Heat Shock Proteins & HSP70 + Factors That Increase Them

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Written by Aleksa Ristic, MS (Pharmacy) | Last updated: March 10, 2023

Heat shock proteins are created by cells under stressful conditions. While they help protect the cells and balance the immune system, they also play roles in different chronic conditions. Read on to learn the roles of heat shock proteins in health and disease + factors that increase them.

What Are Heat Shock Proteins?
Heat shock proteins (HSP’s) are found across all living species, from bacteria to humans. They are a family of proteins created by cells during stressful situations. They can protect the cells from situations and extreme conditions that could otherwise be lethal [1].

HSPs were discovered in relation to heat shock, but they play a role in different types of stress response, including cold exposure, wound healing, infections, and more [2].

Roles & Applications of Heat Shock Proteins

1. Act as Chaperones
   HSPs are also molecular chaperone proteins. Chaperone proteins regulate the folding of proteins, which is important for their specific roles. Proteins which do not fold appropriately can trigger an immune response and a host of other issues [3, 4].

Having too many misfolded or unfolded proteins can lead to improper protein grouping/clumping and potentially result in different diseases like Huntington’s disease or Alzheimer’s. Heat shock proteins help prevent protein from forming aggregates by ensuring adequate folding [4].

A drug named geldanamycin is known to regulate a heat shock protein, Hsp90. Hsp90 can stimulate the production of Hsp70 in the cell, which helps reduce the toxicity in the cell from the mutant and misfolded protein in Huntington’s disease [3].

2. Prevent Cell Death
   When cells are stressed, a common response is to undergo cell death by one of two pathways: necrosis or apoptosis. Heat-shock proteins are responsible for inhibiting both apoptotic and necrotic pathways [5].

3. Regulate the Immune Response
   When a cell is cancerous or infected by a pathogen, it creates proteins that are not normally found in the body. These proteins act as antigens, which are foreign substances that initiate an immune response.

Immune cells must be made aware of these antigens. Heat shock proteins, mainly Hsp70 or Hsp90, alert the immune cells to antigens. They deliver antigens to the immune system’s antigen-presenting cells (APCs) through surface receptors [6].

At the same time, heat shock proteins inhibit certain inflammatory pathways [7].

They make healthy cells stronger by protecting them against stress and injuries [8].

4. Enable Hormone Signaling
   Hsp90 is mostly responsible for the function of the glucocorticoid receptor. When the receptor interacts with the heat shock proteins, expression of the genes is increased [9].

Hsp90 is also responsible for the binding of estrogen, progesterone, androgen, and aldosterone to accompanying receptors [10].

6. Protect the Heart
   HSPs can protect the heart by helping the heart cells adapt to stress [11, 12].

Hsp90 binds both endothelial nitric oxide synthase and soluble guanylate cyclase, enzymes involved in vascular relaxation [13].

Hsp20 phosphorylation is an important process for heart and blood vessel function [14].

7. Participate in Blood Sugar Control
   Low levels of Hsp70 may be associated with insulin resistance in humans [15].

In rats, heat shock proteins interacted with insulin signaling. This lead to less insulin resistance and higher insulin sensitivity [16].

Roles of Heat Shock Proteins in Disease

1. Atherosclerosis
   Atherosclerotic plaque is made of fat, cholesterol, calcium and other substances in the blood. Over time, the plaque hardens and as a result, narrows down the arteries. Atherosclerosis can lead to a heart attack or stroke [17].

HSPs are highly produced in the atherosclerotic lesions of humans. Risk factors for atherosclerosis including infection, oxidative stress, biomechanical stress, all lead to the overproduction of HSPs through the activation of heat shock transcription factor 1 [18].

2. Cancer
   Heat Shock Proteins that stop cell death may be involved in the formation of cancer [5].

They are produced at high levels in cancer and provide an environment for tumor development leading to a poor prognosis and resistance to therapy [19].

HSP production can cause uncontrolled growth, reduced tumor suppression, enhanced cell survival, and metastatic properties. Increased levels of Hsp90 help the formation of new treatment-resistant cells by allowing new traits to develop in tumors. They can also interact with different cancer-causing genes to aid the progression of individual cancers [19].

HSPs may promote uncontrolled cell growth while inhibiting death pathways [20].

HSPs also serve as biomarkers for the formation of cancer in some tissues and show the degree of progression and aggression of some cancers. Also, the increase of some HSPs can predict the response to certain anticancer treatments [21].

Genetics of Heat Shock Proteins
People vary in their natural ability to produce heat shock proteins.

Heat Shock Protein 70:
RS1043618 (HSPA1L)
RS2075799 (HSPA1L)
RS2075800 (HSPA1L)
RS2227956 (HSPA1L)
Factors That Increase HSP Levels
HSP numbers increase due to protein unfolding, misfolding or aggregation, as well as an increase in the production of non-native proteins in the body.

Other reasons for increased production include oxidative stress, nutritional deficiencies, viral infection, some chemicals, and exposure to cytokines (immune mediators) [22].

Exercise
Some of the conditions known to elicit the cellular stress reaction are similar to those experienced by cells in response to physical exercise.

Hyperthermia, ischemia, oxidative, cytokine and muscular stress, glucose deprivation, and alterations in calcium and pH are potent inducers of HSP expression in different types of cells and tissues. Both exercise and calorie restriction are forms of mild stress that temporarily enhance HSP activity [23, 24].

Life Stressors
Infection [25]
Inflammation [25]
UV [25]
Exposure of the cell to toxins (ethanol, arsenic, trace metals, among many others) [25]
Starvation [25]
Hypoxia (oxygen deprivation) [25]
Water deprivation [25]
Foods and Supplements That Increase HSP70
HSPs are a marker of cellular stress. Low or high levels don’t necessarily indicate a problem if there are no symptoms or if your doctor tells you not to worry about it. Increasing your HSP levels won’t necessarily cause improvement in cellular stress, but it can be used as a biomarker.

The following is a list of complementary approaches that might increase HSP levels. Though studies suggest various dietary and lifestyle factors with this potential, additional large-scale studies are needed. Remember to talk to your doctor before making any major changes to your day-to-day routine.

Broccoli sprouts/Sulforaphane [26]
Extra Virgin Olive Oil [27]
Zinc [28]
Curcumin [29]
Resveratrol [30, 31, 32]
Blueberry [33]
Colostrum [34]
Lion’s Mane [35]
Graviola [36]
Lavender Essential Oil [37]
Certain Artemesia extracts [38]
Celastrol [26],
Relevant Mechanisms
Heat Shock Factor 1/HSF-1 [39, 40]
STAT3 [41]
Interferon-gamma/STAT1 [42]
SIRT1 [32, 43]
SOD1 [44]
Heat Shock Factor 1 (HSF1)
Hsf1-deficient mice have a longer free-running period and therefore more active than wild-type mice [45].

The cytokine interleukin 6 (IL-6) has been shown to derepress HSF1 by reducing the activity of GSKb [46].

Cells lacking HSF1 were susceptible to apoptotic cell death following exposure to heat stress. In addition, mice lacking HSF1 also had elevated levels of tumor necrosis factor (TNF-a), which resulted in increased mortality after endotoxin and inflammatory challenge [42, 47].
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