Longevity Support:
NAD+, resveratrol, ergothioneine and the biology of healthy aging
How do NAD+, sirtuins, resveratrol and ergothioneine work complementary in cellular aging? The mechanisms behind mitochondrial deterioration, the “lung elevity vitamin” ergothioneine and the most recent veterinary and human evidence. For dogs, cats and humans.
By Stefan Veenstra DVM
The biology of cellular aging
Aging at the cellular level is driven by a handful of interconnected mechanisms that form the “hallmarks of aging”: mitochondrial dysfunction, epigenetic dysregulation, genomic instability, protein aggregation, cellular senescence, and chronic low-grade inflammation (inflammaging). Central to all these processes is the gradual deterioration of NAD+ levels, which determine the capacity for energy production, DNA repair and sirtuin activity. [1]
In dogs and cats, cellular aging is biologically identical to that in humans, but at an accelerated rate. A 7-year-old medium-sized dog has similar cellular aging parameters as a 45- to 50-year-old human. The decline in NAD+ levels and mitochondrial efficiency begins to be noticeable in dogs as early as 3 to 4 years of age, mechanically justifying earlier preventive support. [2]
NGD Care Aging Protocol: Longevity Support as a Mitochondrial Energy Component
NGD Care Gut Protocol: Longevity Support in Phase 3 in Mitochondrial Exhaustion
NAD+ and sirtuins: the central aging regulation mechanism
NAD+ (nicotinamide adenine dinucleotide) is an essential coenzyme for the mitochondrial respiratory chain (complex I-III), for DNA repair via PARP enzymes (poly-ADP-ribose polymerases) and for the activation of sir gardens. Sirtuinen (SIRT1-7) are a family of NAD+-dependent deacetylases that coordinate cellular stress response, mitochondrial biogenesis, genomic stability, and metabolic regulation. SIRT1 and SIRT3 are the most studied: SIRT1 modulates core processes including autophagy, inflammaging-inhibition and mitochondrial biogenesis via PGC-1alpha activation. SIRT3 modulates mitochondrial antioxidant defense via activation of SOD2. [1]
NAD+ levels decline with age due to two complementary processes: decreased biosynthesis via the salvage route and increased consumption by CD38, a membrane-bound hydrolyase whose expression increases with age. In humans and dogs, NAD+ decreases by 50% or more between young adult and senior age. A study in Scientific Reports (Yamagishi et al., 2024) showed improvement in cognitive function scores in senior dogs after an NAD+ precursor protocol over a controlled study period. [3]
Resveratrol: SIRT1 activator and NAD+ catalyst
Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenol from grapes, berries and certain plants with a complex pharmacological profile. The primary anti-aging action is through two complementary pathways: direct activation of SIRT1 via allosteric binding and indirect increase of NAD+ levels via inhibition of CD38, the enzyme that breaks down NAD+. [4]
SIRT1 activation by resveratrol induces autophagy, the cellular scavenging process that removes damaged mitochondria and protein aggregates. A meta-analysis analyzed 19 studies in six species and concluded that resveratrol via SIRT1-dependent autophagy induction has life-prolonging effects. [5] A study in Antioxidants (2025) showed that resveratrol in dogs positively affects the gut microbiome and gut metabolome, supporting synergy with Prebiotic Fibers and the Gut Protocol. [6]
Resveratrol and NAD+: synergy on three levels
NAD+ precursors increase the availability of NAD+ as a substrate for sir gardens.
Resveratrol activates SIRT1 instantly and makes the system more sensitive to available NAD+.
Resveratrol inhibits CD38 and slows down NAD+ degradation, which makes the combination more effective than either individually.
Ergothioneine: the “lung health vitamin”
Ergothioneine (EGT) is a sulfur-containing amino acid produced exclusively by certain mushrooms (including Maitake, oyster mushrooms and shiitake) and certain bacteria. Humans, dogs and cats cannot synthesize EGT themselves but absorb it through food and through a specific transporter, OCTN1 (organic cation transporter 1), which was discovered in 2005 by Gründemann et al. The presence of a specific and highly selective transporter mechanism, similar to that of essential vitamins, has led to the classification of EGT as a “pulmonary vitamin” or “stress vitamin” by Bruce Ames and others. [7]
A review in Proceedings of the Nutrition Society (2025) synthesizes the complete evidence base for EGT in cognitive health, longevity and healthy aging. Observational data consistently link low blood levels of EGT to cognitive decline, neurodegenerative disorders (Alzheimer’s, Parkinson’s), cardiovascular impairment, frailty, and reduced life expectancy. Intervention trials in older adults show improvement in cognition, memory, and sleep quality with EGT supplementation, with no safety concerns up to 25 mg per day. [8]
Blood-brain barrier and neuroprotection
EGT crosses the blood-brain barrier via OCTN1 transport and accumulates in brain tissue, particularly in areas of high metabolic activity. Paul (2022) described in Antioxidants and Redox Signaling the neuroprotective properties of EGT via mitochondrial protection, anti-neuroinflammation and cytoprotection against oxidative stress in neurodegenerative disorders. [9] Intervention studies in people with mild cognitive impairment and in Parkinson’s models in mice show neuroprotective effects. The relevance for dogs with Canine Cognitive Dysfunction is mechanistically direct: the same EGT-OCTN1 mechanism is present in canine brain tissue.
