podcast Peter Attia 2024-05-06 topics

#300 - Special episode: Peter on exercise, fasting, nutrition, stem cells, geroprotective drugs, and more — promising interventions or just noise?

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Show notes

In this special edition celebrating 300 episodes of The Drive, Peter discusses a variety of popular topics and health interventions and classifies them based on their level of evidence and relevance using the following categories: proven, promising, fuzzy, noise, and nonsense. Peter first delves into the topic of geroprotective molecules, covering rapamycin, metformin, NAD and its precursors, and resveratrol. Next, he explores the significance of metrics like VO2 max and muscle mass, as well as emerging concepts like blood flow restriction and stem cells. The conversation extends to nutrition, addressing questions surrounding long-term fasting, sugar consumption, sugar substitutes, and the contentious role of red meat in cancer. Peter not only provides his current stance on each topic—most of which have been covered in great detail in the previous 300 episodes—but also reflects on how his opinion may have evolved over the years.

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We discuss:

Defining the categories of “proven, promising, fuzzy, noise, and nonsense” [3:15];
Rapamycin [9:30];
Metformin [17:00];
NAD and its precursors [24:30];
Resveratrol [32:45];
The importance of VO2 max, muscle mass, and muscular strength for lifespan [38:15];
Blood flow restriction (BFR) training [44:00];
Using stem cells to treat osteoarthritis or injury [51:30];
Fasting as a tool for longevity (and why Peter stopped his fasting protocol) [55:45];
The energy balance theory [1:06:30];
The idea that sugar is poison [1:12:00];
The idea that sugar substitutes are dangerous [1:22:15];
The debate on red meat and cancer [1:28:45]; and
More.

Show Notes

*Notes from intro :

This special episode of The Drive celebrates our 300th episode
We’re going to do something a little different for this episode, but it’s going to mirror the structure of a recent interview Peter did, which he thought was interesting
For today’s episode, we’re going to cover a variety of topics which you have all weighed in on, and Peter is going to rank them into the following categories: proven, promising, fuzzy, noise, and nonsense
A couple of months ago, some of you may recall, Peter put out a video on social media where he asked people to weigh in on the types of topics that they wanted to hear covered We got thousands of responses We’ve sorted those into different categories and we’re about to cover half of them here Turns out the response was far in excess of what we predicted, and we’ll have to finish this another time
In this conversation, we’re going to cover geroprotective drugs, including rapamycin, NAD and its precursors, metformin, and resveratrol
We’re going to talk about VO 2 max, muscle mass, blood flow restriction, and stem cells
Then we talk about nutrition Specifically questions around long-term fasting, sugar, sugar substitutes, and the role of red meat in cancer
All of these topics have generally been covered in greater detail across the previous 300 episodes and/or across our newsletter over the past 10 years
We will certainly point you back to areas where we go into great detail into these topics, but the goal here today is that if you’re coming to these topics without any background or you just want the TLDR , this is the place for you So as such, if you want to learn more, check out the show notes both here and elsewhere
Before we jump into this, Peter adds, “ I want to thank everybody for being a part of The Drive. Whether this is your first episode or your 300th, it is an absolute honor to be learning in front of you, and that’s exactly how I feel about this. ”
We got thousands of responses
We’ve sorted those into different categories and we’re about to cover half of them here
Turns out the response was far in excess of what we predicted, and we’ll have to finish this another time
Specifically questions around long-term fasting, sugar, sugar substitutes, and the role of red meat in cancer
So as such, if you want to learn more, check out the show notes both here and elsewhere

Defining the categories of “proven, promising, fuzzy, noise, and nonsense” [3:15]

Did you ever think we would get to episode 300 when we started recording the first few 7 years ago?

Peter asks, “ Was it 7 years ago or 6 years ago? ”
It launched in June 2018, but we were recording previous because the original episodes were part of Peter’s research for his book So we started having some of these discussions in 2017
Peter never really thought about it To him it was binary We started it as a 12-part series and thought it was going to be either uninteresting/ unhelpful/useless (in which it dies) or it was going to be potentially interesting/ valuable (and we keep doing it) Once we hit that binary spot after 3 months and decided to keep doing it, he never really thought of the milestones
What we like to do for every hundred episodes is do a special episode, something a little different, and release it to everybody It’s shot as an AMA, but just a little bit of a different style
When we were thinking of how we wanted to do this one, we thought of a recent interview Peter did, which was structured in a way we liked He gave his opinion on various drugs, supplements, behaviors, interventions, and put them in the following categories : proven, promising, fuzzy, noise, nonsense We thought it was a cool way to go through and talk about some of these different things in a little detail and categorize them so people could understand how he thinks about them, how he applies them to his life and his patients
A lot of these topics, are things that we’ve covered in various podcasts, newsletters, and we’ll link to those [see the selected links section at the end]
The goal here isn’t to be super in depth, go through all these studies, all this background research We’ll link to those in the show notes for anyone who is interested
This is going to be more of a conversation where a patient comes to Peter and asks about something
So we started having some of these discussions in 2017
To him it was binary
We started it as a 12-part series and thought it was going to be either uninteresting/ unhelpful/useless (in which it dies) or it was going to be potentially interesting/ valuable (and we keep doing it)
Once we hit that binary spot after 3 months and decided to keep doing it, he never really thought of the milestones
It’s shot as an AMA, but just a little bit of a different style
He gave his opinion on various drugs, supplements, behaviors, interventions, and put them in the following categories : proven, promising, fuzzy, noise, nonsense
We thought it was a cool way to go through and talk about some of these different things in a little detail and categorize them so people could understand how he thinks about them, how he applies them to his life and his patients
We’ll link to those in the show notes for anyone who is interested

We use the terms “proven, promising, fuzzy, noise, and nonsense” as heuristics, but what does Peter really mean by those things?

