https://www.nature.com/articles/s41591-026-04562-9
(1) significantly decreasing epigenetic age in only a handful of generation 2 reliable clocks (smoking cessation—SystemsAge; umbilical cord blood transfusion—DunedinPACE and GrimAgeV2; metformin—SystemsAge, PCGrimAge and PCPhenoAge; hyperbaric oxygen therapy—DunedinPACE; Vegan Diet—DunedinPACE and SystemsAge; TruLacta supplement—DunedinPACE) or (2) not significantly decreasing epigenetic age in any generation 2 reliable clocks (gastric bypass) (Fig. 6b and Supplementary Table 18). The sporadic responsiveness of clocks to the first category of interventions may suggest they are false positives, whereas the lack of responsiveness in the second category may suggest they do not modify epigenetic age. However, we considered the possibility that these interventions simply had very specific effects that may not be detectable using a general aging clock. Accordingly, the SystemsAge components suggested these interventions may be impacting different systems (Fig. 6c, Extended Data Fig. 2 and Supplementary Table 18). For example, the two interventions that did not modify any general Gen 2 reliable clock do show significant decreases in epigenetic age of specific systems (gastric bypass decreases metabolic score with effect size 0.43). Other interventions include smoking cessation seeing maximal decrease in lung (0.20), umbilical cord transfusion in musculoskeletal (0.13) and hyperbaric oxygen therapy in lung (0.27). Although other systems saw multi-system decreases such as metformin with inflammation (0.80), brain (0.70) and metabolic (0.70) decreasing the most. In the vegan diet, the largest decrease was seen in inflammation (0.23) and musculoskeletal (0.17
examined how much of the change in each clock could be attributed to stochastic versus nonstochastic components. For example, we found that Horvath1 was strongly correlated with its stochastic component (R = 0.50), whereas PhenoAge showed almost no correlation with its own stochastic component (R = −0.06), suggesting that PhenoAge reflects more structured biological aging (Fig. 6f,g).
