Applying Hormesis in Aging Research and Therapy A Perspective from Evolutionary Biology
Miriam Hercus, Ph.D.1,2 and Volker Loeschcke, Ph.D.1
1Department of Ecology and Genetics
Institute of Biology
University of Aarhus
Ny Munkegade, Building 540
DK-8000 Aarhus C, Denmark
Fax: (+45) -8612-7191
2Department of Molecular and Structural Biology
University of Aarhus
Gustav Wieds Vej
DK-8000 Aarhus-C, Denmark
The field of gerontology is a growing one and the results have implications across a number of disciplines. Here we respond to the white paper of Suresh Rattan entitled 'Applying hormesis in aging research and therapy' in this issue. We aim to provide a perspective from evolutionary biology on the recent results from a range of laboratories that deal with hormetic agents. To this end, we will present some of the general patterns seen across species in evolutionary biology with respect to longevity and briefly summarize some of the evolutionary theories of aging. We also aim to discuss the concept of fitness and to open the platform for discussion on the definition of terms like 'beneficial' and 'costly'.
It is not really surprising that there is great variation in the processes and changes that occur with age across levels of biological organization from the macromolecule to species. However, this does not mean that there are no general patterns. The main one focused on in the article by Dr. Rattan (2001) is that research suggests that the genes involved in maintenance and repair processes may have an impact on longevity. Many experiments show an influence on life span when organisms are exposed to a mild stress that switches on these pathways (see Minois 2000 for recent review). The exposure to sublethal stress and subsequent improvement in life span has been termed the phenomenon of 'hormesis' and is defined as a situation whereby exposure to low levels of a toxic substance can lead to an increased longevity, or survival capability (Pollycave 1995; Johnson et al. 1996). In some of the work looking at the impact of effects of mild stress on longevity where an increased life span is seen, there is also a suggestion of cross resistance between traits and an association with increased levels of hsp induction (Minois 2000). It could therefore be hypothesized that Hsp proteins, induced during exposure to a stressful environment, play a role in cell maintenance and damage repair, and this may include damage arising as a result of the aging process.
Theories of Aging
Aging can be regarded as being evident by a reduction in the probability of survival and in fertility. The phenomena of mutation-accumulation and antagonistic pleiotropy may be the genetic mechanisms involved in evolutionary theories of aging (see e.g. Rose 1991, 1999; Zwaan 1999). Mutations may accumulate in both somatic cells and germ line cells. Together these mutations may affect fitness levels in progeny. Somatic cells are not replaced and for this reason some theories regard these as playing a part in aging. Holliday (1995) puts forward the theory that eventually organisms will have a breakdown in maintenance and repair mechanisms, resulting in death. Antagonistic pleiotropy is the result of constrained life-history optimization (e.g. Williams 1957), where genes having an effect at one life stage have an opposite effect at another life stage. This is sometimes referred to by the term 'trade-off'. Examples of this in Drosophila include the negative genetic correlations between increased longevity and reduced early fecundity (e.g. Luckinbill et al. 1984; Rose 1984; Service et al. 1985; Hutchinson and Rose 1990).
In addition to the theories of aging mentioned above, other evolutionary theories exist which revolve around the propositions that the force of natural selection declines with increasing age (Medawar 1952; Hamilton 1966), that resources are allocated between reproduction and somatic cell maintenance (see Kirkwood and Rose 1991) and that increased stress resistance can be associated with a decreased metabolic rate and an increased longevity (Parsons 1995, 2000; Hoffmann and Parsons 1989 but see also Harshman and Schmid 1998). There can be positive genetic correlations between stress resistance and life span. The nematode (Caenorhabditis elegans) mutant strain Age has increased longevity as well as higher levels of resistance to starvation, oxidative (Kenyon et al. 1993; Larsen 1993) and temperature (Lithgow et al. 1994; Lithgow et al. 1995) stresses.
