Stress, Immortality, and the Hormesis Hypothesis

Stress, Immortality, and the Hormesis Hypothesis

By Steven V. Joyal, MD

Stress, Immortality, and the Hormesis HypothesisIs low-level stress the secret to immortality?

Longevity scientists have long been puzzled by the fact that stress, when carefully applied, very often results in prolongation of lifespan rather than causing premature death.

We need to be careful by the manner in which we characterize or define stress in the context of lifespan extension. Stress, as a critical causal factor in lifespan extension, is best defined by the term hormesis. When stress, either internal or external, is applied to a living system at a relatively low level so that a beneficial biological adaptation occurs, we define this as hormesis. The capacity of a biological system to adapt and thrive in response to stress is critical to survival. In fact, aging itself can be characterized as the inability to adapt and respond successfully to stress.

We must differentiate chronic stress that overwhelms a biological system and results in damage and decay from the type of low-level stress of hormesis that contributes to a beneficial biological response. For example, chronic stress that causes large bursts of the hormones cortisol and “fight or flight” catecholamines like adrenaline accelerates the aging process and reduces lifespan. In contrast, low-dose radiation with gamma rays and beta radiation has been shown in several studies to stimulate natural chemical and biological processes that are actually protective against cancer.1-4 This may seem surprising to some, but low-level gamma radiation, rather than causing cancer and premature death, has been shown to suppress cancer induction from chemical carcinogens, oncogenic retroviruses, and viral oncogenes like ras and src.5,6

Significant lifespan extension as a result of calorie restriction is probably the best evidence in support of the hormesis hypothesis as applied to longevity. Animals that are calorie restricted are able to significantly suppress chemical and radiation-induced cancers as opposed to peer controls fed ad libitum. Calorie restriction in animals results in an increase in resistance to oxidative stress and the negative effects of excess inflammation as well as the deleterious impact of exhaustive physical exercise.

The beneficial biological response to oxidative stress in calorie restriction is particularly impressive. Animals under calorie restriction have reduced levels of oxidatively damaged proteins, lipids, and DNA. Calorie restricted animals have an amazing capacity to beneficially modify gene expression involved in glucose metabolism, protein synthesis, and cellular energy capacity. Gene expression in calorie restricted animals shows adaptations involving enhancement of detoxification, anti-inflammatory pathways, and DNA repair enzymes.

Do the impressive adaptive benefits of calorie restriction share a common pathway?

The hormesis hypothesis helps provide an answer.

The mild stress of calorie restriction rapidly turns on a variety of gene pathways critical for essential defense and survival of the organism. Gene expression studies show that calorie restricted animals rapidly turn on genes related to stress response and energy metabolism. For example, Lee et al showed that of 6,437 genes activated by calorie restriction, nearly 30% were related to energy metabolism and stress response.7 Hormesis as an explanation for the biological benefits of calorie restriction implies an adaptive mechanism through evolutionary biology. In order to survive, living systems must adapt to an ever-changing barrage of internal and external insults. The low-level stress of calorie restriction produces gene expression changes that create a variety of positive adaptive responses for longevity.

In addition to calorie restriction, other strategies may help mimic the hormetic response. Consistent, mild-to-moderate (never exhaustive) exercise triggers a variety of adaptive mechanisms similar to calorie restriction. Exercise adaptation includes improvements in insulin signaling, mitochondrial energy metabolism, and resistance to oxidative stress, all of which are also known to occur with calorie restriction.

Nutrients, too, have hormetic properties. One example is vitamin D. The past decade has seen a veritable explosion of research supporting beneficial biological roles for vitamin D in the immune system, cardiovascular system, central nervous system, and endocrine system, in addition to control of the cell cycle and cancer pathogenesis.8 There is compelling evidence that vitamin D acts as a hormetic agent. Low doses of vitamin D exert stimulatory effects upon wound healing, while large doses may inhibit psoriatic plaque. A longitudinal, nested, case-control study of prostate cancer showed that both low (</=19 nmol/l) and high (>/=80 nmol/l) 25(OH)-vitamin D serum concentrations were associated with higher prostate cancer risk, while serum concentrations of 25(OH)-vitamin D within the 40-60 nmol/l range comprised the lowest risk of prostate cancer.9 A biphasic, U-shaped response curve is a characteristic of hormesis.

Clearly, more research is needed to understand how best to evaluate the hormesis hypothesis as applied to calorie restriction, physical exercise, and nutrients like vitamin D in the context of longevity science. In the interim, we are left with the intriguing possibility that stress, when applied carefully and strategically, may be the key to living healthier, longer.


  1. Mitchel REJ. Low doses of radiation are protective in vitro and in vivo: Evolutionary origins. Dose-response. 2006;4(2):75–90.
  2. Mitchel REJ. Low doses of radiation reduce risk in vivo. Dose-Response. 2007;5(1):1–10.
  3. Sakai K, Nomura T, Ina Y. Enhancement of bio-protective functions by low dose/dose-rate radiation. Dose-Response. 2006;4(4):327–332.
  4. Sakai K, Hoshi Y, Nomura T, Oda T, Iwasaki T, Fujita K, Yamada T, Tanooka H. Suppression of carcinogenic process in mice by chronic low dose rate gamma-irradiation. Int J Low Radiat. 2003;1(1):142–146.
  5. Bauer G. Low dose radiation and intercellular induction of apoptosis: potential implications for control of oncogenesis. Int J Radiat Biol. 2007;83(11–12):873–888.
  6. Jürgensmeier JM, Schmitt CP, Viesel E, Höfler P, Bauer G. Transforming growth factor beta treated normal fibroblast eliminate transformed fibroblasts by induction of apoptosis. Cancer Res. 1994;54(2):393–398.
  7. Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science. 1999;285(5432):1390-3.
  8. Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008;88(2):491S-499S.
  9. Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, Stattin P, Harvei S, Hakulinen T, Luostarinen T, Dillner J, Lehtinen M, Hakama M. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer. 2004;108(1):104-8.

About Life Extension
The Life Extension Foundation is a nonprofit organization, whose long-range goal is the extension of the healthy human lifespan. In seeking to control aging, our objective is to develop methods to enable us to live in vigor, health and wellness for an unlimited period of time. The Life Extension Foundation was officially incorporated in 1980, but its founder has been involved in antiaging research since the 1960s. The Life Extension Foundation is the largest organization dedicated to investigating every method of extending the healthy human life span. When seeking methods to slow aging, The Foundation often uncovers potential anti-aging supplements to treat conditions associated with aging.

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