End-of-life targeted auxin-mediated degradation of DAF-2 Insulin/IGF-1 receptor promotes longevity free from growth-related pathologies

Abstract Preferably, lifespan-extending therapies should work when applied late in life without causing undesired pathologies. However, identifying lifespan-extending interventions that are effective late in life and which avoid undesired secondary pathologies remains elusive. Reducing Insulin/IGF-1 signaling (IIS) increases lifespan across species, but the effects of reduced IIS interventions in extreme geriatric ages remains unknown. Using the nematode C. elegans , we engineered the conditional depletion of the DAF-2/insulin/IGF-1 transmembrane receptor using an auxin-inducible degradation (AID) system that allows for the temporal and spatial reduction in DAF-2 protein levels at time points after which interventions such as RNAi may lose efficacy. Using this system, we found that AID-mediated depletion of DAF-2 protein efficiently extends animal lifespan. Depletion of DAF-2 during early adulthood resulted in multiple adverse phenotypes, including growth retardation, germline shrinkage, egg-retention, and reducing offspring. By contrast, however, AID-mediated depletion of DAF-2 specifically in the intestine resulted in an extension of lifespan without these deleterious effects. Importantly, AID-mediated depletion of DAF-2 protein in animals past their median lifespan allowed for an extension of lifespan without affecting growth or behavioral capacity. Thus, both late-in-life targeting and tissue-specific targeting of IIS minimize the deleterious effects typically seen with interventions that reduced IIS, suggesting potential therapeutic methods by which longevity and healthspan can be increased in even geriatric populations.