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Longevity has been on ongoing study area for a long time. This is the second section of the RMEHA newsletter series that examines some of the current longevity research developments and how they may help alleviate some of our society's current health issues, such as multiple chemical sensitivity (MCS). The supplements melatonin and PQQ were discussed in the July newsletter.
NAD+ is the acronym for nicotinamide adenine dinucleotide. NAD+ is normally generated internally by the body. It is an internal body enzyme found in virtually all living cells. It turns out to be critical in the internal operation of the body and is essential to sustaining and maintaining all life because it translates the DNA of our bodies into actual cells and supporting life.
The body supply of NAD+ decreases drastically with elder years. A typical person in their 50's may have only half the NAD+ they did in youth. By age 80, NAD+ levels drop to about 1% that they had in their youth. Since the NAD+ levels decrease with age, there is an energy deficit that decreases the body's ability to retain youthful function. And the ailments of aging continue to increase.
NAD+ promotes longevity by facilitating DNA repair and providing cellular benefits associated with caloric restriction and exercise. A deficiency of NAD+ predisposes us to accelerated aging and impedes our ability to fully benefit from resveratrol, for example. Restoring NAD+ is increasingly being viewed as a cutting-edge tool to promote longevity.
The longevity material resveratol, such as found in red wine, turns out to require NAD+ to activate its longevity benefits.
The NAD+ research is promising enough that NASA has written a contract with a British bio-tech company to develop an age reversal or anti-cancer treatment based on this material for astronauts going to Mars.
The NAD+ molecule is unstable, so it cannot be taken directly as an oral supplement. But it is now recognized that supplementing with a vitamin-like precursor of NAD+ called nicotinamide riboside which the body transforms into NAD+ can promote longevity in a wide range of life forms ranging from simple worms to mammals like mice.
One nicotinamide riboside supplementation study showed an average five percent increase in the lifespan of old mice, even though supplementation did not begin until the mice were nearing the end of their natural lifespan of 24 months. That would be the equivalent of gaining nearly an additional four years of human life based on today's average expectancy of 78.8 years.
A rigorous scientific review of NAD+ shows that its many longevity benefits arise from several different, but interrelated, functions. This newsletter includes many of the technical names for some of the body enzymes and proteins that are critical in longevity research, but are hopefully not needed for an overview.
A term now being used in this area is nootropics. It is a general term being for the various materials that promote longevity.
NAD+ is required for proper cellular energy utilization, but its levels decline with age. It is also required for a lot of fundamental processes, each of which contributes to accelerated aging when the NAD+ levels drop. Studies are showing that NAD+ supplementation can slow cellular aging and improve many of the metabolic defects common to the aging process, including obesity, diabetes, cardiovascular disease, and neurodegenerative conditions. Thus supplementation with an NAD+ precursor offers a way of supporting essential body systems.
NAD+ is required for functioning of the sirtuin proteins that contribute to longevity, and specifically to maintaining the length of telomeres.
Telomeres are stretches of repetitive DNA strands that cap the ends of DNA molecules. Telomeres steadily shorten every time a cell replicates itself. Once telomeres reach a critically short length, cell renewal virtually stops, leading to accelerated aging or death of the cell. Telomere shortening is both a marker of cellular aging and a predictor of shortened lifespan.
Certain nutrients, such as resveratrol, can activate sirtuins and contribute to extending lifespan, but current research suggests sirtuins function best with an ample supply of NAD+.
Even though DNA is protected by its chromosomal shelter, it is very vulnerable to a variety of damages. This can lead to broken DNA strands and mutations in crucial genes. Accumulated DNA damage contributes to the aging process and can contribute to specific lifespan-shortening diseases like cancer and poor immune function.
When DNA is damaged, it activates an enzyme known as PARP-1 that carries out DNA repair. To carry out its function, the PARP-1 enzyme consumes huge amounts of NAD+. As NAD+ is depleted, the ability of PARP-1 to repair DNA is significantly hindered.
The result is that replenishing NAD+ to cells can restore DNA repair and prevent cell death under stress. In two different animal models of neurodegenerative disease, increasing cellular NAD+ reduced the severity of the disorder, normalized neuromuscular function, delayed memory loss, and extended lifespan.
So improving DNA repair with NAD+ can slow cellular aging, reduce the persistence of cancer-causing mutations, and play an important role in preventing inflammatory conditions such as atherosclerosis.
