clock is derived from plasma proteins associated with aging. Omega-3 significantly modified three key biomarkers:
- Plasminogen Activation Inhibitor-1 (PAI-1)
- Leptin
- Tissue Inhibitor Metalloproteinase-1 (TIMP-1)
- These changes suggest omega-3 influences metabolic and inflammatory pathways related to aging.
Differences Based on Baseline Nutritional Status
- Participants with higher baseline vitamin D levels (>20 ng/ml) showed a greater response to omega-3 supplementation.
- Women and individuals with lower baseline omega-3 levels also experienced stronger effects on PhenoAge.
Clinical Outcomes in the DO-HEALTH Trial
- Previous analyses of the full DO-HEALTH dataset (2,157 participants) showed:
- Omega-3 reduced infections by 13% and falls by 10%.
- The combination of all three interventions reduced prefrailty by 39% and incident invasive cancer by 61% over 3 years.
- The current study extends these findings to molecular aging measures, suggesting a potential long-term benefit of slowing biological aging.
Discussion
- Omega-3 appears to have a specific, significant effect on slowing biological aging across multiple DNAm clocks.
- The additive effect observed with vitamin D and exercise for PhenoAge suggests a synergistic benefit of combining these interventions.
- The impact of baseline nutrient status on intervention efficacy highlights the importance of personalized nutrition strategies for aging.
- The study aligns with findings from the CALERIE trial, which showed caloric restriction slowed aging but did not significantly impact PhenoAge or GrimAge.
Limitations
- The study analyzed only two time points (baseline and 3 years), which may introduce measurement variability.
- The Swiss cohort analyzed was healthier and more active than the general population, which could affect generalizability.
- The trial lasted only 3 years, so long-term benefits on aging and disease prevention remain uncertain.
Conclusion
- Omega-3 supplementation showed the most consistent effect in slowing biological aging, as measured by DNAm clocks.
- Vitamin D and exercise contributed to an additive benefit, particularly for PhenoAge.
- Personalized interventions may be necessary, as effects varied based on baseline omega-3 and vitamin D levels.
- These findings support the geroscience hypothesis, which proposes that slowing biological aging can help prevent chronic diseases.
Future Directions
- Further analysis of additional biospecimens and longer follow-ups are needed.
- Broader application of epigenetic clocks may enhance the evaluation of aging interventions.
- Future research should explore the clinical significance of slowing DNAm aging in relation to frailty, cognitive decline, and lifespan.
For full details, refer to the original article: https://pubmed.ncbi.nlm.nih.gov/39900648/
