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.

Multiple sclerosis (MS) is a demyelinating disorder predominantly affecting young people. Currently, interferon beta (IFNbeta) is a common treatment for MS. Despite a large effort in recent years, valid biomarkers with predictive value for clinical outcome and response to therapy are lacking. In order to identify predictive biomarkers of response to IFNbeta therapy in relapsing-remitting MS patients, we analyzed expression of 526 immune-related genes with the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA) on total RNA extracted from peripheral blood mononuclear cells of 30 relapsing-remitting MS patients. We used a Wilcoxon signed-rank test to find an association between certain gene expression profiles and clinical responses to IFNbeta. We compared the expression profile of patients who responded to IFNbeta treatment (n=16) and non-responsive IFNbeta patients (n=14). The analysis revealed that the expression of eight genes could differentiate between responsive and non-responsive men (p0.005). This differentiation was not evident in women. We analyzed results from an additional cohort of 47 treated and untreated patients to validate the results and explore whether this eight gene cluster could also predict treatment response. Analysis of the validation cohort demonstrated that three out of the eight genes remained significant in only the treated men (p0.05). Our findings could be used as a basis for establishing a routine test for objective prediction of IFNbeta treatment response in male MS patients.