Reversing ageing: major new breakthrough seen with NMN

The older we get, the less stamina we have. It’s an inevitable regression which, at least for the moment, none of us can escape. The main cause is a gradual decline in our blood vessels, especially their ability to deliver the nutrients needed for the healthy function of muscle tissue.

The good news is that huge progress has been made in recent years in understanding the driving forces behind this decline and reducing its scope. A research team has just found a way of reversing this loss of ability using a compound that promotes the growth of new blood vessels.

Before designing this ground-breaking study, the researchers involved noted the following two points:

• Advancing age leads to a decline in the body’s levels of nicotinamide adenine dinucleotide (NAD) due to reduced NAD production and faster NAD degradation (1-3). NAD is a key coenzyme which is involved in many of the body’s cellular processes (4).
• It appears that NAD activates the genes responsible for production of sirtuins (5-7), proteins which line the inside of blood vessels and which several studies have linked to muscle ageing. Like NAD, sirtuin levels also decline with age, a serious development given that sirtuins, often referred to as "longevity proteins", are involved in numerous mechanisms throughout the entire body. This reduction in sirtuin levels is associated with many age-related health issues (heart problems, neurodegenerative diseases, etc.).

The researchers then posed a number of questions.

1) How do we know if the decrease in sirtuin levels in blood vessels is responsible for declining stamina?

To address this question, they deactivated the SIRT1 gene, which encodes major mammalian sirtuin, in six month-old mice. Without this gene, these mice would theoretically have significantly-reduced sirtuin activity in their blood vessels.

After a period of two months, the sirtuin-deprived mice were seen to have reduced capillary density compared with control mice of the same age, and to run only half the distance of their normal counterparts.

2) What would happen if sirtuin levels were increased in ageing mice? Would it improve their stamina?

Given that a decrease in sirtuin activity leads to a decline in stamina, could it be that increasing this activity would also increase capillary density and thus improve stamina? In order to confirm this theory, the researchers faced another challenge: how to increase sirtuin levels in blood vessels.

The scientific literature shows that supplementing with NAD is not the most appropriate option here as it is not absorbed as such by the body. The study’s authors therefore turned to a molecule which is both able to cross the intestinal barrier and is also converted into NAD in the body – in other words, a precursor. The most direct precursor of NAD, and indeed the one used by the researchers in their study, is NMN (nicotinamide mononucleotide).

After two months’ treatment with NMN, the ageing mice were found to have the same capillary density as their younger counterparts. In terms of exercise endurance, the researchers recorded a 56%-80% improvement in performance in the treated mice compared with untreated mice of the same age. Similar effects were subsequently observed in the mice at the age of 32 months, which corresponds to 80 human years!

Excited by these findings, the researchers immediately saw opportunities for restoring human muscle tissue lost in the course of ageing. Such interventions could help fight the effects of ageing and the fragility which leads to falls, osteoporosis and incapacitating conditions. “There’s a lot of reciprocity between muscle and bone”, commented one of the study’s authors, Leonard Guarente, “ so losing muscle mass can lead to a loss of bone”.

A more detailed look at NAD

What are the various precursors of NAD?

There are three pathways through which NAD is produced in the human body, each involving a different precursor that acts to boost NAD levels in cells.

a) De novo biosynthesis.

Tryptophan, an essential amino acid provided by the diet, is converted into NAD in the body via a number of intermediates.

b) The Preiss-Handler pathway

Niacin (NA), a form of vitamin B3 found in food, is converted first into NMN, and then into NAD.

c) The salvage pathway

The body is able to reform NAD molecules from nicotinamide (Nam) and nicotinamide riboside (NR), which are both precursors and degradation products of NAD. This is why this method is called the salvage pathway. Nam and NR are converted first into NMN and then into NAD.

Why not just supplement with NAD itself?

Studies show that NAD is broken down in the small intestine by intestinal epithelial cells (8). It is converted into NMN by several gut enzymes, and then into various metabolites such as NR and Nam. It is these metabolites which cross the intestinal barrier and then reach the body’s cells as a whole, where they are converted back into NAD.

