NAD+ dosage protocol

What NAD+ is

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that functions as a coenzyme in reduction-oxidation (redox) reactions and as a cofactor for non-redox NAD+-dependent enzymes (PMID 33353981, PMID 39026037). It exists in an oxidized form (NAD+) and a reduced form (NADH) (PMID 39026037). NAD+ is involved in various enzymatic reactions of energy metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle (PMID 33384409). It cannot be taken directly from food (PMID 33384409).

How NAD+ is thought to work

NAD+ influences cellular functions, such as metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell function (PMID 33353981). It is a pivotal co-substrate for proteins that regulate metabolism and longevity, including the sirtuin family of protein deacylases (PMID 32694684). NAD+ is consumed by enzymes like sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38/157 ectoenzymes (PMID 24786309, PMID 33353981, PMID 33384409). The enzyme nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in recovering NAD+ from nicotinamide, generating most cellular NAD+ pools (PMID 33384409).

What laboratory and animal studies report

Studies in multiple model organisms, including rodents, show that aging is accompanied by a gradual decline in tissue and cellular NAD+ levels (PMID 33353981). This decline is causally linked to various aging-associated conditions, such as cognitive decline, cancer, metabolic disease, sarcopenia, and frailty (PMID 33353981). In preclinical settings (animal studies), strategies to increase NAD+ levels have shown beneficial effects (PMID 32694684). Restoring NAD+ levels can dramatically ameliorate age-associated functional defects in animals, counteracting diseases of aging, including neurodegenerative diseases (PMID 24786309). The decline in NAD+ levels affects all hallmarks of aging (PMID 37848251). Low NAD+ can promote the development of cellular senescence and mitochondrial dysfunction (PMID 37424179).

Human evidence so far

Human studies confirm that aging is accompanied by a gradual decline in tissue and cellular NAD+ levels (PMID 33353981). Alterations in NAD+ homeostasis are found in virtually all age-related diseases in humans, including neurodegeneration, diabetes, and cancer (PMID 32694684). Primary deficiencies in NAD+ homeostasis due to impaired biosynthesis, or secondary deficiencies due to increased consumption or dietary lack of B3 precursors, can lead to various pathological phenotypes in humans, from rare inherited defects to common age-related diseases (PMID 34041853). Several clinical trials with NAD+ precursors are underway to address accelerated aging, age-associated dysfunctions, and diseases such as Alzheimer's and Parkinson's (PMID 37848251).

Open questions and limitations

Much remains to be understood about how NAD+ influences human health and aging (PMID 33353981). This includes a deeper understanding of molecular mechanisms regulating NAD+ levels, how to effectively restore NAD+ levels during aging, the safety of NAD+ repletion, and its beneficial effects in aging humans (PMID 33353981). There are ongoing controversies in the field, including the role of the microbiome in modulating NAD+ precursor availability, the existence of distinct NAD+ pools in different cellular compartments, and non-canonical NAD+ degradation pathways (PMID 39026037). A comprehensive understanding of the interplay between NAD+ boosting strategies and senolytic agents is needed (PMID 37424179).

Key terms explained

**Coenzyme:** A non-protein compound that is necessary for the functioning of an enzyme (PMID 33353981).

**Cofactor:** A substance (other than the substrate) whose presence is essential for the activity of an enzyme (PMID 33353981).

**Redox reactions:** Chemical reactions that involve the transfer of electrons, crucial for energy metabolism (PMID 33353981, PMID 39026037).

**Sirtuins:** A family of proteins that regulate metabolism and longevity, consuming NAD+ in the process (PMID 24786309, PMID 32694684).

**Cellular senescence:** A state where cells stop dividing but remain metabolically active, often associated with aging (PMID 33353981, PMID 37424179).

**Homeostasis:** The ability or tendency of an organism or cell to maintain internal equilibrium by adjusting its physiological processes (PMID 33353981).

**NAD+ precursors:** Compounds that the body can use to synthesize NAD+ (PMID 39026037).