Heat-shock response
The heat-shock response (HSR) is a physiological response to exposure to elevated temperatures, in which cells activate various protective mechanisms to prevent damage and promote recovery. This response is mediated by heat-shock proteins (HSPs), such as chaperone and proteases, which play a role in maintaining protein folding and preventing aggregation.
Elevated temperatures can cause proteins to denature and aggregate, leading to cell death. Heat-shock proteins help to prevent this by assisting in the refolding of damaged proteins and facilitating the removal of aggregated proteins. There are two main classes of molecular chaperones: the Hsp70 proteins and the Hsp100 unfoldases.[1]
Heat-shock pathways
The heat-shock response is regulated by several pathways which are part of the proteostasis network, including the ubiquitin/proteasome system (UPS), the chaperone-guided refolding of proteins and lysosomal pathways (also known as autophagy). Rises in temperature or stress cause the accumulation of misfolded proteins in the cell, leading to the activation of proteostasis pathways for clearing.
Heat-shock has shown to induce autophagy in a variety of tissues and to improve proteostasis in nematodes in a manner that is dependent on the transcription factor HSF-1 (Heat-Shock Factor-1).[2] The progressive accumulation of PolyQ aggregates were also reduced in an autophagy-dependent manner after Hormetic heat stress. HSF-1 proved to be required for the survival of C. elegans to high temperatures as well as for downstream autophagy mechanisms. HSF-1 orchestrates the HSP70 family of chaperones, highly upregulated after exposure to heat stress.[3]
Certain metabolic pathways that regulate aging, such as those involving insulin/IGF-1 signaling, dietary restriction, and reduced mitochondrial function, can influence proteostasis and help to preserve a youthful protein makeup for a longer period of time.[4] These mechanisms may be potential targets for preventing and treating age-related diseases. Interestingly, HSF-1 is required for the lifespan extension of caloric restriction interventions as well as for mutants with reduced insulin signalling (also FOXO dependent), demonstrating that HSF-1 and FOXO might have an overlap of downstream targets.
Heat-shock and aging
Studies have suggested that heat-shock proteins may play a role in aging. The aging process is linked to a decline in the ability of cells to handle challenges from the environment, and it is believed to be partly due to a decrease in efficiency of the heat-shock response and a reduction in the production of HSPs.[5]
Additionally, as cells age, they are unable to properly maintain protein balance (proteostasis), leading to a further buildup of damaged and misfolded proteins. This results in a decline in cellular health, an abnormal regulation of cell death and may cause diseases such as Alzheimer's and Huntington's.[4] Aggregation of damaged proteins is a known hallmark of neurodegenerative diseases.
Heat-shock proteins have been shown to promote longevity in some organisms, potentially by helping to maintain the integrity of the genome and preventing the accumulation of damage over time.[6]
Hormesis
The effects of the heat-shock response (HSR) on hormesis have been extensively studied in a variety of animal models, including yeast, nematodes, fruit flies, rodents, and human cell cultures.[7][8][9] In these studies, heat-shock led to increased lifespan and reduced mortality. For instance, research on mild heat shock exposure in human cell cultures led to better preservation of youthful cell appearance, longer replicative lifespan, increased resistance to stress, and enhanced angiogenesis.[10]
However, it is not yet fully understood at what point stress leading to HSR becomes detrimental, and what causes this shift, even though it is clear that hormetic effects are mainly linked to mild heat stress and are triggered by the expression of heat-shock proteins (HSPs). Therefore, repeated exposure to mild heat stress may help maintain the heat shock response and have anti-aging benefits on cells and organisms. However, it is important to note that excessive heat exposure can be harmful, and it is not recommended to use heat-shock as a means to promote longevity.
- ↑ Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell. 2006 May 5;125(3):443-51. doi: 10.1016/j.cell.2006.04.014. PMID: 16678092.
- ↑ Kumsta C, Chang JT, Schmalz J, Hansen M. Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans. Nat Commun. 2017 Feb 15;8:14337. doi: 10.1038/ncomms14337. PMID: 28198373; PMCID: PMC5316864.
- ↑ Bukau B, Weissman J, Horwich A 2006. Molecular chaperones and protein quality control. Cell 125: 443–451
- ↑ 4.0 4.1 Taylor, R.C. and Dillin, A. (2011) “Aging as an event of proteostasis collapse,” Cold Spring Harbor Perspectives in Biology, 3(5). Available at: https://doi.org/10.1101/cshperspect.a004440.
- ↑ Verbeke, P. (2001) “Heat shock response and ageing: Mechanisms and applications,” Cell Biology International, 25(9), pp. 845–857. Available at: https://doi.org/10.1006/cbir.2001.0789.
- ↑ Murshid, A., Eguchi, T. and Calderwood, S.K. (2013) “Stress proteins in aging and life span,” International Journal of Hyperthermia, 29(5), pp. 442–447. Available at: https://doi.org/10.3109/02656736.2013.798873.
- ↑ Dattilo, S., Mancuso, C., Koverech, G. et al. Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases. Immun Ageing 12, 20 (2015). https://doi.org/10.1186/s12979-015-0046-8
- ↑ Mane NR, Gajare KA, Deshmukh AA. Mild heat stress induces hormetic effects in protecting the primary culture of mouse prefrontal cerebrocortical neurons from neuropathological alterations. IBRO Rep. 2018 Nov 14;5:110-115. doi: 10.1016/j.ibror.2018.11.002. PMID: 30519667; PMCID: PMC6260229.
- ↑ Kumsta C, Chang JT, Schmalz J, Hansen M. Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans. Nat Commun. 2017 Feb 15;8:14337. doi: 10.1038/ncomms14337. PMID: 28198373; PMCID: PMC5316864.
- ↑ Rattan SI. Repeated mild heat shock delays ageing in cultured human skin fibroblasts. Biochem Mol Biol Int. 1998 Jul;45(4):753-9. doi: 10.1080/15216549800203162. PMID: 9713698.
