Why does the chance of getting cancer increase as we age? A long-standing hypothesis, supported by compelling evidence in the past several decades, implicates the accumulation over time of damage to cells, organelles, and biomolecules as an underlying cause of aging. This accumulated biomolecular damage, particularly that affecting DNA, along with cells’ declining ability to repair DNA as a person ages, may also lead to cancer, according to the theory.
Now, a new NIA-funded study in mice and tissue-cultured cells suggests a new and plausible explanation of why the ability of cells to repair DNA declines with age. Researchers led by Dr. Jun Li in Dr. David Sinclair’s lab at Harvard Medical School reported that decreasing levels of nicotinamide adenine dinucleotide (NAD+), an essential cofactor that regulates key signaling pathways and declines with age, may affect cellular DNA repair. The findings of this study were published in Science on March 24, 2017.
The researchers investigated whether NAD+ levels can affect DNA repair through poly (ADP-ribose) polymerase 1 (PARP1). Both PARP1 and NAD+ bind to the same domain of another protein, DBC1 (Deleted in Breast Cancer 1), and compete with each other for the binding site on the DBC1 protein. The direct binding of NAD+ prevents DBC1 from forming an inhibitory complex with the DNA-repair protein PARP1. Thus, as NAD+ levels decrease with age, more DBC1 protein is left to bind to PARP1, leading to less free PARP1 to repair damaged DNA.
The researchers also found that NAD+ regulates the interaction of DBC1 and PARP1 through a non-enzymatic function, which is different from most other functions of NAD+. One advantage of this function is that it allows a cell to adapt to fluctuations in NAD+ levels without consuming it. This is particularly important when NAD+ is scarce, which occurs under conditions of genotoxic stress. The study results also suggest that interventions aimed at improving NAD+ levels may help protect against cancer and DNA damage caused by radiation or chemotherapy, or slow some aspects of aging.
Reference: Li, J., et al. A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science. 2017 Mar 24;355(6331):1312-1317. doi: 10.1126/science.aad8242.