A decrease in NAD+ levels associated with ageing leads to increased binding of DBC1 protein to the DNA repair protein PARP1. Increased PARP1-DBC1 complex formation leads to inhibition of PARP1, resulting in a buildup of damaged DNA. Boosting NAD+ levels with nicotinamide mononucleotide (NMN) reduces the PARP1- DBC1 interaction and can, therefore, result in improved DNA repairing capacity and anti-ageing effects. The integrity of the nuclear genome is central to the health of the cells and organisms. DNA damage is a constant threat as nucleic acids are vulnerable to attack by endogenous and environmental factors. As we age, the ability of our cells to mend DNA deteriorates, the reasons for which are not clear as yet. This decline in function allows damage to accumulate. Persistent DNA damage acts as a signal to propel cells into apoptosis or senescence to prevent cancer through replication of the damaged genome. However, on the downside, this mechanism promotes ageing. A team of scientists from Harvard Medical School have recently made an astonishing discovery during their research published in ‘Science.’ They found the significant part nicotinamide adenine dinucleotide (NAD+) plays in aiding the repair of DNA. These researchers revealed that NAD+ works in regulating the protein-protein interactions involved in DNA repair. NAD+ is a naturally occurring molecule in our bodies. Scientists found that replenishing NAD+ levels through nicotinamide mononucleotide (NMN) can enhance DNA repair mechanisms and reverse ageing. The scientists administered NMN to mice in the study. They subsequently observed remarkable improvements in their capacity to repair DNA damage caused by ageing and radiation exposure. NMN DNA repair has even caught NASA’s eye. Considering cosmic radiation inflicts DNA damage in astronauts, NMN may hold the key to their post-mission recovery and aid NASA in its mission to send astronauts to Mars. NAD+ and Protein-Protein Interactions for DNA Repair DNA repair is crucial for life as there is continuous exposure of DNA to a variety of endogenous and exogenous damaging factors. Cells have multiple pathways for recognising and repairing damaged DNA. One of these pathways involves NAD+-dependent protein interactions. Numerous proteins in the body exhibit Nudix homology domains (NHDs). Li et al. found that NAD+ regulates protein-protein interactions critical to DNA repair by binding to specific NHDs on proteins. Regulation of PARP1-DBC1 Interaction by NAD+ The researchers honed in on NAD+’s binding to the NHD domain of a protein named “deleted in breast cancer 1” (DBC1). They found that DBC1 is present abundantly in the human body. However, the functions performed by this protein are not known. In this study, scientists explored whether DBC1 inhibits poly (adenosine diphosphate-ribose) polymerase 1 or PARP1. DBC1 is already known to inhibit sirtuin 1 (SIRT1), but the researchers wanted to examine if DBC1 co-regulates these NAD+-responsive pathways. They found that as NAD+ levels fell in ageing mice, DBC1 increasingly latched onto the DNA repair protein PARP1. This interaction led to PARP1 inhibition, which resulted in a buildup of DNA damage. NMN DNA Repair and Ageing The researchers were able to reverse this detrimental process by replenishing NAD+ levels through NMN supplementation. NAD+ was able to disrupt the PARP1-DBC1 complex in a concentration-dependent manner. Although, a dose of 500μM was needed to affect the SIRT1-DBC1 complex. In a press release, David Sinclair (lead author of the study) was excited to share the results of the research. He said that the cells of old age mice became virtually just like those of younger mice within a week of treatment. Research also shows that interventions to raise NAD+ levels, such as NMN, reduce the interaction between PARP1 and DBC1 in human embryonic kidney cells. This NMN DNA repair capability is another significant addition to the supplement’s already long list of health benefits. These findings indicate that NAD+ directly regulates protein interactions. Consequently, modulating NMN protein through NAD+ supplement holds promise for shielding against DNA damage and the effects of ageing. The study evidently revealed that NAD+ binds to DBC1, preventing its binding to PARP1, thereby enhancing PARP1’s functionality. The study also highlighted a third function of NAD+ in cells: directly regulating protein-protein interactions. The reasons behind the decline in NAD+ levels with age remain elusive, but this research offers a possible explanation for the declining DNA repair capacity associated with ageing. It also suggests that NMN DNA repair by replenishing NAD+ levels could mitigate the harmful effects of chemotherapy and radiation exposure. Which in turn could slow down the natural reduction in DNA repair capabilities as we age.