Nicotinamide adenine dinucleotide (what a way to start right?), or NAD for short, is essential to the inner workings of our cells. It is a molecule that participates in hundreds of processes that work to maintain cellular function. Because of its critical role in numerous metabolic pathways, NAD has become a highly researched molecule, especially in the field of aging (something we all do).
To date, research highlights that increased levels of this molecule are associated with maintaining good health and longevity as we age; while decreased levels are associated with just the opposite, aging. With this knowledge, researchers are now trying to answer the following questions:
- What causes the NAD decline observed during the normal aging process?
- What are the consequences of this NAD decline?
- Which interventions can be used to maintain, or even promote increased production of NAD, as we age?
NAD Declines with Age
In an article titled Why NAD Declines During Aging: It’s Destroyed, scientists Michael B. Schultz and David A. Sinclair from Harvard Medical School state that, “by middle age, levels of NAD fall to half of youthful levels.” According to other scientific groups of, this decline is both a consequence of the aging process and also a contributor to the development of normal, age-related cellular dysfunction.
They suggest that a vicious cycle exists where common mechanisms of aging—such as oxidative stress, decline in mitochondria production and gene expression, DNA damage, and healthy inflammation response—lead to NAD decline. These “aging mechanisms” worsen the process and further disrupt cell function.
More specifically, they are looking at those previously stated “aging mechanisms” and their impact on cellular NAD metabolism during the normal aging process. All in hopes that we can, ultimately, intervene.
Years of research and backing are attempting to explain the age-related reductions in NAD. There are quite a few scenarios that continue to find themselves in the workbooks of scientists:
- NAD synthesis (the production of the compound itself) is decreased during the aging process.
- NAD degradation (the rate at which the compound decreases) is increased during the aging process
- A combination of these two processes is taking place.
Makes sense, at its core aging is the lack of production AND the faster, shorter life-cycle of NAD. And while we don’t have any definitive conclusions, here’s what the research has shown so far.
NAD synthesis is decreased during the aging process
To make the complex molecule, simpler molecules must be combined. These simpler molecules are referred to as “precursors”, which are the raw materials that become NAD through a series of chemical reactions. Not unsimilar to Hydrogen and Oxygen combining to make Water (H₂O), just on a much more complex scale.
Some of the precursors must be obtained through the diet, such as the amino acid L-tryptophan (the stuff in turkey that makes you want to sleep for 2 years after Thanksgiving Dinner). Other precursors can be made by the body naturally, which include nicotinamide riboside (NR), nicotinic acid (NA), nicotinamide (NAM), and nicotinamide mononucleotide (NMN).
To generate NAD, two main pathways are involved. The first is called the de novo pathway, literally meaning “from scratch” or “from the new,” which uses the essential amino acid L-tryptophan. De novo pathways require precursors that can only be obtained from the diet; the body cannot make these molecules from scratch.
The second is called the salvage pathway, which utilizes the molecules NA, NAM, NMN and NR. The salvage pathway actually includes a number of chemical reactions, with each precursor taking a slightly different path as it is converted into NAD.
It is called the salvage pathway as the precursors are recycled parts from partially digested molecules. For example, when NAD-consuming enzymes (e.g., sirtuins) use NAD, they split it into its component parts using only what they need. The rest of the molecule is recycled, serving as the base for now new precursors, starting the cycle all over again (you’re an active daily recycler and you didn’t even know it).
The main source of NAD is the salvage pathway. Unfortunately, this pathway appears to be disrupted with age, possibly due to a reduction in NAMPT (an enzyme that inhibits the salvage pathway).
Awesome. So what does this mean for you, and how can you apply it?
Enzymes are molecules that work to speed up chemical reactions. The rate at which the salvage pathway generates NAD depends on the activation of the NAMPT enzyme. If its activity is low, the whole reaction sequence slows down and less NAD is generated.
If NAMPT activity is high, the reaction sequence speeds up, producing NAD at a faster rate. So a reduction in NAMPT means there is less of the enzyme around, reducing the rate at which precursors can be converted into NAD.
