Inducing the Heat Shock Response as a Potential Treatment for Atherosclerosis

The heat shock response is one of a number of cellular maintenance processes that works to keep cells functional under circumstances of stress. As the name implies, heat is one of those stresses in this case, but the heat shock response is also triggered by other stresses as well. Further, the heat shock response has a role in resolving inflammation. Researchers here note that the heat shock response is suppressed in atherosclerosis, possibly as a result of the chronic inflammation induced by the presence of senescent cells, possibly due to other mechanisms, and that this might be an important factor in the progression of the condition. The study shows that upregulating the heat shock response via heat treatment produces benefits in atherosclerotic mice, and the authors suggest this might function via reductions in cholesterol levels and reductions in inflammation.

While acute inflammatory responses evolved to protect organisms against pathogens and to provide tissue repair under sterile injuries, they are rapidly resolved by several physiological feedback systems aimed at avoiding the perpetuation of inflammation. In this sense, the heat shock (HS) response, i.e., the anti-inflammatory program mainly centered in heat shock factor-1 (HSF1)-dependent expression of heat shock proteins (HSPs) and other anti-aggregative protein chaperones, powerfully resolves acute inflammation by shutting off nuclear factor κB (NF-κB) and other downstream pro-inflammatory signals.

Nevertheless, if injuring stimuli become chronic, HSF1 expression is severely blunted and cells stop producing cardioprotective HSPs (e.g., HSP27, HSP72), which are anti-inflammatory. This is the case of many (if not all) chronic degenerative diseases of inflammatory nature. In contrast, inducers of the HS response clearly reverse vascular lesions in atherosclerotic models. However, the development of atherosclerotic lesions is also associated with the blockade of the expression and activity of sirtuin-1 (SIRT1), which, in turn, underlies both HSF1 expression and transcribing activity. Therefore, in an atherosclerotic milieu, the physiological resolution of inflammation is critically jeopardized thus contributing to foam cell formation and vascular senescence observed in atherosclerosis.

These observations led us to hypothesize that disruption of the anti-inflammatory and anti-senescent HS response pathways could underlie the perpetuation of vascular inflammation in atherosclerosis, as observed in other chronic inflammatory diseases, and that in vivo heat treatment, the most powerful trigger of the HS response, should be effective in re-establishing SIRT1-HSF1-HSP axis in atherosclerotic mice.

Aortic expressions of SIRT1, HSF1, HSP27, HSP72 and HSP73 were progressively depressed in atherosclerotic animals, as compared to normal healthy counterparts, which was paralleled by increased expression of NF-κB-dependent VCAM1 adhesion molecule. Conversely, heat treatment completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of triacylglycerols, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose, and insulin resistance while rising HDL-cholesterol levels. Heat treatment also decreased body weight gain, visceral fat, cellular infiltration, and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance indices. Remarkably, heat-treated mice stopped dying after the third heat treatment session, suggesting a curative effect.

Link: https://doi.org/10.1016/j.biochi.2018.09.011

Comments

Interesting. There's been some discussion on Longecity about this that I thought was pseudo-scientific mumbo jumbo. Perhaps there is something to this after all.

Posted by: Abelard Lindsey at July 8th, 2019 10:12 AM

What about life expectancy or ageing markers on people living in cold vs hot climate? Mediterranean lifestyle includes moderate diet and heat in the summer. What about Sahara or the workers in Saudi Arabia or Dubai? There should be plenty of humans exposed to heat already. Do we see any difference, if we control for diet, exercise and infections?

Posted by: Cuberat at July 8th, 2019 12:07 PM

I wonder if sauna can upregulate heat shock proteins in people suffering from atherosclerosis...

Posted by: marten at July 8th, 2019 2:05 PM

I find this quite interesting and have to wonder if regular hot water baths/showers that we humans have enjoyed over the 20th century and continue to do so have contributed to the life expectancy gains over the last century. Since I also have early onset atherosclerosis, I think I'll crank up the temperature on my hot tub to 104 (40C) and spend a quality 15 minutes a night in it!

