PETCLUBE INSTITUTE OF INTEGRATIVE VETERINARY MEDICINE

NAD+ AS THE CENTRAL AXIS OF CELLULAR BIOENERGETICS: NATURAL NUTRITIONAL SOURCES, ENERGY DISPOSITION, AND INTEGRATIVE STRATEGIES IN NATURAL FEEDING FOR DOGS AND CATS

"NAD+ is not just a coenzyme — it is the bridge between the food the animal consumes and the energy its cells utilize."

16 de maio de 2026

"Without sufficient NAD+, the cell repairs worse, regulates worse, protects worse, and produces energy poorly."

Nicotinamide Adenine Dinucleotide (NAD+) is the central coenzyme of cellular bioenergetics, acting as an indispensable mediator in energy metabolism and the primary activator of sirtuins. This article provides a comprehensive review of the role of NAD+ in the energy disposition of dogs and cats, addressing its physiological decline associated with aging—a process exacerbated by chronic inflammation, oxidative damage, and metabolic stress. We analyze the "three great machines" that consume NAD+: sirtuins (the longevity team), PARPs (DNA repair mechanisms), and the CD38 enzyme (the inflammatory "thief" of NAD+). The study highlights the clinical inefficacy of direct oral NAD+ supplementation due to gastric degradation and molecular size, advocating instead for the superiority of Natural Feeding (NF) as a robust source of bioavailable precursors such as niacin, tryptophan, NMN, and NR. Furthermore, we discuss the nutritional defasage of commercial extruded kibble, where high-temperature processing degrades essential B-complex vitamins. Finally, we explore the therapeutic synergy of NAD+ with mitochondrial peptides SS31 and MOTS-c for mitochondrial repair, offering an integrative framework for managing vitality and longevity in small animal practice.

Keywords: NAD+. Mitochondrial dysfunction. Natural feeding. Sirtuins. Integrative veterinary medicine.

"NAD+ is the central molecule of bioenergetics — without it, the mitochondrial plant stops, and the animal pays the price with fatigue, inflammation, and premature aging."

NAD+ (Nicotinamide Adenine Dinucleotide) is an essential coenzyme present in all living cells, serving as a cornerstone for biological existence. As Cardoso (2025) emphasizes, "NAD+ is not a peptide, it is a coenzyme, a central molecule of bioenergetics" [1]. Its primary biological function is to act as a universal electron acceptor in oxidation-reduction (redox) reactions. This role is critical for the catabolism of macronutrients—carbohydrates, lipids, and proteins—enabling their conversion into usable chemical energy in the form of Adenosine Triphosphate (ATP). Without adequate NAD+ concentrations, the biochemical machinery required for cellular survival becomes sluggish, leading to a systemic failure in energy homeostasis.

The historical trajectory of NAD+ research began with its discovery by Harden and Young in 1906 during studies on yeast fermentation [2]. However, its profound significance in animal physiology was later elucidated by Otto Warburg, who identified it as a key component of cellular respiration. In the context of modern bioenergetics, NAD+ functions as a "transmission cable" that connects the metabolic pathways of the cytoplasm and the mitochondrial matrix. By facilitating the transfer of electrons from the Krebs cycle to the oxidative phosphorylation machinery, NAD+ allows for the massive production of ATP required to sustain complex life [3].

In veterinary clinical practice, the "energy disposition" of dogs and cats is a direct reflection of this mitochondrial efficiency. A pet's ability to perform muscle contractions, maintain thermoregulation, execute cognitive tasks, and mount an immune response is entirely dependent on the organism's capacity to extract energy from food and distribute it effectively. All these high-demand functions require ATP, and ATP production is strictly gated by NAD+ availability. As Cardoso (2025) notes, "without sufficient NAD+ in your body, the cell repairs worse, regulates worse, protects worse, and produces energy poorly" [1]. Consequently, NAD+ deficiency manifests clinically as lethargy, exercise intolerance, and a diminished "spark" in geriatric patients.

Natural Feeding (NF) for dogs and cats, characterized by fresh, minimally processed ingredients, offers a significant physiological advantage in maintaining NAD+ levels. Fresh dietary sources such as beef liver, heart, sardines, eggs, and muscle meats are naturally dense in niacin (vitamin B3), tryptophan, riboflavin (B2), and pyridoxine (B6). These are the essential precursors and cofactors required for the three main NAD+ biosynthetic pathways. Unlike synthetic isolates, the complex food matrix found in NF provides these nutrients in highly bioavailable forms, accompanied by synergistic enzymes and minerals that facilitate their conversion into active coenzymes [4].

