Multilayered regulation of longevity in Caenorhabditis elegans

Aging in Caenorhabditis elegans is regulated by evolutionarily conserved pathways that coordinate cellular maintenance and systemic homeostasis. Here, we review recent advances on four major longevity regimens, including reduced insulin/insulin-like growth factor 1 signaling (IIS), dietary restriction (DR), mild inhibition of mitochondrial respiration, and germline deficiency. Each longevity-promoting regimen enhances protein and RNA quality control, metabolic remodeling, and stress resistance to delay functional declines with age. Reduced IIS strengthens proteostasis and RNA surveillance. DR remodels metabolism and activates autophagy. Mild mitochondrial inhibition elicits adaptive redox signaling and quality control responses. Germline deficiency links reproductive cues to somatic maintenance. We highlight that longevity arises from the integrated regulation of transcriptional, metabolic, and inter-tissue signaling networks. Our review will provide valuable insights obtained from C. elegans into the conserved mechanisms of aging, facilitating the development of interventions that promote healthy longevity in humans.