The core cascade we study: DNA damage activates PARP1, draining NAD⁺ and lowering SIRT1 — which reduces acetyl-CoA, impairs mitochondria and mitophagy, and pushes metabolism toward glycolysis and lactate. NR/NMN and ketones (teal) feed back in as interventions.
DNA damage is not just a structural problem — it is a metabolic one. Activation of the damage sensor PARP1 consumes NAD⁺, depleting a cofactor central to energy production and to the sirtuin enzymes that regulate the cellular stress response. The result is a measurable shift in metabolism: reduced mitochondrial output, altered acetyl-CoA levels, and a remodelled acetylome.
Our work maps how this single class of insult propagates outward through interconnected metabolic networks. We have found that replenishing the depleted metabolites — with NAD⁺ precursors or ketone bodies — can blunt these changes and even alter the rate of aging in model organisms, suggesting that the metabolic consequences of DNA damage are, at least in part, reversible.
Because these pathways are so tightly interconnected, a change in one node ripples through the whole system — and that is also where the opportunity lies. By treating metabolism as a network rather than a set of isolated reactions, we identify the nodes where a targeted intervention has the widest effect, and we test whether restoring metabolic balance can slow aging across tissues rather than in a single organ alone.
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.