Conversely, the reliance on commercial extruded kibble presents a significant nutritional challenge. The extrusion process typically involves high temperatures (ranging from 120°C to 180°C) and high pressure, which significantly degrades heat-sensitive B-complex vitamins. Studies indicate that thiamine (B1), riboflavin (B2), and niacin (B3) can suffer losses of up to 60% during processing [5]. Furthermore, the bioavailability of tryptophan—the essential amino acid precursor for the De Novo pathway—is often compromised by the Maillard reaction during kibble production. It is also critical to note that direct oral NAD+ supplementation is largely ineffective; the molecule's size and charge prevent efficient cellular uptake, and it is rapidly degraded by gastric acid [3]. Therefore, providing the correct precursors through a fresh, species-appropriate diet remains the most effective clinical strategy.

The clinical relevance of NAD+ management cannot be overstated. As the veterinary community shifts toward integrative and preventive models, addressing mitochondrial dysfunction becomes paramount. This article aims to review the biochemistry of NAD+, its biosynthesis pathways, and the impact of nutrition on its levels. By understanding the anti-inflammatory and bioenergetic defense mechanisms mediated by this coenzyme, practitioners can better address the root causes of aging and chronic degenerative diseases in small animals, moving beyond mere symptom management toward true metabolic restoration.

"NAD+ is not a final product — it is the cable that transmits raw energy into the mitochondria, and without it the cellular plant stalls."

The molecular architecture of NAD+ consists of two nucleotides—nicotinamide and adenine—joined by their phosphate groups. Its primary metabolic utility stems from its ability to cycle between two states: the oxidized form (NAD+) and the reduced form (NADH). This redox cycling is the heartbeat of cellular metabolism. The fundamental reaction is represented as:

NAD++H++2e−⇌NADHNAD++H++2e−⇌NADH

In the mitochondrial matrix, NAD+ acts as a high-affinity electron scavenger during the Krebs cycle (Citric Acid Cycle). As acetyl-CoA is oxidized, NAD+ captures the released electrons, transforming into NADH. This NADH then proceeds to the Electron Transport Chain (ETC) located on the inner mitochondrial membrane. Here, NADH delivers its electron payload to Complex I (NADH dehydrogenase), initiating a flow of electrons that powers the pumping of protons across the membrane. This creates the electrochemical gradient (proton motive force) that drives the ATP synthase "turbine" to generate ATP. Cardoso (2025) clarifies this relationship: "NAD+ is the raw form needed in mitochondria to generate ATP, while NADH delivers energy in a more constant form. For NADH to work, you can't take it alone — you need both together" [1].

Beyond its role in ATP production, NAD+ serves a second, equally vital function as a signaling molecule and substrate for specialized enzymes. The most prominent of these are the sirtuins, a family of NAD+-dependent deacetylases. Cardoso (2025) describes sirtuins as "the longevity team — masters of cellular maintenance and adaptation" [1]. When NAD+ levels are high, sirtuins are activated, triggering a cascade of protective mechanisms. SIRT1, located primarily in the nucleus, coordinates DNA repair and activates PGC-1α, which is the master regulator of mitochondrial biogenesis—the creation of new, healthy mitochondria. SIRT3, the primary mitochondrial sirtuin, works to reduce electron leakage and neutralize reactive oxygen species (ROS), while SIRT6 is essential for telomere maintenance and genomic stability.

However, the availability of NAD+ for these protective sirtuins is constantly threatened by other metabolic "consumers." Cardoso (2025) identifies the "three great NAD+-consuming machines" that dictate the coenzyme's fate [1]. The first are the PARPs (Poly ADP-ribose polymerases). These enzymes function as "DNA mechanics." When they detect genomic damage caused by oxidative stress, toxins, or radiation, they consume massive quantities of NAD+ to facilitate repair. In a state of chronic damage—often seen in sedentary, obese, or poorly nourished pets—PARP activity can become so high that it exhausts the cellular NAD+ pool, leaving nothing for the sirtuins to promote longevity.

