Investigating the role of PDK-1 in longevity and healthy ageing using Drosophila Melanogaster

Organismal aging is characterized by a progressive decline in physiological functions, often accompanied by age-related diseases (ARDs) that significantly impair quality of life and lack effective treatments. The insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) networks are crucial regulators of growth, metabolism, and longevity. In Drosophila, phosphoinositide-dependent kinase-1 (PDK-1) plays a key role in modulating these pathways through two distinct activation mechanisms: one involving the pleckstrin homology (PH) domain, and the other through the PDK-1 interactive fragment (PIF) pocket. PH domain-dependent signaling delays development, reduces size and fecundity, but enhances stress resistance and promotes longevity. Notably, intestinal over-proliferation and reduced climbing ability—common ARDs in Drosophila—were delayed in onset and significantly less severe in these mutants. In contrast, mutations in the PIF pocket similarly reduced size and fecundity while boosting stress resistance, lifespan, and healthspan. However, intestinal over-proliferation was not mitigated by PIF mutations. Furthermore, humanizing PDK-1 in Drosophila did not affect lifespan. Understanding the signaling cascades involved in aging opens the potential for repurposing existing FDA and EMA-approved medications to treat age-related diseases, offering a novel approach to combating aging and its associated disorders.