Abstract
Dysregulation of metabolism develops with organismal aging. Both genetic and environmental manipulations promote longevity by effectively diverting various metabolic processes against aging. How these processes converge on the metabolome is not clear. Here we report that the heavy isotopic forms of common elements, a universal feature of metabolites, decline in yeast cells undergoing chronological aging. Supplementation of deuterium, a heavy hydrogen isotope, through heavy water (D2O) uptake extends yeast chronological lifespan (CLS) by up to 85% with minimal effects on growth. The CLS extension by D2O bypasses several known genetic regulators, but is abrogated by calorie restriction and mitochondrial deficiency. Heavy water substantially suppresses endogenous generation of reactive oxygen species (ROS) and slows the pace of metabolic consumption and disposal. Protection from aging by heavy isotopes might result from kinetic modulation of biochemical reactions. Altogether, our findings reveal a novel perspective of aging and new means for promoting longevity.
Highlights
Normal aging is accompanied by progressive metabolism deterioration.[1]
Of 237 metabolites with a KEGG entry, 58 metabolites that showed a decreasing trend with time were shared in both strains, and over-represents a few metabolic pathways, including arginine and proline metabolism and oxidative phosphorylation (Supplementary Table S2), two processes for energy generation and waste disposal in catabolism that decline in aging.[10,11]
We only reported aging-associated heavy isotope decline in a group of small metabolites, amino acids (AAs), but this decline may exist in other metabolites
Summary
Normal aging is accompanied by progressive metabolism deterioration.[1]. Understanding the basic mechanisms involved in aging and how the process can be manipulated will provide useful insights and treatment for this universal process. Adjusting and diverting metabolic flows serve as a major objective to delay aging. Genetic manipulation of a range of metabolic regulators are implicated in lifespan extension in experimental organisms.[1] In budding yeast S. cerevisiae, these include suppression of anabolism through mTOR inhibition,[2] activation of catabolism through AMPK3 and sirtuins activation,[4] and enhancement of bioenergetics through mitochondria.[5] In parallel, calorie restriction (CR, or dietary restriction, DR), as a typical environmental intervention, works well as, or in certain cases, even better than genetic manipulation to extend lifespan.[6] Modulation of metabolism through nutrient uptake may represent a deserving avenue of anti-aging intervention
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