Abstract:DNA-damage response and repair are crucial to maintain genetic stability, and are consequently considered central to aging and longevity. Here, we investigate whether this pathway overall associates to longevity, and whether specific sub-processes are more strongly associated with longevity than others. Data were applied on 592 SNPs from 77 genes involved in nine sub-processes: DNA-damage response, base excision repair (BER), nucleotide excision repair, mismatch repair, non-homologous end-joining, homologous r… Show more
“…Consistent with the findings, over-expression of hif-1 in C. elegans was shown to promote longevity (Zhang et al, 2009), whereas deletion of rif1 and msh6 in yeast (Austriaco and Guarente, 1997; Laschober et al, 2010), knockout of prdx3 in C. elegans (Ha et al, 2006), and disruption of Ercc1 in mouse (Weeda et al, 1997) were all detrimental and led to decreased lifespan. Several previous studies also suggested that long-lived species generally have enhanced DNA repair capacity (Cortopassi and Wang, 1996), higher poly (ADP-ribose) polymerase activity (Grube and Bürkle, 1992), up-regulation of genes in base-excision repair and superoxide metabolic process (Fushan et al, 2015), as well as reduced free-radical production (Perez-Campo et al, 1998), reduced oxidant generation (Sohal et al, 1995), and less oxidative damage to nuclear DNA (Adelman et al, 1988) and mitochondrial DNA (Barja and Herrero, 2000), although the degree of contribution toward the observed differences in lifespan varied and might be affected by several confounding effects (Debrabant et al, 2014; Montgomery et al, 2012; Promislow, 1994). 10.7554/eLife.19130.010Figure 4.Selected genes and stress resistance conditions with significant correlation to longevity.( A ) Pnkp and ( B ) Nadsyn1 show positive correlation with the longevity traits.…”
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
“…Consistent with the findings, over-expression of hif-1 in C. elegans was shown to promote longevity (Zhang et al, 2009), whereas deletion of rif1 and msh6 in yeast (Austriaco and Guarente, 1997; Laschober et al, 2010), knockout of prdx3 in C. elegans (Ha et al, 2006), and disruption of Ercc1 in mouse (Weeda et al, 1997) were all detrimental and led to decreased lifespan. Several previous studies also suggested that long-lived species generally have enhanced DNA repair capacity (Cortopassi and Wang, 1996), higher poly (ADP-ribose) polymerase activity (Grube and Bürkle, 1992), up-regulation of genes in base-excision repair and superoxide metabolic process (Fushan et al, 2015), as well as reduced free-radical production (Perez-Campo et al, 1998), reduced oxidant generation (Sohal et al, 1995), and less oxidative damage to nuclear DNA (Adelman et al, 1988) and mitochondrial DNA (Barja and Herrero, 2000), although the degree of contribution toward the observed differences in lifespan varied and might be affected by several confounding effects (Debrabant et al, 2014; Montgomery et al, 2012; Promislow, 1994). 10.7554/eLife.19130.010Figure 4.Selected genes and stress resistance conditions with significant correlation to longevity.( A ) Pnkp and ( B ) Nadsyn1 show positive correlation with the longevity traits.…”
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
“…Another possible explanation of the missing replicability and missing heritability may be related to the complexity of longevity (Dato et al., 2017), which harbours many heterogeneity sources, including the effect of rare variants, not captured by standard genomewide genotyping, and interactions between different loci, an often‐cited reason for the lack of success in genetic studies of complex diseases (Moore, 2003). With the aim of exploring this poorly investigated genetic effect, we re‐analysed a genetic data set previously described and used for single‐SNP and gene set analyses (Debrabant et al., 2014; Soerensen et al., 2012), for SNP‐SNP interactions. The findings obtained indeed indicate that an epistatic analysis approach is very much applicable for candidate gene/pathway data and hence might contribute to the knowledge concerning the genetics of human longevity.…”
Section: Discussionmentioning
confidence: 99%
“…However, while IIS had many genes associated with the trait, the association of TM with survival was mainly determined by the POT1 gene. Similarly, we previously performed a pathway analysis of 592 SNPs in the DNA repair pathway in the same in the same study population as investigated in the present study indicating association of subprocesses of this pathway in human longevity (Debrabant et al., 2014). Here, we wanted to explore synergies inside a large SNP data set, by applying statistical methodologies allowing us to test the interaction both inside and among SNP variants belonging to three main candidate pathways of human longevity such as IIS, DNA damage signalling and repair, and pro/antioxidant response.…”
SummaryIn human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with small effects, yet not easily replicable in different populations. New insights may come from the combined analysis of different SNPs, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNPs belonging to three candidate pathways, the insulin/insulin‐like growth factor signalling (IIS), DNA repair and pro/antioxidant. We analysed data from 1,058 tagging SNPs in 140 genes, collected in 1825 subjects (1,089 unrelated nonagenarians from the Danish 1905 Birth Cohort Study and 736 Danish controls aged 46–55 years) for evaluating synergic interactions by SNPsyn. Synergies were further tested by the multidimensional reduction (MDR) approach, both intra‐ and interpathways. The best combinations (FDR<0.0001) resulted those encompassing IGF1R‐rs12437963 and PTPN1‐rs6067484, TP53‐rs2078486 and ERCC2‐rs50871, TXNRD1‐rs17202060 and TP53‐rs2078486, the latter two supporting a central role of TP53 in mediating the concerted activation of the DNA repair and pro‐antioxidant pathways in human longevity. Results were consistently replicated with both approaches, as well as a significant effect on longevity was found for the GHSR gene, which also interacts with partners belonging to both IIS and DNA repair pathways (PAPPA,PTPN1,PARK7, MRE11A). The combination GHSR‐MREA11, positively associated with longevity by MDR, was further found influencing longitudinal survival in nonagenarian females (p = .026). Results here presented highlight the validity of SNP‐SNP interactions analyses for investigating the genetics of human longevity, confirming previously identified markers but also pointing to novel genes as central nodes of additional networks involved in human longevity.
“…To our knowledge, it is the first time establishing direct causal links between robust DNA repair machinery and longevity. Supporting this notion, the DNA repair efficacy is found enhanced in long-lived naked mole rat 56 , and human longevity is associated with single nucleotide polymorphisms (SNPs) in DNA repair genes/pathways 57,58 . Specifically, an ATM SNP that could enhance the transcription of ATM is associated with longevity in both Chinese and Italian populations 59,60 .…”
DNA damage accumulates with age 1 . However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that activation of ataxiatelangiectasia mutated (ATM) via low dose of chloroquine (CQ) promotes DNA damage clearance, rescues age-related metabolic shift, and extends lifespan in nematodes and mice. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 in Atm-/-mice extend lifespan, accompanied with restored metabolic homeostasis. In a progeria mouse model with low ATM protein level and DNA repair capacity, the treatment with CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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