Yeast longevity promoted by reversing aging-associated decline in heavy isotope content

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.

Shifts in rotifer life history in response to stable isotope enrichment: testing theories of isotope effects on organismal growth

“…A hypothesis has been put forward that the increased uptake of the heavy isotope in a biological system would affect the kinetics of biochemical reactions, increase the stability of the biomolecules and organism longevity [9,10]. Supporting this view, the relative abundance of heavy isotope-containing metabolites in yeast exhibited an ageing-associated trend, with most abundant amino acids declining in their 13 C and 2 H content in senescent cultures [11]. The authors hypothesized that cells might gradually lose the ability to retain heavy metabolites with ageing and, by introducing D 2 O in the culture medium, they were able to slow down this metabolic deterioration and ageing.…”

Age-related decline in metabolite heavy isotope content in rodent organs

“…We normalized metabolite extraction against tissue weight to ensure that metabolite measurements across different organs and age groups are directly comparable in this study. Untargeted liquid chromatography-mass spectrometry (LCMS) was performed to simultaneously assess the metabolite composition and heavy isotope contents in metabolites, as previously described (Li and Snyder, 2016b). When operating at a mass resolution of 100,000 and acquired in profile mode, monoisotopic mass peaks can be discerned and measured around the M+1 mass peaks for heavy isotopes 13 C, 2 H, 15 N, and 33 S, and around the M+2 mass peaks for heavy isotopes 18 O and 34 S. One example for the metabolite taurine is shown in Fig.…”

“…Since our clustering analysis using only the amino acid profiles could, at least in part, separate different organs of different ages from each other, we wonder whether the common HICs in amino acids could show certain age-related changes, which might also reflect a global change of other metabolites. Taking the advantage of high mass resolution used in our LCMS acquisition, we quantified the common HICs in amino acids as previously described (Li and Snyder, 2016b). As an example, the quantification of total metabolites (total count), as well as the relative abundance of 13 C, 15 N and 34 S isotopic forms of methionine in three organs of three different ages was shown in Fig.…”

“…Living organisms have, besides the heavy hydrogen deuterium, many other types of heavy isotopes. Through a metabolomics study, we have previously examined in amino acids the heavy isotopes for four common organic elements, namely 13 C, 2 H, 15 N and 24 S, in yeast cells that underwent chronological aging (Li and Snyder, 2016b). We found an overall trend of decline, which occurred when yeast cells get old, and elevating the HIC for hydrogen through heavy water feeding extended yeast lifespan by 84%.…”

Hydrogen peroxide induced loss of heterozygosity correlates with replicative lifespan and mitotic asymmetry inSaccharomyces cerevisiae

“…Calorie restriction is found to extend chorological lifespan through moderate increase of hydrogen peroxide that leads to activation of superoxide dismutase and inhibition of superoxide anions (Mesquita et al, 2010; Weinberger et al, 2010). Heavy water can suppress endogenous ROS and extend yeast CLS (Li & Synder, 2016). …”