DNA is a critical part of cells, the instruction manual for building them. While DNA is well protected within the cell nucleus, damage does occur; therefore, DNA repair is absolutely essential for cell function, cell survival, and the prevention of cancer.
The good news is that cells can repair damaged DNA, but the bad news is that this ability declines with aging for reasons that are not yet fully understood.
DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate–ribose) polymerase], a critical DNA repair protein. As mice age and NAD+concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Thus, NAD+directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.
In the recently published review in npj Aging and Mechanisms of Disease, Imai and Guarente have provided a stimulating review about the role of nicotinamide adenine dinucleotide (NAD) in aging. The best known intervention against aging is calorie restriction, which is now recognized to be at the center of aging research. In 2000, Imai et al. published a seminal paper in Nature entitled ‘Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase’. In this paper, they proposed a possible mechanism underlying the benefit of calorie restriction—Sir2 upregulator. Since then, Sir2 family proteins, now called sirtuins, and NAD have attracted researchers’ significant attention for the intervention to promote longevity. The coupling of sirtuin activity and NAD breakdown is a unique mechanism, and the authors portray it with the apt idiom ‘it takes two to tango’. Indeed, as in tango, both sirtuins and NAD are necessary for healthy aging and longevity. When NAD levels decrease with aging, the NAD/sirtuin ‘tango’ falters.
Here’s a paper from a few weeks back that I missed during the holidays: work from the Sinclair labs at Harvard showing a new connection between SIRT1 and aging, this time through a mechanism that no one had appreciated. I’ll appreciate, in turn, that that opening sentence is likely to divide its readers into those who will read on and those who will see the words “SIRT1” or “Sinclair” and immediate seek their entertainment elsewhere. I feel for you, but this does look like an interesting paper, and it’ll be worthwhile to see what comes of it.
Type 2 diabetes is an increasing health problem, and a well-known contributor to this epidemic is consumption of a high-fat diet. Now, Yoshino et al. demonstrate that administration of the naturally occurring molecule nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), promotes NAD+ biosynthesis and is effective in restoring normal blood glucose in mice with type 2 diabetes.