Knowing this, researchers are now trying to understand how NAMPT is down regulated during aging. It is thought that our previously mentioned “aging mechanisms,” most specifically inflammatory cytokines and oxidative stress, may be some contributing factors to the decreased NAMPT expression. However, inflammatory cytokines have been shown to cause both a reduction as well as an increase in NAMPT expression, implying a complex relationship between these two factors.
NAD degradation is increased during the aging process
Another explanation for the age-related decline of NAD is an increase in the activity of enzymes that consume NAD, such as PARPs or CD38 (not to be mistaken with their cousins R2-D2 and C-3PO). Like sirtuins, PARPs and CD38 require NAD to function. When active, they bind and “consume” specific parts of the molecule. The broken down molecule is then released back into the system.
PARPs are enzymes that mediate a wide range of biological processes, including normal DNA repair, transcriptional regulation, and metabolism. In response to DNA damage, the rate of PARP synthesis increases up to 500-fold, which can consume a significant amount of NAD.
Under conditions of persistent DNA damage, often seen with aging, the PARP1 enzyme is continuously activated. This leads to chronic NAD degradation which may exceed the cellular capacity to replenish it. Low levels of NAD then compromise dependent enzymatic activities and likely make the cells more sensitive to exogenous stress.
The CD38 enzyme also regulates many processes, such as cell signaling and the body’s healthy immune response. It has been demonstrated that the expression and activity of this enzyme increases with age and has been linked to the degradation of both NAD and its precursor NMN.
Both PARP activation and increased CD38 activity during the aging process appears to impact normal mitochondrial function by decreasing cellular NAD availability.
Consequences of NAD Decline
Let’s shift gears quickly, and talk about Sitruins.
Sirtuins are a family of proteins that regulate cellular health. They influence a wide range of cellular processes like aging, transcription, the body’s healthy inflammation response, resistance to everyday stress, and energy metabolism. They have also been shown to control circadian clocks and mitochondrial biogenesis.
Sirtuins are NAD-dependent, meaning they can only function in its presence. Age-related reductions in NAD levels have been linked to decreased sirtuin activity, which appears to compromise cell function in the following ways:
- Decreased autophagy – a cellular ‘recycling factory’ that also promotes energy efficiency through ATP generation and mediates damage control by removing non-functional proteins and cell structures.
- Autophagy-dependent degradation of mitochondria, termed mitophagy, is important for maintaining the integrity of these critical cell structures and limiting the production of reactive oxygen species.
- Decreased mitochondrial biogenesis – the growth and division of pre-existing mitochondria which enhances metabolic capacity.
- Decreased regulation of gene expression – sirtuins (histone deacetylases) have been identified as chromatin remodeling factors. Chromatin is a mass of genetic material composed of DNA and proteins that condense to form chromosomes. The major proteins in chromatin are histones, which help package the DNA in a compact form that fits in the cell nucleus.
- Epigenetic events are mediated by chemical modifications of DNA and/or histones. In particular, histone modifications—such as acetylation, deacetylation, phosphorylation, and methylation—bring about transient, non-heritable modifications in the genome. These modifications alter random gene expression rates by changing the property of the chromatin surface.
- Interrupted regulation of the circadian clocks
Research suggests that NAD levels can be recovered through various interventions, which include – NAD precursor supplementation (NMN or NR) as well as PARP and CD38 inhibition. These methods involve overcoming the disruptions in NAD metabolism that appear to be linked with the normal aging process.
Caloric restriction is another intervention believed to positively impact NAD levels. Changes in NAD levels in response to energy intake appear to be caused by changes in NAMPT expression. Caloric restriction has been shown to induce NAMPT expression 2-3 fold in the liver and skeletal muscle, whereas high-fat diet feeding seems to significantly reduce NAMPT levels.
Though findings support the use of NAD precursors and inhibitors as a strategy for healthy aging, their dosages, routes of administration, and efficacy in humans still needs testing to ensure the long-term safety of these interventions.