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.

References:

  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.

Higher vitamin C levels associated with lower blood pressure in young women

Higher vitamin C levels associated with lower blood pressure in young women

In an article published online on December 17, 2008 in Nutrition Journal, Gladys Block of the University of California, Berkeley and her associates report that young women who have higher plasma levels of vitamin C have lower systolic and diastolic blood pressure as well as a reduced increase in blood pressure over a one year period compared with those whose levels of the vitamin are low.

The current analysis included 242 African-American and Caucasian participants in the National Heart, Lung and Blood Institute Growth and Health Study, a ten year longitudinal study designed to evaluate the development of obesity in adolescent girls aged 8 to 11 upon enrollment. Blood pressure was measured at the ninth and tenth annual follow-up visit, and blood samples obtained at the tenth visit were analyzed for plasma ascorbic acid (vitamin C) levels.

Following adjustment for body mass index and other factors, the research team found that women whose plasma vitamin C levels were among the top 25 percent had systolic blood pressure that averaged 4.66 mmHg lower and diastolic blood pressure that averaged 6.04 mmHg lower than women whose vitamin C was in the lowest 25 percent. When blood pressure readings from the tenth year of the study were compared with those of the ninth year, women with plasma vitamin C in the lowest 25 percent were found to have experienced an average diastolic increase of 5.97 mmHg, while those whose vitamin C levels were highest had only a 0.23 mmHg increase. A similar effect was observed for systolic blood pressure.

In their discussion of the findings, the authors remark that the antioxidant effect of vitamin C helps protect against oxidative mechanisms involved in the development of hypertension. Additionally, in a clinical trial conducted by Dr Block and colleagues, vitamin C was shown to reduce C-reactive protein, a marker of inflammation, which is associated with endothelial dysfunction and high blood pressure. “Thus, vitamin C may have a beneficial effect on blood pressure by mitigating the adverse effects of inflammation and oxidative stress,” they write.

The authors note that their results were comparable in magnitude to those of the Dietary Approaches to Stop Hypertension (DASH) trial, which found a 5.5 mmHg average reduction in systolic blood pressure and a 3.0 mmHg average diastolic reduction in participants who consumed the DASH diet. They suggest that increasing plasma vitamin C to levels comparable with those of participants in the top one-fourth of the current study might achieve a similar effect.

“The findings suggest the possibility that vitamin C may influence blood pressure in healthy young adults,” the authors conclude. “Since lower blood pressure in young adulthood may lead to lower blood pressure and decreased incidence of age-associated vascular events in older adults, further investigation of treatment effects of vitamin C on blood pressure regulation in young adults is warranted.”