Hormesis as a tool in Longevity Medicine

In longevity science, “hormesis” refers to adaptive responses to mild stressors, such as fasting, exercising, and exposure to heat and cold. Hormesis elicits beneficial cellular metabolic responses, including sirtuin activation (to be discussed in a separate article), reduction in mTOR activity (see article on rapamycin), and autophagy, the recycling of old cells that promote inflammation. 

Hormesis represents a valuable tool in longevity medicine.

The key to hormesis is to undertake the stressor in a limited way – not crossing the threshold to doing irreversible damage to cells. For example, skydiving teachers that spend a lot of time at altitude are exposed to limited periods of hypoxemia, i.e. low concentrations of oxygen in the blood. 

This stress has beneficial effects on their physiology that promote longevity. Clearly this would not be true if the hypoxemia was prolonged or severe enough to lead to sustained brain or other organ injury. 

Longevity results when organisms are exposed to brief period of heat shock, but excessive temperatures, frequency, or duration of exposures do not prolong life.

Besides heat and cold “shock,” calorie restriction, fasting, and exercising have been shown to have benefits owing to hormesis. Dietary restriction is defined as consumption of 30-50% fewer calories than usual. It is a form of low-intensity stress, or hormesis, that causes a number of mildly adverse events such as release of the stress hormone, cortisol. 

Extended periods of dietary restriction have been found to increase the healthy lifespan of many organisms. The same effects can be achieved with intermittent fasting, e.g. eating during an 8-hour period and therefore fasting for 16 hours per day. Unlike caloric restriction, the benefits of intermittent fasting are not dependent on restricting the total number of calories consumed each day.

Certain dietary supplements, including quercetin and resveratrol, appear to mimic the “stress resistance response” effects of caloric restriction and intermittent fasting (see articles on these 2 supplements). 

During exercise the body is exposed to multiple forms of hormesis, including hypoxic, metabolic, mechanical, oxidative, and thermal stress. These stressors cause the release of a variety of biochemical messengers that are shared by those associated with fasting and heat and cold shock. 

In fact, restricting calories and limiting blood flow and applying heat to muscle for short periods of time may amplify the hermetic benefits of exercise. 

Taking anti-inflammatory and anti-oxidant drugs may actually decrease benefits of exercise, including muscle building and increasing sensitivity to insulin. Also, excessive exercise may be counterproductive. Again, there is a “sweet spot” for hormesis – more stress is not necessarily healthier. 

The type, intensity, and duration of exercise that achieves the greatest hermetic benefit are currently being studied.

Note: Although I am a physician, the content in this article is not meant to diagnose, treat, cure or prevent illness or disease in the reader – it is for educational purposes only.

References

• Calabrese EJ, Dhawan G, Kapoor R, Iavicoli I, Calabrese V. What is hormesis and its relevance to healthy aging and longevity? Biogerontology. 2015 Dec;16(6):693-707.
• Lagisz M, Hector KL, Nakagawa S. Life extension after heat shock exposure: assessing meta-analytic evidence for hormesis. Ageing Res Rev. 2013 Mar;12(2):653-60.
• Calabrese EJ, Nascarella M, Pressman P, et al. Hormesis determines lifespan. Ageing Research Reviews 2024, 94 102181