Molecular Mechanisms involved in heat stress response

Original Article from FoundMyFitness - Saunas

Molecular mechanisms involved in the heat stress response

The hormetic effects of heat stress are facilitated by molecular mechanisms that mitigate protein damage and aggregation and activate endogenous antioxidant, repair, and degradation processes. Many of these responses are also triggered in response to moderate- to vigorous-intensity exercise and include increased expression of heat shock proteins, transcriptional regulators, and pro- and anti-inflammatory factors.

Heat shock proteins

Heat-shock proteins (HSPs) comprise a large, highly conserved family of proteins that are present in all cells. They play prominent roles in many cellular processes, including immune function, cell signaling, and cell-cycle regulation.

Under normal conditions, cells maintain a constant, or "basal," level of HSPs to facilitate several aspects of the protein synthesis machinery, including assembly, folding, export, turn-over, and regulation. However, normal metabolic processes and immune function create reactive byproducts (such as reactive oxygen species and reactive nitrogen species) that can damage proteins and disrupt their structure. Intrinsically disordered proteins are common features in cardiovascular diseases, and damaged, dysfunctional proteins, which can aggregate, or clump together, are strongly implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Increased expression of HSPs prevents protein disorder and aggregation by repairing proteins that have been damaged, and, in fact, animal evidence suggests that HSPs may offer protection against neurodegenerative diseases. 

When cells are stressed due to changes in their environment, cellular proteins can unfold or become damaged, impairing their normal function and further increasing their vulnerability to change. During exposure to stress from temperature extremes, reduced nutrient levels (as in fasting), or hypoxia (reduced oxygen), cells increase expression of HSPs to stabilize unfolded proteins and repair or re-synthesize damaged ones. This phenomenon, referred to as the heat shock response, occurs at the expense of other cellular proteins to protect the cell from damage. 

Heat stress, in particular, robustly activates the heat shock response. For example, after healthy men and women sat in a heat stress chamber for 30 minutes at 73°C (163°F), their levels of HSP72 increased by 49 percent. In a different study, in which healthy men and women were exposed to deep tissue heat therapy for six days, participants' levels of HSP70 and HSP90 increased 45 percent and 38 percent, respectively. In addition, their biomarkers of mitochondrial biogenesis improved, and their mitochondrial function increased by 28 percent compared to baseline levels. This activation of HSPs is sustained over time, suggesting that heat acclimation induces whole-body adaptations that increase heat tolerance, resulting in protective cellular adaptations.

The HSP70 family of proteins is the most abundant of all the HSPs. Data from a longitudinal study of Danish nonagenarians showed that genetic variants of HSP70 influenced lifespan in females, with carriers of one haplotype living approximately one year longer than non-carriers.


Nrf2 is a transcription factor commonly found in a cell's cytoplasm. Upon activation, Nrf2 travels to the nucleus, leading to the orchestrated regulation of a vast network of genes with cytoprotective, antioxidant, and anti-inflammatory functions and providing protection against oxidative stress, electrophilic stress, and chronic inflammation – the underlying causes of most chronic diseases.

Heat exposure activates Nrf2, thereby upregulating a HSP called heme oxygenase-1, or HO-1, an enzyme that breaks down heme (a powerful pro-oxidant) to generate carbon monoxide (an anti-inflammatory gas) and bilirubin (an antioxidant). The downstream effect of HO-1 upregulation includes inhibition of the expression of several pro-inflammatory molecules involved in the pathophysiology of cardiovascular disease, including E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1.


FOXO3 proteins are members of the FOX family of highly conserved transcriptional regulators. They play important roles in human lifespan and healthy aging. FOXO3s regulate a vast number of genes that combat elements of cellular aging, such as damage to DNA, proteins, and lipids, and loss of stem cell function. They also increase the production of genes that regulate DNA repair, tumor suppression, stem cell function, immune function, and protein aggregation to further mediate the deleterious effects of aging. FOXO3s participate in autophagy, but when autophagic mechanisms are disturbed, FOXO3s confer cellular sensitization to apoptosis, a type of programmed cell death.

Following heat stress, FOXO3 proteins form a complex with sirtuin 1, or SIRT1, an enzyme that influences aging and longevity via multiple molecular pathways. Sirtuins regulate a variety of metabolic processes, including release of insulin, mobilization of lipids, response to stress, and modulation of lifespan. SIRT1 enhances FOXO3's resistance to oxidative stress and its ability to induce cell cycle arrest, but it also inhibits FOXO3's ability to induce apoptosis, shifting FOXO3 activities away from cell death and toward stress resistance. Read more about FOXO proteins.

Interleukin-6 (IL-6) & Interleukin-10 (IL-10)

Inflammation is a fundamental cause of chronic disease processes. Maintaining the appropriate balance of pro- and anti-inflammatory factors is crucial for the development and subsequent resolution of an inflammatory response. IL-6 is a pro-inflammatory cytokine that plays an important role in the regulation of central homeostatic and immunological processes. However, IL-6 also dampens the inflammatory response through its activation of IL-10, a potent anti-inflammatory cytokine. Hyperthermia induces a large increase in circulating IL-6 and, potentially, a reciprocal release of IL-10. The role of IL-6, which can be robustly activated by muscle in the context of exercise, may be more complex than simple inflammatory mediator: as a "myokine," it is also necessary for the insulin-sensitizing effects of exercise.