Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians.

Oxidative stress is an important factor in age-associated neurodegeneration. Accordingly, mitochondrial dysfunction and genomic instability have been considered as key hallmarks of aging and have important roles in age-associated cognitive decline and neurodegenerative disorders. In order to evaluate whether maintenance of cognitive abilities at very old age is associated with key hallmarks of aging, we measured mitochondrial bioenergetics, mitochondrial DNA copy number and DNA repair capacity in peripheral blood mononuclear cells from centenarians in a Danish 1915 birth cohort (n = 120). Also, the circulating levels of brain-derived neurotrophic factor, NAD +  /NADH and carbonylated proteins were measured in plasma of the centenarians and correlated to cognitive capacity. Mitochondrial respiration was well preserved in the centenarian cohort when compared to young individuals (21-35 years of age, n = 33). When correlating cognitive performance of the centenarians with mitochondrial function such as basal respiration, ATP production, reserve capacity and maximal respiration, no overall correlations were observed, but when stratifying by sex, inverse associations were observed in the males (p < 0.05). Centenarians with the most severe cognitive impairment displayed the lowest activity of the central DNA repair enzyme, APE1 (p < 0.05). A positive correlation between cognitive capacity and levels of NAD +  /NADH was observed (p < 0.05), which may be because NAD +  /NADH consuming enzyme activities strive to reduce the oxidative DNA damage load. Also, circulating protein carbonylation was lowest in centenarians with highest cognitive capacity (p < 0.05). An opposite trend was observed for levels of brain-derived neurotrophic factor (p = 0.17). Our results suggest that maintenance of cognitive capacity at very old age may be associated with cellular mechanisms related to oxidative stress and DNA metabolism.