Reevaluating the Concept of Aging: Long-Term Stress Adaptation as a Key Factor in Yeast Aging

It has been demonstrated that short-term stress can enhance cellular responses and promote longevity, whereas long-term stress shortens lifespan. Understanding the relationship between short-term and long-term stress could offer new insights into comprehending and modulating age-related diseases. In this study, we investigate this relationship using transcriptomic and metabolomic analyses in the yeast model system (Saccharomyces cerevisiae). We employed three metabolic treatments: firstly, treating yeast cells with threshold levels of benzoic acid for 24 hours (Short-term [ST] Stressed Cells); secondly, treating yeast cells with threshold levels of benzoic acid for 500 hours, with sub-culturing every 24 hours (Long-term [LT] Stressed Cells); and thirdly, allowing the long-term stressed cells to grow for 16 hours without any benzoic acid (Recovered Cells). Here, we propose that aging is an evolutionarily conserved cellular adaptation mechanism in response to long-term stress exposure. Under short-term stressed conditions, prominent lifespan-extending metabolites such as trehalose and metabolites linked to tumor suppression in humans, such as 5-methylthioadenosine, were overexpressed. In contrast, LT Stressed Cells activated genes such as those responsible for epigenetic regulatory enzymes that govern the aging process, and secondary stress response genes, such as heat shock proteins (HSPs) which are associated with adaptation to cell damage but also often associated with aged cells. Chronological lifespan experiments showed that LT stressed cells lived a shorter lifespan compared to ST Stressed Cells. This suggests that the markers of aging (eg. HSPs, certain epigenetic regulators) are expressed in response to long-term stress to enable cell survival but have the long-term effect of reducing lifespan. In support of this hypothesis, we also show that genes exclusively activated in ST Stressed Cells are conserved solely in eukaryotes, while those significantly expressed in LT Stressed Cells (aging related) exhibit high conservation across all domains of life, with a majority having originated from bacteria hinting at the potential evolutionary benefit of aging.