• Since 2018, the World Health Organization has classified aging as a disease. 

• Aging is related to mitochondrial damage in the cells, as well as damage to DNA.

• A family of proteins known as sirtuins is responsible for maintaining the vitality of cells and extending life. 

• Sirtuins are activated by a molecule called NAD+, a critical source of energy present in all living cells. 

• Levels of NAD+ are halved by middle age, leading to poor activation of sirtuins 

• Supplementing with NMN, a precursor of NAD+, could possibly boost NAD+ levels and lead to more robust cell activity 

Most of us know that age is associated with an increased risk for disease; stroke, heart disease, and diabetes all come to mind. Did you know, though, that aging itself is classified as a disease?

In the 11th edition of its International Classification of Diseases in 2018, the World Health Organization (WHO) listed aging as a disease for the first time in its history.  This categorization has opened the door for greater research into the aging process.

Some of the most revolutionary findings yielded by this research concern the role of the body’s nutrient sensing pathways–systems designed to sense and respond to shortages or overabundance of key nutrients–in the progression of age-related disease.  

Studies have found that a compound called nicotinamide adenine dinucleotide (NAD+) is critical in the activation and function of a nutrient sensing pathway known as the sirtuin pathway. Decreases in NAD+ result in lowered sirtuin activity and more rapid aging. Supplementation with Nicotinamide mononucleotide, or NMN, a precursor to NAD+, may help activate sirtuins and thereby slow the aging process. 

 

Sirtuins and longevity

 

The sirtuin pathway comprises a group of seven proteins, each of which plays its own role iin maintaining cellular health. 

DNA repair, mitochondrial health, metabolism, scheduled cell death, and regulation of inflammation all depend heavily upon sirtuins.These processes ensure that cells have a steady supply of energy and nutrients; they also offer protection against tumor formation. 

NAD+, the key to sirtuins’ success

As important as sirtuins are, they cannot carry out their vital functions without the help of NAD+.  NAD+ is found in the mitochondria of every living cell, and it provides an essential source of energy for the biological processes initiated by the sirtuin pathway. 

It all began with beer

 

The molecule we now know as NAD+ was first discovered by British biochemists Arthur Harden and William John Young in 1906 as they researched fermentation. In liquid extracted from brewer’s yeast, they found a “factor” that enhanced the fermentation of sugar into alcohol–NAD+

In 1929, Harden and another research partner, Hans von Euler-Chelpin, won a Nobel Prize for their detailed documentation of the fermentation process. This included the chemical properties and shape of the molecule which would come to be known as NAD+. 

A source of energy 

 

In 1930, Nobel laureate Otto Warburg discovered that NAD+ facilitates several biochemical reactions by carrying electrons from one cell to another. This transfer of electrons provides the energy needed for all biochemical reactions. 

 

NAD+, the miraculous molecule

 

In 1937, American biochemist Conrad Elvehjem and his team successfully cured a dog of pellagra by administering oral nicotinamide. 

The implications were enormous. In 1937, pellagra was a major public health issue in the United States, claiming an average of 7,000 lives a year. 

Elvehjem’s work established that pellagra was not an infectious disease, as many believed at the time, but a deficiency of niacin (vitamin B3), a NAD+ precursor. Without adequate supplies of niacin, the body cannot synthesize enough NAD+ to maintain the sirtuin pathway. The result is a breakdown in tissue repair, recognizable as pellagra symptoms. 

Elvehjem opened the door to a cure, and diet-related pellagra was all but stamped out within just a few years. This gives us a hint of the importance of NAD+ and its precursors.

 

Age and NAD+ decline

 

By the time we reach middle age,  NAD+ levels are halved, leading to lowered activation of sirtuins. Biological functions that depend upon the sirtuin pathways become dysregulated. 

The decline of NAD+ is associated with several age-related diseases, including cognitive decline, cancers of the metabolic system, diabetes, and muscle loss. 

 

 

NAD+ and inflammation

 

Lowered NAD+ appears to be a significant driver of the low-grade inflammation associated with aging. 

T-cells and macrophages are immune cells that defend us from foreign antigens. Lowered NAD+ levels cause dysfunction in these cells. T-cells signal needlessly for pro-inflammatory cytokines. Macrophages respond to the signal and secrete cytokines. The end result is inflammation. 

Mitochondrial dysfunction and DNA mutations

 

Without NAD+, sirtuins cannot repair DNA or damaged mitochondria efficiently, leading to abnormal mitochondrial function and DNA mutations. These mutations are heavily associated with age-related cancers. 

Blood vessel damage

 

As NAD+ declines, sirtuins cannot facilitate efficient repair of damaged blood vessels or the generation of new blood vessels. As a result, the blood vessels lose their integrity. Blood flow to muscles is slowed. Heart disease and stroke become more of a concern.

