In 1841 the average girl born in the United Kingdom was not expected to see her 43rd birthday; whereas a girl born there in 2011 was expected to reach age 83, nearly twice as long. These life expectancy numbers are similar in all industrialized countries today. (1)
A doubling in life expectancy in less than 175 years is not due to an amazing increase in lifespan, but in life expectancy. Lifespan has been remarkably steady over the last 2,000 years; it's life expectancy that has increased so rapidly. The reason life expectancy has doubled stems from the dramatic improvements in healthcare, which has produced a remarkable decline in infant mortality and an improvement in medicine, such as vaccines. (2)
In the modern era, you have an excellent chance of reaching your 60s, 70s and beyond. At the same time, you also have an excellent chance of getting one or more chronic diseases associated with old age, because aging is a major risk factor for disease.
As we grow older, the chances of contracting virtually every chronic disease increase quickly. High cholesterol tends to increase with age - it's a risk factor for heart attack and stroke. Blood sugar tends to increase with age - it's a risk factor for type 2 diabetes, also instigated by body fat, which positively correlates with age. Rather than increase as we get older, our muscles wither, a condition known as sarcopenia.
Arguably, aging is the most dominant cause of chronic disease, and yet it's not being managed. Doctors don’t sit on their hands until you have a heart attack or a stroke - they notice that you have high cholesterol and manage that cholesterol. Likewise, they don’t wait until you have kidney damage caused by diabetes (diabetic nephropathy) - they manage the hyperglycemia. But no one monitors the aging process directly, nor advocates for preventative protocols that could slow down how fast we age.
What we need to do is manage the rate of aging to be able to prevent disease and maintain our physiological and cognitive functionality longer. One way to do that is to activate the cellular signaling pathways that are involved in promoting the only proven method to enhance longevity and healthspan - calorie restriction.
As you'll soon see, Nicotinamide Mononucleotide (NMN) is such an activator. But first let's get some understanding about how it works by mimicking the life-sustaining benefits of caloric restriction.
Reduce Calories = Increase Life Span
Studies done on the dietary regimen known as Calorie Restriction (CR) provide irrefutable evidence of the importance of metabolism in the aging process.(3)
CR has been studied extensively in yeast, worms, mice, monkeys and even humans. In a laboratory you can control the caloric consumption of animals during their lifetime, but humans are too long lived and none would appreciate living their life in a lab. Left unaided by scientists, the long term adherence to a CR dietary regimen for a human is extremely difficult for most to maintain, but some people do.
Today in America, only 22 people per 100,000 live to 100. In the UK that number is also 22. Worldwide, a dismal six. Compare those numbers to Japan, the country that currently has the greatest number of known centenarians of any nation with 67,824 according to their 2017 census, or 35 per 100,000 people. (4)
Why are the Japanese typically the longest lived humans? Fewer calories.
The people of Japan, particular those from Okinawa, eat fewer calories as in proportion to their basal metabolic rate (the rate at which the body uses energy while at rest to keep vital functions going, such as breathing and keeping warm.) Another way of looking at it is that Okinawans thrive on a long-term energy deficit. This isn't because they lack enough food, but by cultural habit, known as hara hachi bu - "to eat until you are 80 percent full." (5)
The good news is that you might be able to improve your healthspan, and possibly lifespan, without reducing your calories by 20%, but by activating the same cellular pathways that caloric restriction does. The solution to experiencing the benefits of long-term CR would be to identify and use compounds which act as “CR mimetics” (6).
Over the past 20 years, scientists have made great strides in understanding the key cellular components involved in mediating many of the metabolic changes that contribute to the aging process. They have discovered how certain compounds are capable of inducing similar cellular changes that are normally seen during CR.
NAD+ Flips the Switch
In their investigation about how CR can improve longevity, scientists discovered a "molecular switch" that is flipped in response to a nutritional deficit. It's been found in a family of protein molecules known as sirtuins. Mammals have seven sirtuins, and collectively they are among the important modifiers for lifespan.
