Hormetic regulation of autophagy in aging

PROJECT SUMMARY Autophagy degrades cytosolic material, such as aggregated proteins, via the formation of autophagosomes that fuse with lysosomes for degradation and is important in the adaptation to metabolic and cytotoxic stressors. Autophagy has been shown to decline with age and is tightly linked to age-related diseases, thus its study is

important for developing future strategies to maintain homeostasis and promote human health. I have found that autophagy is induced in C. elegans upon a short exposure to a heat shock early in life. Such a heat shock leads to organismal benefits including longevity, a conserved phenomenon called hormesis.

Autophagy genes are required for these heat shock-induced benefits, indicating that autophagy is a critical mechanism underlying hormetic stress responses. I have implicated two conserved transcription factors, the helix-loop-helix transcription factor HLH-30, an ortholog of mammalian transcription factor EB (TFEB), and HSF-

1 in regulating autophagy induction upon HS. It however remains unclear when and where autophagy is required to manifest long-term organismal benefits. While I have shown that specific autophagy genes retain elevated transcript levels for days, the tissue-specific and potential long-term transcriptional shifts induced by HS, that

could underlie the hormetic benefits, are unknown. Understanding the effects of heat shock on autophagy, both in the short-term (i.e., immediate response) as well as in the long-term (i.e., sustained changes), is paramount for developing new strategies, such as the concept of heat therapy, to improve autophagy during aging and in

diseases with dysregulated autophagy. Therefore, I here propose to analyze the spatio-temporal requirement for the autophagy-regulating transcription factors HLH-30/TFEB and HSF-1 for heat-induced adaptations and analyze the cell-specific transcriptional changes that are induced by HS and sustained over time.

The ability to mount a beneficial hormetic response declines with age and is accompanied by reduced function of HLH-30/TFEB which is ameliorated by a hormetic HS. HS thus induces sustained changes that affect HLH-30/TFEB function. Controlling the prolonged activation of autophagy, for instance via transcriptional

regulation, could be an important way of manipulating autophagy, which in turn could benefit organismal fitness. Hence, I am proposing to investigate how the autophagy regulator HLH-30/TFEB is regulated by heat shock and age and to identify new regulators of HLH-30/TFEB, that will be validated for conservation in human dermal

fibroblasts. Understanding the regulatory mechanisms by which autophagy ensures cytoprotective effects in vivo using multi-cellular organisms like C. elegans addresses significant gaps in our understanding of the temporal and spatial dynamics of HS-induced autophagy, cell-specific transcriptional responses to HS, and regulatory

mechanisms of transcription factors with HS and age. The impact of these insights could reshape therapeutic approaches, offering more precise interventions for diseases with deregulated autophagy.