A recently published issue of Scientific Reports includes an analysis of the association between the consumption of methyl donor nutrients (MDNs) and phenotypic aging. MDNs are known to play a role in DNA methylation and gene expression, as well as one-carbon and cellular metabolism. Several epigenetic clocks utilize changes in DNA methylation alone to predict “biological age” and subsequent mortality risk. This study examined the relationship between dietary intake of MDNs in a representative sample of the U.S. (NHANES 2005–2018) and PhenoAge, a calculated estimate of phenotypic aging shown to predict both morbidity and mortality. Over 27,000 U.S. adults met the eligibility criteria and were included in this analysis, ranging in age from 20 to 85 years old (mean of 47). Intake of MDNs was assessed by estimating dietary levels of protein, folate, choline, vitamins B2, B6, B12, and zinc, done via interviews and a 24-hour dietary survey. Scored via the methyl-donor nutritional quality index (MNQI), 1 point was awarded for each nutrient consumed with a range between 2/3 of its RDA and its upper limit, and 0 points for intakes above or below this range (protein, folate, and choline were awarded 2 points when in range). A score of 6 or higher was considered high, and below 6 was considered low.
PhenoAge is a composite score that combines chronological age along with 9 blood biomarkers (albumin, creatinine, glucose, C-reactive protein, lymphocyte percent, mean cell volume, red blood cell distribution width, alkaline phosphatase, and white blood cell count). PhenoAge, in turn, was used to calculate PhenoAge acceleration (the ratio of phenotypical age to chronological age), with a score (termed PhenoAge.Accel) greater than 1 indicating accelerated aging (i.e., phenotypically older than chronological age), while a score less than 1 suggests a slowing of the aging process.
Overall, a negative association was found between MNQI and PhenoAge.Accel, suggesting that a higher intake of MDNs is associated with a reduction in phenotypic aging. This was observed in both men and women, but a stronger association was observed in men. Additionally, this association persisted after multivariate adjustment, including adjusting for traditional risk factors, such as obesity, smoking, hypertension, etc.
While this type of study cannot show causation, there are multiple lines of evidence to suggest that increasing intake of MDNs has a protective effect. As reviewed in the article, global methylation decreases with age (though local hypermethylation does occur), and preservation of methylation capacity may slow down the aging process. MDNs modulate metabolism, immune function, and one-carbon metabolism (reviewed here), with differentially methylated genes involved in lipid metabolism, estrogen activity, muscle and mitochondrial function, and multiple other activities related to diseases linked to the aging process. Modulation of the epigenome, largely marked by global hypomethylation, is one of the hallmarks of aging itself.
The authors also point to individual components of the MNQI that may partly account for the apparent slowdown in aging. For example, zinc is involved in DNA repair, hematopoiesis, and zinc deficiency may play a role in immunosenescence, sarcopenia, and frailty in older adults. A more plant-based diet is likely to contain greater amounts of B vitamins, perhaps partly explaining the lower risk for frailty among older adults who consume a more plant-based diet. Indeed, the Twins Nutrition Study found that a vegan diet was associated with significant decreases in epigenetic age acceleration (measured by multiple epigenetic clocks) compared to a healthy omnivorous diet over an 8-week study period, though some of the benefit may have been because of the associated weight loss. Folate alone has been associated with the aging process, with homocysteine a clear risk factor for multiple chronic diseases, including both cardiovascular disease and dementia, and Mendelian randomization studies suggesting that it plays a causal role.
A specific example of how the MDNs may mitigate disease risk can be observed with choline intake. In a small study of older adults living in China, dietary choline levels were found to be inversely associated with risk for stroke. More specifically, methylation at specific CpG sites of the ABCG1 gene (involved in lipid/cholesterol metabolism) was found to directly mediate stroke risk. Choline did not directly impact stroke risk, but only indirectly modulated risk via changes in methylation.
There are multiple other variables that are likely to interact with MDNs to influence the aging process. One clear example is exposure to environmental toxicants; in a study that used data from NHANES (2001–2010), urinary levels of monohydroxy polycyclic aromatic hydrocarbons (OH-PAHs) were found to be associated with faster phenotypic aging, marked by increases in PhenoAge.Accel. For example, a one-unit increase in the sum of hydroxynaphthalene metabolites was associated with a 0.37-year increase in phenotypic age. This same study found that healthier lifestyle behaviors (e.g., lack of drinking, smoking, greater exercise, etc.) were associated with a deceleration of the aging process. At least in women, there appeared to be an interaction between the two variables, with healthier behaviors mitigating some of the risk associated with greater toxicant exposure. Sedentary behavior has also been linked to more rapid aging, emphasizing the importance of considering multiple dietary and lifestyle factors to slow the aging process.