Age‐Dependent Metabolomic Signatures of Dietary Restriction in Mice

Caloric (CR) or dietary (DR) restriction improves health and extends lifespan in multiple species. However, the beneficial effects of DR may diminish if introduced late in life, emphasizing the importance of timing for promoting healthspan and avoiding adverse outcomes. Using a metabolomics approach, we investigated the metabolic responses in plasma, liver, and kidney of mice on acute and chronic DR at various ages. Two hundred and five mice including young (2-month-old; n = 72), middle-aged (6-month-old; n = 76), and old (17-month-old; n = 57) mice for DR were involved. No significant metabolic distinctions were observed during acute DR across different ages. Throughout chronic DR, hepatic glucose, glycogen, and glutathione levels-all of which decreased with age-were elevated in all mice, demonstrating an improvement in energy metabolism and enhanced protection against oxidative stress. We also found age-dependent metabolic responses to DR. Specifically, in young mice, amino acids and lactate contributed to gluconeogenesis in the liver during chronic DR. In contrast, in middle-aged and older mice, only fatty acids played a role in the energy supply within the liver. We noted significant hepatic glycogen accumulation in old mice, along with decreased levels of hepatic betaine and sarcosine in young mice, indicating the negative impact of chronic DR on liver function. The findings suggest that the most substantial benefits of DR occur in the middle stage of life, highlighting the need for tailored dietary intervention strategies to promote health span at different life stages.