To be clear (and people have heard him say this before): in biology there is no such thing as proof

This is not physics or mathematics or even physics
In biology it’s all probability When we say “proven” , what we’re really saying is what we’re talking about has such well-established data that the probability that it is untrue is so small that it would be foolish to not act on it
Conversely, “promising” says the claim looks really good There are a lot of data supporting it, but there’s something that’s missing from a data perspective Either there isn’t just quite enough human data or there just isn’t quite enough RCT data or there’s some slight thing that’s missing that would keep you from saying, this is effectively proven
“Fuzzy” is shorthand for there are some data around this claim, but they might be the best data The data might be inconsistent, they might be contradictory Not just one study is contradicting another study, but it’s like there’s real contradictions here and therefore we clearly need to do more before we could elevate this
“Noise” is an interesting category, and it largely says that the data out there today are not of sufficient quality to make a judgment, but there might be something compelling that could move this in the other direction For example, there might be very compelling mechanistic data There might be a very compelling biochemical story around an idea, but the data have just been too small, too incomplete, to even elevate it up to fuzzy And by the way, noise can quickly turn into nonsense when you shine enough light on it
“Nonsense” basically says, “ No, actually this has been studied and it’s bunk. ” We really have a high degree of confidence in saying that there is nothing there that should be paid attention to And that doesn’t necessarily mean it’s harmful, but it means that this is not doing what people say it is doing
When we say “proven” , what we’re really saying is what we’re talking about has such well-established data that the probability that it is untrue is so small that it would be foolish to not act on it
There are a lot of data supporting it, but there’s something that’s missing from a data perspective Either there isn’t just quite enough human data or there just isn’t quite enough RCT data or there’s some slight thing that’s missing that would keep you from saying, this is effectively proven
Either there isn’t just quite enough human data or there just isn’t quite enough RCT data or there’s some slight thing that’s missing that would keep you from saying, this is effectively proven
The data might be inconsistent, they might be contradictory Not just one study is contradicting another study, but it’s like there’s real contradictions here and therefore we clearly need to do more before we could elevate this
Not just one study is contradicting another study, but it’s like there’s real contradictions here and therefore we clearly need to do more before we could elevate this
For example, there might be very compelling mechanistic data
There might be a very compelling biochemical story around an idea, but the data have just been too small, too incomplete, to even elevate it up to fuzzy
And by the way, noise can quickly turn into nonsense when you shine enough light on it
We really have a high degree of confidence in saying that there is nothing there that should be paid attention to
And that doesn’t necessarily mean it’s harmful, but it means that this is not doing what people say it is doing

All of that takes a long time to explain, so Peter doesn’t want to have to explain it every time, but he thinks explaining it upfront hopefully gives people a sense of where we are

With each example, we’ll provide enough detail to rationalize that position (hopefully)

The beauty of science is that as new evidence comes out, Peter is happy to change his opinion on what he thinks about things

Let’s say we do this in another hundred episodes, then what we’re going to talk about with new evidence can easily move up or down the chain So it’s not like this is how it is and this is how it will be
And if we did this a hundred episodes ago, Peter can even look at this list and tell you things he would’ve said different 100 episodes ago
He would be foolish to suggest that 100 episodes from now, if we come back and revisit this list, he would have the exact same things to say about it That’s very unlikely
So it’s not like this is how it is and this is how it will be
That’s very unlikely

Rapamycin [9:30]

This includes rapamycin, metformin, NAD, and resveratrol

Peter’s definition of a geroprotective drug and how he thinks about that

Geroprotection really talks more broadly about mechanisms that target hallmarks of aging

A geroprotective drug would be a drug or a molecule that you’re taking not because it necessarily provides benefit in 1 arena against 1 chronic disease or 1 symptom, but rather because you believe it is fundamentally altering the biology of aging

And as such, taking this drug moves things in your favor, and that should mean that you would live longer taking this drug That’s a very high bar There are lots of drugs that are really effective at doing things that wouldn’t quite rise to the level of being geroprotective
That’s a very high bar
There are lots of drugs that are really effective at doing things that wouldn’t quite rise to the level of being geroprotective

What category do you put rapamycin in?

