Hormesis in aging

doi:10.1016/j.arr.2007.03.002

Ageing Research Reviews

Volume 7, Issue 1, January 2008, Pages 63-78

https://doi.org/10.1016/j.arr.2007.03.002 Get rights and content

Abstract

Hormesis in aging is represented by mild stress-induced stimulation of protective mechanisms in cells and organisms resulting in biologically beneficial effects. Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food limitation, heat stress, hypergravity, reactive oxygen species and other free radicals have a variety of anti-aging and longevity-extending hormetic effects. Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. A consequence of hormetic amplification is an increase in the homeodynamic space of a living system in terms of increased defence capacity and reduced load of damaged macromolecules. Hormetic strengthening of the homeodynamic space provides wider margins for metabolic fluctuation, stress tolerance, adaptation and survival. Hormesis thus counter-balances the progressive shrinkage of the homeodynamic space, which is the ultimate cause of aging, diseases and death. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in aging research and intervention.

Introduction

Two of the leading biogerontologists, Robin Holliday and Leonard Hayflick, have given almost identical titles to their latest articles, asserting that aging is no longer an unsolved problem in biology (Hayflick, 2007, Holliday, 2006a). This does not imply that every single detail of the phenomenology of biological aging, at all levels of organization, has been elucidated. What is underlined is that the biological basis of aging are now well understood, and general principles of aging and longevity are formulated which can be the basis for future research and intervention towards achieving a healthy old age. One of the main principles to emerge from biogerontological research is that the primary molecular phenotype of aging is the stochastic occurrence and accumulation of molecular damage leading to a progressive increase in molecular heterogeneity and functional impairment (Rattan, 2006). A failure of maintenance and repair pathways effectively determines the course of aging, origin of age-related diseases and eventual death (Holliday, 1995, Holliday, 2000, Rattan, 2006, Rattan and Clark, 2005). Therefore, effective anti-aging strategies can be based in this principle in order to develop methods to prevent and/or to slow down the failure of maintenance. The aim of this article is to discuss one such strategy, hormesis, which makes use of the fundamental characteristic of all living systems—their homeostatic or homeodynamic ability.

Section snippets

Homeodynamics, aging, and hormesis

All living systems have the intrinsic ability to respond, to counteract and to adapt to the external and internal sources of disturbance. The traditional conceptual model to describe this property is homeostasis, which has dominated biology, physiology and medicine since 1930s. However, advances made in our understanding of the processes of biological growth, development, maturation, reproduction, and finally, of aging, senescence and death have led to the realization that homeostasis model as

Radiation hormesis in aging

Although earlier studies on checking the effects of irradiation on biological systems were mainly performed with a view to demonstrate its harmful effects, the observed bi-phasic – low-dose beneficial and high dose harmful – effects can best be understood by invoking hormesis as a plausible explanation.

Whereas high doses of radiation decrease lifespan, low-dose radiation (LDR) is often accompanied by enhanced lifespan, for example as observed in fruitflies (Lamb, 1964, Sacher, 1963) and in

Caloric restriction and hormesis

In more than 70 years of studying the effects of dietary caloric restriction (CR) on aging and longevity, CR is the most commonly used intervention that has shown to extend the lifespan and slow down the onset of a wide range of age-related changes in a variety of organisms, including yeast, insects, rats, mice, and monkeys. The universal applicability of CR as an anti-aging and lifespan extending intervention, especially in human beings, is a highly debated issue at present, based mainly on

Exercise hormesis

The well-documented beneficial effects of exercise occur in a paradoxical background of biochemical framework. It is well known that exercise increases the production of potentially harmful substances such as reactive oxygen and nitrogen species, other free radicals, acids and aldehydes (Alessio and Hagerman, 2006, Ji, 2006, Ji et al., 2006, Radak et al., 2005, Radák et al., 1998). The most significant physiological change that occurs during exercise is up to 20-fold enhanced mitochondrial

Heat stress in organisms

Temperature stress, especially heat stress (HS), is one of those stresses that have been used with a specific aim to test and apply hormesis. The reason for this is not only because HS is easy to implement and gives consistent results, but also because HS mainly acts through an evolutionarily highly conserved stress response pathway known as the heat shock response (Verbeke et al., 2001b). Effects of mild and sever HS have been tested on yeast, nematodes, fruitflies, and rodent and human cells.

Nutritional hormesis and hormetins

Several dietary components, such as vitamins, antioxidants, trace elements, minerals, ethanol, and even herbicides and pesticides have been shown to have typical hormetic dose–response (Calabrese and Blain, 2004). All such compounds (natural or synthetic), which bring about biologically beneficial effects by acting through one or more pathways of maintenance and repair, and stress response, are termed as hormetins (Ali and Rattan, 2006).

