Thanks to advances in modern medicine, individuals around the world have been living longer. In addition to lower mortality and increased survival, a sustained drop in fertility has shifted the proportion of older individuals upwards. According to the World Health Organization, the world’s population of older individuals is expected to reach 2.1 billion by 2050, doubling the aged population.
A longer life, however, does not guarantee a healthy life. As we age, our organs accumulate damage and progressively decline, making us susceptible to diseases. This is why many scientists have shifted their attention towards finding ways to slowdown, prevent, or even reverse aging. If successful, so-called anti-aging therapies could reduce the prevalence of age-related disease and help us live longer and healthier lives.
Currently, one of the most promising anti-aging targets under study is a vital molecule called nicotinamide adenine dinucleotide (NAD+). NAD+ mediates the production of the energy our cells need to function and survive, fueling enzymes key in repairing DNA damage. As we age, this indispensable molecule progressively declines.
Many scientists hypothesize that the age-related decline in NAD+ underlies the organ decline that characterizes aging. It follows that, by restoring NAD+, our cells become healthier, our organs become healthier, and we become healthier. If this can be achieved, a lack of high-mortality age-related diseases like cardiovascular disease, neurodegenerative disorders, and cancer will allow us to live longer.
How can we restore our NAD+ levels? Since NAD+ occurs naturally, our cells have the machinery necessary to make it on their own; they just need the necessary biochemical components. Our cells generate molecules like a factory assembly line where each component is the precursor for the next. The biochemical precursor to NAD+ is called nicotinamide mononucleotide (NMN). Unlike NAD+ itself, NMN can be ingested orally and can thus be taken in supplement form to raise NAD+ levels.
NMN feeds into the production of NAD+, providing our cells with the energy needed to function. There are several factors thought to underly the aging process, a lack of cellular energy being one of them. Genetic instability resulting from DNA damage is also one of these factors. NAD+ plays a key role in activating enzymes that maintain DNA integrity, thus promoting genetic stability. Given its central role in these cellular processes, the potential benefits of boosting NAD+ with NMN extend to nearly all body systems. Below are some of the better-known examples.
Perhaps one of the most devastating age-related diseases is Alzheimer’s disease, whereby the afflicted are robbed of their memories. NMN has been shown to improve cognition in rodents with Alzheimer’s and reduce brain plaques and neurodegenration in Alzheimer’s mice. While Alzheimer’s is an end-stage disease, many older adults also suffer from cognitive impairments — inability to learn, remember, and think properly. These age-related cognitive impairments have been prevented by NMN in mice. Cognitive impairments are sometimes associated with depression, which has also been shown to be alleviated by NMN in mice.
Because our blood vessels become dysfunctional as we age, blood flow to our brain becomes impaired, leading to cognitive impairments. NMN has been shown to increases blood flow to the brain and improve cognitive function in mice. When the blood vessels in our brain become clogged, we can have a stroke, whereby our brain tissue becomes damaged. NMN has been shown not only delay stroke onset, but also to prevent stroke damage, and improve cognition and mitochondrial health after stroke in rodents.
Our blood vessels transport vital nutrients to each of our cells. As we age, our blood vessels become rigid and more susceptible to blockage, which can lead to heart attack or stroke. NMN has been shown to reverse vascular aging by restoring blood vessel elasticity in mice. Senescent cells — growth arrested cells that accumulate with aging — contribute to the aging of many organ systems, including the vascular system. In mice, NMN stops blood vessel aging my reducing senescent cells, leading to alleviation of hypertension. One of the ways senescent cells contribute to aging is by promoting inflammation, which underlies nearly every age-related disease. NMN has been shown to reverse blood vessel dysfunction by reducing blood vessel inflammation in mice.
We rely on our skeletal muscles for movement, stability, and strength. As we age, our muscles lose their ability to regenerate and grow, leading to the age-related decline in muscle strength and size called sarcopenia. Along with muscle weakness, we also become more fatigued and have less physical endurance. NMN seems to reverse these conditions, as one of its transporters has been shown to increase strength and physical endurance in mice. Furthermore, NMN improves muscle strength and performance in older men, and enhances oxygen utilization and exercise endurance in middle-aged runners. On the other hand, another NAD+ precursor called nicotinamide riboside (NR) does seem to improve muscle function.