Peter puts rapamycin in the promising category, but clearly it’s not proven

We’ve covered rapamycin so much in other podcasts, and this podcast is in no way meant to displace or be a substitute for those things [see the selected links section at the end]
At a high level, rapamycin is a substance that was discovered from a bacteria discovered on Easter Island in the mid-sixties The bacteria was Streptomyces hygroscopicus , which at the time was a very novel organism that had never been discovered anywhere else And it secreted this chemical that was named rapamycin to honor the island where it was discovered, Rapa Nui
This molecule was found to be a very potent antifungal and made it a very logical choice for a bacteria to have evolved to produce it Bacteria is trying to fight a fungi by inhibiting them through this molecule
The first thought was, “ Hey, this might be the next cure for athlete’s foot .”
That drug, which almost died a thousand deaths due to lack of interest, finally was championed through a guy named Suren Sehgal (who has since passed away) Suren single-handedly figured out utility for this drug that ultimately put it on the map as a drug with clinical application in organ transplantation as an immune suppressant
In 1999, the FDA approves this drug for solid organ transplantation, and it spends the next decade in relative obscurity
When Peter was in his residency, rapamycin was used amongst a cocktail of other drugs for patients who had received heart transplants, kidney transplants, and liver transplants
Fast-forward to 2009, and a very well-done study is published as part of the Interventions Testing Program (ITP) that looked at the use of rapamycin in a very well-documented strain of mice that are far more representative of what happens in biology than the typical strain of mice that are used in a clinical research setting That study showed more convincingly than any other study in the ITP history that rapamycin extended life in male mice, in female mice, and most importantly, when initiated very late in life (a period of time in which no other drug had ever been able to extend life)
This was replicated many, many times in the ITP and elsewhere
It was also replicated in other model systems, meaning it wasn’t just replicated again in mammals
People went back and asked the question, how does this drug rapamycin (which inhibits mTOR), how does it work in yeast, in fruit flies, in worms This constitutes about a billion years of evolution?
The bacteria was Streptomyces hygroscopicus , which at the time was a very novel organism that had never been discovered anywhere else
And it secreted this chemical that was named rapamycin to honor the island where it was discovered, Rapa Nui
Bacteria is trying to fight a fungi by inhibiting them through this molecule
Suren single-handedly figured out utility for this drug that ultimately put it on the map as a drug with clinical application in organ transplantation as an immune suppressant
That study showed more convincingly than any other study in the ITP history that rapamycin extended life in male mice, in female mice, and most importantly, when initiated very late in life (a period of time in which no other drug had ever been able to extend life)
This constitutes about a billion years of evolution?

It turns out that rapamycin always seems to work

It’s for all of those reasons that Peter says, “ Wow, this is really promising, ” but why can he not say this is proven?

We don’t yet have sufficient evidence in the organism of interest, or the species of interest (which is us)
And the reason for that is that while there have been some interesting studies done in human, there are clearly short-term studies that demonstrate that the differential dosing pattern of rapamycin can actually produce immune augmentation and immune enhancement rather than immune suppression In a previous podcast [ episode #272 ] we discussed work by Lloyd Klipstein and Joan Manic
That doesn’t quite translate to the question that many of us want to know the answer to, which is, “ Hey, if I take rapamycin intermittently, as demonstrated by these shorter human clinical trials, will that translate to not just better immune function but a longer life? ”
In a previous podcast [ episode #272 ] we discussed work by Lloyd Klipstein and Joan Manic

Absent really good biomarkers for some of these hallmarks of aging, we still have a ways to go before we could say the following: rapamycin is geroprotective towards humans, and taking rapamycin according to Protocol X will add years to human life, and presumably improve health span

That’s an enormous claim where Peter thinks a lot of work still needs to be done
Some of that work needs to be done in other animal models, such as what Matt Kaeberlein is doing in the Dog Aging Project
Some of that work actually is going to need to be done in humans using biomarkers that have yet to be developed, that will be substitutes for some of these more important cellular markers of aging

Even though Peter takes rapamycin, that doesn’t mean he thinks everyone should go out and blindly take it

Very few of Peter’s patients are taking it (<10%)
The reason for that quite simply is unless a patient is willing to go down the rabbit hole with him on understanding this and understanding the risks and probabilities and the uncertainty, Peter just doesn’t view this as something that is responsible
Peter knows that there were many physicians out there who are giving out rapamycin like it’s Tic-Tacs and Chiclets, and the truth of it is we’re not seeing a lot of horrible things happening

So clearly in the short run, that doesn’t appear to be a problem, but it’s irresponsible to represent that we know that that’s going to lengthen life

Peter has been taking this drug for the past 6 years, and yet this is the reason for his hesitation in giving it to anybody who walks in the door

Metformin [17:00]

Peter would place metformin in the fuzzy category

A hundred episodes ago, he would’ve put this in the promising category
The podcast with Andrew Huberman last year [ episode #270 ] was a journal club where we talked about what Peter believes are the 2 most important large epidemiologic papers that are trying to address this question indirectly The first study was done in 2014 The second study was done in 2022 These studies represent the bookends of an observation that creates a lot of interest [about metformin] This is a great example of where epidemiology is very helpful
The first study was done in 2014
The second study was done in 2022
These studies represent the bookends of an observation that creates a lot of interest [about metformin] This is a great example of where epidemiology is very helpful
This is a great example of where epidemiology is very helpful

In 2014, Banister et al published something that at the time was almost impossible to believe

Peter remembers getting an embargoed copy before it came out, and just really being shocked
The study at the surface looked at people who had type 2 diabetes who were taking metformin, and people who did not have type 2 diabetes and who were obviously not taking metformin
It asked the question: who had a lower all cause mortality rate? We know that people with type 2 diabetes are going to have their lives truncated by an average of 6-7 years relative to someone without type 2 diabetes So you wouldn’t think that the addition of metformin to somebody with type 2 diabetes would materially affect that Maybe it would close that gap from 6.5 years to 4 years or something like that
What the study found was that people taking metformin with type 2 diabetes actually lived slightly longer than the people who did not
We know that people with type 2 diabetes are going to have their lives truncated by an average of 6-7 years relative to someone without type 2 diabetes
So you wouldn’t think that the addition of metformin to somebody with type 2 diabetes would materially affect that
Maybe it would close that gap from 6.5 years to 4 years or something like that

There was about a 15% reduction in all cause mortality over a three-year follow-up period

