Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone - PubMed (original) (raw)

Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone

James M Harper et al. Aging Cell. 2007 Feb.

Abstract

Fibroblast cell lines were developed from skin biopsies of eight species of wild-trapped rodents, one species of bat, and a group of genetically heterogeneous laboratory mice. Each cell line was tested in vitro for their resistance to six varieties of lethal stress, as well as for resistance to the nonlethal metabolic effects of the mitochondrial inhibitor rotenone and of culture at very low glucose levels. Standard linear regression of species-specific lifespan against each species mean stress resistance showed that longevity was associated with resistance to death induced by cadmium and hydrogen peroxide, as well as with resistance to rotenone inhibition. A multilevel regression method supported these associations, and suggested a similar association for resistance to heat stress. Regressions for resistance to cadmium, peroxide, heat, and rotenone remained significant after various statistical adjustments for body weight. In contrast, cells from longer-lived species did not show significantly greater resistance to ultraviolet light, paraquat, or the DNA alkylating agent methylmethanesulfonate. There was a strong correlation between species longevity and resistance to the metabolic effects of low-glucose medium among the rodent cell lines, but this test did not distinguish mice and rats from the much longer-lived little brown bat. These results are consistent with the idea that evolution of long-lived species may require development of cellular resistance to several forms of lethal injury, and provide justification for evaluation of similar properties in a much wider range of mammals and bird species.

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Figures

Fig. 1

Each scatterplot shows an association between species maximum lifespan and mean LD50 value for each of 10 species (treating laboratory mice and wild-trapped mice as separate species for reasons explained in the text). From left to right, points represent laboratory mouse, wild-trapped mouse, rat, red squirrel, white-footed mouse, deer mouse, fox squirrel, porcupine, beaver, and little brown bat. Formal species names and number of independent samples are given in Table 1. Error bars show standard errors of the mean. The line shows the outcome of a least squares regression. Pearson _R_2 and P values (quoted only where P < 0.1) reflect standard linear regression of maximum lifespan against mean LD50 values for the set of nine species, as in the first column of Table 2. Units for LD50 are in μ

(cadmium and H2O2), m

(MMS and paraquat), J m−2 (UV light) or min at 42 °C (heat).

Fig. 2

As in Fig. 1, except that the vertical axis shows mean ED50 values, i.e. the dose of rotenone or glucose that led to a 50% reduction in WST-1 reduction compared to cultures in control medium, for each of 10 species (treating laboratory mice and wild-trapped mice as separate species for reasons explained in the text). Note that increased resistance to rotenone leads to higher ED50 levels, but that increased resistance to withdrawal of glucose is reflected by lower ED50 values, i.e. a requirement for more extreme removal of glucose to achieve equivalent metabolic inhibition. Units for ED50 are μ

(for rotenone) and mg mL−1 (glucose).

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Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone - PubMed (original) (raw)