The third and perhaps most insidious consumer is CD38, often referred to as the "NAD+ thief." CD38 is an ectoenzyme that degrades NAD+ into nicotinamide and cADPR. Crucially, CD38 expression increases dramatically in response to chronic inflammatory processes. As an animal ages or suffers from metabolic syndrome, systemic levels of pro-inflammatory cytokines such as IL-6 and TNF-α rise, which in turn upregulates CD38. This creates a "sink" for NAD+, where the coenzyme is destroyed faster than it can be synthesized or recycled. This inflammatory depletion of NAD+ is a primary driver of the metabolic decline seen in geriatric dogs and cats [1].

"The NAD+ decline is physiological — aging is, to a large extent, losing the capacity to produce energy."

The aging process in companion animals is inextricably linked to a progressive reduction in systemic NAD+ concentrations. Cardoso (2025) states unequivocally: "the decline is physiological — with aging it is normal for NAD+ levels to fall. The older you get, the less NAD+ you have. And it worsens with inflammation, damage, and metabolic stress" [1]. This decline is not merely a marker of age but a functional cause of the physiological deterioration we observe in senior pets. When NAD+ levels drop below a critical threshold, the cell's ability to maintain homeostasis is compromised, leading to a state of "bioenergetic bankruptcy."

This decline is driven by three primary mechanisms. First, the efficiency of the NAMPT-mediated salvage pathway—the body's primary method for recycling NAD+—diminishes with age. Second, the accumulation of DNA damage over a lifetime leads to chronic overactivation of PARPs, which drain the NAD+ pool. Third, the "inflammaging" phenomenon (chronic, low-grade systemic inflammation) causes a steady increase in CD38 activity, which actively destroys available NAD+ [1, 6]. Together, these factors create a metabolic pincer movement that starves the mitochondria of their essential coenzyme.

The clinical consequences of this decline are most evident in high-energy tissues. In skeletal muscle, low NAD+ contributes to sarcopenia and muscle wasting, as the sirtuin-mediated pathways for muscle protein synthesis and mitochondrial quality control fail. In the liver, NAD+ depletion is a precursor to insulin resistance and hepatic steatosis, as the organ loses its ability to efficiently oxidize fatty acids. In the heart, reduced NAD+ levels are associated with hypertrophic cardiomyopathy and reduced stroke volume, as the myocardium is unable to meet its immense ATP demands [1, 7].

Furthermore, Cardoso (2025) draws a direct connection between NAD+ depletion and "brain rot" or neurodegeneration [1]. The central nervous system is exceptionally sensitive to energy deficits. Sirtuin activation is vital for protecting neurons against the accumulation of toxic proteins, such as beta-amyloid. When NAD+ is low, the brain's resilience to oxidative stress and neuroinflammation collapses. This is often reflected in the elevation of NFL (Neurofilament Light Chain), a biomarker of axonal damage. Clinically, this manifests as Canine Cognitive Dysfunction (CCD), characterized by disorientation, altered sleep-wake cycles, and loss of house training—a tragic "rotting" of the cognitive faculties that can be mitigated by restoring mitochondrial health [1].

"The body produces, recycles, and spends NAD+ — and natural feeding is the most powerful tool to sustain this balance."

To maintain adequate NAD+ levels, the organism relies on three distinct biosynthetic pathways. Understanding these pathways allows the clinician to use Natural Feeding as a targeted therapeutic tool.

This pathway converts nicotinic acid (a form of niacin) into NAD+ through the enzyme NAPRT. It is a highly efficient route for increasing systemic NAD+ levels. The richest natural sources for this pathway are found in animal tissues, particularly beef liver, heart, kidney, and oily fish like sardines and salmon. Incorporating these organ meats into a pet's diet provides a direct "jolt" of nicotinic acid that the liver can readily convert into active coenzymes.

The salvage pathway is the most critical route, responsible for recycling over 85% of the body's daily NAD+ needs. It takes nicotinamide (NAM)—a byproduct of NAD+ consumption by sirtuins and PARPs—and converts it back into NAD+ via the rate-limiting enzyme NAMPT. Cardoso (2025) explains: "NAMPT is the enzyme that helps transform used material back into useful NAD+. But with age, this pathway loses strength and recycling drops" [1]. While this pathway is largely internal, its efficiency is enhanced by lifestyle factors such as physical exercise and the avoidance of excessive caloric intake, both of which are easily managed in a Natural Feeding framework.

