Epigenetic Aging Acceleration in Obesity Is Slowed Down by Nutritional Ketosis Following Very Low-Calorie Ketogenic Diet (VLCKD): A New Perspective to Reverse Biological Age

<b>Background/Objectives</b>: Epigenetic clocks have emerged as a tool to quantify biological age, providing a more accurate estimate of an individual's health status than chronological age, helping to identify risk factors for accelerated aging and evaluating the reversibility of therapeutic strategies. This study aimed to evaluate the potential association between epigenetic acceleration of biological age and obesity, as well as to determine whether nutritional interventions for body weight loss could slow down this acceleration. <b>Methods</b>: Biological age was estimated using three epigenetic clocks (Horvath (Hv), Hannum (Hn), and Levine (Lv)) based on the leukocyte methylome analysis of individuals with normal weight (n = 20), obesity (n = 24), and patients with obesity following a VLCKD (n = 10). We analyzed differences in biological age estimates, the relationship between age acceleration and obesity, and the impact of VLCKD. Correlations were assessed between age acceleration, BMI, and various metabolic parameters. <b>Results</b>: Analysis of the epigenetic clocks revealed an acceleration of biological age in individuals with obesity (Hv = +3.4(2.5), Hn = +5.7(3.2), Lv = +3.9(2.7)) compared to a slight deceleration in individuals with normal weight. This epigenetic acceleration correlated with BMI (<i>p</i> < 0.0001). Interestingly, patients with obesity following a VLCKD showed a deceleration in estimated biological age, both in nutritional ketosis (Hv = -3.3(4.0), Hn = -6.3(5.3), Lv = -8.8(4.5)) and at endpoint (Hv = -1.1(4.3), Hn = -7.4(5.6), Lv = -8.2(5.3)). Relevantly, this slowdown in age is associated with BMI (<i>p</i> < 0.0001), ketonemia (<i>p</i> ≤ 0.001), and metabolic parameters (<i>p</i> < 0.05). <b>Conclusions</b>: Our findings highlight the applicability of epigenetic clocks to monitor obesity-related biological aging in precision medicine and show the potential efficacy of the VLCKD in slowing obesity-related epigenetic aging.