A research duo from WashU and MIT discusses the progress in determining cell enzyme consumers of NAD+ and their link to the anti-aging therapeutic NMN.(Paola Giannoni | iStock)
With age, the levels of nicotinamide adenine dinucleotide (NAD+) — the essential molecule with key roles in generating cell energy and maintaining DNA integrity — fall. This reduction in cell NAD+ levels is linked to many age-related diseases like cardiovascular impairments, metabolic disorders like obesity, and neurodegenerative diseases such as Alzheimer’s disease. But how falling NAD+ levels during aging tie into disease and dysfunction and whether raising NAD+ levels with precursor molecules can mitigate the effects of human age-associated diseases remains somewhat uncertain.
Back in 2014, Imai and Guarente published a review in Trends in Cell Biology describing NAD+’s role in aging and disease. Their review went over ideas about how NAD+ is metabolized for cell energy and what proteins utilize NAD+ during cell maintenance. At this time, scientists were just beginning to find out how these metabolic processes and these proteins relate to NAD+ and how their interactions tie into aging and disease.
NAD+ research got its start when British biochemist Sir Arthur Harden discovered the essential molecule over a century ago. His discovery resulted from the observation of NAD+ as a substance in boiled yeast extract that stimulates alcohol production, showing NAD+ has some key function in metabolism. Subsequent research over the next several decades determined the molecular composition of NAD+, which consists of nicotinamide mononucleotide (NMN) conjoined to adenosine monophosphate (AMP) — a molecule that plays important roles in metabolic reactions.
In this review, Imai and Guarente presented information about how NAD+ regulates metabolism. NAD+ accepts electrons in the mitochondria — commonly referred to as the cell’s powerhouse — to become NADH in metabolic reactions requiring electron exchange. The conversion of NAD+ to NADH generates an NADH electron donor for the production of cellular energy molecules adenosine triphosphate (ATP).
There are a plethora of enzymes that depend on NAD+ for their function. To do so, enzymes first bind to NAD+ and then consume it — that is, they use it to execute a function that results in the conversion of NAD+ to another molecule.
For example, enzymes called poly ADP-ribose polymerases (PARPs) consume NAD+ to facilitate DNA damage repair and chromosome maintenance. In this way, short-term (acute) DNA damage, say, from radiation can trigger PARP stimulation, which would lead to a sudden drop in cellular NAD+ abundance. Since PARP inhibitors prevent DNA repair, they can sensitize tumor cells to cell death (apoptosis). For these reasons, scientists are performing clinical trials to test PARP inhibitors as anti-cancer treatments.
Other enzymes that use NAD+ called sirtuins play key roles in responses to nutritional and environmental alterations like fasting and dietary restrictions. These enzymes also have a role in DNA damage and cellular stress responses from damaging molecules containing oxygen (oxidative stress). Sirtuin activation promotes longevity in many organisms — from single-cell yeast to worms, flies, and mice. Plus, sirtuins can inhibit the progression of diseases like type 2 diabetes, cancer, cardiovascular disease, neurodegenerative diseases, and pro-inflammatory diseases.
Imai and Guarente also touched on information about the NAD+-consuming enzyme CD38. When scientists have experimentally generated mice with genetic mutations that reduce CD38 activity, they see substantial increases in NAD+ levels. This has led scientists to propose that elevated NAD+ from CD38 inhibition allots sufficient NAD+ to sirtuins, which may extend experimental animal lifespan. Along these lines, a pharmacological agent that boosts NAD+ levels was found to do just that — it extended worm lifespan via activation of a specific sirtuin.
A major area of inquiry in the NAD+ field has been the age-related decline of NAD+ levels. Imai and Guarente point to research on PARPs indicating that eliminating a specific PARP, PARP1, produced metabolic benefits like increased ATP generation in mice. Furthermore, PARP activation closely corresponds to NAD+ level reductions since PARPs degrade NAD+. This leads to the subsequent diminished activity of the sirtuin called SIRT1 since sirtuins must bind to and degrade NAD+ as a co-substrate to function. These findings can be explained by their observation that aging associates with increased DNA damage leading to PARP activity along with NAD+ depletion. The subsequent loss of SIRT1 activity would exacerbate DNA damage thereby creating a downward spiral of NAD+ depletion.
To target reduced age-related NAD+ level reductions, Imai and Guarente proposed supplementation with the NAD+ molecular precursor NMN. Importantly, it has been shown that NMN supplementation can increase SIRT1 activity and reverse mouse metabolic decline. These findings suggest NMN could provide a means to mitigate age-related metabolic decline and diseases.
“Supplementation of key NAD+ intermediates, such as NMN and [nicotinamide riboside (NR)], can ameliorate a variety of age-associated pathophysiologies generated by NAD+ decline,” said Imai and Guarente in their publication.
Consumers continue to purchase and use NMN-containing products to boost human NAD+ levels, while the verdict stays out as to whether they effectively combat human aging and age-associated diseases.