Anti-ageing strategies: prevention or therapy?

Abstract

Slowing ageing from within

Biogerontology—the study of the biological basis of ageing—is now a mature research field that could eventually offer effective applications to ease the burden of old age. Unlike other research fields that focus predominantly on producing information, a central characteristic of biogerontology is that it searches for means of preventing the onset of age-related diseases and improving quality of life in old age. Biogerontologists have already produced a large body of descriptive and mechanistic data that allows them to define some general principles of ageing. Although their accumulated research has not yet uncovered any universal markers of ageing, the principles that have been derived could lead to the development of practical and effective anti-ageing strategies based on rational approaches.

First, the 'life-history principle' describes ageing as an emergent phenomenon that takes place primarily in protected environments, and which allows survival beyond the natural lifespan that would occur in the wild. By contrast, the natural lifespan of a species, also termed the 'essential lifespan' (ELS; Rattan, 2000) or 'warranty period' (Carnes et al, 2003), is the time required to fulfil the Darwinian purpose of life; that is, successful reproduction. Species that undergo fast maturation and have an early onset of reproduction with high reproductive potential generally have a short ELS, whereas slow maturation with late onset and low potential is concurrent with a long ELS. For example, the ELS for Drosophila is less than a week but that for Homo sapiens is about 50 years, even though both species can and do live for much longer periods in protected laboratory environments and modern societies, respectively. Consequently, the period of extended survival beyond the ELS is defined as the period of ageing.

Second, the 'non-genetic principle' asserts that there is neither a genetic cause for, nor a programme that controls, the ageing process. Its proponents argue that, unlike development, which is a tightly regulated genetic and epigenetic process, ageing, and therefore the exact lifespan of an organism, is not determined by any specific genes, termed gerontogenes (Rattan, 1995; Partridge, 2001; Kirkwood, 2002). Those genes that do influence ageing and longevity have evolved in accordance with the evolutionary history of a species to assure its ELS, but they do not necessarily control the further progression of the organism beyond reproduction. These arguments follow evolutionary theory in asserting that evolution selects genes that allow us to reach the ELS so we can reproduce, but everything after that age falls into the evolutionary shadow as it does not determine the survival of the species as such. Instead, ample evidence now supports the theory that survival and longevity of a species are a function of the ability of its maintenance and repair mechanisms to keep up with daily wear and tear. There are positive correlations between lifespan and the ability to repair DNA, detoxify reactive oxygen molecules, respond to and counteract stress, and replace worn-out cells. In addition, there is a negative correlation between longevity and the rate of damage accumulation, including mutations, epimutations, macromolecular oxidation and aggregation of metabolic byproducts (Holliday, 2000).

... the “life-history principle” describes ageing as an emergent phenomenon that takes place primarily in protected environments ...

... our bodies have evolved over millions of years and have been optimized through evolution to ensure proliferation and survival of the species, rather than a long lifespan for the individual

However, a lack of specific gerontogenes does not imply that genes have no influence on survival, longevity and ageing. There is ample evidence from studies performed on yeast, fungi, nematodes, insects, rodents and humans that mutations in certain genes can either prolong or shorten lifespan and cause premature ageing syndromes. These genes are involved in a wide range of biochemical pathways and agents, such as insulin metabolism, kinases and kinase receptors, transcription factors, DNA helicases, telomerase, membrane glucosidases, GTP-binding protein-coupled receptors, cholesterol metabolism, heat-shock protein genes, cell-cycle arrest pathways and others (Rattan, 2003). Nevertheless, regardless of their normal function and mechanism of action, these genes did not evolve specifically to accumulate damage, cause age-related changes and eventually kill the organism. Since their influence on ageing and longevity is only indirect, they have been termed 'virtual gerontogenes' (Rattan, 1995).