This was done in an enormous population using a UK Biobank dataset
This more than any other paper, set the stage for the excitement around metformin as a geroprotective compound
What’s clear is that the diabetics taking metformin still had inferior glycemic control to the non-diabetics
In other words, if they’re living longer, it’s not because they have better glycemic control It would seem to be that they’re better because of something else that metformin is doing outside of managing presumably hepatic glucose output
Nir Barzilai has been on the podcast twice [episodes #204 & #35 ], and people who are interested in this should go back and listen to those podcasts because Nir has argued that indeed metformin is geroprotective and that there are many benefits to metformin that completely transcend its properties within the liver for glycemic control But Peter has become less convinced of that
Peter talks in the podcast with Andrew about holes in the Banister study that center around methodology Something called informative censoring, where the patients who were in the metformin diabetes arm were censored out of the analysis that demonstrated a reduced mortality if they were lost to follow-up or if they had a medication change Usually, a medication change on someone who’s only taking metformin is meaning that the disease is progressing, so you’re adding another medication The problem with that is: you realize that you were censoring out people who were sicker and you were actually selecting for the healthiest possible people, not to mention the fact that you’re also not doing this in a randomized fashion
It would seem to be that they’re better because of something else that metformin is doing outside of managing presumably hepatic glucose output
But Peter has become less convinced of that
Something called informative censoring, where the patients who were in the metformin diabetes arm were censored out of the analysis that demonstrated a reduced mortality if they were lost to follow-up or if they had a medication change Usually, a medication change on someone who’s only taking metformin is meaning that the disease is progressing, so you’re adding another medication The problem with that is: you realize that you were censoring out people who were sicker and you were actually selecting for the healthiest possible people, not to mention the fact that you’re also not doing this in a randomized fashion
Usually, a medication change on someone who’s only taking metformin is meaning that the disease is progressing, so you’re adding another medication
The problem with that is: you realize that you were censoring out people who were sicker and you were actually selecting for the healthiest possible people, not to mention the fact that you’re also not doing this in a randomized fashion

The follow-up study (done by Keyes et al in 2022) basically sought to improve on the methodology of the Banister paper

It did something quite clever, which is it repeated the analysis using a different patient cohort (a Danish patient population cohort)
It set up 2 studies within the study: 1 very similar to what the Banister experiment was, and then 1 using a set of twins who differed only in that 1 twin had diabetes and 1 twin didn’t That’s a clever design, and it’s hard to do
They looked at half a million people, but they were still able to find roughly a thousand in each group of the twin and non-twin discordance with respect to type 2 diabetes
That’s a clever design, and it’s hard to do

They actually found the opposite: they found exactly what you would expect to find, which is whether you were talking about identical twins, fraternal twins, unrelated people, if you had type 2 diabetes, even if you were on metformin, your risk of mortality was significantly higher

It varied anywhere from 33% higher to 80% higher depending on the covariate analysis and the cohort that was being looked at
This was much more consistent with what one would expect

This is a better analysis for several reasons

What’s most interesting: they went and did an informative censoring analysis to see if indeed informative censoring was exclusively responsible for the results in the Banister paper, and it turned out it wasn’t In other words, even when they repeated that methodology, they still produced the finding you would expect
In other words, even when they repeated that methodology, they still produced the finding you would expect

The other reason Peter would continue to keep metformin in a fuzzy category (as opposed to a promising category) is that metformin has failed in the ITP

Remember, fuzzy doesn’t mean it doesn’t work
Rich Miller talked about the ITP in detail in 2 podcasts [episodes #281 & #148 ] Why the ITPs are such impressive studies Why so few molecules have succeeded in the ITP, but metformin is not one of them
The only time metformin has ever been positive in an ITP (to Peter’s recollection) was when it was combined with rapamycin Metformin alone did not succeed , whereas other drugs such as canagliflozin, acarbose, rapamycin have succeeded Peter doesn’t want to go on too much further because this content exists elsewhere, and he just wants to really focus people on the high level
Why the ITPs are such impressive studies
Why so few molecules have succeeded in the ITP, but metformin is not one of them
Metformin alone did not succeed , whereas other drugs such as canagliflozin, acarbose, rapamycin have succeeded
Peter doesn’t want to go on too much further because this content exists elsewhere, and he just wants to really focus people on the high level

Peter’s view today is that metformin is in the fuzzy category

One other thing, there is a study that is eventually getting funded: the TAME study

Peter doesn’t know if it’s began enrollment yet
The TAME study is going to attempt to answer this question in humans by studying disease onset in susceptible but otherwise healthy individuals

And that’s why Peter thinks it’s safe to say that whether it’s episode 400 or episode 500, we are definitely going to be talking about metformin again

NAD and its precursors [24:45]

How would you put NAD into a category?

This NAD stuff is noise at the moment

When we talk about NAD , we’re really talking about multiple things We’re talking about NAD itself But Peter is also speaking a little bit more broadly about precursors because NAD can’t be taken orally It could be given intravenously when there are lots of clinics out there that do that But from a practical standpoint, we tend to look at things that you can take orally, so we really tend to be talking about NR and NMN , which are oral precursors that become converted into NAD
Just to provide just a touch of context: NAD was discovered more than a hundred years ago, and over time, people have come to understand it’s a very important signaling molecule It’s a very important part of cellular metabolism Also, it declines with age
We’re talking about NAD itself
But Peter is also speaking a little bit more broadly about precursors because NAD can’t be taken orally It could be given intravenously when there are lots of clinics out there that do that But from a practical standpoint, we tend to look at things that you can take orally, so we really tend to be talking about NR and NMN , which are oral precursors that become converted into NAD
It could be given intravenously when there are lots of clinics out there that do that
But from a practical standpoint, we tend to look at things that you can take orally, so we really tend to be talking about NR and NMN , which are oral precursors that become converted into NAD
It’s a very important part of cellular metabolism
Also, it declines with age

So now you have this thing that’s super interesting and super relevant and completely ubiquitous, and as we age, it goes down

