NAD+ is an indispensable coenzyme for cellular energy and DNA repair. It declines with age due to decreasing production (less NAMPT) and increasing breakdown (more CD38), with wide-ranging consequences for the biology of ageing, although direct causality in humans has not yet been fully proven.
NAD+ stands for nicotinamide adenine dinucleotide and is a coenzyme found in every cell of the body. It is indispensable for redox reactions: chemical processes in which electrons are transferred between molecules. Through those reactions, NAD+ plays a central role in cellular energy production, particularly in the mitochondria, the 'power plants' of the cell.
Beyond energy metabolism, NAD+ serves as fuel for a range of important enzymes that literally consume it. The best known are the sirtuins (such as SIRT1, involved in lifespan regulation), the PARPs (poly-ADP-ribose polymerases, crucial for repairing damage to DNA) and CD38. Without sufficient NAD+, all of these enzymes are unable to carry out their work properly.
NAD+ levels decline gradually with age. This has been observed in multiple tissues, in both rodents and humans, and is considered a consistent hallmark of ageing. There are two well-supported mechanisms that explain this decline. First, with ageing the activity of NAMPT, the key enzyme that produces NAD+ via the body's main biosynthesis route, decreases. Less NAMPT means less production of NAD+.
Second, the enzyme CD38 increases as we get older. CD38 actively breaks down NAD+ and its precursor NMN. This occurs because, with ageing, more CD38-positive immune cells accumulate in adipose tissue and the liver, driven in part by chronic low-grade inflammation and by so-called senescent cells: aged cells that no longer divide but do not die either, and continue to emit inflammatory signals. The combined effect is a double blow: less production and more breakdown of NAD+.
The consequences of the NAD+ decline are wide-ranging. They touch virtually all biological hallmarks of ageing: DNA repair becomes slower, mitochondria function less well, inflammatory regulation goes awry and cellular senescence increases. All of this is associated with conditions such as cognitive decline, muscle loss (sarcopenia), metabolic diseases and certain heart diseases. An important caveat: a large part of this evidence comes from animal research and association studies in humans. That NAD+ decline actually causes these diseases in humans has not yet been fully demonstrated.
All claims are based on PMID 24786309, 33353981, 37848251, 34843394, 33199925 and 32084459. The basic functions of NAD+ are strongly supported. The mechanisms behind the age-related decline (NAMPT, CD38) are moderately supported, largely through animal models and limited human research. Causality in humans has not yet been fully proven for the health consequences.