Longevity Support:
NAD+, resveratrol, ergothioneine, astragaloside IV and the biology of healthy aging

How do NAD+, sirtuins, resveratrol, ergothioneine and astragaloside IV work complementary in cellular aging? The mechanisms behind mitochondrial decline, telomere shortening, the “lung evity 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. In addition, telomere shortening plays a separate but equally fundamental role: with each cell division, the protective DNA end of the chromosome shortens slightly, until the cell reaches a senescent state.^[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]

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]

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]

Astragaloside IV: telomere preservation and immune modulation

Astragaloside IV is a triterpene saponin and the main active compound from the root of Astragalus membranaceus, a plant that has been used for centuries in traditional Chinese medicine as a general vitality herb. Whereas NAD+, resveratrol and ergothioneine mainly intervene in energy metabolism and oxidative damage, astragaloside IV intervenes in another fundamental aging mechanism: the telomeres. ^[10]

Telomeres are the repeating DNA protein structures at the end of chromosomes that protect the genome from instability. With each cell division, they become slightly shorter, to a critical length after which the cell goes into senescence or dies. Research in human fibroblasts and nucleus pulposus cells shows that astragaloside IV activates telomerase, the enzyme that counteracts telomere shortening, via signaling pathways including PI3K/Akt and SIRT1. In these models, this slows down the shortening of telomeres and reduces the senescence markers in the cell. ^[11]

Antioxidant and immune-modulating effect

In addition to the telomerase effect, astragaloside IV has been extensively studied for antioxidant and immune-regulating properties. It regulates both the innate and adaptive immune responses, modulating the balance between regulatory T cells (Treg) and Th17 cells, two cell populations that are more likely to become unbalanced with age and contribute to chronic low-grade inflammation. This immune-regulatory action is via cytokine modulation without overstimulating the immune system, which distinguishes astragaloside IV from general immune stimulants. ^[12]

Neuroprotection and mitochondrial protection

Astragaloside IV also crosses the blood-brain barrier and protects neurons from oxidative damage and mitochondrial dysfunction, two processes underlying neuronal aging. It inhibits oxidative stress, dampens neuroinflammatory signals, and contributes to the maintenance of mitochondrial integrity in brain tissue, mechanisms that overlap with those of ergothioneine but are via different molecular pathways. ^[13]

It is important to add a nuance here: the available evidence for astragaloside IV comes mainly from cell culture and animal models. It supports telomere preservation, antioxidant protection, and immune balance at the mechanistic level, but there is no evidence that it extends lifespan itself. The value of astragaloside IV in Longevity Support lies in adding a fourth, complementary mechanism to the formula, not in a stand-alone longevity claim.

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, EGT and astragaloside IV have improved oral bioavailability but benefit from liposomal protection in the gastrointestinal tract, particularly relevant in animals with chronic intestinal problems where absorption capacity is reduced.

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.