Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes

Abstract

The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan.

Activated SKN-1 alters the aging trajectories of long-lived C. elegans mutants

“…Reduced feeding rate via eat-2lf mutation results in dietary restriction, several factors such as pha-4 and hlh-30 feed into eat-2lf mediated dietary restriction generally resulting in increased autophagy and proteasomal turnover, which promotes longevity 12,13 . Lastly, under nominal conditions, insulin-IGF1-like signaling opposes SKN-1 activation by signaling through to kinases such as SGK-1 which in turn phosphorylate SKN-1 and inhibit its nuclear accumulation 14 . A reduction in insulin-IGF1-like signaling (IIS) causes an increase in SKN-1 activity that promotes stress resistance and longevity 15 .…”

“…SKN-1 is a multifaceted transcription factor that regulates the response to xenotoxins, unfolded proteins, and metabolic stress by upregulating appropriate stress response pathways to mitigate the stressful condition 14,16 .…”

“…Loss of SKN-1 function results in a diminished stress response and a reduction in lifespan 14,16 . Although, mild overexpression of SKN-1, albeit without additional genetic or environmental activation was shown to increase lifespan 16 , investigations utilizing a genetically encoded constitutively activated skn-1 mutation determined that longevity is severely diminished SKN-1 activity cannot be turned off 14,17 .…”

“…Loss of SKN-1 function results in a diminished stress response and a reduction in lifespan 14,16 . Although, mild overexpression of SKN-1, albeit without additional genetic or environmental activation was shown to increase lifespan 16 , investigations utilizing a genetically encoded constitutively activated skn-1 mutation determined that longevity is severely diminished SKN-1 activity cannot be turned off 14,17 . Constitutively active skn-1 mutants display a remarkable resistance to acute exposures to stress 17 , but at the cost of dysregulated lipid metabolism and mobilization 18 that ultimately reduces overall lifespan 14,17,18 .…”

“…Although, mild overexpression of SKN-1, albeit without additional genetic or environmental activation was shown to increase lifespan 16 , investigations utilizing a genetically encoded constitutively activated skn-1 mutation determined that longevity is severely diminished SKN-1 activity cannot be turned off 14,17 . Constitutively active skn-1 mutants display a remarkable resistance to acute exposures to stress 17 , but at the cost of dysregulated lipid metabolism and mobilization 18 that ultimately reduces overall lifespan 14,17,18 . This phenomenon is also observed in wild type animals exposed to pathogens 19 , but importantly represents a tradeoff between organismal stress responses and cytoprotection that influences survival that is mediated through lipid storage and distribution.…”