Episode #27 on Peter Attia Podcast Notes

Sirtuins

• David never subscribed to the idea of death genes (i.e., group selection)
• David believed longevity genes could evolve — and he pitched Melton with this idea
• Silent information regulator (Sir), Sir-2 in yeast (the mammalian homolog is SIRT3) seemed to regulate aging
• Sirtuins play a dual role: gene silencing and DNA repair — and they can’t do both simultaneously
• You don’t want to be mating and dividing if you have a broken chromosome: this system of coordination in the sirtuins ensures this doesn’t happen
• Knocking out Sir-2 led to accelerated aging
• They then tried the opposite: overexpressed Sir-2, with the prediction they would get more genomic stability at the rDNA in the nucleolus, and the yeast cell lives longer
• David found sirtuins were necessary and sufficient to get the full benefits of calorie restriction
• Sirtuins sense biological stress in the environment (e.g., DNA damage, change in temperature, a lack of nutrients, a burst of cosmic rays) — and allow the organism to hunker down and survive (and stop breeding)
• The biggest insult to any life form are chromosome breaks

NAD and Sirtuins

• Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all cells
• NAD exists in two forms: NAD+ (oxidized form) and NADH (reduced form)
• A few major things happened in 1999
• The DNA repair connection was found
• NAD+ is a requirement for sirtuin activity was determined
• Connection to CR was happening around that time
• NAD is the most important ubiquitous molecule in the cell but varies day to day and with age in both cytoplasm and mitochondria
• The mitochondrial oasis hypothesis: as long as the mitochondria stayed active with their NAD, the cell could survive, and recover from that stress, even when the NAD disappeared from the cell — mitochondrial NAD levels were more important than cytosolic NAD levels for survival
• NADP, NADH don’t activate sirtuins, only NAD+ will do that: Combination of the charge and size
• Stress response turning on NAD production and activating sirtuins
• PNC1 is turned on by heat, CR, low AA, high salt
• Defense pathways to deal with the stress

Resveratrol

• Found in grapes, so went viral (wine)
• Rob Zipkin saw the molecules and saw similarities in structure between SIRT 1 to resveratrol
• Found a Sir-2 dependent lifespan extending molecule
• The mouse paper in Nature in 2006 made the story go global: “Resveratrol improves health and survival of mice on a high-calorie diet”
• Resveratrol was also acting on AMPK (2006 supplemental of the Nature paper) at high doses
• Fat mice taking resveratrol were healthier and lived longer than ones who didn’t
• Resveratrol is not very soluble: you get better absorption with fat → so drinking wine not all that effective.
• David says studies showed what we already knew: If you give resveratrol in regular food it doesn’t extend lifespan

NAD precursors (NR, NMN) and pterostilbene. Developing Supplements

• Nicotinamide riboside (NR) in the body is converted to NMN
• NMN is then immediately converted to NAD+
• Very difficult to determine if the NAD is being taken up by the muscle cells and the brain for example, and measuring if this is occurring
• Pterostilbene (PT) is essentially methylated resveratrol
• Guarente’s company sells a supplement that contains NR and PT
• Another company, Chromadex, sells NR (Niagen)
• Sinclair is looking at NMN, but he’s going down a different route
• David receives a lot of claims via email from people taking NR or NMN and improving athletic performance
• David is working on NAD precursor molecules at Metro Biotech

The nine “hallmarks of aging”

1. genomic instability,
2. telomere attrition,
3. epigenetic alterations,
4. loss of proteostasis,
5. deregulated nutrient sensing,
6. mitochondrial dysfunction,
7. cellular senescence,
8. stem cell exhaustion, and
9. altered intercellular communication.

A unifying theory of aging

• The compact disc (CD) of our lives (i.e., our genome) is still intact as we’re old, but it’s as if we have a scratched CD, and the cells don’t read the right genes (i.e., our epigenome) at the right times anymore, and they lose their identity
• The genome is digital information: the genome is fairly intact in old people and old animals
• So what’s going wrong? The other information you inherit from your parents is the epigenetic information: the pattern of gene expression: which genes are turned on and off, and at which time
• That is analog information, instead of just being a single code it has to operate in three dimensions
• Aging is just a loss of information (2nd law of thermodynamics), but it’s not the genome
• There are a lot of mutations that don’t accelerate aging
• If there was a loss of information in aging, we couldn’t sequentially clone animals as we do
• The genome is digital information, hard to lose that information
• There’s an analog system on top of that: that’s the reader of the CD
• In the cell, those are the readers of the gene
• So we don’t lose information in the genome, but the epigenome: The structure of how the DNA is read
• If that’s true, it’s good news because mutations are pretty hard to reverse, but turning on and turning off genes is not hard to reverse, you just need to know how to tell the cell how to do it
• It’s the equivalent of getting a polish of your CD and fixing something of the scratches and the ability to read all of the DNA — If you’re 60-80, all of the information to be young is still in your body, your cells just lost the ability how to read it

Waddington’s epigenetic landscape

• Conrad Waddington’s landscape: our cells viewed as marbles that start at the top of a mountainscape and roll down to become the type of cell they were meant to (brain, hair, skin, liver ,etc)
• With aging, there is a vibration of noise over time, and we lose our patterns of gene expression, we lose that information, and these loops become dysregulated over time, and the cells change shape
• How can we get the marbles to go back into the valleys in which they came from? That’s the secret to immortality: to get the cells to start acting the way they did when we were 20 years old
• Why do you get loss of gene regulation? DNA breaks in the broken chromosomes distract the SIR complex and they move away and you get the expression of genes that have no right being on
• Insults to the genome: one of the major insults is a double-strand break
• Healthy function: Eventually, these proteins will go repair those breaks and then go back to where they came from to settle down the response, to turn off the inflammation, to turn off the DNA repair when it’s not needed
• But the problem may be antagonistic pleiotropy
• Peter Medawar and others (like George C. Williams and J.B.S. Haldane) in the 50s speculated that things that are really good for you when you’re young come back to bite you in the ass when you’re older
• Response to these stresses, like a DNA break, end up not just distracting these proteins but end up disrupting the actual structure of our chromatin, and these proteins don’t always go back to where they came from 100%
• Do that for 70 or 80 years, and it’s not surprising that the genes that were once perfectly programmed and turned on at the right time lose their ability to do that: and we’ve got remnants of that program when we’re 70 and 80
• What’s exciting is that information is still there to be accessed

Testing combinations to extend lifespan

• There are several pathways (and overlap in those pathways) that may be involved in slowing the aging process
• David has some early data on genetically modifying adult mice with adeno-associated virus (AAV), put all seven sirtuin genes into old mice and also gave them NMN
• There are additive effects when you do both of those things
• In theory, all seven sirtuins should be good, and their lack of NAD+ could be the problem in older people
• Instead of just activating one sirtuin, activating all seven and replenishing what’s been lost over time: seven sirtuins should be better than one