Long-Term Stress Adaptation as a Highly-Conserved Key Factor in Yeast Aging.

Aging is commonly viewed as a passive consequence of accumulated damage; however, emerging evidence suggests that it may also represent an adaptive response to environmental stress. Here, we combined transcriptomic and metabolomic profiling of Saccharomyces cerevisiae to investigate how short-term, long-term, and recovery phases of stress exposure shape cellular physiology and lifespan. Short-term stress-induced protective pathways and longevity-associated metabolites, including trehalose and 5'-methylthioadenosine, consistent with enhanced stress resilience and proteostasis. In contrast, prolonged stress activated heat shock proteins and epigenetic regulators, coupled with metabolic signatures associated with loss of proteostasis, reduced energy homeostasis, and shortened chronological lifespan. Upon recovery, beneficial metabolites such as S-adenosylhomocysteine were restored, highlighting the reversibility of stress-induced aging trajectories. Phylogenetic analysis demonstrated conservation of these stress- and aging-related genes across eukaryotes and prokaryotes, suggesting an evolutionary basis for aging as a long-term stress adaptation. Together, these findings suggest that aging-associated molecular changes are closely linked to conserved stress response pathways, with implications for understanding the hallmarks of aging.