Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications allow adaptation of yeast cells to ER stress independently of the unfolded protein response, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. Moreover, the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP--acetylglucosamine-1-P transferase (), a subunit of the 20S proteasome (), and induced tunicamycin resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin-resistance phenotype. Together, our data demonstrate that aneuploidy plays a critical role in adaptation to ER stress by increasing the copy number of ER stress protective genes. While aneuploidy itself leads to proteotoxic stress, the gene-specific effects of chromosome II aneuploidy counteract the negative effect resulting in improved protein folding.

Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently reduce cellular lifespan. Human cancers driven by a mutator phenotype represent an intriguing model to test this hypothesis, since they carry the highest mutation burdens of any human cell. However, it remains technically challenging to measure the replicative lifespan of individual mammalian cells. Here, we modeled the consequences of cancer-related mutator phenotypes on lifespan using yeast defective for mismatch repair (MMR) and/or leading strand (Polε) or lagging strand (Polδ) DNA polymerase proofreading. Only haploid mutator cells with significant lifetime mutation accumulation (MA) exhibited shorter lifespans. Diploid strains, derived by mating haploids of various genotypes, carried variable numbers of fixed mutations and a range of mutator phenotypes. Some diploid strains with fewer than two mutations per megabase displayed a 25% decrease in lifespan, suggesting that moderate numbers of random heterozygous mutations can increase mortality rate. As mutation rates and burdens climbed, lifespan steadily eroded. Strong diploid mutator phenotypes produced a form of genetic anticipation with regard to aging, where the longer a lineage persisted, the shorter lived cells became. Using MA lines, we established a relationship between mutation burden and lifespan, as well as population doubling time. Our observations define a threshold of random mutation burden that consistently decreases cellular longevity in diploid yeast cells. Many human cancers carry comparable mutation burdens, suggesting that while cancers appear immortal, individual cancer cells may suffer diminished lifespan due to accrued mutation burden.

The mechanistic target of rapamycin (mTOR) is a central regulator of growth and proliferation and mTOR inhibition is a promising therapy for a variety of diseases and disorders. Inhibition of mTOR complex I (mTORC1) with rapamycin delays aging and increases healthy longevity in laboratory animals and is used clinically at high doses to prevent organ transplant rejection and to treat some forms of cancer. Clinical use of rapamycin is associated with several unwanted side effects, however, and several strategies are being taken to identify mTORC1 inhibitors with fewer side effects. We describe here a yeast-based growth assay that can be used to screen for novel inhibitors of mTORC1. By testing compounds using a wild-type strain and isogenic cells lacking either TOR1 or FPR1, we can resolve not only whether a compound is an inhibitor of mTORC1 but also whether the inhibitor acts through a mechanism similar to rapamycin by binding Fpr1. Using this assay, we show that rapamycin derivatives behave similarly to rapamycin, while caffeine and the ATP competitive inhibitors Torin 1 and GSK2126458 are mTORC1 inhibitors in yeast that act independently of Fpr1. Some mTOR inhibitors in mammalian cells do not inhibit mTORC1 in yeast, and several nutraceutical compounds were not found to specifically inhibit mTOR but resulted in a general inhibition of yeast growth. Our screening method holds promise as a means of effectively assaying drug libraries for mTOR-inhibitory molecules in vivo that may be adapted as novel treatments to fight diseases and extend healthy longevity.

At the cellular level, many aspects of aging are conserved across species. This has been demonstrated by numerous studies in simple model organisms like Saccharomyces cerevisiae, Caenorhabdits elegans, and Drosophila melanogaster. Because most genetic screens examine loss of function mutations or decreased expression of genes through reverse genetics, essential genes have often been overlooked as potential modulators of the aging process. By taking the approach of increasing the expression level of a subset of conserved essential genes, we found that 21% of these genes resulted in increased replicative lifespan in S. cerevisiae. This is greater than the ~ 3.5% of genes found to affect lifespan upon deletion, suggesting that activation of essential genes may have a relatively disproportionate effect on increasing lifespan. The results of our experiments demonstrate that essential gene overexpression is a rich, relatively unexplored means of increasing eukaryotic lifespan.