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Restoring cellular NAD: a possible new key to anti-aging

Finding effective anti-aging treatments has always seemed daunting and understandably so. Aging is believed to be an exceedingly complex process involving many disparate biological mechanisms, including unrepaired DNA damage, free radicals, waste accmulation, inflammation, mitochondrial burnout, gene disregulation, stem cell dysfunction, and others (see the complete list). Even if you netralized one "enemy" from that "evil gang", the others would still get you soon enough, wouldn't they? Indeed, while the average human lifespan has risen considerbly in modern times (mainly due to sanitation, antibiotics, safer working conditons and lower child mortality), the maximum human lifespan remans depressingly unchanged despite continues progress in our understanding of the aging process.

The good news is that the outlook seems to be changing. In particular, recent research indicates that nomalizing the level of nicotinamide adenine dinucleotide in the cell of older animals inhibits multiple mechanisms of aging and may slow down and even reverse several aspects of the aging process.

Nicotinamide adenine dinucleotide (aka NAD or NAD+ to indicate its positive charge), is a molecule found in vitually all forms of life. It plays a key role in many metabolic reactions including being a co-enzyme and regulator in the process of energy production. In aerobic (oxygen-breathing) organisms, which include almost all animals, NAD is critical for proper function of mitochondria, cellular organelles responsible for power generation.

As we age, the cellular level of NAD declines, which appears to contribure to multiple mechaninsm of aging. In particular, without sufficient NAD, motochondira do not function properly, partly because low NAD in the cells's nucleus causes imbalance in the prodction of mitochondrial proteins (some of which are encoded in the nucleus while others in mitochondria themselves). As a result of this imbalance, instead of producing lots of usable energy (in the form of ATP) and very little toxic waste (in the form of oxygen free radicals), motochondira begin producing less energy and a lot of harmful free radicals. Excess free redicals damage DNA, proteins and other key molecules, whereas energy deficiency weakens the cell's repair and waste disposal systems designed to mitigate the damage and/or clean up its consequences. The low level of NAD also appears to contribute, directly or indirtectly, to gene disregulation, stem cell dysfunction, inflammation and possibly other machnisms of aging. Also notable is the finding that NAD levels affect the activity of sirtuins (particularly the sirtuin called SIRT-1), the regulatory enzymes largely responsible for the anti-aging effects of caloric restriction. High sirtuin activity, for which high level of NAD is required, is associated with reduced rate of aging seen during caloric restriction in many specias.

It is tempting to suppose that raising the level of NAD back to the youthful norm may improve mitochondrial function and inhibit many aspects of the again process. In fact, recent research appears to support that idea. In a 2013 study, Dr Ana Gomes and others have shown that restoring NAD levels in 2-year old mice to the youthful norm (the level of 6-month old mice), largely reversed the age-related impairment of mitochondrial function a.k.a. mitochondrial burnout. In another study, Dr Jun Yoshino and others have shown that restoring NAD levels reversed diet and age-related diabetes in mice. In fact, an array of animal studies demonstrated a variety of anti-aging and therapautic effects of restoring NAD levels, from cancer rate reduction to amelioration of neurodegenerative diseases to improved stem cell function (see the review here). All this indicates that restoring NAD level might to some extent inhibit the aging process as a whole and not just one particular aspect of it.

Unfortunately, little research has been done so far on the benefits of restoring NAD levels to the youthful norm in humans. However, the core metabolic and regulatory processes in which NAD plays a role are essentially the same in all mammals and one can reasonably hope that humans will respond at least somewhat similarly to mice. In fact, a 2016 study by Dr Charles Brenner and colleagues published in the journal Nature Communications showed that NAD level can be reliably and seemingly safely raised in humans (at least in the short-term) by simple means used in some animal studies. What is needed are human clinial trials of the health and anti-aging benefits of restoring NAD to youthful levels. A few such trials are under way and more will hopefully follow.

How can cellular level of NAD be raised?

The bad news is that ingesting NAD has little or no effect on its level in the cells, possibly because it is metabolized in the liver before getting there. Intravenous infusion of NAD may also be insufficiently effective and is not feasible for practical use anyway. The good news is NAD does not have to be devivered directly into the body to raise its level in the cells. It is usually sufficient to enhance the body's ability to produce its own NAD.