The De Novo pathway synthesizes NAD+ from the essential amino acid tryptophan. However, this pathway is notoriously inefficient, with only about 1-2% of dietary tryptophan being converted to NAD+ in most mammals. Furthermore, this conversion is "expensive" in terms of cofactors, requiring vitamin B6 (pyridoxine), vitamin B2 (riboflavin), and Iron as obligatory catalysts. Natural sources rich in both tryptophan and these cofactors include eggs, turkey, chicken, and ruminant meats. A deficiency in any of these cofactors—common in highly processed diets—will stall this pathway, leading to metabolic bottlenecks.

While NAD+ itself is not easily absorbed, its intermediates are. Nicotinamide Riboside (NR) is found in trace amounts in fresh milk. Nicotinamide Mononucleotide (NMN) is found in various fresh vegetables such as avocado, broccoli, cabbage, and cucumber [8]. While the concentrations in these foods are lower than in organ meats, they provide a steady, natural supply of precursors that support the salvage pathway without the risks associated with high-dose synthetic isolates.

"Physique is a consequence of good habits — and the mitochondria respond first to the quality of what the animal ingests."

The superiority of Natural Feeding (NF) in supporting NAD+ levels lies in its preservation of micronutrient integrity and bioavailability. Commercial kibble, by its very nature, is a product of extreme processing. The extrusion process (120-180°C) not only destroys a significant portion of the B-vitamin complex but also creates advanced glycation end-products (AGEs) that trigger the very inflammation that activates the "NAD+ thief," CD38 [5]. By transitioning a pet to NF, we remove these pro-inflammatory triggers while simultaneously providing a dense array of bioavailable precursors.

Organ meats, specifically the liver and heart, should be viewed as "mitochondrial superfoods." The heart is an exceptionally rich source of both niacin and Coenzyme Q10, which works alongside NAD+ in the electron transport chain. The liver provides the full spectrum of B-vitamins (B2, B6, B12) and iron necessary for the De Novo pathway. In NF, these nutrients are delivered within a biological matrix that includes fats and proteins that facilitate their absorption, a synergy that is often lost in the "purified" environment of a synthetic supplement added to kibble [9].

Cardoso (2025) emphasizes that "it's useless to use a peptide or coenzyme if the base isn't correct — diet, training, and sleep need to be aligned. Physique is a consequence of good habits" [1]. In the veterinary context, this means that NAD+ support must be part of a holistic lifestyle change. "Training" for a dog involves consistent physical activity and environmental enrichment that stimulates NAMPT activity. "Sleep" involves providing a stress-free environment where the animal can enter deep restorative phases, allowing sirtuins to perform their maintenance work without the interference of high cortisol levels.

For geriatric patients or those with chronic illness, the strategy should be "supplementation via the food matrix." This involves fortifying a fresh diet with specific high-precursor foods. For example, adding small amounts of sardines (rich in niacin and Omega-3s) or lightly steamed broccoli (source of NMN) can provide a steady influx of NAD+ building blocks. This approach is far more sustainable and physiologically sound than attempting to bypass the digestive system with oral NAD+ capsules, which Cardoso (2025) notes are largely ineffective [1].

Ultimately, the goal of NF is to restore the animal's metabolic flexibility. By providing a diet that is low in inflammatory carbohydrates and high in mitochondrial precursors, we lower the activity of CD38 and PARPs while fueling the sirtuins. This shift allows the animal to move from a state of "survival metabolism" to one of "thriving metabolism," where energy is available not just for basic life support, but for repair, play, and cognitive engagement.

"Without sufficient NAD+, the mitochondrial plant doesn't stop completely, but it loses efficiency and creates chaos in metabolism."

NAD+ is the ultimate mediator between catabolism (breaking down food) and anabolism (building and repairing the body). When NAD+ levels are insufficient, the Krebs cycle slows down, and the Electron Transport Chain (ETC) fails to receive a steady supply of electrons. This leads to a "stalling" of the mitochondrial plant. Cardoso (2025) explains the fallout: "Low NAD+ worsens fat oxidation, worsens energy production, and increases ROS (reactive oxygen species). It creates chaos in metabolism" [1]. This metabolic chaos is characterized by an increase in oxidative stress, which further damages the mitochondria, creating a self-perpetuating cycle of decay.

