Identifying the genomic determinants of aging and longevity in human population studies: Progress and challenges

Deelen, Joris; Beekman, Marian; Capri, Miriam; Franceschi, Claudio; Slagboom, P. Eline

doi:10.1002/bies.201200148

Cited by 80 publications

(54 citation statements)

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“…Despite more than 20 years of research into the genetic basis of human longevity, only alleles in the APOE and FOXO3 genes have repeatedly been shown to be associated with survival to very advanced ages (Schächter et al ., 1994; Willcox et al ., 2008; Flachsbart et al ., 2009; Soerensen et al ., 2010; Deelen et al ., 2013). APOE and FOXO3 were initially detected in candidate‐driven case–control investigations, but APOE has since then been confirmed in a number of genome‐wide association studies (GWAS).…”

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confidence: 99%

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

et al. 2016

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SummaryHuman longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long‐lived individuals (LLI) and 8919 younger controls. First, we performed a large‐scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune‐associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip‐wide significant signal (PI mmunochip = 7.01 × 10–9) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip < 5 × 10–4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta‐analysis of the combined French and Danish data after adjusting for multiple testing. In a meta‐analysis of all three samples, rs2706372 reached a P‐value of PI mmunochip+Repl = 5.42 × 10−7 (OR = 1.20; 95% CI = 1.12–1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.

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confidence: 99%

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

et al. 2016

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“…However, since the association between FOXO3A variation and longevity only becomes apparent for extremely old age (≥95 years of age), prospective studies are difficult because of the extremely low prevalence of the phenotype (0.01-0.02 %, Perls 2006) and the long follow-up period required. Therefore, case-control studies almost inevitably have become the most popular design for the investigation of longevity (Deelen et al 2013). Moreover, as has been pointed out above, our study was not intended to investigate the effect of smoking on longevity per se, which would be difficult to do in a case-control design anyway.…”

Section: Discussionmentioning

confidence: 99%

Adjustment for smoking does not alter the FOXO3A association with longevity

Däumer

Flachsbart

Caliebe

et al. 2013

AGE

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Human longevity is a multifactorial phenotype influenced by both genetic and environmental factors. Despite its heritability of 25-32 %, the genetic background of longevity is as yet largely unexplained. Apart from APOE status, variation in the FOXO3A gene is the only confirmed genetic contributor to survival into old age. On the other hand, FOXO3A activity is known to be downregulated in various cancers, and the gene was recently identified as a novel deletion hotspot in human lung adenocarcinoma. In view of the strong association between smoking and lung cancer, we set out to explore whether smoking modifies the known association between FOXO3A variation and longevity. To this end, we conducted a case-control study in two different populations, drawing upon extensive collections of old-aged individuals and younger controls available to us (1,613 German centenarians/nonagenarians and 1,104 controls; 1,088 Danish nonagenarians and 736 controls). In the German sample, 21 single nucleotide polymorphisms (SNPs) from the FOXO3A gene region were genotyped, whereas 15 FOXO3A SNPs were analyzed in the Danish sample. Eight SNPs were typed in both populations. Logistic regression analysis revealed that adjustment for smoking does not systematically alter the association between FOXO3A variation and longevity in neither population. Our analysis therefore suggests that the said association is not largely due to the confounding effects of lung cancer.

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“…The effect on longevity was observed in heterozygotes only. Three novel loci associated with longevity were iden fied by linkage analysis on chromosomes 3, 9 and 12 [1255,1256].…”

Section: Haplogroupmentioning

confidence: 99%

DNA repair systems

Chakarov¹,

Petkova²,

Russev³

2014

Biodiscovery

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This paper provides detailed insight into the mechanisms of repair of different types of DNA damage and the direct molecular players (enzymes repairing the damage or tagging the damaged site for further processing; damage sensor molecules; other signalling and effector molecules). The gene c bases of diseases and condi ons associated with defec ve DNA repair are comprehensively reviewed, from the 'classic' severe diseases such as xeroderma pigmentosum and Cockayne syndrome to the much more subtle UV sensi vity syndromes. The review analyses the basic molecular mechanisms underlying the rela vely rare monogenic diseases of DNA repair and management of genome integrity as well as the common mul factorial diseases and condi ons with late onset that are associated with increased levels of oxida ve stress (metabolic syndrome, diabetes type 2, cardiovascular disease) and with accumula on of 'errors' in DNA (normal and pathological ageing phenotypes, various cancers). The role of cell cycle checkpoints in dividing cells and the mechanisms of decision-making for the fate of a damaged cell are discussed with regards to the cell homeostasis in normal and cancerous ssues. The role of major DNA damageassociated signalling and effector molecules (p53, ATM, poly-(ADP-ribose)-polymerase, DNA-dependent protein kinase, BRCA proteins, re noblastoma protein, and others) is discussed and illustrated with examples in the context of health and disease. DNA repair and programmed cell death are viewed together as a unified mechanism for limi ng the presence of damaged cells and cells with poten ally oncogenic transforma on in mul cellular organisms. Special a en on is paid to ageing as a natural phenomenon and an adap ve evolu onary mechanism, with a brief outline of 'successful ageing'. The differen al rates of repair of DNA in transcribed and nontranscribed regions of the genome and the specifici es of DNA repair profile in some types of cells (terminally differen ated cells, pluripotent stem cells, etc.) and in certain taxonomic groups (e.g. 'the rodent repairadox') are discussed with regards to replica ve ageing and the evolu onary processes on microand macroscale. The role of mutagenesis as a 'hit and miss' mechanism and the 'leakiness' of DNA repair for increasing gene c diversity in the course of individual life and on evolu onary scale and the phenomenology of ongoing molecular evolu on are extensively reviewed. Conflict of Interests:No poten al conflict of interest was disclosed by any of the authors. Types of DNA repair systemsIf you wish for peace, prepare for war.Publius Flavius Vege us Renatus, De Re Militari (circa 380 AD).DNA damage is a very broad term, encompassing many different types of lesions in DNA.Accordingly, DNA repair comprises many different types of pathways and mechanisms covering virtually every possible type of injury to the sequence or the structure of DNA.Accep ng Lewin's defini on of DNA damage "... any change that introduces a devia on from the usual double-helical structure" [1] , we may pre...

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Identifying the genomic determinants of aging and longevity in human population studies: Progress and challenges

Cited by 80 publications

References 100 publications

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

Adjustment for smoking does not alter the FOXO3A association with longevity

DNA repair systems

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