Understandably, in the early 2000s, it became a very high interest topic

It further became of interest when it became linked to something called sirtuins

Sirtuins are proteins that require NAD to deacetylase lysine residues Which is just fancy chemical talk for: it changes the modification of an amino acid
This is something that occurs so much and is so important to maintaining DNA integrity and managing oxidative stress that basically there were 2 hypotheses broadly speaking
1 – One hypothesis is the reason NAD levels decline with age is because DNA damage goes up with age (we know that that’s true) Are those two causally related? Is the rise in DNA damage with age driving an increase in NAD utilization and that’s why NAD is going down?
2 – Or are these uncoupled? Is DNA damage going up with age, which it is, and is NAD abundance going down with age for a separate reason and oh, if we only had more NAD, we could offset more DNA damage?
Which is just fancy chemical talk for: it changes the modification of an amino acid
Are those two causally related?
Is the rise in DNA damage with age driving an increase in NAD utilization and that’s why NAD is going down?
Is DNA damage going up with age, which it is, and is NAD abundance going down with age for a separate reason and oh, if we only had more NAD, we could offset more DNA damage?

It’s safe to say we don’t yet know the answer to that

Nevertheless, a cottage industry around NAD has come up which says, “ Look, we know the answer to this, or at least we’re going to postulate that the answer is, of course NAD is going down with age. Whether or not that’s causal or not, giving more NAD is going to be a better thing. ”
What does the data have to say? This is an area where there is a remarkably booming industry around the administration of NAD and its precursors
This is an area where there is a remarkably booming industry around the administration of NAD and its precursors

It’s actually surprising how little data is out there

The most promising data

Remember, Peter thinks, “ This NAD stuff is noise at the moment. I’m putting this in a category even below fuzzy, but to be clear, I’m not putting it in the nonsense category. ” What that means is there may still be clinical scenarios under which this makes sense, even if it is not geroprotective (a very important distinction)
There are a couple of studies in neurodegenerative disease (one in ALS , one in Parkinson’s disease ) that are both so small Peter doesn’t want to be disparaging to the studies, but they’re not amazing studies They’re reasonable first attempts at looking that maybe there’s something there and maybe in these scenarios there is a benefit
Again, we’re asking this through the lens of geroprotection, and we’re really asking the question in this context of, “ Hey, if I take a bunch of NAD, or a bunch of NAD precursors such as NR and NMN, am I going to live longer or even live significantly better? ”
What that means is there may still be clinical scenarios under which this makes sense, even if it is not geroprotective (a very important distinction)
Peter doesn’t want to be disparaging to the studies, but they’re not amazing studies
They’re reasonable first attempts at looking that maybe there’s something there and maybe in these scenarios there is a benefit

The answer to that question is noise

The ALS study gave patients pretty high dose of a combination drug of nicotinamide riboside (NR) , and pterostilbene for 4 months, and then it followed symptoms of ALS on a functional scale

Unfortunately for anybody who has known a patient with ALS (or a family member), it’s in the top 3 most debilitating diseases in the history of our species Unfortunately there is no cure, and the end is just a very tragic end
What this study was basically asking is, “ Look, can we delay this in any way, shape or form? ” The answer appeared to be yes This compound of nicotinamide and pterostilbene actually delayed progression by a short period of time for these patients On one of the functional scales of progression
This was a very small, phase I study In a phase I study , first and foremost, you’re making sure there’s no toxicity (which there wasn’t)
Peter thinks a phase II study is ongoing A phase II study is significantly larger, has robust endpoints, and therefore can shed light on this question
Let’s be clear, if there is a compound out there that can keep a patient off a ventilator longer when they have ALS or can prevent secretion issues longer or respiratory distress longer, by all means, that’s a very important thing to know
Unfortunately there is no cure, and the end is just a very tragic end
The answer appeared to be yes
This compound of nicotinamide and pterostilbene actually delayed progression by a short period of time for these patients On one of the functional scales of progression
On one of the functional scales of progression
In a phase I study , first and foremost, you’re making sure there’s no toxicity (which there wasn’t)
A phase II study is significantly larger, has robust endpoints, and therefore can shed light on this question

The other study was also a very small study that was done in 20 patients with Parkinson’s disease (PD)

10 were put on nicotinamide riboside , 10 on a placebo for 4 weeks
It saw some change in 1 of the movement disorder rating scales that’s used to subjectively quantify movement in patients with PD But there’s a bit of a catch because there was a confounder in that some of those patients were closer in their last dose to levodopa (which is a medication that in the early stages of the disease is quite effective at improving movement)
It was not a very well-done study, and the most charitable thing one could say about that study is that it maybe suggests that there’s something they’re worth looking at Peter doesn’t think that that would even rise to the level of being as compelling as the standard therapies that are used for patients with PD
But there’s a bit of a catch because there was a confounder in that some of those patients were closer in their last dose to levodopa (which is a medication that in the early stages of the disease is quite effective at improving movement)
Peter doesn’t think that that would even rise to the level of being as compelling as the standard therapies that are used for patients with PD

There’s one other study that looked at MCI (mild cognitive impairment) and NAD use

As Peter recalls, it was studying some aspects of memory and physical function
It showed some improvements in physical function (which would not be the primary concern for MCI), but it did not show any improvement in cognitive impact
It might mean that there is an improvement in cognitive impact, but not over such a short timeframe Because it was a Phase I study, it was too small to actually see a signal It wasn’t powered to see a signal (which is not always the case in a Phase I)
Because it was a Phase I study, it was too small to actually see a signal
It wasn’t powered to see a signal (which is not always the case in a Phase I)

Peter thinks that the evidence that NAD and its precursors is geroprotective (meaning we are going to take a bunch of people who don’t have disease and we’re going to make them live longer) is a very, very low probability but not zero

He thinks the probability that we’re not going to be talking about this one in another 100 episodes is pretty low

In the spirit of, “ How much do I believe in this? ”

Peter doesn’t take these compounds He doesn’t take NAD infusions, NR, or NMN
It’s certainly not because there isn’t an abundance of those things out there, but this tells you his level of confidence in this
He doesn’t take NAD infusions, NR, or NMN

Resveratrol [33:00]

The final geroprotective drug that we get asked about a lot is resveratrol. Where would you rank that, and how do you think about that compared to the three we’ve talked about so far?