Our heart can barley afford to skip a beat before death ensues, leaving little room to wonder why heart disease is the worldwide leading cause of death.
As we age, our heart becomes more susceptible to irregular beats, which have devastating outcomes, such as heart failure. NMN has been shown to protect against heart failure in mice. Our heart tissue is precious, as it is not known to regenerate. Instead, damaged tissue manifest in scarring (fibrosis), leading to heart dysfunction. NMN recovers mouse heart function by reducing scarring. Beating constantly and evermore, the heart requires large quantities of energy. For this, it needs healthy mitochondria. NMN improves heart metabolism and protects against heart failure, in part by rejuvenating mitochondria.
Our heart is part of the cardiovascular system, pumping oxygen-containing blood to the rest of our organs. When the blood vessels surrounding our heart become clogged, the adjacent tissue becomes damaged and dies due to a lack of oxygen. This is called ischemia and commonly leads to heart attacks. In mice, NMN protects the heart from ischemic injury. This protection is synergistically improved with stem cell therapy and melatonin. Enhances Cancer Suppression
One of the most new and promising therapies against cancer are called immunotherapies. These therapies utilize immune cells to suppress tumor growth. Immunotherapies have not been perfect, but in rodents NMN has been shown to enhance the tumor killing capabilities of several different types, including natural killer cell therapy, CAR-T cell therapy, and PD-1 mediated therapy.
While immunotherapies may be a cancer therapy of the near future, chemotherapies are still used widely but come with many harmful side effects. NMN has been shown to reduce these unwanted side effects, such as heart tissue damage and cognitive impairments in mice.
Obesity is linked to a wide array of metabolic deficiencies, including insulin resistance — when are cells cannot utilize glucose due to impaired insulin signaling — which can lead to diabetes. Mitochondria are the final cellular destination for the food we eat to be converted into energy, making them of key importance in metabolism and related diseases. NMN has been shown to double the amount mitochondria in the livers of obese mice, which could protect against obesity. Stimulating fat breakdown with NMN could also help obese individuals lose fat. Furthermore, NMN improves the metabolism and health of mice born to obese mothers.
Eating too much and becoming obese wreaks havoc on our metabolism and can lead to diabetes. Aging makes both of these conditions worse. In mice, NMN has been shown to reverse diet and aged induced diabetes and prevent the kidney disease and neuron degeneration associated with diabetes, suggesting that NMN can protect against these metabolic impairments. To support this, NMN has been shown to improve muscle insulin sensitivity in older women. Thus, While lifestyle adjustments like consistent exercise and a healthy diet are of paramount importance, NMN may protect against obesity and diabetes.
Macular degeneration is an age-related disease involving the degeneration of a region of the retina that allows us to see clearly. Thus, more severe forms of macular degeneration can cause blindness. NMN has been shown to repair the mitochondrial dysfunction associated with macular degeneration in mice.
As we age, our eyes become dry and inflamed. NMN has been shown to reduce inflammation and increase oil secretion, treating dry eye in mice. NMN has also been shown to reduce cell death and wound size after eye injury.
In addition to slowing down aspects of the aging brain, vasculature, muscle, heart, metabolism, and eye, NMN has also been shown to rejuvenate bone stem cells and promote bone formation in rodents. It also reverses intestinal aging, protects against age-related kidney deterioration, and inhibits the onset of liver fibrosis in rodents. Thus, NMN also slow aspects of aging bone, intestines, kidney and liver.
With age comes fertility problems, especially with women. This stems from problems with oocyte (egg) quality. NMN has been shown to improve the age-related decline in oocyte quality and number, as well as female fertility in mice. NMN also protects oocytes from toxins in pigs.
Our DNA codes for the building blocks of our cells but accumulates damage as we age. Repairing DNA damage can prevent age-related diseases. NAD+ fuels enzymes called sirtuins — sometimes thought of as the guardians of our healthspan. Sirtuins play a key role in repairing DNA.