Sirtuins are responsible for critical biological functions like DNA expression, cellular health and various aspects of aging. However, sirtuins can only function in the presence of NAD+ (nicotinamide adenine dinucleotide), a coenzyme found in all living cells. (7)
NAD+ is a major metabolic signaling molecule. They are plentiful when we're young, but decline precipitously as we age. At the age of 50, your NAD+ levels are at about half the level as in your youth. By 80 years of age, NAD+ levels drop to only 1 to 10% of your youthful levels. (7)
One way CR slows down the aging process is by reversing the age-related decline of bioavailable NAD+. This key metabolite plays a crucial role in regulating the activity of many important signaling molecules involved in age-related diseases.
So, given that NAD+ is essential to longevity, but declines as we age, how do you boost it?
The answer is that you must activate its production indirectly. Feeding or administering NAD+ directly into the body is impractical, because the NAD+ molecule cannot readily cross cell membranes to enter cells, and therefore would be unavailable to positively affect metabolism. Instead, precursor molecules to NAD+ - such as NMN - must be used to increase bioavailable levels of NAD+.
Although it's true that niacin is one such metabolic precursor of NAD+, niacin is separated by many metabolic steps upstream of the final production of cellular NAD+, and thus has a limited impact on the magnitude of NAD+ bioavailability. (8)
Boost NAD+ With Nicotinamide Mononucleotide
In a study published in 2013, Ana P. Gomes, PhD. and her collaborators showed that by administering the NAD+ precursor NMN (Nicotinamide Mononucleotide) in normal drinking water to older mice, NAD+ levels were restored to those normally associated with younger healthy animals. Old mice fed Nicotinamide Mononucleotide for just one week experienced a restoration in muscle mitochondrial function to levels seen in younger mice.
Mitochondria are cellular organelles that function as power plants within a cell. In the same way that a local power plant produces electricity for an entire city, mitochondria are responsible for the production of energy derived from the breakdown of carbohydrates and fatty acids.
Mitochondria oxidize or “burn” carbohydrates, amino acids and fatty acids for energy, yielding ATP. ATP is the cellular form of energy utilized by cellular processes all throughout the body, providing the energy to pump your heart, power neurons in your brain, contract muscles in your limbs, exchange gases in your lungs, extract nutrients from food and regulate body temperature, to name just a few.
In order to provide the massive amounts of ATP needed for movement and exercise, your muscles contain the highest mitochondrial content of any tissue in your body, which is why the finding that NMN restores youthful mitochondrial function in muscle was so important.
But, as the TV commercials say, "That's not all."
A 2016 study conducted by Kathryn F. Mills, PhD and 11 of her associates concludes that:
- NMN is well-tolerated without any obvious harmful effects.
- NMN suppresses age-associated body weight gain and enhances energy metabolism.
- NMN improves insulin sensitivity, eye function, and other features with no toxicity.
- NMN prevents age-associated gene expression changes in a tissue-specific manner.
- NMN is an effective anti-aging intervention that could be translated to humans.
Nicotinamide Mononucleotide Increases NMN in Blood and NAD+ in Tissues
In the 2016 study, researchers confirmed that NMN entered the bloodstream within 2.5 minutes of oral consumption and increases in NAD+ levels were observed in the liver, skeletal muscle, and cortex of the brain. In addition, they found that the NMN synthesized NAD+ in tissues of the liver and soleus muscle.
These results suggest that orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+ in major metabolic tissues.
Nicotinamide Mononucleotide Suppressed Age-Associated Body Weight Gain
The average numbers of percent body weight reduction in NMN-fed mice was dose-dependent, and was between 4% and 9% less, depending on the amount of NMN ingested, than the control group that was not fed NMN. At 12 months, the higher dose NMN group had a decreased fat mass and an increased lean mass compared to controls - meaning that they were both less fat and more muscular.
Nicotinamide Mononucleotide Enhanced Energy Metabolism and Higher Physical Activity
The researchers measured oxygen consumption, energy expenditure, and respiratory quotient for the NMN-fed mice and control group, and found that as compared to the control, the NMN-fed mice experienced:
- Significantly increased oxygen consumption.
- Increased energy expenditure.
- Significantly decreased respiratory quotient, suggesting that NMN-fed mice switched their main energy source from glucose to fatty acids.
