Mini-ReviewRelationship between increased longevity and stress resistance as assessed through gerontogene mutations in Caenorhabditis elegans
Section snippets
Identification of gerontogenes
The genetic approach was pioneered by four labs in the early 1980s. There are many advantages of using the genetic approach to study aging and senescence (or any other biological process for that matter). The genetic approach, at its best, uses an unbiased assessment strategy for identifying long-lived mutants. The increased longevity of these mutants must have resulted from altering ‘… primary rate-limiting processes that determine life span’ (Johnson and Wood, 1982, p. 6606).
A gerontogene is a
The stress response hypothesis
A prediction of the stress-response hypothesis (Johnson et al., 1996) is that increased longevity is associated with increased resistance to everyday stressors. This hypothesis makes the assumption that exogenous stress is in some way a surrogate marker of endogenous stress, so that assessment of resistance to an exogenous stressor is a marker of resistance to endogenous stress generated by a variety of endogenous metabolic pathways (Finkel and Holbrook, 2000). If this hypothesis is true, we
Are gerontogene mutants more stress resistant?
Larsen, 1993, Vanfleteren, 1993 were the first to show that increased longevity is associated with increased resistance to stress; both focused on oxidative stress. Larsen, using H2O2, found that the LD50 of age-1 mutants occurs at about a three-fold higher concentration, as compared with wild type at 15 days of age. Vanfleteren (1993) found that age-1 mutants were several-fold more resistant to paraquat. Both labs showed that older worms had elevated resistance, as compared with younger worms
Are higher levels of stress resistance systems found in age mutants?
What is the mechanism underlying these increases in resistance to environmental stressors? Larsen, 1993, Vanfleteren, 1993, Vanfleteren and De Vrees, 1995 found that enzymatic activities of both CuZn and Mn superoxide dismutase (SOD) and catalase increased with increasing chronological age in the age-1 mutant. In parallel with the increase in resistance to oxidants, Larsen (1993) noted a 60% increase in catalase activity and an almost four-fold increase in SOD activity at the oldest ages in
Can increased stress resistance be used as a surrogate marker for extended longevity?
Four studies have shown that increased stress resistance is a good surrogate marker for extended longevity. The Murakami and Johnson (1998) study used UV resistance and identified a long-lived variant by this means. Walker et al., 1998 found that six of 11 mutants that were isolated on the basis of increased heat resistance are also long-lived, while Yang and Wilson (2000) found that all three of their thermotolerant strains were Age. Similarly, we ( Johnson et al., 2000) have found that
Can life extension can be achieved by non-genetic means involving increased stress resistance
Two non-genetic methods of extending longevity have been reported in C. elegans: hormesis and drug treatment. Hormesis can be defined as ‘stimulatory effects of low doses of substances known to be toxic at higher doses’ and has been reported at least as far back as 1887 (for review, see http://www.belleonline.com/index.htmi). Hormesis is characterized by maximum stimulatory effects typically 40–60% greater than controls; these maximum effects are typically found in response to doses of 20–25%
Does reducing the level of stress resistance lead to shortened life span?
In addition to mutants that increase longevity, mutations in several genes coding for proteins involved in either the production of or the protection from reactive oxidants have been studied. The best studied of these is mev-1, which encodes succinate dehydrogenase cytochrome b (Ishii et al., 1998) and the interested reader is referred to a recent review (Ishii and Hartman, 2000). These mutants are invariably short lived and sensitive to stress. Although consistent with the stress-response
Conclusions
Multiple genetic mechanisms affect the specification of life span in C. elegans with as many as nine distinct phenotypic classes now known.
Every Age gene identified in the worm is associated with antagonistically pleiotropic effects between longevity and function in development, fertility, and or behavior.
The central unifying principle from these studies is that life extension is universally (so far) associated with increased resistance to stress.
It is unclear whether unifying principles from
Acknowledgements
We wish to thank numerous members of the Johnson lab over the years for their help in collecting data cited here. This work was supported by grants from the National Institutes of Health (PO1 AG08761, RO1-AG12423, R01-AG16219 and KO2-AA00195) and by gifts from the Ellison Medical Foundation and the Glenn Foundation for Medical Research. Some nematode strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Center for Research Resources (NCRR) of the NIH.
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