NAD+

Molecular identity

Sequence

Not a peptide — a dinucleotide coenzyme: nicotinamide mononucleotide joined to adenosine monophosphate through a pyrophosphate bridge (C21H27N7O14P2, MW 663.4, CAS 53-84-9)

Formula

C21H27N7O14P2

Molecular weight

663.4 g/mol

CAS

53-84-9

PubChem CID

5892

What it acts on

• Redox enzymes of energy metabolism — NAD+ cycles between its oxidised and reduced forms, carrying electrons from one reaction to the next; the cited reviews describe this as its classical coenzyme role in every living cell.
• Sirtuins — here NAD+ is not a catalyst but a consumed cosubstrate; the 2014 review describes NAMPT-driven NAD+ supply and SIRT1 acting together to regulate metabolism and circadian rhythm, and the fibroblast study attributes part of its readouts to increased sirtuin activation.
• Poly(ADP-ribose) polymerases (PARPs) — a second family of NAD+-consuming enzymes, named in the reviews alongside the sirtuins and drawing on the same cellular pool.
• CD38/CD157 ectoenzymes — a further NAD+-consuming family; the 2024 fibroblast study reports that suppressing CD38 expression with a quercetin and enoxolone complex increased the measured effects of exogenous NAD+.
• NAMPT and the salvage biosynthetic route — the pathway the 2014 review singles out; NAD+ availability is set by the balance between this synthesis and the consuming enzymes, and all three reviews report that cellular NAD+ concentrations change with age.

What the studies report

Each item below summarises the paper it is numbered to, written from that paper's own abstract. The badge says how the evidence was produced.

1. 1.
   reviewEndocr Rev (2023)

   A 2023 critical appraisal in an endocrinology review journal, covering the clinical pharmacology and the preclinical and clinical evidence for NAD+ precursors in age-related conditions, with a cardiometabolic focus. In model organisms given NAD+ precursors it reports improved glucose and lipid metabolism, attenuated diet-induced weight gain, diabetes, diabetic kidney disease and hepatic steatosis, reduced endothelial dysfunction, protection of the heart from ischaemic injury and increased health span. Early human work is reported to raise NAD+ in blood and some tissues through oral precursors, with suggested effects on blood pressure and lipid profile in older adults with obesity or overweight, on kidney injury in at-risk patients, and on inflammation. The authors state plainly that clinical pharmacology, metabolism and therapeutic mechanisms remain incompletely understood, and frame the whole body of findings as a rationale for adequately powered randomised trials that have not yet been run.

2. 2.
   reviewScience (2015)

   A 2015 Science review of NAD+ in aging, metabolism and neurodegeneration. It sets out the dual role — coenzyme for the enzymes that fuel reduction-oxidation reactions, cosubstrate for the sirtuins and PARPs — reports that cellular NAD+ concentrations change during aging, and states that modulating NAD+ production or usage can prolong both health span and life span in the systems reviewed. The paper is explicitly framed as a survey of the factors regulating NAD+ and of precursor supplementation as a possible therapeutic opportunity, particularly in neurodegenerative disease; it is a discussion of an opportunity, not a demonstration of one.

3. 3.
   reviewTrends Cell Biol (2014)

   A 2014 review centred on the NAD+-consuming enzymes — sirtuins, PARPs and the CD38/157 ectoenzymes. It describes NAMPT-driven NAD+ biosynthesis and SIRT1 as acting together to regulate metabolism and circadian rhythm, reports that NAD+ levels decline during aging with consequent nuclear and mitochondrial defects and age-associated pathology, and states that supplementing NAD+ intermediates ameliorates those defects in the models reviewed. The authors' own wording is conditional at the load-bearing steps — the decline 'may be' the weak point, and combined sirtuin activation with NAD+ intermediates 'may be' an effective intervention — so the conclusion is a proposal resting on preclinical work rather than a demonstrated result.

4. 4.
   in vitroCells (2024)

   The only primary study in this reference set: human fibroblasts in culture, testing exogenous NAD+ on its own and combined with a phytochemical complex of quercetin and enoxolone that suppresses CD38 expression. Exogenous NAD+ is reported to protect the cells against both ultraviolet-induced extrinsic aging and intrinsic aging, with the effect significantly increased by the co-treatment, and the authors attribute the readouts to improved sirtuin activation, autophagy and mitochondrial functionality. They open by stating that the pharmacological activity of NAD+ on skin, and even its mechanism, had not been elucidated, and the work does not go beyond cultured cells — no intact tissue was tested.

Used in research on