So supplementing with NAD (or NADH) is by no means ineffective, but it is generally better to supplement direct with NMN, NR or Nam, in order to avoid these successive breakdown and reconversion stages. However, as NAD supplements are much less expensive than these precursor supplements, they are still an option worth considering.

Can NAD precursors be found in the diet?

To ensure de novo synthesis of NAD, the body needs tryptophan, the best sources of which are brown rice, meat, dairy products, eggs, soya protein, peanuts, pulses and nuts.

Nicotinamide riboside (NR) is found in milk (9), but the best sources of NAD precursors are raw foods (plant- or animal-source). The human digestive system, helped by gut flora, breaks down NAD from other organisms into various compounds which can be used to reform NAD via the ‘salvage pathway’ (10).

How can we increase our NAD levels?

1) Through supplementation with NAD precursors

NA (niacin) is a recognised NAD precursor but it often causes mild flushing (vasodilation) on the face and neck (11) when supplementation first begins. As for Nam (nicotinamide), while its ability to be converted into NAD is beyond doubt, it may moderate increases in sirtuin activity (12). The following two forms are therefore preferable:

• NR (nicotinamide riboside), more effective at boosting NAD levels and less expensive than either NA or Nam, and very well-tolerated (13). Supersmart offers a nicotinamide riboside supplement in the form of 125mg capsules.
• NMN (nicotinamide mononucleotide), the most direct precursor of NAD. It’s no coincidence that this was the compound used in the study referred to in this article: it’s considered by far the best in its category. It is not so widely-available but can be found in pro-longevity supplements such as Supersmart’s NMN supplement which comes in 50mg capsules. It has rapidly become the first choice supplement for those wishing to slow down the ageing process, despite its cost which matches its high popularity.

These are all forms of vitamin B3, a compound which is essential for every cell in the body. Deficiency in this vitamin is common and may manifest in tingling, loss of appetite, fatigue and mood swings.

2) Through increased physical activity and a healthier diet

The study’s authors found that exercise also stimulates the growth of new blood vessels and boosts muscle mass. However, when they deactivated the SIRT1 gene in the endothelial cells of certain mice and then subjected them to a four-week treadmill running programme, they found that exercise did not produce the same muscle gains as those seen in normal mice.

Previous studies had demonstrated the link between increased NAD levels and physical activity (14), as well as calorie restriction (15), two factors associated with longevity. In contrast, a high-fat diet (16-17) appears to accelerate the decline in NAD levels over the long-term …

Key points of the article

• Administration of NMN to ageing mice increased their capillary density and produced significant improvements in their exercise capacity.
• NMN is converted in the body into the coenzyme NAD, production of which declines with age. It plays a role in encoding proteins called sirtuins which are essential for healthy blood vessel and muscle function.

Will we one day know how to reverse the ageing process? And will we all be able to truly benefit from such an advance? One thing’s for sure: this study marks a turning point in the fascinating quest for immortality and clearly demonstrates that the limits of life expectancy can be pushed back still further. Provided, that is, that we rapidly take on board the new barriers to such progress: endless industrialisation of our food and the widespread prevalence of chronic stress.

Study at the centre of the article

Abhirup Das, George X. Huang, Michael S. Bonkowski, Alban Longchamp, Catherine Li, Michael B. Schultz, Lynn-Jee Kim, Brenna Osborne, Sanket Joshi, Yuancheng Lu, Jose Humberto Treviño-Villarreal, Myung-Jin Kang, Tzong-tyng Hung, Brendan Lee, Eric O. Williams, Masaki Igarashi, James R. Mitchell, Lindsay E. Wu, Nigel Turner, Zolt Arany, Leonard Guarente, David A. Sinclair. Impairment of an Endothelial NAD -H 2 S Signaling Network Is a Reversible Cause of Vascular Aging. Cell, 2018; 173 (1): 74 DOI: 10.1016/j.cell.2018.02.008