Discussion
brain atrophy, Atrophy, adiposity, Hypertension, weight loss
BRAIN ATROPHY, ADIPOSITY, HYPERTENSION, ATROPHY
In this randomized trial, we observed no reductions in biological aging among the three diet intervention groups. However, we found that beyond weight loss, adherence to a Green-MED diet regimen, especially with a greater intake of specific polyphenol-rich foods, might be associated with slower biological aging. In addition, mAge changes corresponded to the dynamic of specific urine polyphenols, previously identified as related to a beneficial effect on adiposity and brain anatomy outcomes in the DIRECT PLUS. To the best of our knowledge, this is the first clinical trial suggesting a specific link between polyphenol intakes and less biological aging.Our study has some limitations. First, the GMD score is calculated based on self-reports and not on objective measurements. However, the dietary questionnaires used for this score were previously validated [Similar to previous studies, we observed a strong correlation between mAge and chronological age. It has to be noted that the chronological age was about 12 years lower than the mAge for both men and women. This may be due to several reasons, including lack of calibration, applying 207 CpGs out of 239 from the original Li mAge formula, for example, but may also reflect poor health status. Besides the association with age at baseline, we also assessed the cross-sectional association of mAge with dietary intake pre-intervention. Although weakly correlated, age and mAge by different clocks were significantly associated with fruit, vegetable, fish, and legume intake. However, we found no association between these foods and age acceleration. In previous studies, age acceleration was directly associated with fish, poultry, and fruit intake and inversely associated with alcohol across different mAge clocks [In this study, we could not find any between-group differences in mAge change between the interventions. Few intervention studies examined the differences in mAge changes between dietary intervention groups. An 8-week diet and lifestyle treatment led to a lower mAge change vs. a control group [The combination of 9 dietary changes that included the intake of fruits, green tea, walnuts, green Mankai, fish, legumes, vegetables, and reduced red and processed meat was jointly associated with less biological aging and age acceleration. It has to be noted that we could detect associations between the change in two clocks (Li mAge and Hannum mAge) and GMD score, and not across all six epigenetic clocks estimated in this study. This finding, in addition to our report of favorable difference between the observed and expected Li mAge at the end of the intervention, should be interpreted with caution, as a number of measured and unmeasured confounders can explain these findings. We have tried to overcome this issue by using multivariate models adjusting for potential confounders such as age, sex, baseline mAge, and 18-month weight loss. However, the setting of the study does not allow any inference on a causal effect of polyphenols on biological age. Future studies should increase power by exploring the green diet pattern in a larger sample size, although it may be challenging to explore changes in epigenetic clocks since these require measuring DNA methylation at two time points in a setting of a clinical trial oriented to explore increased intake of polyphenols. Two observational studies have found an inverse association between mAge signatures and dietary scores of Dietary Approaches to Stop Hypertension diet (DASH), the Healthy Eating Index–2015, Alternative Healthy Eating Index (aHEI-2010), and the Alternative Mediterranean diet [The Li mAge was trained and tested on a set of 258 and 281 (respectively) Chinese and validated in two sets of 450 and 160 Chinese and Caucasians using whole blood methylation data [Lower methylation aging was associated with increased urolithins and tyrosols. Urolithins are the intestinal microbial metabolites from ellagic acid found in fruits, nuts, and seeds [The DIRECT PLUS trial included three lifestyle interventions: healthy dietary guidelines, the MED diet with the addition of 28 g/day of walnuts, and a Green-MED diet that included walnuts, green tea, and green Mankai shake while reducing the intake of red and processed meat. We showed previously that the Green-MED diet was effective in reducing liver (33) and visceral (28) fats and cardiometabolic risk (36) and is potentially neuroprotective for age-related brain atrophy (29). In a subgroup analysis, we observed that men above 50 benefited more in terms of aging attenuation following the Green-MED diet. This finding corresponds to previous work on age-related brain atrophy in older participants compared with younger participants. Atrophy was accelerated among those ≥ 50 years old, and brain atrophy was attenuated in groups receiving different-style MED diets, with the best outcomes among Green-MED diet participants [