Science/Research thread by @siimland

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NAD is considered a longevity molecule

It decreases with age and low levels of NAD accelerate the hallmarks of aging

But most people go about raising NAD levels the wrong way

Here's a thread about how to maximize your natural NAD production and minimize its loss⬇️⬇️

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First, what is NAD

NAD or Nicotinamide Adenine Dinucleotide is a co-enzyme that’s found in all living cells

You need NAD for:
- energy production
- metabolic processes
- mitochondrial function
- antioxidant defense
- DNA repair
- circadian rhythm

PMID: 26118927

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With age, you see a decrease in NAD levels primarily due to increased oxidative stress and reduced antioxidant defense (PMID: 22848760)

This increases hallmarks of aging, such as cell senescence, DNA damage, and mitochondrial dysfunction (doi: 10.1016/j.tma.2018.08.003)

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What's the reason NAD levels decline with age?

Primarily because it's degraded and destroyed by oxidative stress

The primary protein responsible for that is CD38 - with age you see an increase in CD38 and a corresponding decrease in NAD levels (PMID: 27825999)

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So, step number 1 is to prevent losing NAD to CD38, which is primarily raised by inflammation

This includes some of the fundamentals of a healthy lifestyle:
- avoiding becoming overweight and obese
- avoiding hyperglycemia and dyslipidemia

(PMID: 27825999)

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There are also specific compounds that act as CD38 inhibitors, thus helping to raise NAD levels

They include flavonoids like:
- apigenin (parsley, chamomile)
- quercetin (onions)
- luteolin (radicchio)
- kuromanin (elderberries, blackberries)

pmc.ncbi.nlm.nih.gov/articles/PMC36…

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Now, let's move forward with raising NAD

There are 3 main pathways by which you can make NAD
1. De Novo biosynthesis pathway that uses tryptophan as a precursor
2. Preiss-handler pathway that uses nicotinic acid
3. And the Salvage pathway (recycling of NAD)

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Supporting pathways 1 & 2 is relatively easy - tryptophan and nicotinic acid are abundant in the average person's diet 

But these pathways don't matter as much as the salvage pathway

Why? Because the vast majority of your daily NAD is produced by the salvage pathway

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The salvage pathway has a bottleneck called NAMPT

NAMPT is the rate-limiting enzyme in the NAD salvage pathway, meaning it controls how much NAD gets recycled

PMID: 17268245

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How do you activate NAMPT?

Through AMPK - the fuel sensor that gets activated under physiological stress, such as exercise, calorie restriction, or fasting

PMID: 23918774

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However, there's a condition for NAMPT as well

NAMPT is SIRT1 dependent, which means that it's dependent on circadian rhythm regulation

PMID: 24003918
PMID: 19286518

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Disrupting circadian rhythms suppresses the NAD+ dependent SIRT1 gene which then lowers the availability of NAD+

Circadian rhythms of NAD+ are driven by the circadian clock called CLOCK:BMAL1 which regulates the circadian expression of NAMPT

PMID: 18662547

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Thus, the cornerstone to making NAD on autopilot via the salvage pathway is circadian rhythm alignment

The top other ways to increase NAD naturally via recycling NAD are:
- exercise
- calorie restriction
- dietary phytonutrients

But circadian alignment is key

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NAD boosters like NMN or NR are worth only to the degree of how well your salvage pathway is working

Because all the NAD you create through any pathway (NAD boosters or diet) will be directed back into the salvage pathway where it will meet the bottleneck NAMPT

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Here's the hierarchy of raising NAD levels and maintaining them during aging:
1. Minimize NAD loss by inhibiting inflammation and CD38
2. Maintain circadian rhythm alignment to keep NAMPT online
3. Activate AMPK that stimulates NAMPT with exercise
4. Dietary precursors to NAD

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Siim

NAD is considered a longevity molecule It decreases with age and...

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