Why NAD+ Declines During Aging

NAD+ is a molecule that is present in all living cells and is essential for a myriad of cellular processes, including regulating metabolism, performing signaling, facilitating DNA repair and blood vessel growth, and regulating some aspects of aging.

In the body, NAD+ is created from simple building blocks, such as the amino acid tryptophan, and it is created in a more complex way via the intake of food containing nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and other NAD+ precursors.

These different pathways ultimately feed into a salvage pathway, which recycles them back into the active NAD+ form. This salvage pathway, shown on the bottom right of the diagram, includes NAM, NMN, NAD+, and their associated steps.

A 2012 study reported that NAD+ levels decrease dramatically during aging in skin, and while the exact level of decline was not worked out, the average level of concentration seems to fall by a minimum of 50% during adult aging. The difference between newborns and adults, for example, appears to be several-fold lower, according to the study data.

For the brain, two studies used MRI to examine NAD+ and how its level changes during aging. The first study, conducted back in 2015, saw researchers measuring intracellular NAD+ and NADH concentrations and the NAD+/NADH ratio in the human brain, detecting the age-dependent changes in NAD contents and the redox state associated with aging.

The second study from 2019 also concluded that an age-dependent decline of the NAD+ levels in the brain was also observed. Taken together, these two studies suggest that there is a decline of NAD+ in the brain of between ~10% to ~25% between the period of young adulthood and old age.

Another study has come along to muddy the waters and contradict the previous two. In biology, nothing is ever simple, and according to this 12-person, placebo-controlled randomized trial, there was no appreciable difference in NAD+ levels in the brain between young and old trial participants.

The researchers of this new study suggest that their results show that NAD+ decline is not associated with chronological aging per se in human muscle or brain, though they do suggest that brain and muscle tissue can benefit from supplementation with nicotinamide riboside, a precursor of NAD+.

It should be noted that this study is currently in preprint on Biorxiv and has not as yet passed peer review. It is also worth noting that at least one of the authors (Charles Brenner) has a stake in patents and the company that owns and licenses the sale of nicotinamide riboside.

For the liver, a previous study showed that liver samples from people aged 60 had around 30% lower concentrations of NAD+ compared to people aged 45.

Finally, the level of NAD+ present in the bloodstream has also been shown to decrease rapidly during aging, according to the results of a 2019 study. This more recent study improved upon an older study, which suggested that there was only a small decrease in NAD+ levels; this was due to the newer study using a superior methodology compared to the older one, thus giving a more accurate view of what happens to NAD+ in the bloodstream during aging.

The most obvious and direct way in which NAD+ is reduced is via the activity of an NAD+ consuming enzyme linked to inflammation called CD38, which destroys NAD+, and its activity steadily rises during aging as systemic inflammation levels increase.

CD38 is a membrane-bound NADase that hydrolyzes NAD+ to nicotinamide and (cyclic-)ADP-ribose. It is associated with immune responses and energy metabolism, but it is also a NADase whose levels rise with aging, with a corresponding increase in NADase activity and a decrease of NAD+.

Therapies that reduce inflammation, particularly the age-related chronic systemic inflammation known as “inflammaging”, could reduce the presence of CD38, thus offering the potential to increase NAD+.

Poly-ADP-ribose polymerases (PARPs) are a group of related proteins involved in a number of cellular processes, such as DNA repair, genomic stability, and the programmed cell death known as apoptosis, which damaged cells undergo to remove themselves from the system.

PARP is a key driver of NAD+ catabolism, a set of metabolic processes that break down large molecules, including breaking down food molecules to provide energy and molecular components for anabolic reactions, using that released energy to repurpose the broken-down molecules for growth.

Specifically, PARP1 activity can be increased further in response to DNA damage and genotoxic stress, and given that DNA damage typically increases with age, that would mean more PARP activity and thus more NAD+ consumption. In this way, PARP1 activity may serve as a regulator of NAD+ and mediate its age-related decline as the result of ever-increasing genomic instability that comes with age.

The most important reason is that our mitochondria function is being damaged. Mitochondria is a organelle present in every cell. 80% of the energy required for cell life is provided by mitochondria. Generally speaking, mitochondria is the powerhouses of cells.

Mitochondrial morphology plays an important role in maintaining normal physiological metabolism and body development. If mitochondrial structure and function are abnormal, it will cause disease.

In recent years, mitochondrial research has become a research hotspot in life sciences and medicine. Mitochondrial gene mutations, respiratory chain defects, changes in mitochondrial membranes and other factors will affect the normal function of the entire cell, resulting in pathological changes, including degenerative diseases, metabolism disorders, genetic diseases, tumors, etc.

The decline of mitochondrial quality is an important factor resulting in aging. It controls the lifeline of cells, while cells support all life functions of human beings. Therefore, mitochondria is the health community of human life.

CELFULL look forward to bringing more solutions to human diseases and aging through further research and development towards mitochondrial medicine, thus restoring vitality!