NAD+ restoration is being investigated to slow cellular aging, due to its ability to positively impact the Hallmarks of Aging.

At a cellular level NAD+ restoration has been shown to enhance mitochondrial function (by increasing mitophagy and mitochondrial biogenesis), increase energy metabolism, activate sirtuins (longevity genes), and increase DNA damage repair.

At a whole-body level NAD+ restoration has been demonstrated to restore age-associated muscle loss, increase endurance and strength, increase neurogenesis, improve cognitive function, improve markers of metabolic health, and enhance immune function all of which positively impact healthspan.  

Figure from ‘NAD+ metabolism and its roles in cellular processes during ageing'. 

Further evidence surrounding the benefits and potential therapeutic applications of NAD+ restoration continue to emerge. NAD+ boosting therapies are currently being investigated as potential treatments for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, skin conditions such as psoriasis, metabolic diseases such as diabetes, cardiovascular disorders, sarcopenia, chronic fatigue and long covid.  

Chronic fatigue

While the aetiology of chronic fatigue syndrome (CFS) is not fully understood, there are several cellular changes that are routinely seem in CFS patients. These include:

• Mitochondrial dysfunction and impaired energy metabolism
• Increased oxidative stress
• Increased expression of pro-inflammatory factors
• Cognitive impairment (‘brain fog’)
• Reduced immune function

It is now known that many of these cellular processes are dependent on NAD+ and increasing cellular NAD+ levels may help to alleviate symptoms in CFS patients.  

For example, adequate NAD+ levels are critical for normal mitochondrial function. During the production of ATP, NAD+ acts as an electron donor / acceptor and therefore its loss impairs cellular energy production, contributing to fatigue. 

NAD+ and the sirtuins also work together to maintain mitochondrial health by activating proteins which regulate mitochondrial biogenesis, mitophagy, and antioxidant pathways (e.g. PGC-1α, FOXO). The loss of NAD+/Sirtuins increases the production of free radicals, leading to mitochondrial damage and dysfunction, which has been linked to other classic symptoms of CFS such as brain fog. 

NAD+ and the Sirtuins are also involved in regulating circadian rhythm. The production of many hormones, metabolites, and NAD+ itself are linked to the circadian rhythm. Therefore, loss of NAD+ disrupts this rhythm further contributing to fatigue symptoms.

It is now clear that increasing NAD+ levels is beneficial against many symptoms of CFS.

Menopause

The average age a woman enters menopause is 51 and by this time her NAD+ levels will have declined drastically. The loss of estrogen and NAD+ combined creates a perfect storm for cellular dysfunction.

Some of the most of common symptoms experienced during menopause are linked to estrogen and NAD+ decline:

• Reduced energy levels – both NAD+ and estrogen contribute to mitochondrial function and normal energy production. During menopause, levels of these molecules become low leading to reduced energy production. By increasing NAD+, ATP production is increased, supporting optimal mitochondrial function and energy production.

• Brain fog – estrogen has neuroprotective functions; loss of estrogen impairs ATP production in neurons but also the function of key brain regions such as the hippocampus and the frontal lobe. NAD+ dependent enzymes are involved in synaptic plasticity and neuronal stress resistance and loss of NAD+ contributes to brain aging. Recent studies are investigating NAD+ therapy for neurodegenerative diseases.

• Accelerated biological aging – hormones are important in regulating biological age (the rate at which cells are aging and functioning), with recent studies showing that peri/menopause can accelerate aging and rapidly increase a woman’s biological age. NAD+ is known to promote youthful cellular function and reverse biological age.

Inflammation

Inflammation is beneficial for short periods of time in response to infection, injury, or wound healing, however, long term chronic inflammation which occurs during aging and in certain diseases can accelerate aging and is damaging to organs and tissues.

NAD+ via sirtuins activation mediates immune cell function and suppresses chronic inflammation. Sirtuins suppress NF-κβ which prevents aberrant expression of pro-inflammatory cytokines such as IL-6, IL-10 and TNF-α.

Interestingly, excessive inflammation depletes NAD+ levels. This is because inflammation increases the number of senescent cells in the body which in turn increases expression of the ectoenzyme CD38, which is the largest NAD+ consumer, therefore depleting NAD+ and causing further inflammation.

Post-Acute COVID-19 Syndrome

Those most susceptible to infection by viruses particularly COVID-19 are older individuals and those with co-morbidities. This is because they have reduced immune function which has been linked to  reduced levels of cellular NAD+.

Recent studies investigating Post-Acute COVID-19 Syndrome (PACS) suggest that NAD+ supplements can be beneficial for these patients. This is because COVID-19 depletes NAD+ levels to support its own replication. COVID-19 creates a highly inflammatory environment within cells, via overactivation of T-cells, this causes overactivation of PARP1 which drains cellular NAD+ and ATP levels. Leaving many critical cellular repair processes without sufficient NAD+ contributing to COVID-19 and PACS symptoms.

Replenishment of cellular NAD+ levels is being tested to enhance the antiviral capabilities of cells and suppress uncontrolled inflammation.

Overall, NAD+ has many vital functions and NAD+ deficiencies are seen in a variety of conditions. Current knowledge of NAD+ suggests it may have particular therapeutic benefits for those with CFS, menopause, chronic inflammation and PACS.