Peter was really surprised when the team sent him the list with resveratrol on it Because the implication is that it had been asked enough in that survey we put out there that people wanted to hear about it All he has to say is, “ Wow. I’m amazed people are still talking about resveratrol. This is absolute nonsense .”
Because the implication is that it had been asked enough in that survey we put out there that people wanted to hear about it
All he has to say is, “ Wow. I’m amazed people are still talking about resveratrol. This is absolute nonsense .”

I’m just saying we’re going to put this in the nonsense category, and we never need to talk about this again

In other words, there’s not just an absence of evidence; there’s actually evidence of absence here
Resveratrol is a phenol , it’s a chemical that activates sirtuins
Understandably, in all the early 2000s hoopla around sirtuins, the view was, “ Oh my god, sirtuins are good. They’re repairing DNA damage. Resveratrol is an activator of sirtuins. That’s got to be good. Away we go .”
A landmark study in 2006 garnered an unbelievable amount of attention The attention was just as much from the fact that in minuscule amounts resveratrol is found in red wine It wasn’t just that, “ Oh, we have another molecule that in some obscure mouse model maybe seems to extend life .” It was about this molecule at about 1/100th the level is found in red wine On a serious level, is this an explanation for the French paradox? On a clickbait level does this mean we should just be drinking as much wine as possible? That’s the only explanation Peter has for why this story gathered traction and why it continues to this day to cloud the judgment of folks
The attention was just as much from the fact that in minuscule amounts resveratrol is found in red wine
It wasn’t just that, “ Oh, we have another molecule that in some obscure mouse model maybe seems to extend life .”
It was about this molecule at about 1/100th the level is found in red wine
On a serious level, is this an explanation for the French paradox?
On a clickbait level does this mean we should just be drinking as much wine as possible? That’s the only explanation Peter has for why this story gathered traction and why it continues to this day to cloud the judgment of folks
That’s the only explanation Peter has for why this story gathered traction and why it continues to this day to cloud the judgment of folks

In the first episode with Rich Miller [ episode #148 ], the 2006 mouse resveratrol study was at best misinterpreted

There was indeed a longevity benefit, but it’s a very obscure model
It was a mouse model where the mice were fed a diet of 60% coconut oil Consider that mice are herbivores and wouldn’t be eating coconut oil or that much fat
You have these mice on a 60% coconut oil diet and the cause of death was so much fat accumulation in the liver that the liver expanded into the hemithorax and collapsed their lungs Again, usually when we do experiments with mice, they die based on their genetic predilection to die of cancer We’re typically trying to ask the question, “ Hey, in the case of rapamycin, you give rapamycin to these mice, they get less cancer than these mice .”
Consider that mice are herbivores and wouldn’t be eating coconut oil or that much fat
Again, usually when we do experiments with mice, they die based on their genetic predilection to die of cancer
We’re typically trying to ask the question, “ Hey, in the case of rapamycin, you give rapamycin to these mice, they get less cancer than these mice .”

Here we’re force-feeding them coconut oil to turn their livers into big blobs of fat that expand into their chest and compress their lungs; and it turned out that under those conditions, there was a longer time to death (on average median lifespan) if they were on resveratrol than if they were not

By the way, there was no difference in maximal lifespan You didn’t shift the curve of mortality for the top 10% of mice You just shifted it for the median mice
Somehow that generated all of the interest in this drug, and very few people paid attention when the ITP came along and said, “ We’re going to study this really, really rigorously. We’re going to study this in mice that are not chromogenic mutants and we’re not going to force-feed them fat. We’re going to give them normal mouse food and watch them die of normal mouse deaths. ” And it made no difference
They gave them 300 mg of resveratrol per kilo of food (which is 300 PPM), and nothing happened
Just for comparison’s sake, wine is less than 2 PPM (parts per million) of resveratrol
The folks who say resveratrol works have criticized that study saying the bioavailability is low, and therefore you need much, much, much more than the 300 PPM that was given in that study But again, that was a concern and a criticism that was only voiced after the study The proponents of resveratrol were involved in that study and they signed off (they’re on the paper); this was their view
You didn’t shift the curve of mortality for the top 10% of mice
You just shifted it for the median mice
And it made no difference
But again, that was a concern and a criticism that was only voiced after the study
The proponents of resveratrol were involved in that study and they signed off (they’re on the paper); this was their view

Peter has a hard time believing that there is any value in resveratrol, and that’s why he doesn’t take it independent of the fact that it’s still a ubiquitous compound that’s found everywhere

The importance of VO2 max, muscle mass, and muscular strength for lifespan [38:15]

Start with a few anchoring things that you talk about often just so people can understand where you put the importance of VO 2 max and muscle mass on this scale

Where would you rank them on the scale that we’re using today?