The anti-inflammatory defense provided by NAD+ is primarily mediated through sirtuin signaling. SIRT1 is a potent inhibitor of NF-κB, the master switch for the body's inflammatory response. By deacetylating NF-κB, SIRT1 prevents the transcription of pro-inflammatory genes, effectively "cooling down" systemic inflammation. SIRT3 protects the mitochondria by deacetylating and activating antioxidant enzymes like SOD2 (Superoxide Dismutase), which neutralizes the ROS generated during ATP production. SIRT6 further modulates the inflammatory response by suppressing TNF-α expression.

Cardoso (2025) warns that "inflammation accelerates NAD+ depletion" [1]. This creates a dangerous feedback loop: chronic inflammation (from poor diet or obesity) activates CD38, which destroys NAD+. The resulting low NAD+ levels mean sirtuins cannot inhibit NF-κB, leading to even more inflammation. This cycle is the "root cause" of many age-related diseases in pets, from osteoarthritis to chronic kidney disease.

Natural Feeding is the most effective way to break this cycle. By providing natural antioxidants—such as the polyphenols found in berries or the sulforaphane in cruciferous vegetables—we directly reduce systemic inflammation. This lowers the demand on CD38, preserving the NAD+ pool for sirtuin-mediated repair. Thus, NF acts as both a "fuel provider" (precursors) and a "shield" (anti-inflammatories) for the animal's bioenergetic system [10].

"NAD+ fuels the mitochondria — SS31 and MOTS-c structure them. Together, they attack the root cause of aging."

The clinical efficacy of NAD+ is heavily dependent on the structural integrity of the mitochondria. The inner mitochondrial membrane contains a unique phospholipid called cardiolipin, which acts as a scaffold for the ETC complexes. Over time, cardiolipin becomes oxidized and damaged, causing the ETC complexes to drift apart and lose efficiency. Cardoso (2025) suggests a synergistic approach: "NAD+ pairs beautifully with MOTS-c and SS31, especially if you're thinking about mitochondrial repair or optimization" [1].

SS31 (Elamipretide) is a peptide that specifically targets and protects cardiolipin, restoring the structural organization of the ETC. When SS31 "fixes the machinery," the NAD+ provided through diet or precursors can be used much more efficiently to produce ATP. MOTS-c, a mitochondrial-derived peptide, acts as a metabolic regulator that enhances glucose metabolism and increases the expression of NAMPT, thereby boosting the NAD+ salvage pathway. Together, these interventions address both the "fuel" (NAD+) and the "engine" (mitochondrial structure).

Cardoso (2025) also clarifies the distinction between NAD+ and NADH in therapy: "NAD+ is the raw form to give that jolt to mitochondria to refeed them and restart energy production. NADH provides a more consistent, constant energy balance. But it only does this if it has energy. Without NAD+, you don't have enough energy in the mitochondria. That's why some people take NADH thinking they'll improve energy and they improve nothing — you need both together" [1]. In a clinical setting, focusing on NAD+ precursors through Natural Feeding ensures that the "raw form" is always available to maintain this balance.

The timeline for observing significant clinical results in mitochondrial restoration is typically 3 to 6 months. As Cardoso (2025) notes, "it takes months to change habits and see mitochondrial restoration" [1]. This requires patience from both the clinician and the pet owner, emphasizing that true health is a long-term investment in cellular bioenergetics rather than a quick fix.

"Don't underestimate your health — the lack of a simple coenzyme in the body can cost the patient's vitality."

The management of NAD+ levels represents a paradigm shift in integrative veterinary medicine. As Cardoso (2025) concludes, "the anti-aging process is linked to countless factors. The lack of a simple coenzyme can bring several health problems and metabolic consequences" [1]. By recognizing that aging and chronic disease are essentially energy crises at the cellular level, veterinarians can move toward more sophisticated and effective interventions.

The transition to Natural Feeding is the foundational step in this process. By providing a diet rich in bioavailable precursors and cofactors, we support the body's natural biosynthetic and recycling pathways. This nutritional base, combined with a lifestyle that promotes physical activity and reduces inflammatory stress, creates the ideal environment for NAD+ to perform its dual roles in energy production and cellular defense.

In conclusion, addressing mitochondrial dysfunction through the NAD+ axis offers a powerful tool for restoring vitality in our patients. Whether through the strategic use of organ meats in Natural Feeding or the synergistic application of mitochondrial peptides, the goal remains the same: to ensure that the "mitochondrial plant" of our dogs and cats has the fuel and the structure it needs to thrive. By attacking the root cause of biological failure, we provide our patients not just with more years of life, but with more life in their years.

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