Ageing, NAD+ and Biological Complexity


Ageing and biological complexity

Ageing is incredibly complex. In fact, ageing might well be the most complex disorder we know.  But scientific understanding of how and why we age has come a very long way in recent years. We now understand that ageing involves multiple failures of cell and tissue function, which are locked together in a complex and accelerating spiral of decline. Epigenetics, mitochondrial changes, inflammation, disordered energy metabolism, senescent cell population growth, disordered signalling, diminished DNA repair ... the list of “contributors” continues to grow.

To add to this complexity, each contributing dysfunction itself involves hundreds of different proteins operating in networks. Viewed overall, then, the whole of age-related decline is a colossal cascade of complexity, spinning ever faster toward inexorable system failure.


The Magical Thinking Bullet

In light of all this complexity, it seems strikingly unlikely that doing only *one* thing to fix it all, is going to be enough to beat age-related disease and physical decline. Taking one molecule to try to make this mortal engine spin back up to full function is not going to cut it.

So, if we want to have a meaningful impact on ageing, it is clear that several issues have to be tackled simultaneously, and we’re going to have to do lots of targeted interventions at the same time.


NAD+ and biological complexity

Let’s contrast that insight with the idea of taking one molecule to try to affect ageing. 

We all now pay more attention to individual ingredients in products. Attention has recently been paid to NAD+ precursor molecules, such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) and nicotinamide (NAM). These molecules are currently being consumed as supplements by those wishing to boost their falling NAD+ levels. 

At first sight, an NAD+ precursor seems a good idea – you are giving the cells more of the raw material that they need to be able to synthesise NAD+. But let’s examine whether this simple idea is really consistent with the underlying complexity, and whether it’s going to give the benefits that people hope for.

These NAD+ precursors are intended to benefit older peoples’ cells and tissues. But their cells and tissues differ in important ways from young ones, and several of these changes relate to NAD+ metabolism. Older people, for example, often suffer from increased inflammation, which is associated with greater expression of the CD38 protein, which uses up great quantities of NAD+. Similarly, cells’ ability to make and recycle NAD+ declines with age over time. One of the main enzymes (NAMPT) that generates most of our NAD+ from endogenous precursors declines in abundance with age. In healthy young cells, as NAD+ is used up by cellular processes, it is converted into nicotinamide, and NAMPT recycles this nicotinamide back into fresh NAD+. Older cells don't have sufficient NAMPT to do this efficiently, and so nicotinamide is methylated and excreted at a greater rate than for young cells. The net effect of these changes over time is a decline in NAD+ levels, but it is clear that the root of the problem is not simply a shortage in the supply of NAD+ precursor to the cell.

These considerations remind us that cellular NAD+ metabolism is in itself a perfect example of a biologically complex system with many moving parts that become dysregulated with age. With this in mind, might it be a little naïve to think that falling NAD+ levels could be fixed with a precursor alone?  How might the real biological complexity trip up this simple precursor approach?

 

The lone NAD+ precursor

Taking an NAD+ precursor alone does result in a small uplift in NAD+. What else happens? We know that in older cells the enzymes in the metabolic network around NAD+ have a reduced capacity to synthesise and recycle NAD+, and that they have significant capacity both to degrade NAD+ via CD38 and to methylate and excrete NAD+ breakdown products. These features of an older network mean that at least three unwanted, self-defeating effects are likely:

(1) NAD+ boosting can empower, via CD38, the SASP and inflammation, and so promote senescence;

(2) an increase in waste nicotinamide may suppress Sirtuin activity and DNA repair, so suppressing DNA repair and cell maintenance; and

(3) increased flux of breakdown products can cause methyl depletion and stress liver and kidney function.

Hence, it is probable that NAD+ precursor supplementation alone yields a small step forward, and three giant leaps back.

 

Designing better NAD+ interventions

Is it possible to do better than that by taking account of the complexity of NAD+ metabolism in older cells and tissues? Would it be more scientifically plausible to take a multitargeted approach? Just how many targets would one actually need to address before you really begin to make a beneficial impact? How can you really get your NAD+ back up to youthful levels and gain the benefits of doing that?

Firstly, let’s look at what happens when you take a precursor supplement (e.g. NR, NMN, Niacin, niacinamide).  Products containing these ingredients have been shown to boost cellular NAD+ levels by around 60% on average – but this is immediately confronted by the fact that the cells’ ability to synthesise and recycle NAD+ from precursors is disrupted.

So how about an NAD+ precursor plus promotion of NAD+ synthesis enzymes and the networks that promote those (e.g. NAMPT, NQO1, AMPK). This would be better - but it still doesn’t address the fact that this combination is going into older cells that have more of the enzymes that break down NAD+ (e.g. CD38).

This implies an approach that not only promotes NAD+ synthesis, but also discourages degradation. For example, an NAD+ precursor plus promotion of NAD+-synthesis enzymes plus suppression of NAD+-destroying enzymes (e.g. CD38) - but isn’t that going into older cells that breakdown and excrete all NAD+ above a relatively low level?

It soon becomes evident that in order to restore NAD+ to youthful levels, a multitargeted strategy far more complex than a single precursor is required: An NAD+ precursor plus promotion of NAD+-synthesis enzymes plus suppression of NAD+-destroying enzymes plus suppression of NAD+ excretion (e.g. NNMT) in favour of NAD+ salvage.

Based on this strategy, let’s look at the “targets” that we’ve arrived at, and then relate them to Nuchido’s TIME+ ingredients. The targets we have are:

 

NAD+ precursor - promotion

NAMPT – promotion

NQO1 – promotion

AMPK – promotion

CD38 – suppression

NNMT - suppression

Now let’s look at the chemical biology of TIME+ ingredients, for example:

 

Niacinamide (NAD+ precursor)

Parsley (apigenin) (promotes AMPK, suppresses CD38)

Green tea extract (EGCG) (suppresses NNMT, promotes NQO1)

Rutin (promotes NAMPT, AMPK, suppresses CD38)

Alpha Lipoic Acid (promotes NQO1, AMPK)

So, we have a many-to-many mapping between our desired targets in NAD+ metabolism and TIME+ ingredients:

 

Nuchido Time+ ingredients give these effects via their detailed chemical biology, mostly by affecting expression of the targets.

 

TIME+ and systems design for NAD+

So, what evidence is there that this “systems” approach to NAD+ restoration is an improvement over a precursor alone?

First, TIME+ typically boosts NAD+ about four times more than is achieved with a precursor. It does this with a less bioavailable precursor than NR, and so this much improved uplift in NAD+ can only derive from successful intervention on NAD+ metabolic enzymes.

Second, on the way to refining TIME+, closely related combinations showed direct evidence of NAMPT abundance being promoted.

Third, one of those combinations without any precursor produced NAD+ elevation similar to that from a precursor alone.

Fourth, these combinations showed direct evidence of the upregulation of SIRT1, which would not have happened if sirtuin function were diminished by methylation products of excess NAD+.

Hence, TIME+ systems design does address the problems that a precursor alone cannot, to deliver the beneficial effects we all want. Restored NAD+; DNA repair potentiation; without driving inflammation and senescence; and without stressing excretory systems. Four steps forward!