NAD is produced in the body via several converging biochemical pathways most of which start with a form of vitamin B3. The most common forms of vitamn B3 are nicotinic acid and niacinamide. Ingesting nicotinic acid or niacinamide can raise cellular NAD levels, but the effect is modest and the required doses high enough to potentially cause short and long-term side effects. Whereas nicotinic acid and niacinamide are easily available and inexpensive, they do not seem to be suitable as a means of raising cellular run in a sustained manner. (Notably, niacinamide is somewhat more effective that nicotinic acid).

Enter nicotinamide riboside (NR), a natural substance sometimes considered a more exotic form of vitmain B3. Nicotinamide riboside is two metabolic steps away from NAD. In the body, it is converted to nicotinamide mononucleotide (NMN) which then is converted to NAD. As far as rasing NAD via NAD precursors is concerned, this pathway appears to be the most effective. Several animal studies have shown that ingesting NR or NMN leads to a reliable increase in the level of NAD in the cells. NR supplementation has been shown to increase NAD in humans without any apparent side effects at least in the short term (as reported here). A clinical trial using NMN to raise NAD levels in humans is under way. Considering that NMN works in animals and is one metabolic step closer to NAD than NR there is a good chance it works as well.

Both NR and NMN appear to be the agents that can be taken orally and appear capable of raising NAD level in the cells to the youthful norm. Both are found in nature and considered to be forms of vitamin B3. As a result, they can be sold without prescription as food supplements of vitamins. In theory, MNM might be more effective because it is just one conversion step away from NAD, whereas NR is two steps away. However, this may be of little prectical significance because the conversion of NR to MNM does not appear to be rate limiting. Forthermore, as of the time of this writing, NR is easily available as a nutritional supplement while NMN is not. NR also has more safety data ragarding use in humans.

All in all, as of the time of this writing, if one were to treat low NAD levels in humans, NR supplementation would appear a better choice. Unfortunately, the long-term effects of NR use in humans are unknown and the best treatment pratices are unclear. Based on the very limited human research available, the optimal daily dose of NR (at least for a short-term course) seems to be somewhere between 250 mg and 500 mg per day (as discussed here).

In the light of the above, a prudent course of action is to wait for more human data on NR or NMN suplementation before trying it out. However, this may take years or decades. Some people are trying NR already hoping for health and longevity benefits and lack of side effects. Whether such an "educated gamble" is worthwhile is ultimately a personal choice that should be made only after getting as well-informed as possible.

Raising NAD may help rejuvenate the skin

Skin aging is driven by a combination or external and internal factors. The former are sun exposure (UV), detergents, environental irritants, and the like while the latter are the mechanisms of aging occurring in all cells and tissues. The external factors are easier to neuralize (see our skin-protection section) but that only gets you so far. To further slow down or perhaps even partially reverse skin aging, one needs to inhibit the intrinsic mechanism of aging in the skin. As we discussed above, rasing NAD may help inihibit several mechanisms of aging at once and thus appears a highly promising approach to skin rejuvenation.

Unfortunately, as of the time of this writing, there is virtually no direct research data on the benefits of boosting NAD in the human skin, nor on the best way to do so.

We can speculate that the aforementioned oral treatment with nicotinamide riboside (NR) would likely raise NAD levels in skin cells just is it does so elsewhere in the body, potentially resulting in noticeable skin rejuvenation. However, attempting an oral treatment with NR may be premature until more research is available.

On the other hand, we know that niacinamide, a form of vitamin B3 that modestly raises cellular levels of NAD, has multiple skin benefits when used topically (see our niacinamide article). If the skin benefits of topical niacinamide are due to increased NAD levels, then topical NR is likely to be even more effective. Furthermore, topical NR is likely to raise NAD in the skin but not elsewhere in the body, minimizing the risk of systemic side effects if any. The downside is that optimal NR concentration and topical delivery vehicle (for the purpose of achieving youthful NAD levels in the skin) have not been established. Furthermore, no skin care products with NR are available as of the time of this writing. Therefore, if you nonetheless want to try topical NR, you will have to make it yourself. This is actually relatively straightforward (for details see DIY Anti-Aging Skin Care Infopack).


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