As we age, our immune cells lose their focus. Some become overactive, contributing to autoimmune disease by releasing materials called cytokines, while others slow down, which increases the risk of infection. This process, called immunosenescence, is intimately related to mitochondrial function and energy balance, both of which depend on NAD+ activity.
Intracellular levels of NAD+ regulate immune and inflammatory pathways, including the cytokine TNF-alpha, a critical signaling molecule. So adequate intracellular NAD+ is vital for youthful cellular energy, a critically important factor in fending off immunosenescence and maintaining defenses against infections and autoimmune disease.
A basic feature of aging is the loss of cellular energy, which results in diminished ATP levels and inadequate cellular fuel necessary to power your body. One cause of this energy loss is a breakdown in the efficiency of the electron transport chain, the main pathway through which we extract energy from food. Disorders ranging from obesity and diabetes to bone loss have been associated with loss of this vital pathway.
Studies now show that restoring electron transport chain function by raising levels of NAD+ is a fast and efficient means of promoting the essential enzymes involved in energy extraction and sustaining youthful cell function. This helps to reduce physiological decline and provides protection from age-related disease. So improving the energy-extraction process in all cells with NAD+ increases their capacity to do the work they are specialized for. It also protects mitochondria from early death, a benefit that is associated with reduced cellular aging and lowered risks for cardiovascular and brain disease.
Our chromosomes are complex structures housing our DNA. Access to the DNA strands for "reading out" genetic instructions requires biochemical control of those proteins to make sure each gene functions correctly.
But chromosomes can become unstable. If that happens, it triggers errors in the ways our genes are interpreted, which ultimately contributes to deleterious changes in cell structure. Aging is accelerated in the presence of increased chromosome instability.The enzymes involved in sustaining stable chromosomal structures require NAD+ in order to function properly.
In animal models showing that NAD+ contributes to longevity, a significant factor has been shown to be sufficient availability of a nutrient, such as NAD+. Some studies show that when enzymes that require NAD+ are inactive, chromosome structure suffers and cells replicate abnormally. Thus NAD+ supplementation is a promising cutting edge strategy to improve chromosome stability, a treatment that may slow down cellular aging (senescence) and lower the risk of cancer.
Neurotransmitters are brain chemicals that relay signals between nerve cells. In doing so, they help regulate body-wide functions such as mood, appetite, and stress. NAD+ has been found to meet all criteria for a neurotransmitter.
Evidence for NAD+'s neurotransmitter function has now been found in intestinal and blood vessel smooth muscles, as well as in the brain itself. So adequate NAD+ nutrition appears essential for sustaining brain health.
Proteins called sirtuins are major regulators of cellular aging because they manage many fundamental functions such as DNA repair and inflammatory responses. They also influence whether cells enter a replicative cycle of healthy body support or die a programmed death (apoptosis). Compounds that activate sirtuins are sought as chemical "fountains of youth." Familiar supplements like resveratrol and quercetin have been evaluated as promising sirtuin activators.
Now it is recognized that NAD+ is required for sirtuins to function. Sirtuin activation has shown great promise in fighting cardiovascular disease and preserving aging brain function, but these longevity-promoters cannot function without sufficient NAD+.
NAD+ was first discovered as an important part of the process that channels chemical energy from foods into the ATP fuel our cells require. Recent studies have now shown that NAD+ is itself a form of "energy currency" similar to ATP.
NAD+ is also a functional signaling molecule in processes related to energy production, including PARP-1 and sirtuins. In addition, high levels of NAD+ can activate sirtuins, permitting them to carry out their metabolic and stress-protective responses and contributing to longevity.
So efficient energy production and adequate ATP levels requires consistent and abundant NAD+. This is critical because decreasing energy supplies contribute to the aging process.
Nicotinamide riboside boosts NAD+ and is useful in preventing diseases associated with abnormal energy utilization. These include obesity, diabetes, and atherosclerosis, which are components of metabolic syndrome.
A mouse study showed that prediabetic mice given nicotinamide riboside/NAD+ have better glucose tolerance, less weight gain and liver damage, and slower development of fatty livers. Similarly, in diabetic mice, nicotinamide riboside/NAD+ markedly reduced blood sugar, weight gain, and liver fat, while also preventing diabetic nerve damage.