Can NAD+ decline be combated?

The loss of NAD+ is so thoroughly intertwined with the aging process that one paper defines aging as the ”cascade of robustness breakdown triggered by a decrease in systemic NAD+ biosynthesis and the resultant functional defects in susceptible organs and tissues.”

Researchers have found that it is possible–at least in mice–to slow NAD+ decline and reverse the aging process. This is where NMN comes in. 

 

 

A brief history of NMN

 

In 1958, molecular biologists Jack Preiss and Philip Handler identified the pathway by which nicotinamide is converted to NAD+. This discovery spurred more interest in NAD+’s precursors. 

In 1963, European scientists discovered that one of NAD+’s precursors, a molecule called nicotinamide mononucleotide (NMN), is an important source of energy for the production of enzymes within cells. 

 

It’s a NAD+ world

 

In 2009, Dr.Shin-ichiro Imai, MD, PhD of Washington University, proposed that age-related declines in the synthesis of NAD+ leads to faulty sirtuin signaling, dysfunctional metabolism, and tissue damage. 

Dr. Imai created a conceptual framework that he dubbed “the NAD+ World.” Within this framework, Dr. Imai sees NMN as “a critical, systemic signaling molecule” that supports the biosynthesis of NAD+ and the “biological robustness” of various systems in the body. 

 

Of mice and men

 

In the wake of Dr. Imai’s research, mouse studies on NAD+ and NMN proliferated rapidly. A 2011 study showed that oral NMN improved the secretion of insulin and offered protection against diabetes in mice selected for their predisposition to diabetes. 

In 2014, another mouse study found that supplementation of NMN reversed age-related muscle loss. That same year, a separate study found that NMN helps prevent heart disease and blood vessel insufficiency (ischemia). In 2016, it was seen to slow cognitive decline and neuron loss in mice with age-related neurodegenerative diseases. 

The few human studies done on NMN supplementation are promising. In 2016, researchers at Keio University School of Medicine launched the first-ever human clinical study of NMN. They found that oral doses between 100 and 500 mg of NMN were metabolized effectively by their subjects with no adverse effects. 

More recently, a 2023 study found that subjects taking 600-900 mg of NMN daily increased their endurance and walked farther in a six-minute walking test than the placebo group. After 60 days, the NMN group’s blood biological age remained stable; the placebo group uniformly saw significant increases in their blood biological age. 

 

 

Where do we go from here?

 

In mice, NMN seems to confer protection against diabetes, neurodegenerative disease, cardiovascular disease, and inflammation. 

In human studies, NMN supplementation seems to be metabolized well with no adverse effects. It correlates with greater responsiveness to insulin, lowered blood biological age, and greater muscular strength and stamina. 

With so many obvious benefits and an apparently good safety profile, NMN supplementation seems like a no-brainer for those interested in slowing or reversing the aging process. Is it really the miracle it appears to be? 

The downsides of NMN supplementation

 

Lack of availability

 

The most obvious obstacle currently is the lack of approval by the Food and Drug Administration (FDA). In 2021, the regulatory agency reversed its previous position on NMN as a food product, saying it was marketed initially as a medicine and must be regulated as such. Sales were halted. The FDA insists upon more research before NMN can be sold. 

 

Few human studies

 

Mouse studies are helpful in predicting the action of molecules within the human body, but they are not identical. While NMN had dramatic effects in mouse studies, these successes have not yet been replicated in human studies. 

So far, human studies suggest that NMN is safe, but these studies are too few and too small to draw a conclusion. Most of what we currently know about NMN and the human body comes from anecdotal reports–this includes Dr. David Sinclair’s enthusiastic reports on his own experiences with the supplement. 

 

Many studies are supported or commissioned by supplement companies

 

For many, this raises a red flag about the reliability and factual accuracy of claims. 

 

 

In summary

 

The sirtuin pathway is responsible for maintaining many vital biological functions in the body. Sirtuins regulate metabolism, cell death, blood vessel repairs, DNA repairs, and neuronal regeneration–and these are only a few of the roles sirtuins play. 

Sirtuins are activated by a coenzyme called NAD+. This molecule powers cell activities. By middle age, our NAD+ levels drop off sharply. This decline causes a loss of sirtuin activity, and the result is the dysregulation of processes attributed to sirtuins. We recognize this dysregulation in the many symptoms of the aging process. 

A precursor to NAD+ called NMN seems to increase NAD+ synthesis and sirtuin activity, reversing the effects of aging and extending the life of cells. In mouse studies, NMN supplementation had dramatic effects, lengthening life span and interrupting disease processes such as Alzheimer’s and diabetes. 

While there have been few human studies, NMN supplementation might one day offer unprecedented opportunities to address aging and the diseases associated with it.