Taken together, these results strongly suggest that NMN has significant preventive effects against age-associated impairment in energy metabolism.
Nicotinamide Mononucleotide Improved Insulin Sensitivity and Blood Lipid Profile
NMN-fed mice showed significantly improved insulin sensitivity compared to the control group consisting of body weight-matched individuals. Consistent with this improved insulin sensitivity, triglyceride levels (body fat stores) - a surrogate of insulin resistance - were lower in NMN-fed mice.
As we age, typically insulin sensitivity declines, fasting and average blood glucose levels increases and we gain weight; however the results of this mouse study suggest that long-term NMN consumption can ameliorate age-associated decline in insulin sensitivity, independent of its effect on body weight.
Moreover, the NMN-fed mice experienced less age-associated increases in adipose tissue (body fat) inflammation, a hallmark of obesity and insulin resistance.
Long-Term Nicotinamide Mononucleotide Consumption Significantly Improves Eye Function and Bone Density
NMN prevented the decline in rod cell function in aged NMN-fed mice. Rod cells are photoreceptor cells in the retina of the eye that can function in less intense light than the other type of visual photoreceptor, called cone cells. In addition to these effects of NMN on eye function, the researchers detected small but significant increases in bone density in the NMN-fed mice.
In conclusion, the 2016 Kathryn F. Mills NMN study, as reported in Cell Metabolism, provides:
"... compelling support to an effective anti-aging intervention using NMN, a key NAD+ precursor... it will be of great interest to translate our study from mice to humans and examine whether this endogenous compound, NMN, is also an effective intervention that prevents age-associated physiological decline in humans."
Of Mice and (Wo)Men
To date, no studies on the ability of NMN to increase NAD+ levels in humans have been published. That's not to say that such a study hasn't actually been done.
In 2016, Nature published a report: The first human clinical study for NMN has started in Japan, which said:
- An international collaborative team between Keio University School of Medicine in Tokyo and Washington University School of Medicine in St Louis has started the Phase I human clinical study for NMN to assess the safety and the bioavailability of NMN in humans.
- NAD precursors and sirtuin activators are attracting significant attention owing to the vast amount of data accumulated in the last 16 years since the discovery of the NAD+ and sirtuin interaction. Although NAD+ itself is difficult to administer directly to humans, its precursors - NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) - are promising natural compounds with which to augment NAD levels in the cells and the body.
- This phase I study is not planned for a pharmaceutical development, but for a nutraceutical (vitamin) development.
According to a BusinessWire report, "there are no plans for public disclosure of the clinical research results"; however, based on the results of these clinical studies, the intention is "to create products based on the newly discovered effects of NMN."
Moreover, Shinkowa Pharmaceutical Co., Ltd., which funded the human NMN trial will establish an NMN manufacturing facility, continue with human clinical trials and "seek business tie-ups with companies that are actively looking to invest in the NMN business and the field of productive aging."
Although we don't know yet the specific outcome of the human trial begun in 2016, it seems apparent from Shinkowa's actions that they were favorable.
Joe Garma has written more than 670 articles on his anti-aging blog, GarmaOnHealth, and is currently writing a book, The Ageproof Method, 12 Biohacks for A Long and Strong Life. Prohealth Longevity readers can get his four-part guide, Transform Your Body and Mind here.
- Office for National Statistics: How has life expectancy changed over time?
- Benjamin Radford: Human Lifespans Nearly Constant for 2,000 Years
- Richard Conniff: The Hunger Gains: Extreme Calorie-Restriction Diet Shows Anti-Aging Results
- Wikipedia: Centenarian
- Jeremy Chan: Longevity In A Bottle
- NCBI - Pubmed.gov: Calorie restriction mimetics: can you have your cake and eat it, too?
- Laboratory of Molecular Bases of Aging, Department of Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Pasteur Str. 3, 02-093 Warsaw, Poland Wioleta Grabowska, Email: email@example.com. : Sirtuins, a promising target in slowing down the ageing process
- John M.Denu: Vitamins and Aging: Pathways to NAD+ Synthesis