Temporal Requirements of SKN-1/NRF as a Regulator of Lifespan and Proteostasis inCaenorhabditis elegans

Abstract

Lowering the activity of the Insulin/IGF-1 Signaling (IIS) cascade results in elevated stress resistance, enhanced protein homeostasis (proteostasis) and extended lifespan of worms, flies and mice. In the nematode Caenorhabditis elegans (C. elegans), the longevity phenotype that stems from IIS reduction is entirely dependent upon the activities of a subset of transcription factors including the Forkhead factor DAF-16/FOXO (DAF-16), Heat Shock Factor-1 (HSF-1), SKiNhead/Nrf (SKN-1) and ParaQuat Methylviologen responsive (PQM-1). While DAF-16 determines lifespan exclusively during early adulthood and governs proteostasis in early adulthood and midlife, HSF-1 executes these functions foremost during development. Despite the central roles of SKN-1 as a regulator of lifespan and proteostasis, the temporal requirements of this transcription factor were unknown. Here we employed conditional knockdown techniques and discovered that in C. elegans, SKN-1 is primarily important for longevity and proteostasis during late larval development through early adulthood. Our findings indicate that events that occur during late larval developmental through early adulthood affect lifespan and proteostasis and suggest that subsequent to HSF-1, SKN-1 sets the conditions, partially overlapping temporally with DAF-16, that enable IIS reduction to promote longevity and proteostasis. Our findings raise the intriguing possibility that HSF-1, SKN-1 and DAF-16 function in a coordinated and sequential manner to promote healthy aging.

SKN-1 is a metabolic surveillance factor that monitors amino acid catabolism to control stress resistance

“…Titration of SKN-1 expression is important for the pro-longevity nature of this transcription factor. Moderate overexpression of SKN-1 or mutation of the negative regulator wdr-23 extends the lifespan of C. elegans , while hypomorphic mutants or worms treated with skn-1 RNAi exhibit a shortened lifespan (Grushko et al, 2021; Ganner et al, 2019; Tullet et al, 2017; Tang and Choe, 2015; Tullet et al, 2008). However, gain-of-function animals with constitutive expression of SKN-1 and animals containing high-copy arrays of SKN-1 exhibit a mild decrease in lifespan (Paek et al, 2012; Tullet et al, 2008).…”