ReviewHormesis in aging
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.
References (217)
- et al.
Life-lengthening effects of gamma-radiation on the adult housefly, Musca domestica
Mech. Ageing Dev.
(1982) - et al.
Temporal and substrate-dependent patterns of stress protein expression in the hypothalamus of calorie restricted rats
Mech. Ageing Dev.
(1994) - et al.
Kinetin—45 years on
Plant Sci.
(1999) - et al.
Evidence for the presence of kinetin in DNA and cell extracts
FEBS Lett.
(1996) - et al.
The anti-ageing effects of calorie restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically
Biomed. Pharmacol.
(2003) - et al.
Hormesis and debilitation effects in stress experiments using the nematode worm Caenorhabditis elegans: the model of balance between cell damage and HSP level
Exp. Gerontol.
(2001) Hormesis: changing view of the dose-response, a personal account of the history and current status
Mutat. Res.
(2002)Hormesis: from marginalization to mainstream: a case for hormesis as the default dose-response model in risk assessment
Toxicol. Appl. Pharmacol.
(2004)- et al.
Longevity of atomic-bomb survivors
Lancet
(2000) - et al.
Age-related decline in chaperone-mediated autophagy
J. Biol. Chem.
(2000)
The biocultural paradigm: the neural connection between science and mysticism
Exp. Gerontol.
Caloric restriction in humans: potential pitfalls and health concerns
Mech. Ageing Dev.
Photo-acoustic stimulation increases the amount of 70 kDa heat shock protein (Hsp70) in human saliva. A pilot study
Int. J. Psychophysiol.
Nucleotide excision repair of actively transcribed versus nontranscribed DNA in rat hepatocytes: effect of age and dietary restriction
Exp. Cell Res.
Medicinal plants: traditions of yesterday and drugs of tomorrow
Mol. Asp. Med.
Age-related alterations in the activation of heat shock transcription factor 1 in rat heapatocytes
Exp. Cell Res.
A re-examination of the effects of ionizing radiation on lifespan and transformation of human diploid fibroblasts
Mutat. Res.
The effect of radiation on the longevity of female Drosophila subobscura
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
Nature
Altered skeletal muscle subsarcolemmal mitochondrial compartment during catch-up fat after caloric restriction
Diabetes
Curcumin: old spice is a new medicine
Altern. Complement. Ther.
Multiple stressors in Caenorhabditis elegans induce stress hormesis and extended longevity
J. Gerontol. Biol. Sci.
Hormesis in Caenorhabditis elagans dauer-defective mutants
Biogerontology
Cancer biomarkers—an invitation to the table
Science
Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice
Proc. Natl. Acad. Sci. U.S.A.
Cited by (398)
60 years of healthy aging: On definitions, biomarkers, scores and challenges
2023, Ageing Research ReviewsA critical scientific and policy opinion on reuse and reclamation of contaminated wastewater for agriculture and other purposes
2023, Journal of Environmental Chemical EngineeringMetabolism, homeostasis, and aging
2023, Trends in Endocrinology and MetabolismOxidative stress, inflammation and hormesis: The role of dietary and lifestyle modifications on aging
2023, Neurochemistry InternationalRefracture risk and all-cause mortality after vertebral fragility fractures: Anti-osteoporotic medications matter
2023, Journal of the Formosan Medical Association