In Aging Cell, researchers have published their surprising findings that epigenetic clocks are not significantly related to most measurements of metabolic health after weight loss interventions.
The utility of clocks
These researchers begin by discussing epigenetic clocks and how much the measured alterations in gene expression cause other aspects of aging, the details of which remain unclear [1]. Accelerated aging, as measured by these clocks, is associated with cardiometabolic diseases [2]; if altering the expression of clock-related genes is demonstrated to have benefits in this area, it could pave the way for interventions; if this method is demonstrated not to be beneficial, then they may remain useful simply as clocks. There is also the question of generalizability: whether or not clocks are equally valuable across populations.
Limited connections between clocks and metabolites
Here, the researchers focused on obese people by using data from the MACRO trial, which was conducted to test the effects of weight loss interventions between 2008 and 2011 [3].
This trial utilized 148 participants between 22 and 75 years of age who had high BMI indices (between 30 and 45) but did not have such metabolic diseases as cardiovascular disease or type 2 diabetes. They were divided into low-carbohydrate and low-fat groups; the low-carb group was reported to have more weight loss than the low-fat group. Adherence to these diets was high.
These researchers used three samples from each person: at baseline, 3 months, and 12 months. To minimize noise, two principal component-based clocks, PCPhenoAge and PCGrimAge, were used along with the DunedinPACE clock that natively measures age acceleration. Age, sex, ethnicity, body weight, education, smoking, and alcohol use were all factored in as covariates.
Interestingly, lower total cholesterol was found to be associated with more rapid aging, according to both PCPhenoAge and DunedinPACE. Other metabolic factors were found to be associated with accelerated aging, including reduced levels of ghrelin and adiponectin along with higher levels of insulin, the insulin resistance marker HOMA-IR, and C-reactive protein (CRP). PCGrimAge did not have any statistically significant association between metabolic factors and epigenetic aging.
After dietary interventions, however, most of these correlations disappeared; the only ones that remained were the low adiponectin and the high CRP according to the DunedinPACE clock.
The interventions themselves had noticeable effects. Only three months of dieting did not yield any statistically significant effect on epigenetic aging. However, after 12 months, despite the dets being more effective for weight loss, PCPhenoAge and PCGrimAge reported increased epigenetic aging in the low-carb group compared to the low-fat group. DunedinPACE, however, reported that epigenetic age acceleration was decreased in both groups.
As expected, the dietary interventions had significant benefits for metabolic issues. However, critical to this study, the reseachers found that none of these benefits were mediated by epigenetic alterations as measured by these clocks: “Specifically, all indirect effects and proportions mediated were non-significant (FDR > 0.05), suggesting that the observed associations were not driven through changes in epigenetic aging.”
A clock may not always reflect health
These results, or lack thereof, led the researchers to suggest that the health benefits of moderately rapid weight loss are not well-captured in epigenetic clocks designed to measure aging. Specifically, they note that there is an “uncoupling” between the metabolic benefits observed in these studies and clock measurements. They further suggest that this may be due to the time periods involved; DunedinPACE “may be more indicative of cumulative biological burden that changes gradually over time” and less sensitive to relatively short-term effects.
The researchers highlight that their study is in line with previous work on this topic; the CALERIE trial found that caloric restriction, a well-known longevity intervention, had some effects on DunedinPACE but fewer effects on PCPhenoAge and PCGrimAge [4]. In total, their findings led the researchers to specifically warn against the use of epigenetic clocks as surrogate endpoints in metabolism-related interventions, suggesting instead that they “should remain exploratory and be interpreted with more established physiological markers.”
Literature
[1] Ferrucci, L., Barzilai, N., Belsky, D. W., & Gladyshev, V. N. (2025). How to measure biological aging in humans. Nature Medicine, 1-1.
[2] Lo, Y. H., & Lin, W. Y. (2022). Cardiovascular health and four epigenetic clocks. Clinical Epigenetics, 14(1), 73.
[3] Bazzano, L. A., Hu, T., Reynolds, K., Yao, L., Bunol, C., Liu, Y., … & He, J. (2014). Effects of low-carbohydrate and low-fat diets: a randomized trial. Annals of internal medicine, 161(5), 309-318.
[4] Waziry, R., Ryan, C. P., Corcoran, D. L., Huffman, K. M., Kobor, M. S., Kothari, M., … & Belsky, D. W. (2023). Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging, 3(3), 248-257.
View the article at lifespan.io
