Nicotinamide adenine dinucleotide (NAD⁺) is found in every
living cell, serving as an essential cofactor — the compounds necessary for the
activity of molecular machines (enzymes) — involved in fundamental biological
processes. Initially
discovered in 1906, NAD⁺ has seen a resurgence in research continually
showing that NAD⁺ is critical for maintaining the health of our
cells, tissues, and bodies.
The problem is that as we age, we see a gradual
decline in cellular NAD⁺ levels. This decline in NAD⁺ is linked to numerous age-associated diseases, including cognitive
decline, cancer, metabolic disease, sarcopenia (age-related loss of muscle mass
and strength), and frailty. Many of these diseases can be slowed down or even
reversed by restoring NAD⁺ levels.
So, what exactly is NAD⁺, how is it made, and how is it used by our cells? Answering these
questions will help us understand the roles of NAD⁺ in
maintaining healthy aging and whether and how NAD⁺
deficiencies can be treated.
Where is NAD⁺ Found
in the Cell? NAD⁺ is compartmentalized into different structures
within each cell. It’s found in the gelatinous liquid that fills the cell
(cytoplasm), the cell’s battery packs (mitochondria), and where the cell houses
genetic information (nucleus). These subcellular pools of NAD⁺ are regulated independently of each other, and consistent with this,
the enzymes involved in the biosynthesis or degradation of NAD⁺ are highly compartmentalized as well.
How do Cells Make NAD⁺? NAD⁺ mediates multiple major biological processes
and is always in high demand. NAD⁺ is constantly synthesized, metabolized, and
recycled in the cell to maintain stable intracellular NAD⁺
levels. Some cells, mostly in the liver, can synthesize NAD⁺ from scratch (de novo) using multiple dietary sources. NAD⁺ can be made de novo from L-tryptophan or vitamin precursors, such as
nicotinic acid (NA).
Outside the liver, most cells do not express the
full array of enzymes necessary to convert tryptophan to NAD⁺. But it can also be recycled or salvaged from nicotinamide (NAM), a
by-product of when enzymes use NAD⁺ as a cofactor. Most tryptophan is metabolized
to NAM in the liver, where it is released into the serum, taken up by
peripheral cells, and eventually converted to NAD⁺. In
this pathway, NAM is converted to nicotinamide mononucleotide (NMN) by an
enzyme called NAMPT, which can be converted to NAD⁺. NMN
also forms from nicotinamide riboside (NR).
What Enzymes Consume NAD⁺? NAD+ is also continually turned over by three
classes of NAD+-consuming enzymes: sirtuins, PARPs, and the NAD+
glycohydrolases — also referred to as NADases (CD38, CD157, and SARM1).
Sirtuins With efforts to understand how NAD⁺ impacts aging, sirtuins have emerged as key actors. Since their
discovery, the sirtuins have received much attention because they regulate key
metabolic processes, stress responses, and aging biology.
PARPs The human PARP protein family is composed of 17
proteins. Briefly, the PARP-mediated cleavage of NAD⁺ produces NAM and ADP-ribose as by-products. Overall, targeting PARPs,
in particular PARP1, is a promising therapeutic strategy in the aging field.
However, more studies are needed to fully understand the contribution of PARPs
to the age-related decline in NAD⁺ levels.
NADases CD38 and CD157 are multifunctional ectoenzymes —
enzymes found outside or on the outer membrane of a cell. CD38 modulates
essential cell processes, such as immune cell activation, survival, and
metabolism. Importantly, other than NAD⁺, NMN
is emerging as an alternative substrate of CD38, whereas CD157 consumes NR as
an alternative substrate. Very little is known about the purpose of CD157
enzymatic functions in cellular biology and aging. However, recent evidence
shows that, like CD38, CD157 is upregulated in aging tissues and may have a
role in aging-related diseases, such as rheumatoid arthritis and cancer.
SARM1 was only very recently assigned to the
NADase family along with CD38 and CD157. SARM1-mediated NAD+ degradation plays
a key role in axonal degeneration after axonal injury. SARM1 is primarily found
in neurons and promotes neuronal morphogenesis and inflammation., but it is
also found in certain immune cells, such as macrophages and T lymphocytes, and
regulates their functions. SARM1 is emerging as a therapeutic target to prevent
or ameliorate neurodegenerative diseases and traumatic brain injuries.
How Else is NAD⁺ Used
in the Cell? Beyond the main groups of enzymes that consume NAD⁺ discussed so far, NAD⁺ is widely used as a cofactor or substrate for
biochemical reactions. Over 300 enzymes are known to rely on NAD⁺ for their activity. Accordingly, NAD⁺ is a
mediator of key cellular functions and adaptation to metabolic needs. Some of
these critical cellular processes include metabolic pathways, maintenance and
repair of DNA to safeguard genomic stability, and autophagy — the cell’s
recycling mechanism. Collectively, these functions are important for
maintaining systemic health and balance. However, during aging, declining NAD⁺ levels can impinge on these processes and exacerbate aging-related
diseases.
How is NAD⁺
Related to Aging? During aging, NAD⁺ levels
decline, and many enzymes associated with NAD⁺
degradation and biosynthesis are altered. Many of the cellular processes that
influence or are influenced by aging — such as metabolic dysfunction, DNA
repair failure, genomic instability, inflammation, cellular senescence, and
neurodegeneration — are regulated by NAD⁺ levels. Also, this decline in NAD⁺ levels during aging has been linked to the development and progression
of aging-related diseases, including atherosclerosis, arthritis, hypertension,
cognitive decline, diabetes, and cancer.