Associations between Traits at the Phenotypic Level can Influence Evolution
Associations or interactions between traits at the phenotypic level can influence evolutionary change by both enhancing and limiting the potential for adaptation to changing environments. There is evidence from laboratory experiments that levels of stress resistance and longevity are phenotypically correlated across organisms. Selection experiments on life history traits in Drosophila have resulted in changes to the levels of stress resistance. In D. melanogaster, for instance, Service et al. (1985) selected for increased senescence and observed an associated increase in the level of resistance to desiccation and starvation in the selected lines (but see Force et al. 1995). Similarly, selection for increased desiccation resistance in both D. melanogaster and D. simulans was accompanied by a reduction in early fecundity but increased longevity (Rose et al. 1992; Hoffmann and Parsons 1993).
Evolution will not favor genes directly that cause aging, but aging may become a by-product of processes that favor early reproduction or other components that affect fitness early in life. Therefore aging may well have different appearances, as it is not a fitness component itself. From an evolutionary perspective, the terms 'gerontogenes' and 'private gerontogenic pathways' by themselves can be misleading as they give the impression that there are evolutionary processes that favor aging by itself. Processes that may affect longevity include a low metabolic rate, a low energy budget, down-regulation of certain proteins and the DNA repair mechanisms suggested to be triggered by exposure to a mild stress. Kirkwood and Shanley (2000) suggest the hormetic affects of caloric restriction could be the result of a redirection of resources towards maintenance, which could give the effect of a hormetic agent an evolutionary basis under certain environmental conditions.
The Concept of Fitness
The term 'fitness' is fundamental in evolutionary biology and refers to those traits that directly contribute in the passing of genetic material to the next generation: fecundity (the number of eggs/progeny), development time and viability. To apply the concept of Darwinian fitness to modern humans is a more complicated task, especially with respect to concerns about trade-offs or negative fitness effects, as technology often outweighs biology and the focus on a good life at old age seems reasonable. To understand the mechanisms of aging and hormesis, however, we believe that humans have to be seen as part of the bigger picture and therefore the concept of fitness must be addressed in any study looking at the impact of a potentially hormetic agent. From an evolutionary point of view the extended mean life span observed after exposure to a hormetic agent cannot be considered as beneficial without considering the potential side-effects of the mild stress on fitness components.
The study of a trait in a single environment may not necessarily be enough of an investigation into any potential fitness effects, given the impact the environment may play in determining any given phenotype. This holds true for studies looking at hormesis and life span too. It is well known that many factors can influence life span. Examples from Drosophila include the impact of temperature (Partridge et al. 1995), population density (Luckinbill and Clare 1984) or sexual activity (Partridge and Farquhar 1981). Genotype-environment interactions for quantitative trait loci (QTL) affecting life span in D. melanogaster are very common and the majority of QTL found was shown to have sexually antagonistic or antagonistic pleiotropic effects in different environments (Vieira et al. 2000).
Some Questions of Uniformity
We believe it is important to try to establish some uniformity across disciplines with respect to the definition of 'beneficial'. One can certainly say that an agent can provide beneficial affects in terms of one trait, but how does one define a beneficial effect if there is a fine line between the negative and positive effects of a hormetic agent? Furthermore, what is considered 'too costly' in terms of any potential negative fitness affect? The impact of brief exposure to a heat stress in Drosophila has been measured as costs to productivity (Krebs and Loeschcke 1994). Recent results from our laboratories (M. Hercus, V. Loeschcke and I. S. Rattan, unpublished) suggest that there can be increases in mean life span in female D. melanogaster when they are repeatedly exposed to a mild heat stress inducing 30% of maximal Hsp70 response in young flies. Such increases in life span are in the same order of magnitude as those seen with a single bout of exposure to a higher level of stress (Khazaeli et al. 1997). However, the beneficial affect of a 10% increase in mean life span seen in our studies is accompanied by a decreased lifetime fecundity of 6%. Can this fitness effect be considered minimal; can it be ignored?
This also leads us to ask the question of whether or not an agent considered to have hormetic effects at one stage of life can be regarded as being more stressful later in life. It is well known that the ability of an organism to respond to stress decreases with age and this would mean that the definition of a cost to exposure to a stress would change as well. The stress response mechanism (Hsps) switched on during periods of stress and suggested to be associated with increased mean life span, is not a longterm response to stress, and there is a sharp decrease in Hsp expression with age (J. G. Sørenson and V. Loeschcke, unpublished). In addition, regular exposure to (mild) stress seems to result in down-regulation of Hsps (Sørensen et al., 2001).
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