Every one of our cells sustains tens of thousands of DNA lesions a day. Most are repaired within minutes, but repair is never perfect and never free: the response to damage draws on the same metabolic pool the cell needs for energy, signalling and maintenance. Over a lifetime that trade-off compounds, and a growing body of evidence places the accumulation of DNA damage and the signalling it triggers among the causal drivers of aging.
The clearest evidence comes from the premature-aging syndromes. Inherited defects in DNA repair — Cockayne syndrome, xeroderma pigmentosum, ataxia telangiectasia — compress a lifetime of degeneration into a few years, and they do so with a striking bias toward the nervous system. Neurons are largely post-mitotic, their repair capacity is comparatively low, and their energy demand is relentless, so lesions and failing mitochondria accumulate where they can least be replaced. We use these disorders as accelerated windows onto normal brain aging, and ask which of their features reappear, more slowly, in common age-related neurodegeneration.
So the question becomes where this accumulation of damage can be slowed. To answer it we follow the signalling cascade that a lesion sets off. Persistent lesions keep the sensor PARP1 active; PARP1 consumes NAD⁺; and falling NAD⁺ weakens sirtuin signalling, mitochondrial quality control and the cell's capacity to repair the next lesion. What makes this cascade interesting is that it is druggable at almost every step — the sensor, the cofactor pool, the metabolites that feed it, and the repair machinery itself are all accessible to small molecules. The figure below maps those entry points as we currently understand them.
DNA damage activates the sensor PARP1, which consumes NAD⁺ and lowers acetyl-CoA — together dampening sirtuin (SIRT1) activity and accelerating aging. Each red label marks a point where we can intervene: PARP inhibitors to spare NAD⁺, NR/NMN and ketones to replenish it, and DNA-repair or SIRT1 activators to restore the downstream response.
Following the same cascade further out leads into metabolism as a whole. NAD⁺ depletion does not stay local: acetyl-CoA production falls, glycolysis tips toward lactate, and the acetylation state of the cell shifts with it. Aging is legible in this network as a coordinated perturbation rather than a single broken reaction, which is why we profile metabolism as a network — in cells, in mouse models and in human cohorts — and look for the nodes where one intervention propagates widest.
Red marks pathways that increase with damage, blue those that decrease. As PARP1 drains NAD⁺, glycolysis shifts toward lactate and acetyl-CoA production falls — weakening SIRT1 and tipping the balance between energy supply (ATP) and the acetylation state of the cell. Ketones feed back into this network as an alternative acetyl-CoA source.
See the full list of the lab's publications on Google Scholar.