Third, the 'mechanistic principle' explains ageing as a progressive failure of homeostasis or homeodynamics—the ability of our bodies to maintain a steady balanced state. This malfunction eventually leads to the accumulation of damage to nucleic acids, proteins and lipids, and to the progressive impairment of functional abilities in all tissues and cells. Since homeostasis or homeodynamics primarily depend on an organism's maintenance and repair processes, it is the progressive failure of these mechanisms that causes ageing and age-related diseases (Holliday, 1995). The first two principles of ageing and longevity explain why these processes have not evolved to function accurately and efficiently for indefinite periods. Together, the three principles state that our bodies have evolved over millions of years and have been optimized through evolution to ensure proliferation and survival of the species, rather than a long lifespan for the individual. The occurrence of ageing beyond the ELS, the onset of age-related diseases and eventual death thus appear to be the 'normal' sequence of events after we have reproduced and therefore fulfilled our evolutionary purpose.

These principles and the underlying knowledge will soon allow researchers to develop reasonable therapies that intervene in the ageing process and treat various age-related diseases and frailties. It is an ironic twist, therefore, that while research in biogerontology has made huge advances over the past decade, it still has a bad reputation. In fact, the history of anti-ageing research is replete with fraud, pseudoscience, quackery and charlatanism, which together have given it a bad name. Even today, in our supposedly enlightened age, claims of miraculous remedies and therapies to overcome ageing run rampant, despite many of these products having no effects whatsoever. Most of these anti-ageing therapies promise a total elimination of ageing, disease and death, or aim to slow down the ageing process, thus delaying the onset of diseases and extending our healthy lifespan. Few of them actually work.

Another, more rational, approach involves targeting specific age-related diseases. Although this is usually effective in curing or halting a specific disease, it does not address ageing itself. Cancer therapy, for instance, will ideally eliminate cancerous cells and restore the affected organ or tissue to its original disease-free state. Nevertheless, although it reduces the risk of dying from cancer, it does not address other age-related diseases and disorders such as Parkinson's or Alzheimer's diseases, dementia, progressive organ failure or cardiovascular diseases. It also means that a 'cure for ageing' will most likely not succeed. How would such a 'treatment' look and to what original 'age-free' stage should one be restored—to day 1, year 1, 10, 30 or 50? Defining ageing as a disease and then trying to cure it is unscientific and misguided.

Instead, rational anti-ageing strategies based on scientific evidence aim to slow down the ageing process by preventing and/or delaying physiological decline and regaining lost functional abilities. Some approaches include supplementation with hormones, including the growth hormone dehydroepiandrosterone (DHEA), melatonin and oestrogen, and nutritional supplements that contain synthetic and natural antioxidants in purified form or in plant extracts. Although some of these therapies have demonstrated various clinical benefits in the treatment of the elderly, none really modulate the ageing process itself (Olshansky et al, 2002). Paradoxically, studies performed on nematodes, insects and rodents have shown that lifespan extension is almost always associated with a reduction in the levels and activities of several hormones and hormonesignalling pathways, including insulin, growth hormone and sex steroids (Gems & Partridge, 2001; Bartke et al, 2003; Tatar et al, 2003). Increasing the levels of various hormones through supplementation may therefore actually shorten lifespan. Similarly, therapies that use high doses of vitamins and antioxidants due to their supposed anti-ageing and life-prolonging effects are backed by very little scientific evidence (Le Bourg, 2005).

Cosmetic treatments of ageing are at best only superficial and temporary, and cosmetics are not legally allowed to affect or modulate underlying cellular and biochemical processes. Yet research has discovered various natural and synthetic compounds that have a much greater potential as gerontomodulatory molecules than in their limited use in cosmetics (Rattan, 2002). For example, N⁶-furfuryladenine or kinetin, a cytokinin growth factor, has been shown to provide anti-ageing and other beneficial effects, such as maintaining the youthful morphology of human cells, protecting DNA and proteins from oxidative damage, stimulating antioxidant enzymes in fruit flies, inhibiting platelet aggregation and pulmonary thrombosis in mice, and rescuing missplicing of RNA in familial dysautonomia genetic disorder (Rattan, 2002; Hsiao et al, 2003; Slaugenhaupt et al, 2004). Similarly, carnosine, a β-alanyl-L-histidine dipeptide, has beneficial effects such as the prevention and reversal of the ageing phenotype in human cells, prevention of oxidative damage to proteins and scavenging of free radicals (McFarland & Holliday, 1994, 1999; Hipkiss & Brownson, 2000).

