CD38 is a protein drawing significant attention in metabolism and longevity research. It functions as a widespread enzyme with a profound influence on cellular health across the human body. This molecule is increasingly recognized as a major regulator of a fundamental coenzyme, and its activity links directly to the processes of aging and chronic inflammation. Understanding its mechanics offers insights into the metabolic shifts that occur over a lifespan. The role of CD38 in controlling cellular energy status and immune function makes it a subject of intense scientific investigation.
Defining the CD38 Protein
CD38 is formally classified as a cluster of differentiation (CD) marker, a term originating from its initial identification as a surface molecule on various immune cells. Structurally, it is a glycoprotein, meaning it has sugar molecules attached, and it is anchored to the cell membrane as a type II transmembrane protein. This structure features a short portion that extends into the cell’s interior, a small segment that spans the membrane, and a large catalytic domain that resides on the cell’s outer surface. The protein is highly expressed on the surface of many white blood cells, including T cells, B cells, and macrophages. Its presence on these immune cells meant CD38 was initially studied as a marker of cell activation and differentiation within the hematopoietic system.
The Role in Cellular Signaling and NAD+ Regulation
The primary function of CD38 is its enzymatic activity as a nicotinamide adenine dinucleotide (NAD) glycohydrolase. This activity involves breaking down NAD+, a molecule universally recognized for its participation in energy metabolism, DNA repair, and cellular signaling. CD38 is considered the main enzyme responsible for consuming NAD+ in mammalian tissues, thereby playing a major role in regulating cellular NAD+ levels. The breakdown of NAD+ by CD38 primarily yields nicotinamide and ADP-ribose.
CD38 is also an ADP-ribosyl cyclase, meaning it can convert a small portion of NAD+ into cyclic ADP-ribose (cADPR). The rate at which CD38 hydrolyzes NAD+ is significantly higher than its rate of cADPR synthesis. This dual enzymatic function is central to its metabolic impact. The product cADPR acts as an important secondary messenger within the cell. Upon its formation, cADPR triggers the release of calcium ions from internal storage compartments, such as the endoplasmic reticulum. This calcium mobilization is a fundamental signal used by cells to regulate a wide array of processes, including cell activation and muscle contraction.
CD38’s Influence on Inflammation and Aging
CD38 activity increases substantially with chronological age. This age-related increase in the enzyme’s expression and function is a primary driver of the decline in cellular NAD+ levels observed in older tissues. The resulting depletion of NAD+ is linked to metabolic dysfunction, as less NAD+ is available to support crucial NAD-dependent enzymes like sirtuins, which are involved in regulating metabolism and DNA stability.
The link between CD38 and aging is often mediated by chronic, low-grade inflammation, a state sometimes referred to as “inflammaging.” Inflammatory factors, such as specific cytokines, can enhance the expression of the CD38 enzyme. This creates a self-perpetuating cycle where inflammation increases CD38, which consumes NAD+, and the resulting metabolic stress can further promote inflammatory signaling.
This cycle is particularly pronounced in immune cells like M1 macrophages, which are known to be pro-inflammatory. These cells exhibit high CD38 activity in aged tissues, making them a major source of systemic NAD+ depletion. Furthermore, the increase in CD38 is influenced by the Senescence-Associated Secretory Phenotype (SASP), which is the release of inflammatory molecules from senescent cells. By contributing to NAD+ decline and chronic inflammation, CD38 is implicated in the functional decline of the immune system, a process known as immunosenescence.
Therapeutic Approaches Targeting CD38
The discovery of CD38’s central role in NAD+ metabolism and age-related decline has established it as a promising therapeutic target. Interventions can be broadly categorized as either directly inhibiting the enzyme or indirectly compensating for its activity. Direct targeting is most clinically advanced in the field of oncology, particularly in the treatment of multiple myeloma.
Monoclonal antibodies, such as daratumumab and isatuximab, are designed to bind directly to the CD38 protein expressed on the surface of myeloma cancer cells. These antibodies promote the death of the malignant cells, making them a backbone for current multiple myeloma treatment regimens. Beyond cancer, research is exploring whether these antibodies, or similar small molecule inhibitors, can be used to block CD38’s NADase activity in other age-related conditions.
Indirect strategies focus on boosting the cellular supply of NAD+ to overcome the enzyme’s consumption. This approach utilizes NAD+ precursors like Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which are raw materials the cell can use to synthesize new NAD+. The goal is to increase the amount of NAD+ available to the cell’s metabolic machinery, effectively overwhelming the degradative action of CD38. Certain naturally occurring compounds, such as the flavonoid apigenin, have also been identified as small molecule inhibitors that can directly suppress the enzymatic activity of CD38.