If you spend any time reading longevity research, you will encounter NAD+ within the first few pages. Nicotinamide adenine dinucleotide is not a new discovery — it was first described over a century ago — but its central role in ageing has only become clear in the past two decades. The short version: NAD+ levels decline substantially with age, and that decline appears to drive dysfunction across multiple biological systems simultaneously.

What NAD+ Does

NAD+ is a coenzyme found in every living cell. It participates in hundreds of metabolic reactions, but its two most important roles in the context of ageing are energy metabolism and cellular maintenance.

In energy metabolism, NAD+ is essential for the function of the mitochondrial electron transport chain. It acts as an electron carrier, shuttling electrons from nutrient breakdown to ATP production. Without adequate NAD+, mitochondrial energy output drops — and as we have covered elsewhere on this blog, mitochondrial function is foundational to virtually every other cellular process.

In cellular maintenance, NAD+ serves as the substrate for sirtuins — a family of enzymes that regulate DNA repair, gene expression, inflammatory response, and stress resistance. Sirtuins cannot function without NAD+. When NAD+ levels fall, sirtuin activity falls with it, and the protective processes they govern become less effective.

Why NAD+ Declines With Age

The decline in NAD+ is not simply a matter of reduced production. It is driven by increased consumption. One of the primary consumers is CD38 — an enzyme whose expression increases with age and with chronic inflammation. CD38 degrades NAD+ directly, and its upregulation in ageing biological structures is now thought to be a major contributor to age-related NAD+ depletion.

PARP enzymes — involved in DNA repair — also consume NAD+ as a substrate. As DNA damage accumulates with age, PARP activity increases, creating further demand on an already shrinking NAD+ pool. The result is a supply-and-demand imbalance: the body needs more NAD+ for repair at exactly the point when less is available.

The Downstream Effects

The consequences of NAD+ decline are broad and interconnected. Reduced sirtuin activity leads to impaired DNA repair, which leads to genomic instability. Mitochondrial function degrades as the electron transport chain loses efficiency. Inflammatory signalling increases as the regulatory mechanisms that keep it in check lose their substrate. Stem cell function deteriorates. Circadian rhythm regulation weakens.

This is not a list of separate problems — it is a cascade, and NAD+ sits near the top. This is what makes it such a compelling target for research: intervening at the NAD+ level has the potential to influence multiple downstream pathways simultaneously.

Research Approaches

The most studied approach to addressing NAD+ decline involves precursor supplementation — primarily NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside), which are converted to NAD+ through different biosynthetic pathways. Animal studies with NMN have shown improvements in insulin sensitivity, mitochondrial function, vascular health, and exercise capacity in aged mice. Human trials are now underway, with early results showing increases in blood NAD+ levels and some functional improvements.

But precursor supplementation is not the only angle. Research is also examining CD38 inhibitors — compounds that reduce NAD+ degradation rather than increasing its production. There is also growing interest in how certain peptides may interact with NAD+-related pathways, whether through effects on mitochondrial function, sirtuin activity, or inflammatory signalling that drives CD38 expression.

The Bigger Picture

NAD+ is not a magic molecule, and restoring its levels will not single-handedly reverse ageing. But its position at the intersection of energy production, DNA repair, inflammation, and gene regulation makes it one of the most strategically important targets in ageing research. Understanding why it declines and what happens when it does provides a framework for understanding ageing itself.

For researchers working in the peptide and longevity space, NAD+ biology is essential context. Many of the pathways that peptides modulate — mitochondrial function, inflammatory signalling, growth factor activity — are influenced by NAD+ availability. The two fields are deeply interconnected, and the most informative research will increasingly reflect that.

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