NAD IS Much More Than a Sirtuin Cofactor
Epigenetics and Aging (14)
In the initial reports of SIRT-1’s putative anti-aging effects, not much was made of NAD (nicotinamide adenine dinucleotide), the cofactor (https://doi.org/10.1016/j.cell.2005.01.029). Sirtuins were certainly known to be NAD dependent, but the emphasis was on the sirtuins. Things have change fairly dramatically in this regard. Leonard Guarente, in whose lab at MIT the sirtuin research began, is representative of this somewhat belated recognition of the importance of NAD. About ten years after publication of the initial sirtuin reports, he coauthored a paper titled: It Takes Two to Tango (https://doi.org/10.1038/npjamd.2016.17 ), in which NAD got top billing. And well it should.
If there were no NAD in a cell, the sirtuins would be dormant. If there were no sirtuins in a cell NAD would still be busy. Sirtuins engage in a wide range of metabolic processes. But it’s a fraction of those in which NAD is involved (10.1007/s13668-023-00475-y). Sirtuins are but one of many enzyme groups for which NAD is essential. NAD is a “mother node” for the metabolic processes that occur within cells. Sirtuins are but a sub-node. By NAD, I mean both NAD+ (the oxidized form) and NADH (the reduced form). But NAD+ and NADH have very distinct roles. Moreover, It’s the ratio of NAD+/NADH that matters most. This ratio changes with age (10.1126/science.aac4854; 10.1038/nature02583)—it becomes lower, throughout the body, but especially in skeletal muscles and skin (https://doi.org/10.1038/s43587-022-00174-3). This ratio is also reduced in cancer environments (10.1177/1535370220929287), and those of several other disease states.
There are two ways to lower the ratio. Reduce the amount of NAD+, or increase the amount of NADH. Turns out the two are related. In part, the increase of NADH is because of the conversion of NAD+ to NADH. But mostly because NAD+ levels drop with age (10.1016/j.exger.2020.110888). NAD+ levels could diminish for one of two reasons. Production decreases or consumption increases. It’s the latter. Cells in the aging body continue to produce NAD+ at about the same rate as cells in a young body. But cells in an aging body consume NAD+ at a higher rate than cells in a young body (https://doi.org/10.21203/rs.3.rs-86538/v1).
Consider the production side. There is more than one way to make NAD+. One is to produce it de novo, beginning with the essential amino acid, tryptophan. The tryptophan would come with a normal diet. Another way is to recoup the NAD+ component parts and glue them together again. This is called the salvage pathway. It is the salvage pathway that NAD+ supplements are meant to augment. Three of the most important bits retrieved in the salvage pathway are nicotinamide riboside (NR), nicotinamide (NAM), and nicotinamide mononucleotide (NMN). NMN, in particular, is promoted by David Sinclair of resveratrol fame, so buyer beware. Also worth noting: NMN is banned in Europe; in the U.S., large retailers (like Amazon and Costco) are barred from selling NMN. It is offered at your local supplement (“nutrition”) store, however, along with all the other unregulated products available there. Safer (and cheaper) to obtain NMN and other NAD metabolites through diet and exercise (10.1007/s13668-023-00475-y).
There is a third cellular pathway to NAD+. It was because of malfunctions in this pathway that the detrimental effects of low NAD levels were first recognized (10.3390/cells12030500). Low NAD levels cause a disease called pellagra, often characterized by the three Ds: dermatitis, diarrhea and dementia. (The dermatitis is stimulated by the U.V in sunlight.) Some add a fourth D, for death, which occurs if pellagra is left untreated. The treatment for pellagra is vitamin B3 (niacin) which is another substrate through which NAD can be generated, through the so-called Preiss-Handler pathway. Pellagra can be cured through a niacin boost.
The Epigenetic Dimension
The epigenetic effects of NAD, particularly NAD+, are primarily through its interactions with SIRT-1 and SIRT-6 (and possibly SIRT-7). As described in previous posts in this series, the NAD-activated sirtuins act on histones. More specifically, they remove acetyl groups, as a result of which the histones bind the DNA more tightly, thereby restricting gene activity. So, like all deacetylases, Sirtuins 1 and 6, in combination with NAD+, are epigenetic repressors.
Recently, another epigenetic activity of NAD has been reported. And this one doesn’t involve sirtuins at all. This epigenetic effect is more indirect, through an NAD derivative called NADP. (The “P” stands for phosphate; the process through which phosphate is added to the NAD is called phosphorylation.) Like NAD, NADP comes in two flavors, the same two flavors as NAD: oxidzed (NADP+) and reduced (NADPH). Like NAD, NADP is at the intersection for many cellular metabolic processes, albeit a somewhat smaller intersection than NAD. (But still a larger intersection than that of all sirtuins combined). But unlike NAD, NADP has sirtuin-independent epigenetic effects ( 10.1038/s42255-020-00330-2).
NADPH, in particular, is epigenetically noteworthy. To understand How this works, it helps to break the process down into steps. Ultimately, NADPH molecules regulate histones, the proteins with which DNA is intertwined. They cause the removal of acetyl groups from histones, which causes the histone to bind the DNA more tightly, a more condensed state. Any adjacent genes are inactivated thereby. But NADPH doesn’t’, itself, do the deacetylation; it effects the histones more indirectly.
Any enzyme that removes acetyl groups from proteins is called a deacetylase (DAC). Only those deacetylases that remove acetyl groups from histones are of epigenetic significance. They are called histone deacetylases (HDACs). There are lots of histone deacetylases, each with its own fingerprint. But they can be divided into several groups, called classes: I, IIa, IIb and III. Sirtuins belong to class III, probably because they were the last to be recognized as such. NADPH does not affect them. Rather, it deactivates one of the class I HDACs. Hence, it inhibits an inhibitor of gene activity, a derepresser. The upshot is an active gene.
The next step is to determine which gene or genes are derepressed, to determine if or how they function in aging and age-related diseases.