In a recently published article Hayes has critically

Hypergravity

Hormetic effects of hypergravity have been studied in Drosophila. Whereas life long exposure to hypergravity decreases the lifespan in rodents and fruitflies, a 2-week exposure to 3 or 5 g at earlier stages in life, resulted in an increase of 15% in the lifespan of male but not of female D. melanogaster (Le Bourg et al., 2000, Minois, 2006). In addition to longevity, other physiological and behavioural parameters, such as fecundity, fertility, locomotor activity, antioxidant enzyme activity, HSP

Hormesis potential, challenges and unresolved issues

Since hormetic effects of mild stress are normally observed to be quite moderate and not so dramatic, some people find it difficult to envisage the biological significance of hormesis in terms of its application in human aging intervention and prevention (Thayer et al., 2006, Zapponi and Marcello, 2006). However, it should be pointed out that although the initial hormetic effects may be relatively small when studied at the level of an individual biochemical step, often the final biological

Acknowledgements

Research grants from the Danish Medical Research Council (FSU), Carlsberg Fund, and Ferrosan A/S are acknowledged.

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ReviewHormesis in aging

Abstract

Introduction

Section snippets

Homeodynamics, aging, and hormesis

Radiation hormesis in aging

Caloric restriction and hormesis

Exercise hormesis

Heat stress in organisms

Nutritional hormesis and hormetins

Hypergravity

Hormesis potential, challenges and unresolved issues

Acknowledgements

Mech. Ageing Dev.

Mech. Ageing Dev.

Plant Sci.

FEBS Lett.

Biomed. Pharmacol.

Exp. Gerontol.

Mutat. Res.

Toxicol. Appl. Pharmacol.

Lancet

J. Biol. Chem.

Exp. Gerontol.

Mech. Ageing Dev.

Int. J. Psychophysiol.

Exp. Cell Res.

Mol. Asp. Med.

Exp. Cell Res.

Mutat. Res.

J. Insect Physiol.

Curcumin's biphasic hormetic response on proteasome activity and heat shock protein synthesis in human keratinocytes

Ann. N.Y. Acad. Sci.

The allele (A)-110 in the promoter region of the HSP70-1 gene is unfavourable to longevity in women

Biogerontology

Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie restriction

Proc. Natl. Acad. Sci. U.S.A.

Hormesis/preconditioning mechanisms, the nervous system and aging

Age. Res. Rev.

Exercise training modulates heat shock protein response in diabetic rats

J. Appl. Physiol.

Mortality of employees of the United Kingdom Atomic Energy Authority, 1946–97

Occup. Environ. Med.

Reseveratrol improves health and survival of mice on a high-calorie diet

Nature

Mild heat stress stimulates proteasome and its 11S activator in human fibroblasts undergoing aging in vitro

Cell Stress Chaperon.

Sugar-induced premature aging and altered differentiation in human epidermal keratinocytes

Ann. N.Y. Acad. Sci.

Single nucleotide polymorphisms: aging and diseases

Biogerontology

A mechanism converting psychosocial stress into mononuclear cell activation

Proc. Natl. Acad. Sci. U.S.A.

The dietary restriction effects in C. elegans and humans: is the worm a one millimeter human?

Biogerontology

The failure of dose-response models to predict low dose effects: a major challenge for biomedical, toxicological and aging research

Biogerontology

The hormetic database: an overview

Toxicol. Appl. Pharmacol.

Cancer biology and hormesis: human tumor cell lines commonly display hormetic (biphasic) dose response

Crit. Rev. Toxicol.

Horemtic dose-response relationship in immunology: occurrence, quantitative features of the dose response, mechanistic foundations, and clinical implications

Crit. Rev. Toxicol.

The effects of gamma rays on longevity

Biogerontology

Hormesis: a generalizable and unifying hypothesis

Crit. Rev. Toxicol.

U-shaped dose-responses in biology, toxicology, and public health

Annu. Rev. Public Health

Toxicology rethinks its central belief

Nature

Effect of continuous gamma irradiation at a very low dose on the life span of mice

Gerontology

The quest for genetic determinants of human longevity: challenges and insights

Nat. Rev. Genet.

Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase

Science

Effects of aging and anti-aging caloric restrictions on carbonyl and heat shock protein levels and expression

Biogerontology

Red wine procyanidins and vascular health

Review
Hormesis in aging