David Sinclair's Theory of Aging

LifeSpan book notes, Why I take NMN, Sirtuins, NAD+,

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Epigenetic Theory of Aging Series

As many of you know, I’ve been writing an Aging series where I distill some of the basics around the Epigenetic theory of Aging. This post is Part 4 in the series and discusses Dr. David Sinclair’s Informational Theory of Aging and notes from his popular book LifeSpan. I’ve broken out the previous posts in order below so it’s easy for you to go back and read them or follow along.

Aging: the what, the why, the fix series:

  1. Part 1: Gene Expression and Aging

  2. Part 2: DNA Methylation - Why You Age

  3. Part 3.1: Epigenetic Clocks - Know Your Time to Death

  4. Part 3.2: Epigenetic Clocks - How to Measure Your Biological Age

  5. Part 4: David Sinclair’s Theory of Aging


David Sinclair’s Informational Theory of Aging

Doug: Hey Molly, your story on King Caputi made it incredibly easy to understand DNA methylation and its link to aging. Thanks for making science so digestible. If you recall, your Aging series began with my question on the hype around NAD+ and how it can reverse aging...

Molly: Yes, yes NAD+. Let’s dive right in. You might be familiar with Dr. David Sinclair - he runs an Aging lab at Harvard and wrote a massively popular book called LifeSpan: Why We Age - and Why We Don’t Have To. He has been instrumental in pioneering support for the Aging field. 

Today, I will explain his theory of aging which also convinced me to supplement with NMN.

Let’s begin with a quote from the book LifeSpan:

“The loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.”

I will unpack this quote for you.

Epigenetic Modifications, Gene Expression, and Aging

Molly: In Part 1, I explained to you that even though gene regulation and gene expression is stable in our youth, the expression of genes can go haywire as we age. In Part 2, I discussed how epigenetic modifications such as DNA methylation regulate gene expression. As we age, we see abnormalities in DNA methylation, resulting in abnormalities in gene expression, resulting in aging. 

Abnormalities in DNA Methylation -> Abnormalities in Gene Expression -> Aging

Histone acetylation / deacetylation1 is another epigenetic modification that regulates gene expression.

My point in bringing this up is that a key crux of the epigenetic theory of aging is that abnormalities in epigenetic modifications (DNA methylation and histone acetylation) results in dysregulation of gene expression, thereby resulting in aging. 

Doug: Okay, so then my next question is what is causing these abnormalities in epigenetic modifications and how we can prevent it?

Molly: Yes, so we discussed DNA methylation already. Let me now turn to histone acetylation which is where Sinclair’s theory comes in2.

Sirtuins and their role in longevity

Enter sirtuins. Sirtuins are enzymes that play an important role in the healthspan and longevity of humans and other organisms. They protect against major diseases of aging such as heart disease and Alzheimers, they boost your mitochondria, they help with DNA repair, improve memory, increase exercise endurance, and even control reproduction. In short, they are critical to several important processes in the body. There are 7 sirtuins3 in mammals and each one has an important role to play.

Some sirtuins have a double role to play - they control epigenetic processes as well as help in DNA repair. One such epigenetic process that is regulated by sirtuins is histone acetylation / deactylation - essentially sirtuins will help remove acetyl tags from histones, ensuring that your DNA packaging is in order, and thereby regulate gene expression4.

Doug: Okay, so we have established that sirtuins are essential because they regulate epigenetic processes in the body and help with DNA repair. 

Molly: Yes and the issue starts to kick in because they can’t do both at the same time. 

Whenever there is DNA damage, sirtuins are called upon to initiate the process of DNA repair. When sirtuins are engaged in repairing the DNA, their other function of regulating the epigenome is on pause. And by now you know what happens when there is dysregulation in epigenetic functions..

Doug: Yes - it messes up gene expression which results in aging!

Molly: Yep! Quoting from the book LifeSpan:

“Whenever epigenetic factors (sirtuins) leave the genome to address damage, genes that should be off, switch on and vice versa. Wherever they stop on the genome, they do the same, altering the epigenome in ways that were never intended when we were born.

Cells lose their identity and malfunction. Chaos ensues. The chaos materializes as aging. This is the epigenetic noise that is at the heart of our unified theory.”

Essentially, when sirtuins engage in DNA repair, they cannot regulate epigenetic functions, thereby resulting in abnormalities in gene expression, which ultimately causes cells to lose their identity and shows up as aging.

