Fasting requires Peroxiredoxin 2 and Peroxiredoxin 6 to coordinate redox dependent mitochondrial and lipid...

Fasting induces conserved metabolic and redox adaptations that promote stress resistance and longevity. However, the molecular mechanisms linking transient redox changes and altered metabolism to downstream signalling events remain incompletely understood. Using Caenorhabditis elegans, the roles of peroxiredoxins in coordinating redox-dependent responses to fasting and refeeding were determined. A 4-hr fasting protocol over 5 days extended lifespan, improved late-life physiological activity, reduced age-related lipofuscin and lipid accumulation. The fasting protocol generated a transient increase in mitochondrial ROS, promoted mitochondrial turnover, and attenuated age-related mitochondrial fragmentation. These adaptive responses required the activation and nuclear localisation of the stress-responsive transcription factors DAF-16/FOXO and SKN-1/Nrf2. However, these adaptive responses were abolished in prdx-2 and prdx-6 mutant strains, which exhibited persistent redox imbalance, mitochondrial fragmentation, altered stress resistance, and disrupted DAF-16 and SKN-1 signalling. Mechanistically, loss of 2-Cys PRDX-2 impaired activation of the p38 MAPK PMK-1 pathway, resulting in defective SKN-1 activation. In contrast, loss of 1-Cys PRDX-6 disrupted lipid metabolic signalling, preventing induction of NHR-80 and downstream fatty acid desaturases required for metabolic adaptations. Despite distinct initial signalling pathways, both peroxiredoxins converged on the regulation of DAF-16 and SKN-1. Together, these findings identify PRDX-2 and PRDX-6 as redox sensors that translate a fasting-induced transient ROS signature into mitochondrial and lipid remodelling pathways to promote healthy ageing.