Those are the 2 closest things you could put to proven

They would be right up there with smoking cessation and blood pressure management
We really think of muscle mass as a proxy for strength (which is the better predictor)

You can’t prove anything in biology, but the probability that having a high VO 2 max, high muscle mass, and high muscle strength are going to increase the length of your life and improve the quality of your life, that probability is so high that to act in disregard of that is irresponsible

There’s very little on this topic Peter has not expounded on both on this podcast and on others and social media

“ This is a topic I can’t say enough about because the magnitude of the effects is so much greater than everything else .”‒ Peter Attia

You can see why Peter gets animated when people ask him about resveratrol and sirtuin activators and NAD and NR and they’re not exercising Or they’re exercising, but their exercise is totally JV It’s like, “ Wait a minute, you are picking up pennies in front of a steam train fighting over basis points of theoretical possible benefits of something, and you’re completely missing this other thing over here. ”
You’ve heard Peter tease folks (including patients sometime) and say, “ Look, once you’ve got your VO 2 max here and your muscle mass here and your strength here, then we can talk about the 37 supplements that you’re interested in taking. ”
It’s helpful for people to understand where these things rated and how they compare to others
Peter hit a really important point: if you’re worried about taking all these geroprotective drugs and you want to take them, that’s your prerogative, but if you think that’s going to save you from exercising, needing to have muscle strength, needing to have a higher VO 2 max ‒ maybe that’s not the best risk mitigation strategy Look at this as how you mitigate the risk of not being capable of having a longer lifespan and even more importantly, a better healthspan
Peter often says, “ Even if exercise had no effect on lifespan (so it was lifespan neutral or be more dramatic, even if exercise slightly shortened your lifespan by a year), it’s undoubtedly worth it for the improvement in the quality of your life, both physically and cognitively and in many cases emotionally. ”
Or they’re exercising, but their exercise is totally JV
It’s like, “ Wait a minute, you are picking up pennies in front of a steam train fighting over basis points of theoretical possible benefits of something, and you’re completely missing this other thing over here. ”
Look at this as how you mitigate the risk of not being capable of having a longer lifespan and even more importantly, a better healthspan

Peter points out why VO 2 max, muscle mass and strength stand out as the greatest predictors of lifespan

These stand out as far greater predictors of lifespan than cholesterol levels, blood pressure, blood glucose, all of these things that clearly relate to how fast you’re going to live or die
Even smoking is a worse predictor of lifespan than your fitness level

This speaks to how potent exercise is as a tool to impact the cellular processes of aging, but it also speaks to the fact that you can’t cram for the test when it comes to these tests

If a person has a high VO 2 max, they have been doing a lot of exercising for a long time It doesn’t have to mean their whole life, but they didn’t just decide a week ago If your VO 2 max is in the top 2 or 3% of your age group, you’ve been at this for a while
It doesn’t have to mean their whole life, but they didn’t just decide a week ago
If your VO 2 max is in the top 2 or 3% of your age group, you’ve been at this for a while

Therefore, the VO 2 max measurement is really an integration of work that you have done; and the same is true for muscle mass and more importantly for muscle strength

Things like why does grip strength always come up as this incredible predictor of mortality?

Is it because being able to squeeze things with your hand is especially important? Yeah, there’s probably some edge cases
What does it imply if you have high grip strength? You didn’t just wake up and have high grip strength, by definition, you have been lifting and carrying heavy things You have been using your hands aggressively, manipulating things, carrying, squeezing, all of these things, pulling, and it’s that work that is being captured through the integral of the final metric or the test
Yeah, there’s probably some edge cases
You didn’t just wake up and have high grip strength, by definition, you have been lifting and carrying heavy things
You have been using your hands aggressively, manipulating things, carrying, squeezing, all of these things, pulling, and it’s that work that is being captured through the integral of the final metric or the test

Is it ever too late to start exercising?

Maybe you’re in the older category where you don’t want to get hurt
We will have a special episode that will be coming out in a few weeks dedicated to this topic

Blood flow restriction (BFR) training [44:00]

Blood flow restriction (BFR) is used when people are dealing with injuries or don’t want to lift heavy weights
We got a lot of questions about this after the podcast with Jeremy Loenneke [ episode #179 ]

Where would you rank blood flow restriction in this ranking system?

Peter would put BFR in the promising category

Is the question: Does using BFR and higher reps, lower load weights, produce superior results to the same reps, the same weights without BFR?

That is clearly the case

It’s promising/ proven

To back up for those who didn’t hear the podcast (or who need a refresher)

This became a topic of interest not that long ago (maybe 25 years ago) when it was demonstrated that if you applied a tourniquet around a limb as it was exercising, you would see superior improvements in strength and muscle size relative to an untourniqueted limb Provided they were both doing the same amount of work
The question is: Why?
Anybody who’s done BFR can tell you it’s not very comfortable
When you impair venous return slightly (and that’s really the goal of blood flow restriction … It’s not complete occlusion, it’s partial occlusion), you are allowing the accumulation of metabolites at a much higher rate More lactic acid is pooling, more metabolites of metabolism beyond that
The thought is that something about that is creating more of a stress signal than would otherwise be present absent the tourniquet
An immediate use case became around injury: we use far lighter weights, but still produce a profound amount of discomfort
Using Peter as an example , when he had shoulder surgery, he wanted to be able to still exercise that arm, but for months after surgery, he could not carry a barbell that was the same weight that he would’ve carried before It was still too much pressure on the humerus in its newly-repaired joint around the labrum
What if he used a third of the weight that he might’ve previously used? He’d do a lot more reps, but he’ll create this blood flow restriction around it, and he will experience a much higher training effect The data have largely borne this out
What makes this type of research really elegant, is every patient can be their own control, because you’re doing limb isolation It’s a little goofy for the patient because you’re going to have one leg that might get bigger or stronger than the other, but every patient can be their own control
Jeremy Loenneke did a large meta-analysis in 2011 that showed that if you look at low load resistance training in BFR and without BFR
Provided they were both doing the same amount of work
More lactic acid is pooling, more metabolites of metabolism beyond that
It was still too much pressure on the humerus in its newly-repaired joint around the labrum
He’d do a lot more reps, but he’ll create this blood flow restriction around it, and he will experience a much higher training effect The data have largely borne this out
The data have largely borne this out
It’s a little goofy for the patient because you’re going to have one leg that might get bigger or stronger than the other, but every patient can be their own control