Posted by: Jeremy O'Neal at July 8th, 2019 3:32 PM

@Jeremy O'Neal
I am a bit skeptical. We would have witnessed much less of cardiovascular b issues in Finland already. A few years ago there was a craze about infrared saunas. People claimed it rejuvenated your skin. Go figure. Probably they weren't that full of sh7t after all

Posted by: Cuberat at July 8th, 2019 6:13 PM

Hi all! Just a 2 cents.

Jeremy, I sympathize immensely, I share what you have and hope you can beat it/revert it. I had late onset atherosclerosis, where is was silent and 'came to me' in the late point where your chances of reverting all nearly nill and it can cause sudden death/heart arrest/ischemia artery death (nearly caused me so as had pulmonary embolism and blood clots form silently and block my large artery); but I survived it.

Yes, heat shock is good for the body but it must be carefully dosed.
It is a Hormesis effect (heat stress causeing HSF-1/HSPs chaperoning/autophagy activation) - Hormesis as long as you dose it, becauses it can kill you - Also.

Excess heat, if HSPs/HIF-1 drop, will cause scabs/burns and your body will activate autophagy excessively (I went to extreme scald-burning shower...to test it and I 'primed' my body to such heat...I toughed it a lil...but it was too much at a certain point, the skin almost seems will melt...and the 'hormesis Heat-Shock response' works up to a certain point.

Autophagy is toxic - when in very high activity/dose...it'S why when I took way too many boiling showers my body was becoming 'damaged' by the 'autophagic Overhormetic stress' (not so much the 'burning' by hot water - but the autophagic priming of body is harsh). When hormesis happens the body produces 'stress granules', these granules affect eIF2-4 (eukaryotic Initiation Factor) which means the cell 'halts' DNA synthesis. Thus, it is a stress and the ER (Endoplasmtic Reticulum) will feel it as it will show ER stress. Once the heat or Cold-Shock is stopped the granules are 'dismantled'....and then eIFs are returned to normal. Durning the granules, the autophagy system is activated - leading to formation of HSPs chaperones who will dock the crap, in/at the lysosomse/autophagosome.

Plus, heat shock makes you burn fat, visceral fat and WAT/BAT.
Again - only - dosed hormesis is beneficial. It also activates UCPs Uncoupling Proteins which burn the WAT/BAT and dissipate the proton gradient (uncouple it) to reduce mtROS caused by mitochondrial membrane potential.

It's why you cannot stay in a heating sauna or burning shower forever.
It should be dosed for a lil bit time.

And, yes, it did help my atherosclerosis. IT drops your LDL, reducing plaque size.

But don'T overdo it - because it Will Cause atherosclerosis, if you over do it. Only hormetic 'smalll heat shock' in low dose is good, because that is the hormesis effect. Higher than that..and you cause severe heat-damage, as HSPs/HSF-1 response is no longer 'curbing the excess heat'.

Same goes for Cold Shock....same HSPs are activated under cold water/air. Although, different genes/proteins for cold...but, essentially, same thing; hormesis cold-stress effect leading to autophagy once more. Basically, any stress.

Cold is very dangerous because your heart can slow down (bradycardia), you have to be VEry careful while taking Freezing shower/bath...check your vitals/signs...to make sure you don'T lose conscience/heart drops too much.
OR, it may even increase in speed 'Trying to compensate' for slowing metabolism under cold and 'keeping the heat/37oC of body'...causing possibly arhytmia or heart tumbling/fumbling, which is deadly.
Hypothermia or Hyperthermia - both can happen in scaling shower/bat or freezing shower/bath.h

The 'old' trick (from centenarians):

TAke a shower that is 'mildly hot'...and then jack it up to burning point...sustain in there....minute...and then immediately switch to cold water (very Cold), do not gradually go down - it must be a 'shock/stress'...but not so bad you can't take it neither. STay under very freezing water for a few seconds...then again jack it up again to boiling water (not gradual, turn it in one immediate swing)....do this 2 or 3 times in the shower...you will get full hormesis benefit. It is the secret of people living long lives (like one centerian chinese women said her trick was having 'hot bottles' of water sitting on her body...all the time...she was 'in heat' all the time because she would always have these boiling bottles of water on her body; this means she overactivated HSF/HSP..even outside the shower/bath).

