Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

Abstract

Accumulation of DNA lesions compromises replication and transcription and is thus toxic to cells. DNA repair deficiencies are generally associated with cellular replicative senescence and premature aging syndromes, suggesting that efficient DNA repair is required for normal longevity. It follows that the evolution of increasing lifespan amongst animal species should be associated with enhanced DNA repair capacities. Although UV damage repair has been shown to correlate positively with mammalian species lifespan, we lack similar insight into many other DNA repair pathways, including base excision repair (BER). DNA is continuously exposed to reactive oxygen species produced during aerobic metabolism, resulting in the occurrence of oxidative damage within DNA. Shortpatch BER plays an important role in repairing the resultant oxidative lesions. We therefore tested whether an enhancement of BER enzyme activities has occurred concomitantly with the evolution of increased maximum lifespan (MLSP). We collected brain and liver tissue from 15 vertebrate endotherm species ranging in MLSP over an order of magnitude. We measured apurinic/ apyrimidinic (AP) endonuclease activity, as well as the rates of nucleotide incorporation into an oligonucleotide containing a single nucleotide gap (catalyzed by BER polymerase β) and subsequent ligation of the oligonucleotide. None of these activities correlated positively with species MLSP. Rather, nucleotide incorporation and oligonucleotide ligation activities appeared to be primarily (and negatively) correlated with species body mass.

Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

“…Consistently, several studies overexpressing antioxidant enzymes in mice failed to exert positive effects on lifespan or associated parameters (Jang et al 2009, Muller et al 2007, Perez et al 2011. Accordingly, several long-lived species were found to have a relatively lower expression of antioxidant genes than short-lived ones (Brown and Stuart 2007, Lopez-Torres et al 1993, Page et al 2010, Page and Stuart 2012, Salway et al 2011. In the fruit fly Drosophila melanogaster, increasing levels of mitochondria-derived ROS were found during aging, but were not altered through interventions that increase longevity (Cocheme et al 2011).…”

Mitochondrial free radical theory of aging: Who moved my premise?

“…If oxidative status is a determinant of lifespan as MFRTA deduces, the exposure to a highly‐oxidative cellular environment without sufficient anti‐oxidative defense should become detrimental for the naked mole rat, and thus incompatible with its extended lifespan. In fact, long‐lived species, whether it being the naked mole rat or pigeon, do not necessarily have higher levels of anti‐oxidants or better repair systems . What they do have in common, though, is a more oxidation‐resistant cell composition (for example, lower level of unsaturated fatty acids in membrane composition), which helps them cope with a more oxidative cellular environment.…”

Mitochondrial reactive oxygen species (ROS) in animal cells: relevance to aging and normal physiology

“…While we have focused primarily on comparisons between species with profoundly disparate MLSPs to address this question, the majority of experiments with single gene mutant mice with increases in lifespan on the order of several months have also generally failed to support the theory. We have also found little evidence for enhanced rates of macromolecular damage repair (e.g., DNA or protein) associated with greater longevity among vertebrate species (Page and Stuart 2012), with the exception that the steady-state levels of some heat shock proteins (HSP) appear to correlate with species MLSP (Salway et al 2011;Fig. 2).…”