Elderly populations are increasing not only in the superaged society of Japan, but across the world, and this has created newfound interest in extending healthy lives. This field asks whether it is possible to continue aging while retaining high mental and physical functions. Nicotinamide mononucleotide (NMN) is attracting high attention from researchers across the world as a substance that may realize this. The following is from an interview with Shin’ichiro Imai, a pioneer in NMN research in the Departments of Developmental Biology and Medicine at Washington University in St. Louis, through which he provided us with hints regarding how we might reveal mechanisms that allow for more enjoyable, positive aging.
What is aging in the first place?
What are the causes behind aging phenomena?
Research on aging and life extension has been an eternal theme for humanity and continues throughout the world. Shin’ichiro Imai is a leading researcher in this field. In 2000, he and Massachusetts Institute of Technology professor Leonard Guarente announced discovery of a relation between lifespan and the functioning of sirtuin genes, also called “longevity genes.”
“Aging refers to a phenomenon in which various bodily functions decline over time,” Imai says. “One example of aging phenomena is increased blood glucose levels and high blood pressure, which occur due to reduced organ functioning. The rate and pattern at which such phenomena appear varies in individuals, but is overall a characteristic of aging.”
According to Prof. Imai, both environmental and genetic factors impact aging phenomena. Environmental factors such as nutritional status and the stimuli behind and extent of stress combine with inherent genetic factors to determine the rate and extent to which aging phenomena emerge.
“Aging itself is not an illness. However, aging can cause problems according to the degree to which body and organ functions deteriorate. For example, when aging causes a certain type of protein to accumulate in the brain, neuronal functioning gradually decreases, and this functional reduction is known to cause Alzheimer’s disease. In other words, aging can be considered as a factor in certain diseases.”
Recent research has shown that aging and life span are controlled by the hypothalamus, which regulates autonomic nervous (sympathetic and parasympathetic) functions such as hormone secretion, body temperature, and heartbeat. The hypothalamus can be thought of as the control center running the autopilot functions of an aircraft. Mouse studies have shown that the hypothalamus contains a very important population of neurons that control aging and lifespan, and functional deterioration of these nerve cells causes various aging phenomena.
Sirutin genes produce proteins called sirtuins in many organisms, from bacteria to mammals. Mice whose genes have been modified so that the level of these proteins is increased only within the brain showed activated nerve cells in the hypothalamus, improving sleep quality and lengthening the healthy lifespan of males by 9% and of females by 16%. Converted to human values, this is equivalent to 7–8 years for men and 13–14 years for women. Sirtuins thus play a crucial role in controlling aging and lifespan, and it is NMN that activate them. Indeed, mice given NMN over one year showed remarkable anti-aging effects. (See the sidebar.)
Diet, life rhythms... What lifestyle habits can delay aging?
NMN has been acknowledged as having remarkable anti-aging effects when administered to mice, and Washington University in St. Louis, where Prof. Imai works, is advancing to clinical studies on humans. Verifying any effects on humans will likely take a little more time, but in the meanwhile Prof. Imai is treating himself with a lifestyle of moderate exercise and attention to his circadian rhythm as a way of raising his NMN levels. The circadian rhythm, also called our “internal clock,” is a rhythmic 24-hour cycle that follows the earth’s revolution. According to Prof. Imai, we can delay aging by aligning our life rhythm accordingly.
“Most important to regulating our circadian rhythm is breakfast. Starting the day with high energy intake resets the needle on our internal clock, thereby maintaining our circadian rhythm. I expect that maintaining an empty stomach for twelve hours between breakfast and dinner the night before will further enhance anti-aging effects. I maintain a routine in which I eat a light dinner at eight o’clock each night, followed by a high-volume breakfast at eight the next morning. This is also an effective way of overcoming jet lag.”
While carbohydrates are often considered something to avoid, Imai says they are an important part of meals.
“Low-carb diets were once a fad in Japan, but carbohydrates are extremely important from the perspective of longevity science. In experiments comparing mice given a diet high in carbohydrates and low in protein with those fed a low-carbohydrate, high-protein diet, the latter were slimmer and sleeker, but died sooner than did the former. Once we reach a certain age, a somewhat high BMI—around 24 to 26 for men, 22 to 24 for women—in other words, a slight chubbiness, correlated with the lowest death rates. Being too fat or too thin are both negative factors, because we have found that a special enzyme secreted by fat tissue produces NMN, supporting the functioning of a specific group of nerve cells that manage aging within the hypothalamus. It has also been demonstrated that moderate exercise increases the amount of this enzyme and enhances the production of NMN.”
If NMN can be shown to affect aging in humans, to compensate for the decreased NAD production that accompanies age (see sidebar) we will likely ingest NMN in the form of supplements and learn to follow a life rhythm that activates sirtuins. So what possibilities may arise in such a society?
“First off, we should see improvements in social problems related to elderly care. NMN intake is highly expected to extend healthy life expectancy and decrease the number of bedridden elderly. We may thus be able to reduce the social security expenditures that are such a burden on national finances. When the elderly become more active in society, this will improve problems related to labor shortages, further allowing them to escape reliance on pension systems supported by the young.”
Professor Imai expects this to lead to “productive aging,” a new way of getting older while experiencing a fulfilling personal life and further contributing to society. This is a perfect fit with the improvements in future quality-of-life that Teijin aims at.
“Japanese has a wonderful expression, pin-pin-korori, describing a healthy, active life right up until the time one dies. I consider that to be the ultimate quality-of-life for the future.”
When nicotinamide mononucleotide (NMN) is absorbed into the body, enzymes convert it into nicotinamide adenine dinucleotide (NAD). Professor Imai’s research has shown that NAD activates sirtuins that regulate aging. NAD levels are known to decrease with age, and these decreased NAD levels are considered to be one trigger for aging phenomena. In experiments in which age-related lower NAD levels in mice were supplemented through administration of NMN, the subjects showed increased energy metabolism, improved blood cholesterol and neutral fat values, and improved functioning of organs such as the pancreas and liver. Further, there were improvements in bone mineral density and immune cell counts, which also decrease with aging. Muscle stimulation through moderate exercise and a lifestyle rhythm that follows the circadian rhythm are also understood to enhance NAD activity.
Nature Digest (aging control and prevention) [in Japanese]