Boosting stress responses to promote healthy aging

Aging is marked by a decline in physiological functions and increased disease susceptibility. As the global population ages, understanding aging's biological mechanisms is vital for developing strategies to extend healthy lifespans. "Chronological age" measures time elapsed, but it doesn't account for individual aging rates influenced by genetics, lifestyle, and environment. This thesis introduces "biological age," a more nuanced measure using biomarkers reflecting physiological and molecular changes. Chapter 2 discusses transcriptome-based approaches to estimate biological age and explores compounds like HSP90 and HDAC inhibitors that mimic longevity signatures. The thesis also explores aging interventions, focusing on computational drug screening. Chapter 3 identifies Cmpd60, a selective HDAC1/2 inhibitor, as a potential geroprotector, improving age-related phenotypes in mice. Chapter 4 discovers amonafide, which extends lifespan and healthspan in C. elegans by activating stress response pathways. Mitochondrial function is crucial for longevity, with low-level stressors enhancing cellular resistance through "mitohormesis." In Chapter 5, the gene K04C2.2 is identified as essential for activating the mitochondrial unfolded protein response (UPR^MT). Chapter 6 reveals that the gene C32E8.9 is necessary for lifespan extension via mitochondrial translation inhibition. This thesis highlights key genes and pathways involved in aging, suggesting novel therapeutic targets for healthy aging and extended lifespan.