Another preventive approach calls for altering our bodies in order to improve the basic molecular and genetic processes of maintenance and repair so that they either work more efficiently or for longer. These so-called 'strategies for engineered negligible senescence' (de Grey, 2000) require redesigning functional units of the body at the level of genes, gene products, macromolecular interactions, molecular-milieu interactions, and so on. Considering how little information and knowledge we have at present about these interacting factors, it is not clear how such an approach would work in practical terms. Similarly, although piecemeal replacement of nonfunctional or damaged body parts with natural or synthetic parts may provide a temporary solution to the problems of age-related impairments, it does not modulate the underlying ageing process per se.

Even today, in our supposedly enlightened age, claims of miraculous remedies and therapies to overcome ageing run rampant, despite many of these products having no effects whatsoever

A more realistic and promising approach in ageing intervention and prevention makes use of the body's intrinsic capacity for self-maintenance and repair. It is based on observations that exposure to low levels of otherwise harmful conditions can stimulate homeodynamic adaptive responses that benefit individual cells as well as the whole organism. The theory behind the approach—that low doses of toxic or harmful substances have a protective effect—is known as hormesis. Although the hormesis concept has been defined in different contexts such as pharmacology and toxicology (Calabrese & Baldwin, 2000; Parsons, 2000), hormesis in ageing is characterized by the beneficial effects that result from cellular responses to mild repeated stress (Rattan, 2001). Exposing cells and organisms to brief periods of stress should therefore slow down ageing, since the hormetic response to the stressor not only defends the organism against the stress but also over-reacts to remove other accumulated damage in cells and tissues. The paradigm for hormesis is exercise, an activity that is both stressful and damaging due to the production of free radicals, acids, stress hormones and cell and tissue breakage. But as an inducer of repair and maintenance processes, the hormetic effect of this strenuous activity has a wide range of health-promoting effects.

We have demonstrated the hormetic effects of repeated mild heat stress (RMHS) on cultures of human cells that undergo ageing. A mild stress regimen that exposed human skin fibroblasts in vitro to 41°C for 1 hour twice a week throughout their replicative lifespan caused several beneficial and anti-ageing effects (Table 1). It is important to note that while RMHS affected several age-related phenomena, it did not modify the proliferative capacity of these cells. This has implications in differentiating the phenomenon of ageing from longevity. It appears that the progression of cellular ageing in vitro—increasing molecular disorder—can be slowed down without upsetting the regulatory mechanisms of the cell cycle. Thus, the cells' quality of life in terms of their structural and functional integrity can be improved by mild stress without pushing these cells into a potentially carcinogenic hyperproliferative mode.

Table 1. Hormetic effects of repeated mild heat shock on ageing human fibroblasts in vitro.

Characteristic	Hormetic effect	Reference
Cell size	Reduced enlargement	(Rattan, 1998)
Cellular morphology	Reduced irregularization
Glycation, furasine level	50–80% reduction	(Verbeke et al, 2001)
Glycoxidation level	10–30% reduction
CML-rich protein level	20–85% reduction
Lipofuscin pigment level	6–29% reduction
Protein carbonyl levels	5–40% reduction
Reduced glutathione level	Threefold increase
Oxidized glutathione level	Twofold reduction
Induction of sugar-induced protein damage	Tenfold reduction
H2O2 decomposing ability	50–140% increase	(Fonager et al, 2002)
Survival after H2O2 exposure	10–18% increase
Survival after ethanol exposure	10–40% increase
Survival after UVA exposure	5–17% increase
Hsp27 level	20–40% increase
Hsc70 level	20% increase
Hsp70 level	7–20-fold increase
Hsp90 level	50–80% reduction
Proteasome activities	40–90% increase	(Beedholm et al, 2004)
20S proteasome content	No change
19S activator content	No change
11S activator content	Increase
11S activator binding	Increase

