Molecular mechanisms and biomarkers of aging and lifespan extension

The aim of this thesis was to identify novel regulators of longevity, test pharmacological interventions, and explore the role of lipid metabolism in aging using both genetic and systems-level approaches. In Chapter 2, we identified the opioid antagonist naltrexone as a potential geroprotective compound by mimicking the FOXO3A pathway in silico. In C. elegans, low-dose naltrexone extended healthspan and lifespan via SKN-1/NRF2-mediated regulation of innate immunity and stress resistance. Chapter 3 utilized 85 recombinant inbred lines (RIAILs) of C. elegans to integrate transcriptomic, proteomic, and lipidomic data with lifespan and other life-history traits. We observed substantial variability in longevity, positively associated with developmental time, and mapped both established and novel regulators, including rict-1, gfm-1, and mltn-1. In Chapter 4, we investigated mitochondrial stress response (MSR) activation by doxycycline across the same RIAIL panel. Lifespan extension was highly strain-specific, and QTL mapping identified fipp-1/FIP1L1 as a new regulator of the UPRmt, validated in worms and human cells. Chapter 5 extended this work to human plasma lipidomics, revealing triglyceride accumulation with age, modulated by physical activity. Chapter 6 further identified lipid acyl-chain lengthening as a conserved hallmark of aging in worms, flies, mice, and humans, and linked it to cardiovascular disease progression. Knockdown of lipid elongation enzymes in C. elegans extended lifespan and reversed lipid remodeling. Finally, Chapters 7 and 8 integrate these findings, highlighting new therapeutic targets, molecular biomarkers, and lipid remodeling mechanisms in aging and lifespan regulation.