A nadase is an enzyme that consumes or breaks down the molecule Nicotinamide Adenine Dinucleotide (NAD+). This process, called hydrolysis, splits NAD+ into two parts: nicotinamide and ADP-ribose. This action is a regulated part of cellular activity that helps manage NAD+ availability for many biological functions, from energy metabolism to immune responses. By controlling the levels of NAD+, these enzymes play a background role in maintaining a healthy cellular environment.
The Role of NAD+ in the Body
Nicotinamide Adenine Dinucleotide (NAD+) is a coenzyme present in every cell, where it participates in a wide array of biological processes. One of its primary functions is in metabolism, acting as an agent in redox reactions that convert nutrients from food into cellular energy. It is necessary for energy-producing pathways like glycolysis, the citric acid cycle, and oxidative phosphorylation. This role makes NAD+ a central molecule in maintaining a cell’s energy balance and metabolic health.
Beyond energy production, NAD+ serves as a substrate for several families of enzymes that regulate cellular processes. Sirtuins, for example, use NAD+ to perform functions that include influencing gene expression, managing stress responses, and maintaining mitochondrial health. Another group, poly (ADP-ribose) polymerases (PARPs), consume NAD+ to repair damaged DNA. This repair mechanism addresses damage from environmental factors and normal cellular operations.
The molecule also functions as a signaling molecule, helping to regulate pathways that control cell growth, cell death, and stress responses. The levels of NAD+ within a cell can influence whether a cell grows, enters a self-destruction process known as apoptosis, or activates defense mechanisms. Maintaining an adequate supply of NAD+ is connected to overall health and cellular resilience, as declining levels are associated with various age-related conditions.
Nadase Function in Human Biology
Within the human body, several enzymes perform nadase functions, but two of the most well-understood are CD38 and SARM1. These enzymes have specific roles tied to particular cell types and physiological situations. Their activity is a programmed part of how certain systems operate, demonstrating that NAD+ consumption is a regulated biological process.
CD38 is a glycoprotein found on the surface of immune cells, such as T cells, B cells, and natural killer cells. It functions as an ectoenzyme, meaning its active part faces the outside of the cell. A primary role is in cell signaling involving calcium, where CD38 breaks down NAD+ to produce molecules like cyclic ADP-ribose (cADPR). This molecule acts as a second messenger to trigger the release of calcium ions, a process involved in immune functions like T-cell activation.
SARM1, or Sterile Alpha and TIR Motif Containing 1, is a nadase with a highly specialized function in axonal degeneration, the self-destruction of damaged nerve cell axons. Under normal conditions, the nadase activity of SARM1 is inactive. However, when a nerve axon sustains significant injury or severe metabolic stress, SARM1 becomes activated.
Once active, SARM1 rapidly consumes the NAD+ located within the axon. This depletion of NAD+ leads to a local energy crisis and metabolic failure, which initiates the fragmentation and clearance of the damaged axon segment. This process of controlled self-destruction is a protective mechanism, ensuring that damaged neural connections are removed to allow for potential repair.
Nadases in Disease and Aging
While nadases perform scheduled functions, their activity can become dysregulated and contribute to disease and the aging process. The connection often lies in chronic inflammation, a state of prolonged immune system activation that becomes more common with age, sometimes called “inflammaging.” This environment can lead to an increase in the expression and activity of certain nadases, particularly CD38.
CD38’s expression is strongly upregulated by inflammatory signals. As organisms age, the accumulation of senescent cells—cells that have stopped dividing and secrete inflammatory compounds—contributes to the inflammaging environment. This leads to more immune cells expressing high levels of CD38, making it a major consumer of NAD+. The increased activity of CD38 in multiple tissues during aging is directly linked to the decline in overall NAD+ levels in older individuals.
This over-activity of CD38 creates a cycle where inflammation drives up CD38, which depletes NAD+, leading to mitochondrial dysfunction and further cellular stress. Some bacteria have also evolved to use nadases as weapons. These bacteria produce nadase toxins that they inject into human cells, rapidly degrading the host cell’s NAD+ to disrupt metabolism and help establish an infection.
Therapeutic Targeting of Nadases
Given the link between nadase over-activity and the age-related decline of NAD+, scientists are exploring ways to therapeutically target these enzymes. The primary strategy involves developing nadase inhibitors, which are molecules designed to bind to an enzyme and block its activity. The goal is to obstruct enzymes like CD38 or SARM1 from breaking down NAD+, thereby preserving the body’s natural supply.
By blocking the accelerated NAD+ degradation seen in aging and chronic inflammation, these inhibitors are intended to boost and stabilize cellular NAD+ levels. Research into small-molecule inhibitors for CD38 has shown that natural compounds, like the flavonoid apigenin, can reduce its nadase activity. This work has led to more potent synthetic inhibitors being studied to counteract age-related metabolic issues.
Similarly, developing inhibitors for SARM1 is an active area of research for conditions involving nerve damage, such as chemotherapy-induced peripheral neuropathy. The aim of SARM1 inhibitors is to prevent the NAD+ depletion that triggers axon self-destruction, thereby protecting nerve fibers from degenerating after an insult. This approach could offer a way to preserve neurological function in various neurodegenerative diseases.