Studies have verified animals/people who did that...and, clearly, hours later the HSPs/HIF...chaperons and autophagy were strongly activated.;..still long after the shower was done. This means you get a long lasting effect of 'heat shock/cold shock'/benefits...and they say that they lost weight (a good thing...as long as you are not anorexic...because for me at a certain point it made me lose Too much weight since I was already very underweight BMI (it is a stress after all)..which was dangerous when you are sick...you need a few pounds (of healthy subcutaneous fat and msucle) on you othewise you will become frail (hot shower or not)).

Well, yes, certain centenarians are from Africa and from very warm/hot places...like the longest living woman was 120 or something I don't remember and yeah..she came from a very hot place...she was already experiencing heat shock her whole life. But she survived it - which means 'hormesis/heat stress resistance = lifespan elongation (through autopahgy mostly)).

Same thing for some people from very cold places...Russia...some became centenarians..and the cold helped because it slows metabolism and reduce damages from metabolism (slower cumul, leading to cold shock stress resistance). The inverse, the people in hot places, activate the heat shock stress resistance. Hot/Cold, gives same effect.

I would say though...that Both Cold and Hot...if are Very Sudden...and Abrupt/Extreme...can be devastating if the body cannot 'prime/set up response'...it will kill you. I remember certain times when winter or summer arrived...and I switched Suddenly from a normal warm temperature - To Very Hot outdoor temperature or Very Cold outdoor temperature - that was Very Toxic...and could easily destabilize the plaques in arteries..as it causes the sudden temperature stress shit..the body Must respond by the heat-shock response..but that does not always happen immediately or so well...at that moment you can feel Extreme pain because you know that this temperature change f'd...your arteries... and the arteries oftenly respond with Extreme HyperSensitivity to these temperature changes. Like Sudden Tugging and Pulling/Rupturing feel inside artery (it's freaky scary just like having a blood clot jamm one or someone snapping an artery like a twig). This tells you that the temperature is just too dramatic change/too quick...to allow body to adapt to it (by doing HSF stress response).
I would say the cold was much more affecting on me...and it was harder to survive in ver cold temperature..but arteries litterally jammed up under extreme cold and caused Intense ISCHEMIA/necrosis of endothelial cells (just like stabbing in artery) - cold can Increase LDL levels and reduce O2 blood levels....but, thankfully, hormesis cold response protein/chaperone Stops this LDL elevation due to cold. But, it needs to be 'dosed'...only adaptation/low-to-mild cold allow body to respond with Cold shock stress response (HSFs) to 'overcome the cold' and then your arteries will subside and calm down.

Just a 2 cents.

Posted by: CANanonymity at July 8th, 2019 7:05 PM

Finns have high cardiovascular disease rates mainly because their per capita alcohol consumption is massive. Also, apparently they are among biggest fat and sugar eaters (https://yle.fi/uutiset/osasto/news/finns_among_worlds_biggest_fat_and_sugar_eaters_new_figures_claim/7790325).

This makes quite a deadly duo. As for beneficial effects of sauna, there was a study on that: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262976/

Although atherosclerosis is not mentioned in that one, that's why I'm wondering.

Posted by: @Cuberat at July 9th, 2019 12:29 AM

I think most beneficial is heat and cold shock. For over 25 years I'm living in Northern Canada, go to the sauna as much as possible and have a hot shower followed by a cold shower every morning.

I also had the opportunity to visit a unique ( at least in North America, it's more common in Europe ) cryotherapy. A three chamber system: first 10 seconds at -12, then 10 seconds at -60, then 3 minutes at -110. Then going back through the second and first chamber. (All temperatures in degree Celsius)

It's recommended to do 10 therapies within 5 days for healing effects to be noticeable.

Posted by: Stephan at July 9th, 2019 1:08 AM

@Stephan
The turkey of the linked article says it all Sauna bathing is associated with reduced cardiovascular mortality .

Posted by: Cuberat at July 9th, 2019 11:40 AM

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