Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression

Guedj, Avital; Geiger-Maor, Anat; Benyamini, Hadar; Nevo, Yaval; Elgavish, Sharona; Galun, Eithan; Amsalem, Hagai; Rachmilewitz, Jacob

doi:10.18632/aging.101120

Cited by 16 publications

(20 citation statements)

References 41 publications

(40 reference statements)

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“…We have recently demonstrated that the efficiency of diethylnitrosamine (DEN)-induced DNA damage repair declines at the relatively early age of 6 months 6. DEN is metabolically activated by cytochrome P450-enzymes (predominantly CYP2E1) into metabolites that alkylate DNA 17.…”

Section: Resultsmentioning

confidence: 99%

“…A tacit assumption in this field has been that ‘aged’ cells have an inherent imperfection in the DNA repair system and are defective in their DNA damage capabilities due to reduced expression and/or function of various components of the DNA repair machinery 4 5. However, our recent study6 demonstrated that the decline in DNA damage repair in the tissue is evident at relatively early age, before intrinsic DNA damage repair deficiencies are documented in ‘aged’ cells. Moreover, given that this early age decline in DDR precedes ‘old age’, it may be a driving force of the ageing process rather than merely a phenotypic consequence of old age.…”

Section: Introductionmentioning

confidence: 86%

“…Immunohistochemical analysis of liver tissues was performed as described previously 6 15. For more details see online supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction, RNAseq analysis, bioinformatics and quantitative PCR (qPCR) assay were performed as described previously 6. For more details see online supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

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Gut microbiota shape ‘inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair

Guedj

Volman

Geiger-Maor

et al. 2019

Gut

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ObjectiveFailing to properly repair damaged DNA drives the ageing process. Furthermore, age-related inflammation contributes to the manifestation of ageing. Recently, we demonstrated that the efficiency of repair of diethylnitrosamine (DEN)-induced double-strand breaks (DSBs) rapidly declines with age. We therefore hypothesised that with age, the decline in DNA damage repair stems from age-related inflammation.DesignWe used DEN-induced DNA damage in mouse livers and compared the efficiency of their resolution in different ages and following various permutations aimed at manipulating the liver age-related inflammation.ResultsWe found that age-related deregulation of innate immunity was linked to altered gut microbiota. Consequently, antibiotic treatment, MyD88 ablation or germ-free mice had reduced cytokine expression and improved DSBs rejoining in 6-month-old mice. In contrast, feeding young mice with a high-fat diet enhanced inflammation and facilitated the decline in DSBs repair. This latter effect was reversed by antibiotic treatment. Kupffer cell replenishment or their inactivation with gadolinium chloride reduced proinflammatory cytokine expression and reversed the decline in DSBs repair. The addition of proinflammatory cytokines ablated DSBs rejoining mediated by macrophage-derived heparin-binding epidermal growth factor-like growth factor.ConclusionsTaken together, our results reveal a previously unrecognised link between commensal bacteria-induced inflammation that results in age-dependent decline in DNA damage repair. Importantly, the present study support the notion of a cell non-autonomous mechanism for age-related decline in DNA damage repair that is based on the presence of ‘inflamm-ageing’ cytokines in the tissue microenvironment, rather than an intrinsic cellular deficiency in the DNA repair machinery.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

“…Immunohistochemical analysis of liver tissues was performed as described previously 6 15. For more details see online supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction, RNAseq analysis, bioinformatics and quantitative PCR (qPCR) assay were performed as described previously 6. For more details see online supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Gut microbiota shape ‘inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair

Guedj

Volman

Geiger-Maor

et al. 2019

Gut

Self Cite

View full text Add to dashboard Buy / Rent full text

show abstract

“…Because cancer development is primarily a consequence of mutations and epigenetic effects leading to unconstrained propagation of the clonal cell population, in the long term, cancers are inevitable for most multicellular organisms, including humans (Marusyk and DeGregori, 2008;Tomasetti and Vogelstein, 2015;Guedj et al, 2016;Ribezzo et al, 2016;Nelson and Masel, 2017). Due to cancer's constant heritability with age, the effect of age is likely to be insignificant for GWASs' discovery of cancer polygenic scores and their corresponding predictive power.…”

Section: Supplementarymentioning

confidence: 99%

Age-related late-onset disease heritability patterns and implications for genome-wide association studies

Oliynyk

2018

Preprint

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Background: Genome-wide association studies and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called "missing heritability" problem. Methods:Computer simulations of polygenic late-onset diseases in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer's disease, coronary artery disease, cerebral stroke, and type 2 diabetes. Results:The incidence rate for late-onset diseases grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for genomewide association studies overrepresent older individuals with lower polygenic risk scores, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and genome-wide association studies. It also explains the relatively constant-with-age heritability found for late-onset diseases of lower prevalence, exemplified by cancers. Conclusions:For late-onset polygenic diseases showing high cumulative incidence together with high initial heritability, rather than using relatively old agematched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genomewide association studies.Algorithm 1: Sampling individuals diagnosed with a disease proportionately to their polygenic odds ratio and incidence rate. for age = 1 to M axAge do number I ll T hisYear = I(age)· N // N is unaffected population for i = 1 to number I ll T hisYear do HRsum = 0 // will recalculate sum of all HRs for u = 1 to N do HRsum = HRsum + ORt oHR(G u ) // calculate the HR total LOOKU P(add, HRsum, u) // add u th individual to the lookup table r and = RandomN umber(0, HRsum) // pick a random number ill = LOOKU P( f ind, r and, N ) // found newly diagnosed N = N − 1 // decrement in number of healthy individuals P r ocessAndAnal yze(ill) Note: an individual makes a sampling target proportionate to the hazard ratio (HR) in the LOOKU P() table.Odds ratios (ORs) are converted to HRs, similar to the approach taken by . An individual with an HR of 15 will be 150 times more likely to be sampled than an individual with an HR of 0.1. P r ocessAndAnal yze() moves newly diagnosed individual from the healthy to the ill population pool, accounts for allele distribution, case/control ORs, etc.Descriptively, the algorithm works as follows. In this prospective simulation, each next individual to be diagnosed with an LOD is chosen propo...

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Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression

Cited by 16 publications

References 41 publications

Gut microbiota shape ‘inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair

Gut microbiota shape ‘inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair

Age-related late-onset disease heritability patterns and implications for genome-wide association studies

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