The Heat Shock Connection of Metabolic Stress and Dietary Restriction

Abstract

Molecular chaperones and the heat shock response guard and modulate protein conformation, protect proteins from misfolding and aggregation, and maintain signalling and organellar networks. Overnutrition and the metabolic syndrome represent a pro-aging condition, and dietary restriction is the most robust environmental intervention that induces longevity from yeast to mammals. In recent years a considerable effort has been made to elucidate the signaling pathways involved in metabolic signaling. Here we review the current understanding on the connection between metabolic stress, dietary restriction and the heat shock response and highlight results showing chaperone induction as a promising therapeutic strategy to promote healthy aging and to prevent metabolic disorders.

Hsp90 chaperones PPARγ and regulates differentiation and survival of 3T3-L1 adipocytes

“…32 Chaperone induction by different approaches, including a modest pharmacologic Hsp90 inhibition, has been widely shown to combat various age-related diseases. 24,49 Accordingly, these findings suggest that upregulation of the Hsp90 chaperone complex could strengthen adipocyte proteostasis and boost optimal PPARg/client and adipose function.…”

“…31 However, the impact of proteostasis on Hsp90-client interactions remained elusive. Despite the increased awareness of the role of the heat-shock response in metabolic stress and obesity, 32 the involvement of Hsp90 in these conditions is, yet, similarly unclear. In this study, we investigate how Hsp90 and proteotoxic stress regulate adipogenesis and delineate the potential molecular mechanisms involved.…”

Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity

“…Consistent with this notion, although protein aggregation is hazardous under certain circumstances, the creation of apparently less-toxic large aggregates is protective. This hypothesis is the basis of the therapeutic potential of heat shock proteins (HSPs), which prevent protein misfolding and aggregation (Dancsó et al, 2010;Ono et al, 2009). Cellular stress response is regulated at the transcriptional, translational and post-translational levels by a family of heat shock transcription factors (HSFs) that are expressed and maintained in an inactive state under non-stress conditions (Westerheide et al, 2009).…”

Metabolic control of the proteotoxic stress response: implications in diabetes mellitus and neurodegenerative disorders

“…For example, metabolic dysregulation in diabetes induces protein aggregation in pancreatic β-cells [74, 75]. In rodents, the metabolic disturbance induced by high-fat diets or associated with diabetes promotes β-amyloid deposits in the brain [76, 77].…”