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Synergistic effect of DNA damage and oxidative stress in aging

Final Report Summary - DNA-DAMAGE REDOX AGE (Synergistic effect of DNA damage and oxidative stress in aging)

Population aging is a critical public health challenge in western society. During aging, brain functions sharply decline, and aging also constitutes the principal risk factor for neurodegenerative diseases. It is therefore critical to understand its molecular mechanisms in the brain and to identify potential sites of intervention, which might enhance health and wellness in elders. The principal mechanisms associated with the aging process include genomic instability and impaired DNA repair, increased production of reactive oxygen species, and mitochondrial dysfunction. It remains unclear, however, whether one of these mechanisms predominates and is causative of the others. The ultimate goal of this project is to elucidate the interplay between these factors and to identify a causative, upstream mechanism that can be targeted to procrastinate aging. These objectives will be achieved using mouse models with genomic instability caused by defective nucleotide excision repair, which are known to recapitulate crucial features of natural aging. Importantly, increased DNA damage is the upstream effect in this particular experimental setting, and thus the model is amenable to establish causal relationships between the studied phenomena.

In the initial phase of the project, the researcher sought and obtained additional, essential funds to launch his research group, and to obtain state-of-the-art instruments to study the proposed problems. The experiments provided highly innovative and unexpected results demonstrating that genomic instability does not induce oxidative stress per se, and is instead intrinsically associated with metabolic redesign to potentiate the antioxidant capacity of the cell. These finding offer a highly new perspective into the consequences of DNA damage accumulation in aging and in human pathologies such as Cockayne syndrome and pave the road for new rather work has been successfully in demonstrating initiated and preliminary results indicate that mild genomic instability impairs mitochondrial function and in particular reduces coupling between electron transport and proton extrusion. This condition is associated with increased mitochondrial superoxide production and therefore oxidative stress.

We also performed biomarker research in a disease of aging, Parkinson’s disease (PD). We investigated dermal fibroblasts obtained from skin biopsies of idiopathic patients, in basal condition and under stress (i.e. after administration of pro-oxidants), and analyzed a large number of biological parameters that included tolerance to exogenous toxins, protein homeostasis and degradation, bioenergetics and mitochondrial function, redox homeostasis, and autophagy. We found that fibroblasts from PD patients exhibit higher vulnerability to necrotic cell death induced by complex I inhibitor rotenone, reduced function of the ubiquitin-proteasome system, and decreased maximal and rotenone-sensitive mitochondrial respiration. Taken together these parameters allow reliable discrimination between specimens from PD patients and healthy controls.

Our studies on accelerated aging mutant mice have profound scientific impact as they provided evidence for novel biological mechanisms integrating essential basic processes such as metabolism, DNA repair, and control of redox homeostasis. They also underlie important differences between natural and accelerated aging, both in mouse models and humans, and demonstrate that these processes are not fully comparable, and address a critical issue in the aging field. These discoveries may have also important societal repercussion because they open possibilities for future and innovative therapeutic approaches, which can be based on strategies to limit the reductive stress observed in accelerated aging. This could be achieved, for instance, by exposure of patients with progeroid syndromes to mild pro-oxidant conditions (e.g. high oxygen). Certainly, our findings cast serious doubts on the possibility that antioxidants might ameliorate pathology in progeroid syndromes.

Our studies on biomarkers in PD patients’ dermal fibroblasts provided a panel of indicators allowing discrimination between diseased and healthy subjects. We are expanding this set of indicators in ongoing studies, with the ultimate goal of obtaining a reliable biomarker platform. Development of this tool has obviously great societal impact.