The journal Nature Aging recently published a post hoc analysis of the 3- year DO-HEALTH trial evaluating the effects of supplementation with omega-3 fatty acids (1g per day), vitamin D (2,000 IU per day), simple home exercise, and their combinations on DNA methylation (DNAm) clocks of biological aging among adults 70 and older. The larger DO-HEALTH trial had over 2,000 participants and reported that omega-3 supplementation alone significantly reduced the rate of upper respiratory infections (10%), urinary tract infections (62%), and falls by 10%; and, when in combination with vitamin D and exercise, reduced prefrailty by 39% and incident invasive cancer by 61%. Known as the DO-HEALTH Bio-Age trial, this new post hoc analysis included data from 777 participants in the original trial who had DNAm clocks measured at baseline and 3 years. The primary analysis was of three 2nd-generation epigenetic clocks (PhenoAge, GrimAge, GrimAge2) and one “3rd-generation” (DunedinPACE) clock, though 1st-generation clocks and DNAm surrogate markers of plasma proteins were also included in the analysis.
Omega-3 supplementation reduced either the age-acceleration or pace-of-aging in three of the four clocks in the primary analysis, while vitamin D and exercise alone did not have any significant effects on any of the clocks. However, in the PhenoAge clock, all three interventions combined had additive benefits, similar to the reductions in prefrailty and cancer incidence in the larger trial. There was also an additive effect of all 3 interventions on four of seven GrimAge plasma proteins (PAI-1, B2M, TIMP-1, and GDF-15) associated with multiple age-related conditions and metabolic dysregulation. Effect sizes ranged from 2.9 to 3.8 months (in PhenoAge and GrimAge2) over this 3-year period, a sizeable effect, especially at the population level. Individuals with lower baseline levels of omega-3s (DHA/EPA) showed larger epigenetic shifts with omega-3 supplementation, with larger shifts due to omega-3 supplementation also observed among individuals with a baseline 25(OH)D level of ≥20 ng/ml, suggesting that targeted interventions may be of even greater benefit. It’s also worth noting that this was not a population at high-risk, but enrolled generally healthy and active older adults across 5 European countries. Eighty-eight percent were physically active, and over half were free of major chronic diseases, disabilities, cognitive impairments, and mental health conditions.
Lastly, this analysis did not discuss possible mechanisms, but given the reduction in infections observed in the larger DO-HEALTH trial with omega-3 alone, it seems likely that immunomodulation may be at least part of the mechanism of action. As discussed in a recent review published in Frontiers in Immunology, immunosenescence and inflammaging are “deeply interconnected processes that mutually reinforce each other.” A continuous low level of inflammation may limit effective immune responses (and adversely impact multiple body systems). Supplementation with omega-3 fatty acids (notably EPA and DHA are precursors for specialized pro-resolving mediators (SPMs)), lifestyle interventions (e.g., sleep, a Mediterranean diet, etc.), and other micronutrients have been shown to help with low-grade inflammation among older adults, plausibly also reducing their biological age.