Also, each time our cells divide, the DNA at the ends of our chromosomes (telomeres) grow shorter. At a certain point, this telomere shortening begins to damage our genes and cells. Sirtuins slow this process by stabilizing telomere length.
Since sirtuins rely upon NAD+ to function, there has been an effort to enhance sirtuin activity through NAD+ boosting methods. Along these lines, studies have demonstrated that feeding mice NMN activates sirtuins. NMN also repairs DNA damage resulting from radiation and old age in mice. Furthermore, in both mice and humans, NMN increases telomere length.
Research in animal studies has shown that increasing NAD+ levels can reverse various age-related illnesses such as heart diseases, diabetes, and neurodegeneration. Boosting the molecule even extended the lifespans of yeast, worms, and mice. NMN’s NAD+-boosting ability in animals and its healthspan-promoting properties led scientists to believe in the molecule’s therapeutic potentials. Now, scientists are starting clinical trials to understand whether NMN is safe, how much we should take, and what it does to our body.
An international team of researchers ran the first human clinical study for NMN in Japan to investigate the safety of the molecule. Although the size of the Phase 1 clinical trial was small, the study showed that dosages up to 500 mg of orally administered NMN are safe in humans, implicating a potential therapeutic strategy. The results appeared in the journal Endocrine, November 2019.
NMN’s safety as a dietary supplement has been proven in a number of FDA-approved clinical trials.
Other clinical trials registered with the World Health Organization (WHO) are also examining the safety and efficacy of NMN. In the US, researchers at Washington University School of Medicine are running a clinical trial to test NMN’s effect on cardiovascular and metabolic health with a daily dosage of 250 mg. Another clinical study at Brigham and Women’s Hospital in Boston is also testing the supplement’s effects on the body and if there are any side effects.
Although researchers still need to conduct more studies to determine the efficient dosage for humans, clinical trials of other NAD boosters have shown that 1 gram of oral supplement every day can stimulate NAD+ metabolism in healthy middle-aged and older adults.
With clinical studies still underway, some scientists are confident enough in NAD+’s benefits for aging and are already taking supplements themselves.
David Sinclair, a Harvard professor who studies aging, talked about taking NMN to remain healthy and prevent aging on The Joe Rogan Experience podcast. Sinclair takes 1 gram of NMN every day, along with other supplements including resveratrol, metformin, and aspirin. When asked if there are any downsides of the supplements, Sinclair said he hasn’t experienced anything other than stomach upset so far, and to him, “anything’s better than what’s coming” — aging.
Currently, no side effects of nicotinamide mononucleotide have been documented in humans. Researchers have conducted the majority of studies on NMN in rodents, which revealed positive effects on metabolism, brain function, liver, skin, muscle, bone structure, heart health, reproduction, immunity, and lifespan. Long-term mice study also showed no toxicity, serious side effects, or increased mortality rate throughout the 12 month intervention period.
A single study of NMN in humans reveals no safety concerns following single oral doses of 100, 250, and 500 mg of NMN. Five hours following the single oral administration of NMN, scientists found no changes in heart rate, blood pressure, blood oxygen levels, or body temperature. Laboratory analyses of blood did not show significant changes, except with levels of four molecules in the blood, which fell within normal ranges. This study also measured sleep quality and found no differences before and after the NMN consumption.
Scientists need to conduct further studies of NMN administration in humans to determine whether side effects come from consuming it. Scientists could look at doses higher than 500 mg to find whether they induce side effects. Research could also look at whether long-term consumption of NMN causes side effects.
Since NMN has benefits in various mouse models of human disease, several clinical trials of NMN have been conducted to investigate its clinical applicability
Recounted by various nations around the world for thousands of years, emperors and kings alike searched every corner they could reach for the Fountain of Youth. The tale remains a mystery to this day, but instead of explorers, scientists are on the quest.
Studies in animals showed NMN’s promising properties in NAD+-boosting and anti-aging. Now, researchers are moving forward with clinical trials to investigate the safety and efficacy of the molecule in humans. With the research efforts that are pouring into the field of anti-aging by institutions and private entities, researchers will start getting answers soon. To scientists, the ultimate goal is to develop treatments that slow, stop or even reverse aging — for people to live a long and healthy life.