Nicotinamide riboside/NAD+ is especially beneficial in combatting nonalcoholic fatty liver disease (NAFLD), which is considered the liver manifestation of metabolic syndrome. Interventions that reduce NAFLD generally improve all-around metabolic health. Studies in animal models of NAFLD have shown that nicotinamide riboside/NAD+ supplementation corrects biochemical and microscopic liver changes in mice fed a high-fat diet.
In another study of obesity induced by a high-fat diet, supplementation with nicotinamide riboside definitely increased NAD+ levels, activated sirtuins, and protected against the oxidative stresses and other damage induced by the diet.
Brain tissue is highly sensitive to alterations in NAD+ levels. A mouse study showed that supplementation with nicotinamide riboside increased NAD+ levels in the brain, slowed cognitive decline in mice with Alzheimer's, and improved the plasticity in neurons that underlies learning and memory.
Regular exercise minimizes for several of the ageing processes in our bodies. Recent studies are showing that nicotinamide riboside helps improve exercise performance by improving mitochondrial action and muscle function.
In laboratory animals that had undergone removal of part of their livers, researchers showed that nicotinamide riboside supplementation promoted new DNA synthesis, cell replication, and increased liver mass, a vivid demonstration of its healing powers.
NAD+ is biologically unstable so it is not suitable for oral supplementation. About a decade ago, researchers discovered that the compound nicotinamide riboside is rapidly converted by natural enzymes into active NAD+. Studies now show that supplementing with nicotinamide riboside is an effective means of increasing NAD+ levels. Nicotinamide riboside is now widely available for oral supplementation, and it is bioavailable. These benefits make nicotinamide riboside the best oral candidate to date to boost cellular NAD+.
NAD+ beneficially enhances several basic cellular anti-aging mechanisms. When these cell functions are impaired, the consequence is accelerated aging that contributes to disorders as diverse as Alzheimer's and osteoporosis. Restoring cell NAD+ levels has been shown to preserve youthful function, and even reverse some age-induced deterioration.
Nicotinamide riboside has also been shown not only to restore NAD+ levels in tissues, but also to provide more NAD+ activity than can be obtained from diet alone. Supplementation with nicotinamide riboside can slow cellular aging and improve many metabolic defects common to degenerative processes, including diabetes, declining heart function and neurodegenerative conditions.
Current research suggests, beginning about age 45, we should supplement with nicotinamide riboside at some 500 mg/day. Life Extension Foundation makes an "Optimized NAD+ Cell Regenerator with Resveratol" with 250 mg of nicotinamide riboside and 100 mg of resveratol.
A person with serious MCS, which is a hypersensitivity to a wide variety of petrochemical derived materials, reports that nicotinamide riboside supplementation does not alter the basic MCS neural injury reaction, but does promote building up the body so a person can better tolerate the many side effects of MCS. No adverse effects were noted.
One person with MCS also developed a serious nocturia problem. Nocturia is having to get up to go to the bathroom two or more times a night. It is a problem for some 20 to 30 percent of the elder population, but it is poorly known and supported. (There is speculation that one of the causes of nocturia is that it is one of the side effects of the limbic injury that causes MCS. More research is needed in this area.) A consequence of nocturia, which amounts to not getting enough sleep, is a body wasting and weakness that fits the medical diagnosis of frailty. It was reported that NAD+ supplementation definitely did alleviate much of the frailty condition.
AMPK (adenosine monophosphate activated protein kinase) is a natural body enzyme, which is found in all living creatures. This enzyme is involved in many reactions that support longevity. Primarily by promoting autophagy and regulating the energy levels within our cells. Since the AMPK enzyme helps regulate the energy expenditure and health of our cells, it also aids in overall well being in the body as a whole. There is a growing body of evidence that suggests that boosting AMPK activity can prevent, and even reverse, life-shortening effects of aging. This includes disorders as disparate as cardiovascular disease, diabetes, liver and kidney failure, neurodegenerative diseases (such as Alzheimer's), cancers. Some researchers are referring to AMPK as literally a suppressor of aging itself.
AMPK has been referred to as a "metabolic master switch." AMPK controls a wide range of metabolic pathways that enables us to extract energy from food, distribute and store that energy safely through the body, and ultimately use that energy for all body functions.
The basic function of AMPK is to sense each cell's energy status at every moment, and to trigger responses that maintain the cell's energy at precisely the optimum level. Too little available energy starves the cell, while too much energy can exhaust and disrupt cellular components. In either case, the cell functions inefficiently. That energy inefficiency ultimately leads to the dysfunctions we call the diseases of aging.
