Conservation of pro-longevity genes among mammals

Abstract

Genes which confer a relative longevity advantage may be regulated at the level of transcription or translation. Alternatively, pro-longevity genes may mediate their effects at the level of protein structure-functional relationships that are beneficially optimized in long-lived species. Longevity associated genes (LAGs) may be operationally defined as genes that confer beneficial effects and are relatively more conserved among long-lived species. Global and local protein sequence alignments of over 10,000 genes across at least 30 mammalian species were examined to identify LAGs. Known LAGs, including growth hormone receptor (GHR), and breast cancer 1, early onset (BRCA1), have strong associations with maximum lifespan by our analysis. Several common categories of protein function were observed among genes ranked with the strongest associations with MLS identified by all regression models. These genes included those that function in the immune system, cell cycle regulation, and DNA damage response. We provide a ranking of genes with the strongest associations with species maximum lifespan (MLS) by several phylogenetic generalized least squares regression models, including adjustment for confounding variables such as body weight and gestation length.

Keywords: Aging; Genes; Genetics; Homology; Longevity.

Figure 1. Relationships of alignment scores for homologous genes and maximum lifespan

(a) Alignment scores for three hypothetical genes were plotted against the maximum lifespan (MLS) of the species. Hypothetical LAGs may have a steep, positive or negative slope and a correlation approaching ± 1. The hypothetical highly evolutionarily conserved gene (HECG) is a horizontal line indicating that the gene is completely conserved across all species. (b) The alignment scores for the known LAG, BRCA1, and the HECG, NADH dehydrogenase (NDUFV2), are plotted against species MLS. As can be seen from the figure BRCA1 has a steeper slope compared to NDUFV2.

Figure 2. Distribution of p-values (p_MLS) suggests de facto relationship between protein homology and MLS

The distribution of p values for the slope of the regression model with MLS as the independent variable of interest for univariable (a), multivariable including confounders (b), Speakman_GL (c), and Speakman_BW (d) models is shown. For each model, smaller p-values are over-represented compared to the uniform distribution expected for the case where alignment score and MLS are truly unrelated. The uniform distribution for this data is represented by the horizontal line.