Telomere length and body temperature—independent determinants of mammalian longevity?

WHY DO SPECIES DIFFER IN LIFESPAN AND WHAT ARE THE DETERMINANTS OF THEIR LONGEVITY? Understanding the main factors that determine variation in species longevity may provide a clue into the leading mechanisms of aging and—what is even more important—outline the key targets for longevity-promoting interventions. Comparative studies on longevity in mammals revealed numerous variables that correlate with maximum lifespan (MLS). However, because of the intangibly intertwined biological relationships, only a limited number of the variables could be considered independent determinants of longevity. Most other correlations reflect intermediated (formal) co-variations rather than the “cause-andeffect” links. It is obvious that manipulations of the formal correlates have little chances to effect the longevity-ensuring systems, and thus be helpful for developing experimental strategies of lifespan extension. Therefore, in comparative longevity studies, it is important to discriminate the independent determinants from the formal correlates. One of the simple criteria to distinguish determinants of longevity is consistently high correlation of a given variable with MLS observed in various model systems. The other approach is based on more ambiguous statistical methods, multivariate analyses included (see, for example, Lehmann et al., 2008a). In particular, we have previously shown that body mass (BM) or resting metabolic rate alone explain around 40–50% of the variation in mammalian longevity, whereas their combination with mitochondrial DNA (mtDNA) GC content could explain over 70% of the MLS variation (Lehmann et al., 2008a,b). Consequently, we hypothesized that other putative players in MLS determination should have relatively small contribution or their effects should be mediated by the above factors. Recent finding by Gomes et al. (2011) demonstrating a strong negative correlation (p = 0.0032) between telomere length and MLS in 59 mammalian species calls for re-evaluation of this hypothesis. Indeed, the coefficient of MLS determination (R2) calculated using the data in their paper indicates that the telomere length could alone explain more than 1/3 of the variation in the lifespan of mammals. Here, we explore whether the telomere length has an independent impact on mammalian longevity or its effect is attributed to co-variation with other determinants of MLS, such as BM and mtDNA GC content. Our analysis was based on the set of mammalian species with the telomere length records presented in Gomes et al. (2011) (n = 55; four species from the orders Monotremata and Diprotodontia, with unusually short telomeres of 1 kb, were not included in the analysis). The MLS, BM, and body temperature (Tb) records were retrieved from the AnAge database (Tacutu et al., 2013; http://genomics. senescence.info/species/). Calculation of the mtDNA GC content was described elsewhere (Lehmann et al., 2008a). To ensure linear relationships, MLS and BM values were ln-transformed, i.e., MLS was presented as a natural logarithm of MLS (lnMLS) and BM was presented as a natural logarithm of BM (lnBM). Re-evaluation of combined effect of lnBM and mtDNA GC on lnMLS in the set of species analyzed by Gomes et al. (2011) gave an extremely significant coefficient of MLS determination (R2 = 0.713, P = 6.2E-10, n = 37), which is very close to that obtained on much bigger dataset of mammals (R2 = 0.703, P < E− 25, n = 215; unpublished data). The telomere length significantly correlates with both lnBM (R = −0.479, P = 0.00025, n = 55) and mtDNA GC content (R = −0.44, P = 0.006, n = 37), suggesting that the relationship between lnMLS and telomere length (R = −0.609, P = 1.2E-10, n = 54) could, at least in part, be due to the telomere length association with lnBM and/or mtDNA GC. Nevertheless, partial correlation and multivariate analyses showed that the telomere length has an independent impact on longevity determination. The partial correlation analysis allows eliminating the co-variation effects. We found that the correlative links between telomere length and BM or mtDNA GC do not significantly alter its association with longevity. Indeed, removing the effects of lnBM or GC or both did not affect the correlation between lnMLS and telomere length (coefficients of partial correlations are −0.421, −0.608, and −0.442, respectively; P < 0.01). Moreover, the links between telomere length and lnBM or mtDNA GC are apparently mediated via longevityassociated factors because removing the effect of MLS resulted in an insignificant correlation of telomere length with lnBM (P > 0.5) or GC content (P > 0.4).