Mitochondrially encoded cysteine predicts animal lifespan

Abstract

SummaryThe role of genetic factors in the determination of lifespan is undisputed. However, numerous successful efforts to identify individual genetic modulators of longevity have not yielded yet a quantitative measure to estimate the lifespan of a species from scratch, merely based on its genomic constitution. Here, we report on a meta-examination of genome sequences from 248 animal species with known maximum lifespan, including mammals, birds, fish, insects, and helminths. Our analysis reveals that the frequency with which cysteine is encoded by mitochondrial DNA is a specific and phylogenetically ubiquitous molecular indicator of aerobic longevity: long-lived species synthesize respiratory chain complexes which are depleted of cysteine. Cysteine depletion was also found on a proteome-wide scale in aerobic versus anaerobic bacteria, archaea, and unicellular eukaryotes; in mitochondrial versus hydrogenosomal sequences; and in the mitochondria of free-living, aerobic versus anaerobic-parasitic worms. The association of longevity with mitochondrial cysteine depletion persisted after correction for body mass and phylogenetic interdependence, but it was uncoupled in helminthic species with predominantly anaerobic lifestyle. We conclude that proteincoding genes on mitochondrial DNA constitute a quantitative trait locus for aerobic longevity, wherein the oxidation of mitochondrially translated cysteine mediates the coupling of trait and locus. These results provide distinct support for the free radical theory of aging.

Mutational Bias Plays an Important Role in Shaping Longevity-Related Amino Acid Content in Mammalian mtDNA-Encoded Proteins

“…In other words, we found that although cysteinyl residues were actively avoided, there were no differences between short-or long-lived species. This observation contrasts with previous results reporting a negative relationship between cysteine usage and longevity, across a wide range of animals covering mammals, birds, reptiles, amphibians, fishes, insects, crustaceans, and arachnids (Moosmann and Behl 2008). Nonetheless, when the correlation analyses were focused on the class Mammalia after correction for the effects of Fig.…”

“…and methionine are particularly sensitive to oxidation (Berlett and Stadtman 1997). Interestingly, mitochondrially encoded cysteine and methionine have both been correlated negatively with longevity (Moosmann and Behl 2008;Aledo et al 2011). Even though both cysteine and methionine are negatively related to longevity, it may be that cysteine is a pro-oxidant while methionine is an anti-oxidant, as we have previously argued (Aledo et al 2011).…”

“…This point is well illustrated by the finding that the mitochondrial membrane peroxidizability index is inversely related to maximum life span in mammals (Pamplona et al 1998). Along the same lines, different authors have suggested that concerted changes in mtDNA-encoded proteins leading to mitochondrial proteomes better endowed to resist oxidative stress may have evolved in response to selective pressures (Moosmann and Behl 2008;Kitazoe et al 2008;Aledo et al 2011).…”

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

“…There is little evidence for greater antioxidant enzyme capacity in longer-lived species (reviewed in Perez et al 2009b; also see Page et al 2010a). Protein oxidative damage could also be prevented in longer-lived species by the systematic evolutionary replacement of cysteine residues with amino acids less susceptible to oxidative modification (as Moosmann and Behl (2008) demonstrated for mitochondrial DNA-encoded proteins); however, there is no evidence that this has occurred in nuclear DNA-encoded proteins that function either in the mitochondria or cytosol (Moosmann and Behl 2008). Similarly, proteins of naked mole rats actually have higher cysteine content than shorter-lived mice (Perez et al 2009a).…”

Mitochondrial whims: metabolic rate, longevity and the rate of molecular evolution

“…One suggestion, however, is that long-lived mammals and birds may have adapted to an increased lifespan by evolving macromolecular components more resistant to oxidative damages (Pamplona & Barja 2007;Min & Hickey 2008;Moosmann & Behl 2008). This conclusion points to a new hypothesis potentially explaining the variations of mtDNA substitution rate across species-longevity-dependent selection.…”