Mitochondrial protection and cardiovascular
EGT directly protects mitochondrial membranes through its unique chemical structure as a thiolamino acid: it selectively neutralizes reactive oxygen and nitrogen species in mitochondria without becoming pro-oxidative itself, a property that most other antioxidants lack. EGT also inhibits mitochondrial permeability transition, a key mechanism in mitochondrial cell death in ischemia. Cardiovascular studies show protection of endothelial cells and cardioprotective effects in animal models. [8]
Liposomal Formulation in Fat-Soluble and Water-Soluble Pulmonary Tissue Molecules
Resveratrol has low oral bioavailability due to rapid metabolization (glucuronidation and sulfation) in intestinal epithelium and liver. Liposomal encapsulation protects resveratrol from first-pass metabolism and significantly increases plasma concentrations. NAD+ precursors and EGT have better oral bioavailability but benefit from liposomal protection in the gastrointestinal tract, particularly relevant in animals with chronic intestinal problems where absorption capacity is reduced.
Longevity Support Application Area: Dog, Cat and Human
Senior dogs and cats with age-related declines in vitality, cognition, and energy. Preventive pulmonary evity support from middle age in dogs and cats. Mitochondrial energy support in chronically burdened or sick animals. Cognitive support for Canine Cognitive Dysfunction. Part of the Old Age Protocol. Phase 3 component of the Bowel Protocol in mitochondrial exhaustion. People with increased aging pressure due to chronic disease, oxidative stress or increased metabolic requirement.
Conclusion
Longevity Support combines three mechanistically complementary lung evity molecules: NAD+ as an upstream energy substrate for sirtuinen and DNA repair, resveratrol as a SIRT1 activator and CD38 inhibitor that keeps NAD+ available for longer, and ergothioneine as a mitochondrial antioxidant, neuroprotector and candidate “lung evity vitamin” with a growing evidence base in cognitive health and healthy aging.
Veterinary evidence is growing rapidly: NAD+ precursors in dogs (2024), resveratrol in dogs (2025), and the mechanistic translatability of the extensive human ergothioneine literature. Longevity Support is widely applicable to aging and preventive from middle age. Always in consultation with an (integrative) veterinarian.
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Literature
- Reduce E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015; 350(6265):1208-1213.
- Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013; 153(6):1194-1217.
- Yamagishi K, Hatakeyama Y. Nicotinamide mononucleotide administration improves cognitive function in senior dogs: a randomized controlled trial. Sci Rep. 2024; 14(1):5678. [First Veterinary RCT NAD+ Precursor in Cognition Senior Dogs, 2024]
- Baur YES, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006; 5(6):493-506.
- Hu Y, et al. Effects and mechanisms of resveratrol on aging and age-related diseases. Oxid Med Cell Longev. 2021;2021:9932218. [Meta-analysis resveratrol life-prolonging effect via SIRT1 autophagy]
- Rapin A, Neyrinck AM, Pot B, Delzenne NM. Effects of resveratrol on lipid metabolism and inflammation in obese cats: a randomized controlled trial. Antioxidants. 2025. [Resveratrol in Cats, Gut Microbiome and Metabolome 2025]
- Halliwell B, Cheah IKM, Tang RMY. Ergothioneine: a diet-derived antioxidant with therapeutic potential. FEBS Lett. 2018; 592(20):3357-3366. [Ergothioneine as a “lung vitamin vitamin” and stress vitamin candidate]
- Cheah IKM, et al. Ergothioneine for cognitive health, longevity and healthy ageing: where are we now? Proc Nutr Soc. 2025. doi:10.1017/S0029665125100354. [Most Complete Review of Ergothioneine in Cognition and Aging 2025]
- Paul BD. Ergothioneine: a stress vitamin with antiaging, vascular, and neuroprotective roles? Antioxid Redox Signal. 2022; 36(16-18):1306-1317.
This information is educational in nature and based on available scientific literature. The studies mentioned are not always directly veterinary or specific to the formulation described here. This text does not replace a veterinary consultation and does not contain any therapeutic claims.