The detailed operation of AMPK: Every cell in the body depends on a steady supply of energy in the form of chemical bonds. When one eats and absorbs nutrients, energy from the chemical bonds in food is released and passed down a complex series of enzymes until it is stored again in a molecule called adenosine triphosphate (ATP). The more ATP that is present in the cell, the higher the cell's available energy supply. When ATP is broken down to release energy for cellular work, a major end product is adenosine monophosphate, or AMP.
If a cell were to use up all the energy from its ATP, it would fill up with low-energy AMP molecules. It would then run out of energy, and then it would collapse and die, unable to sustain even the simplest energy-requiring processes.
AMPK is biologically activated by the presence of rising levels of AMP (and decreasing levels of ATP). Activated AMPK, in turn, increases fatty acid oxidation and glucose transport, thereby releasing additional energy from available or stored sources (fats and sugars).
These processes all work together to provide a balanced cellular metabolism which keeps a tight control over cellular energy levels so that they never fall low enough to impair cellular activity, and never rise high enough to damage the cellular machinery.
AMPK activity fades with age. Also, when too many calories are available, the result is accelerated tissue aging. Boosting AMPK activity will keep body tissues young and slow aging throughout your body.
There are many benefits of AMPK activation. This includes enhancing cognition and increasing longevity. Also, AMPK signals cells to devour stored fat in response to perceived energy (food) shortages. AMPK activation promotes a process known as "autophagy", which helps to rid cells of metabolic waste. If there is restricted food intake, AMPK turns down cell proliferation to conserve energy.
Another long-term benefit of AMPK boosting is the creation of new mitochondria. Mitochondria are the "powerhouse" of the cell where much of our energy is derived. There is also evidence that the AMPK activator has a crucial role as an antioxidant, which can reduce oxidative stress.
AMPK is useful for longevity support and anti-aging by itself because it activates many pathways that increase longevity. One animal study showed AMPK activation alone could increase lifespan by 15%.
AMPK is a vital enzyme that affects many aspects of the brain, it can have many neural benefits. Also, AMPK activation can protect against cancer by reducing DNA damage from oxidative stress. But it also promotes glucose uptake by cells, which means cancerous cells may have some of the same advantages as normal body cells.
There is mixed evidence on whether AMPK increases risk of diseases such as Alzheimer's and Huntington's disease. Some studies suggest that activation of AMPK is detrimental while other studies show the opposite. There appears to be more evidence in favor of AMPK helping in these neurodegenerative diseases than against it, but it is an open issue at the moment.
Metabolic Syndrome or Quetelet Syndrome is a medical concept that measures waist and height. It turns out to be a good predictor of serious future health issues caused by excess visceral belly fat. BMI is calculated by dividing the weight (in kg) by the height squared. The normal range is 18.5 to 24.9. Any value greater than that is considered overweight that it may be desirable to remove. AMPK boosting helps remove such fat by effectively telling cells to stop storing the fat and use it for producing energy. AMPK boosting products are being marketed for just this purpose.
There are several natural AMPK activator mechanisms. Here are some of the most common nootropics for boosting AMPK -
Anyone contemplating a weight-loss program that involves reducing calorie intake along with greater physical activity should ensure they get maximum results by increasing their cellular AMPK activity.
AMPK activation can be accomplished with a once-daily nutrient combination of standardized extracts of Gynostemma pentaphyllum and hesperidin. Life Extension makes an AMPK booster called "AMPK Metabolic Activator." It contains 500 mg hesperidan, and 450 mg gynostemma.
Whether you choose to incorporate more of these lifestyle habits into your life or opt for nootropic supplementation, AMPK boosting influences aging and optimal cognitive performance. It is only one of the many factors involved with aging, but optimizing can have positive long-term effects.
A person with MCS, found that AMPK boosting supplementation does not obviously alter the basic MCS neural injury reaction, but does promote building up the body so a person can better tolerate the many side effects of MCS. No adverse effects were noted.
One person with MCS also developed a serious nocturia problem. Nocturia is having to get up to go to the bathroom two or more times a night. It is a problem for some 20 to 30 percent of the elder population, but it is poorly known and supported. Using an AMPK booster definitely did decrease the number of bathroom calls to some half the previous times. Research is needed in this area.
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