Some other mild stresses have been reported to delay ageing and prolong longevity on the level of the whole organism in various experimental animals. These include temperature shock, irradiation, heavy metals, pro-oxidants, acetaldehyde, alcohols, resveratrol, hypergravity, exercise and caloric restriction (Minois, 2000; Hercus et al, 2003; Rattan, 2004; Wood et al, 2004). Similar responses to mild under-nutrition in human beings have also been reported. For example, peripheral blood lymphocytes that were isolated from people with low body-mass index, such as those who live on a calorie-restricted diet, had higher DNA repair capacity and higher levels of DNA polymerase β, which were also maintained during ageing (Raji et al, 1998). Intermittent fasting also has beneficial effects on glucose metabolism and neuronal resistance to injury in mice (Anson et al, 2003). In addition, various nutraceutical and pharmacological agents that mimic hormetic stress responses are now under development. For example, bimoclomol, a nontoxic hydroxylamine derivative (Vigh et al, 1997), and celastrol, a quinone methide triterpene (Westerheide et al, 2004), both induce heatshock proteins with chaperoning and protein-protective effects and are now being tested for their long-term cytoprotective action. Curcumin, an Indian yellow spice, has also been shown to have cytoprotective effects through its hormetic action in stimulating the synthesis of heat-shock proteins (Kato et al, 1998). Other chemical mimetics of caloric restriction, such as 2-deoxy-D-glucose and its analogues, and resveratrol—a polyphenol found in red wine—are being investigated for their use as anti-ageing hormetic agents (Wood et al, 2004).

Defining ageing as a disease and then trying to cure it is unscientific and misguided

However, before hormesis can be used as an effective way to modulate ageing and prevent the onset of age-related impairments and pathologies, there are several questions and problems that need to be resolved. Research has to establish biochemical and molecular criteria for quantifying the hormetic responses to different stresses, to identify the differences and similarities in stress response pathways that are initiated by these stressors, and to determine the interactive and pleiotropic effects of these pathways. In addition, clinical research is required to adjust the level and duration of mild stress for age-related changes in the sensitivity to stress. Resolving these issues requires a better understanding of the genetic and epigenetic interactive pathways of maintenance and repair networks, and how small changes in one component of the network can bring about equal or larger effects elsewhere in the organism. Furthermore, we need to understand the biochemical basis of age-related alterations and their responses to different kinds of stresses, and how this can be used to define an effective hormetic level of mild stress.

... hormesis amplifies adaptive responses to stress, which in turn improves overall cellular functions and performance

Since hormetic effects are usually moderate, the biological significance of hormesis in terms of its application to human ageing is not yet clear. However, it should be pointed out that, although the hormetic effects may be relatively small when studied at the biochemical or molecular level, the final outcome—such as overall stress tolerance, functional improvement and survival—is often much more significant. This suggests that hormesis amplifies adaptive responses to stress, which in turn improves overall cellular functions and performance. Exercise is a good example because it is not only the specific target muscles that benefit, but also the immune system, cardiovascular system, sex hormones, libido and mood. Nevertheless, we still need to learn more about the interactive biochemical pathways which, through a process of biological amplification, cause maintenance and/or improvement of physiological functions. In the case of humans, research has just begun to investigate the role of the mental state and psychological stress in modulating various physiological functions, such as the immune response, stress hormone synthesis, gene expression, cardiac output and muscle strength (Bierhaus et al, 2003; Padgett & Glaser, 2003).

Applying hormesis to slow down ageing from within, prevent the onset of age-related diseases, and maintain physical and mental abilities in old age is a real possibility. But much more research on the molecular and physiological effects of mild stresses on the human body is needed before we can develop effective means of ageing intervention and prevention.