title: Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression.
abstract: Aging is associated with progressive decline in cell function and with increased damage to macromolecular components. DNA damage, in the form of double-strand breaks (DSBs), increases with age and in turn, contributes to the aging process and age-related diseases. DNA strand breaks triggers a set of highly orchestrated signaling events known as the DNA damage response (DDR), which coordinates DNA repair. However, whether the accumulation of DNA damage with age is a result of decreased repair capacity, remains to be determined. In our study we showed that with age there is a decline in the resolution of foci containing γH2AX and pKAP-1 in diethylnitrosamine (DEN)-treated mouse livers, already evident at a remarkably early age of 6-months. Considerable age-dependent differences in global gene expression profiles in mice livers after exposure to DEN, further affirmed these age related differences in the response to DNA damage. Functional analysis identified p53 as the most overrepresented pathway that is specifically enhanced and prolonged in 6-month-old mice. Collectively, our results demonstrated an early decline in DNA damage repair that precedes 'old age', suggesting this may be a driving force contributing to the aging process rather than a phenotypic consequence of old age.
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avital
authors.identifier: ORCID
authors.initials: A
authors.lastname: Guedj
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Geiger-Maor
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
authors.affiliation: Bioinformatics Unit, of the I-CORE Computation Center, the Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Hadar
authors.initials: H
authors.lastname: Benyamini
authors.affiliation: Bioinformatics Unit, of the I-CORE Computation Center, the Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yaval
authors.initials: Y
authors.lastname: Nevo
authors.affiliation: Bioinformatics Unit, of the I-CORE Computation Center, the Hebrew University and Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Sharona
authors.initials: Sh
authors.lastname: Elgavish
authors.affiliation: Department of Obstetrics and Gynecology, Hadassah University Hospital-Mount Scopus, Jerusalem, Israel.
authors.forename: Hagai
authors.initials: H
authors.lastname: Amsalem
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rachmilewitz
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins; D015870:Gene Expression; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones
keywords: DNA repair; KAP-1; RNAseq; aging; p53; γH2AX