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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online June 3, 2003 as doi:10.1096/fj.02-1092fje. |
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,
,,
,2
* Department of Pathology,
Geriatrics Center and
Institute of Gerontology, University of Michigan Medical School; and
Ann Arbor VA Medical Center, Ann Arbor, Michigan, USA
2Correspondence: 5410 CCGCB, Box 0940, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0940, USA. E-mail: millerr{at}umich.edu
SPECIFIC AIM
Mutations that extend nematode longevity by interference with IGF-I/insulin sensing pathways lead to resistance to multiple forms of stress. The aim of the study was to test the hypothesis that the Snell dwarf mutation, already known to extend life span and delay aspects of aging in mice, also renders cells resistant to a variety of forms of stress.
PRINCIPAL FINDING
Fibroblasts from dwarf mice show resistance to a variety of forms of lethal injury, including ultraviolet light, heat, paraquat, H2O2, and the toxic metal cadmium
In Snell dwarf mice, mutation of the Pit-1 (pituitary transcription factor-1) gene leads to declines in growth hormone and IGF-I, thyroid hormones, and prolactin. This altered hormonal profile leads to dwarfism, deceleration of several aspects of aging, and a 40% increase in life span. However, the mechanism by which the altered hormonal profile leads to life extension is unknown.
We investigated whether fibroblasts from young Snell dwarf mice show resistance to cytotoxic stresses. Fibroblasts were grown from tail skin of young dwarf (dw/dw) mice and from their phenotypically normal littermates (dw/+). Third or fourth passage cells were arrested at the G0/G1 phase by a 27 h period of serum starvation, then exposed to agents that induce cellular injury. Figure 1
shows LD50 values for fibroblasts from dwarf and control mice in responses to each of five forms of stress. Dwarf cells were significantly more resistant to each stress than were control cells. The effects on LD50 ranged from a 45% change for UV light to a 180% change for cadmium, and all were significant by ANOVA at P < 0.01. Additional details of the statistical analysis are shown in Table 1
. Dose response curves also established that cells from the dwarf mice were relatively resistant to each stress over a wide dose range (not shown). An independent set of experiments using dwarf mice on a different genetic background produced similar outcomes (data not shown). The difference between dwarf and normal mice was also seen when the test for viability depended on uptake of tritiated thymidine into DNA rather than using measures of mitochondrial function as employed in Fig. 1
. We also tested stress resistance of proliferating fibroblasts cultured without a period of serum starvation before stress exposure. Under these conditions we found no consistent or significant differences between dwarf and control cultures (data not shown).
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CONCLUSIONS AND SIGNIFICANCE
Here we show that skin-derived fibroblasts from young dwarf mice are resistant to multiple forms of cellular injuries caused by UV light, heat, paraquat, H2O2, and cadmium. Thus, the altered hormonal profile in the dwarfs causes long-lasting physiological changes in cells, leading to multiplex stress resistance. The results support the theory that modulation of cellular stress resistance regulates life span in mammals. Figure 2
summarizes our model for regulation of longevity and stress resistance.
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Our findings have several interesting implications. First, they support the idea that the extended longevity and delayed aging of Snell dwarf mice may reflect increased resistance of cells to stress. It is noteworthy that a mutation at the p66-shc locus that renders mouse fibroblasts resistant to UV-induced apoptosis also extends longevity in homozygous mice. It will be worthwhile to delineate the steps that connect cellular stress resistance to its pathological result, disease resistance, in these and other models of decelerated aging. Second, the data suggest that resistance to multiple varieties of stress may be coordinately regulated by hormone-sensitive pathways in mice. Defining the molecular basis for this coordinate control may lead to important insights into the relation of cellular differentiation to organismal aging and provide biochemical targets for potential interventions. Ames dwarf mice, similar in many respects to the Snell dwarfs, have higher levels of catalase in liver and kidney, and it will be of interest to determine what other forms of cellular defense may be bolstered in these and other cells in dwarf mice. Third, the data suggest that the stress resistance property of slow-aging mice extends to cells, like dermal fibroblasts, that may play little role in resistance in most forms of lethal disease but which are easily accessible and thus useful for tests of genetic and pharmacological antigenic interventions.
Last, the parallelism between the worm and mouse results suggests that the connections between cellular stress resistance and modulation of life history trajectories may have ancient evolutionary roots.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-1092fje; doi: fj.02-1092fje 
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