Doug: And as we get older, there is more DNA damage, and more need for DNA repair, which means sirtuins don’t regulate epigenetic activities as much, causing abnormalities in gene expression.

Molly: Spot on! Again, quoting from the book:

“When sirtuins shift from their typical priorities to engage in DNA repair, their epigenetic function at home ends for a bit. Then, when the damage is fixed and they head back to home base, they get back to doing what they usually do: controlling genes and making sure the cell retains its identity and optimal function.

But what happens when there’s one emergency after another to tend to? The repair crews (sirtuins) are away from home a lot (their normal function of regulating the epigenome). The work they normally do piles up.

What would cause so many emergencies? DNA damage. And what causes that? Well. over time, life does. Malign chemicals. Radiation. Even normal DNA copying. These are the things that we’ve come to believe are the causes of aging...what’s happening every day is that the sirtuins and their co-workers that control the epigenome don’t always find their way back to their original gene stations after they are called away.” 

And this is when cells begin to lose their identity and malfunction, resulting in aging.

Summary of the Informational Theory of Aging:

Sirtuins have a double role to play in regulating gene expression and conducting DNA repair, but they cannot do both at the same time. When there is DNA damage, sirtuins are called upon to conduct DNA repair, thereby halting the regulation of gene expression. Temporarily this is okay, but when DNA damage keeps accumulating with age, sirtuins have to constantly engage in DNA repair. As such, they cannot conduct their function of regulating gene expression. This results in gene expression being dysregulated, cells losing their identity, and eventually manifesting as aging.

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Sirtuins and NAD+

Doug: Thanks for explaining that - I now see why sirtuins are so important! But where does NAD+ fit in?

Molly: Yes, so sirtuins require a co-factor called NAD+ to carry out their functions. As we age, NAD+ levels decline. (So far the research says that one of the reasons might be a protein called CD38. But the topic of why NAD+ levels decline with age is for another day.)

The important point to know here is that as NAD+ levels decline with age, sirtuin activity is reduced since sirtuins need NAD+ to carry out their functions. Which means that DNA repair activities and gene regulation activities are reduced. The worst part is that with age, DNA damage accumulates resulting in a need for increased DNA repair activity, and an increased need for sirtuins to play a role. But given that NAD+ levels decline with age, sirtuins in fact are worse off at carrying their functions when we need them the most. 

Doug: It’s like everything comes crashing down at the same time with age.

NMN Supplementation to boost NAD+

Molly: Unfortunately, yes. But, if we find a way to boost our levels of NAD+ levels with age, sirtuin activity won’t decrease and perhaps they can even become better at carrying out DNA repair and also regulating gene expression.

Doug: So if we can boost NAD+ levels, we can increase sirtuin activity, thereby enabling better regulation of gene expression and DNA repair, and hence slowing aging.

Molly: Yes, that is one such theory proposed by Dr. David Sinclair. And one way to boost NAD+ levels is to supplement with NMN or NR, both of which are precursors to NAD+. And this is why I supplement with NMN!

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P.S. Mice studies show great promise of NMN. In mice, NMN has been shown to boost exercise performance, strength, memory and can protect against kidney damage, neurodegenerative diseases, and mitochondrial diseases.

However, please note that human studies on NMN supplementation are ongoing and there is no data yet. If you choose to supplement with NMN / NR, please do so at your own risk. I supplement with NMN because I believe in David Sinclair’s theory and he has mentioned in the past how he supplements with NMN too. Plus, even if it doesn’t have any positive effects, I don’t think it would have negative effects, but again no human studies have been done!

If you don’t want to supplement with NMN to raise your NAD+ levels, other ways to boost NAD+ include exercise, fasting and caloric restriction! I’ll also be posting some foods that can boost NAD+ on my Instagram, so follow me there if you’re curious to know.

Until next time! Stay in good health and do not hesitate to give feedback or comment with your questions!

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1

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/histone-acetylation-and-deacetylation

2

In fact, DNA methylation and histone acetylation are linked. Biology rarely works in silos and several processes in your body relate to each other

3

“SIRT 1, SIRT 6 and SIRT 7 are critical to the control of the epigenome and DNA repair. SIRT 3, SIRT 4, SIRT 5 reside in the mitochondria where they control energy metabolism. SIRT 2 buzzes around the cytoplasm where it controls cell division and healthy egg reproduction.” - from book LifeSpan

4

DNA -> RNA -> Protein Synthesis -> Gene expression