Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity

Abstract

Mammalian lifespan differs by >100 fold, but the mechanisms associated with such longevity differences are not understood. Here, we conducted a study on primary skin fibroblasts isolated from 16 species of mammals and maintained under identical cell culture conditions. We developed a pipeline for obtaining species-specific ortholog sequences, profiled gene expression by RNA-seq and small molecules by metabolite profiling, and identified genes and metabolites correlating with species longevity. Cells from longer lived species up-regulated genes involved in DNA repair and glucose metabolism, down-regulated proteolysis and protein transport, and showed high levels of amino acids but low levels of lysophosphatidylcholine and lysophosphatidylethanolamine. The amino acid patterns were recapitulated by further analyses of primate and bird fibroblasts. The study suggests that fibroblast profiling captures differences in longevity across mammals at the level of global gene expression and metabolite levels and reveals pathways that define these differences.DOI: http://dx.doi.org/10.7554/eLife.19130.001

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

“…This should not be surprising as a decrease in stem cell functionality is an integrative hallmark of aging (Lopez‐Otin, Blasco, Partridge, Serrano & Kroemer, 2013), while the maintenance of it is a cornerstone of naturally evolved mechanisms of fighting aging. Different invertebrate and vertebrate long‐lived species developed independent strategies for repressing aging, but often their life trajectory is related to cell cycle control, telomere and genome maintenance, and tumor suppression (Gorbunova, Seluanov, Zhang, Gladyshev & Vijg, 2014; Ma et al., 2016). …”

Molecular signatures of longevity: Insights from cross-species comparative studies

“…Aligning reads to the genome of a related species is often far from ideal: for example, only 13% of the reads of African grass rat fibroblasts could be uniquely mapped to the mouse genome (even though both belong to the same Family Muridae), and the alignment rate was even lower for the red squirrel (about 5%) (Ma et al, 2016). The identification of gene orthologs (i.e.…”

“…using Trinity (Grabherr et al, 2011)) can be used to recover the coding sequences, whereas gene ortholog sets can be defined as reciprocal best hits in BLAST (Altschul et al, 1997; Tatusov et al, 1997). While these methods are less stringent than those used in phylogeny reconstruction, they can typically identify 5,000~10,000 orthologs (Brawand et al, 2011; Fushan et al, 2015; Ma et al, 2016), which will be sufficient as a starting point for cross-species analyses.…”

“…In another study, primary skin fibroblasts were obtained from 13 species of rodents, 2 species of bats, and 1 species of shrew and subjected to RNA sequencing and metabolite profiling (Ma et al, 2016). Phylogenetic regression was performed to identify gene expression with significant association to maximum lifespan or female time to maturity.…”

Molecular Mechanisms Determining Lifespan in Short- and Long-Lived Species

“…Comparison of liver transcriptomes between mice, naked mole rats, and humans found that long-lived species have upregulated DNA repair genes and DNA damage signaling pathways compared to shorter-lived species [60]. A transcriptomics study of fibroblasts from 16 mammalian species, which aimed to identify longevity-associated gene expression signatures, found that expression of several DNA repair genes positively correlated with species MLS [61]. Several other DNA repair genes were found to be upregulated in long-lived species in a transcriptome study of liver, kidney, and brain from 33 mammalian species [62].…”