Nicotinamide adenine dinucleotide (NAD) and the sirtuin family of proteins govern cellular function and metabolism. This system directly links a cell’s energy status to its ability to manage stress and maintain its genetic material. The interplay between this coenzyme and these proteins is central to understanding how cells respond to environmental changes, particularly nutrient availability.
Defining Sirtuins and NAD
Sirtuins are a family of seven proteins, labeled SIRT1 through SIRT7, that are highly conserved across nearly all living organisms. These proteins are distributed across different locations within the cell, allowing them to regulate processes specific to those compartments. SIRT1, SIRT6, and SIRT7 are primarily found in the cell’s nucleus, where genetic material is housed. Meanwhile, SIRT3, SIRT4, and SIRT5 are located within the mitochondria, the cell’s powerhouses. The final member, SIRT2, is mainly found in the cytoplasm. Their shared characteristic is their dependence on a specific molecule to perform their function.
That molecule is Nicotinamide Adenine Dinucleotide (NAD), an essential coenzyme present in every living cell. NAD is a dinucleotide that exists in two primary forms: the oxidized form, NAD+, and the reduced form, NADH. NAD’s main function involves carrying electrons in fundamental metabolic processes, acting as a shuttle that moves energy between different reactions. This role is foundational to the generation of Adenosine Triphosphate (ATP), the cell’s main energy currency.
The Enzymatic Partnership
The functional relationship between sirtuins and NAD+ is defined by a specific chemical reaction that establishes sirtuins as metabolic sensors. Sirtuins are classified as NAD-dependent deacetylases, meaning they require NAD+ to execute their enzymatic activity. This dependency provides a direct molecular link between the cell’s energy level and its regulatory responses.
The core of their partnership is the deacetylation reaction, where a sirtuin removes an acetyl group from a target protein. This removal acts like a molecular switch, changing the function or activity of the target protein. The sirtuin consumes NAD+ as a co-substrate, not just a helper molecule.
During the process, the NAD+ molecule is cleaved, and a portion of it is used to bind with the removed acetyl group. This reaction results in the target protein being deacetylated, and the NAD+ being converted into nicotinamide (NAM) and O-acetyl-ADP-ribose. The consumption of NAD+ is stoichiometric, meaning one molecule of NAD+ is used for every acetyl group removed. Sirtuin activity is tightly regulated by the cellular NAD+/NADH ratio. When the cell is in a state of low energy or stress, such as during fasting, the NAD+ levels increase relative to NADH, which consequently activates the sirtuins. Conversely, high levels of nicotinamide, the reaction byproduct, can inhibit sirtuin activity, forming a self-regulating feedback loop.
Cellular Regulation and Biological Impact
The activation of the NAD/sirtuin axis translates the cell’s energy status into diverse biological outcomes. One major area of influence is metabolic homeostasis. SIRT1, located in the nucleus, regulates the production of glucose in the liver and the storage of fat. It enhances the oxidation of fatty acids, promoting the use of fat for energy during periods of low nutrient availability.
Within the mitochondria, sirtuin family members are directly involved in energy production and quality control. SIRT3, a mitochondrial sirtuin, deacetylates and activates enzymes involved in the tricarboxylic acid (TCA) cycle and fatty acid oxidation. This ensures the cell’s power generators operate efficiently and respond appropriately to energy demands.
A separate role is the maintenance of genome stability. Nuclear sirtuins (SIRT1, SIRT6, and SIRT7) are recruited to sites of DNA damage to help initiate repair processes. By modifying proteins involved in packaging DNA, they facilitate access for DNA repair machinery, minimizing the accumulation of genetic errors.
Modulating the NAD/Sirtuin Axis
Understanding the NAD/sirtuin axis has opened new avenues for influencing cellular health through external factors. Simple lifestyle choices can effectively engage this regulatory system. Calorie restriction and intermittent fasting, for instance, increase cellular NAD+ levels by simulating a state of nutrient scarcity. Regular physical activity also positively affects the axis. Exercise increases the demand for energy, which upregulates the enzymes involved in NAD+ synthesis.
Beyond lifestyle, scientists have focused on pharmacological ways to enhance the axis, primarily through NAD precursors and sirtuin-activating compounds.
NAD Precursors
Precursors like Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR) are molecules that the cell can readily convert into NAD+. Supplementing with these precursors is a strategy designed to directly replenish the cellular NAD+ supply.
Sirtuin-Activating Compounds (STACs)
Another approach involves Sirtuin-Activating Compounds (STACs), with resveratrol being a widely studied example. These compounds do not directly increase NAD+ levels, but instead bind to the sirtuin protein, particularly SIRT1, changing its shape. This allosteric modulation makes the sirtuin more efficient, allowing it to function better even at existing NAD+ concentrations.