BFR clearly results in greater muscle strength and hypertrophy improvements

It’s not subtle; these are really pretty big effects
Peter adds, “ There’s still a question that I don’t think we know the answer to, which is how does BFR training at higher reps lower weight compared to non-BFR training with higher weight and presumably lower reps? ” That’s a much harder head-to-head to design because the question is how do you design the protocol in each, because now you’ve broken one of the constants that have been preserved across all of these studies
That the answer there is still unknown
That’s a much harder head-to-head to design because the question is how do you design the protocol in each, because now you’ve broken one of the constants that have been preserved across all of these studies

As such, Peter wouldn’t recommend that somebody exclusively rely on BFR

First of all, it’s not that comfortable and you can’t do it for everything It’s very limb-centric
Even if you were just to talk about restricting it to how you train your arms and your legs, there are lots of scenarios where using BFR doesn’t make sense
Peter really likes to use BFR as finishers He’ll do some sort of upper body finishers and lower body finishers (on upper body and lower body days respectively) But it’s not really the bulk of what he’s doing
It’s very limb-centric
He’ll do some sort of upper body finishers and lower body finishers (on upper body and lower body days respectively)
But it’s not really the bulk of what he’s doing

This is disproportionately useful in the case and setting of a person who is rehabbing something

Peter uses it liberally with patients, trying to get them moving immediately post-surgery Even just using their own body weight For example, a patient that’s had knee surgery, the minute we get permission from the surgeon, we’ve got them doing leg extensions with just the weight of their leg, but doing it with a BFR cuff There’s actually a training effect in the quads, but without overloading the knee
Even just using their own body weight
For example, a patient that’s had knee surgery, the minute we get permission from the surgeon, we’ve got them doing leg extensions with just the weight of their leg, but doing it with a BFR cuff There’s actually a training effect in the quads, but without overloading the knee
There’s actually a training effect in the quads, but without overloading the knee

What brand BFR cuff do you use?

Peter has no affiliation with them He doesn’t get paid by them or anything It’s just one he’s tried a lot and found real enjoyment with
He doesn’t get paid by them or anything
It’s just one he’s tried a lot and found real enjoyment with

A brand called KAATSU

Peter uses 2 different types of KAATSU devices, one is his go-to where he puts the armbands on and leg bands on, inflates to pressure, and then exercises He apologies that he doesn’t remember the exact name (maybe it’s called the C3)
They have another one that he likes, and it does what are called “passive cycles” You use these during recovery It does a 20-second inflate, hold, deflate, repeat If Peter is sitting at the computer, he’s got this thing cycling on his arms or legs, and it just feels great
There is a real art to this There’s a clinical way that you want to be able to go about doing this, where it’s not just put a tourniquet on Which is what Peter used to do and hope for the best because you have to make sure the pressure is such that you are still allowing both blood in and blood out You’re just trying to blunt that somewhat
He apologies that he doesn’t remember the exact name (maybe it’s called the C3)
You use these during recovery
It does a 20-second inflate, hold, deflate, repeat
If Peter is sitting at the computer, he’s got this thing cycling on his arms or legs, and it just feels great
There’s a clinical way that you want to be able to go about doing this, where it’s not just put a tourniquet on Which is what Peter used to do and hope for the best because you have to make sure the pressure is such that you are still allowing both blood in and blood out You’re just trying to blunt that somewhat
Which is what Peter used to do and hope for the best because you have to make sure the pressure is such that you are still allowing both blood in and blood out
You’re just trying to blunt that somewhat

Using stem cells to treat osteoarthritis or injury [51:30]

What is your current thinking about stem cells?

It’s come up on a few podcasts with Alton Barron [ episode #232 ] and Adam Cohen [ episode #264 ] looking at the upper body, lower body

This is an area that is really complicated, and Peter puts it “somewhere between noise and fuzzy”

He’s talking about this through one application: osteoarthritis Where it’s most talked about and most studied in animals
He still finds it very plausible that there are arenas in which stem cells could be beneficial
There are actually scenarios under which Peter would take stem cells if he had a certain injury If he tore his rotator cuff and it was a marginal call as to whether it was surgical, then he would absolutely start with a stem cell injection If it could mean avoiding surgery and waiting for a repair
Peter would love nothing more than to see an actual randomized clinical trial that takes patients who have torn their rotator cuff Again, let’s try to take people with comparable injuries and randomize them into 3 groups: stem cell injection, surgical repair, non-surgical repair, rehab We could debate the merits of each of these approaches, but he would really love to see that provided there was a way to create a uniform protocol around what it means to get stem cells
Where it’s most talked about and most studied in animals
If he tore his rotator cuff and it was a marginal call as to whether it was surgical, then he would absolutely start with a stem cell injection If it could mean avoiding surgery and waiting for a repair
If it could mean avoiding surgery and waiting for a repair
Again, let’s try to take people with comparable injuries and randomize them into 3 groups: stem cell injection, surgical repair, non-surgical repair, rehab
We could debate the merits of each of these approaches, but he would really love to see that provided there was a way to create a uniform protocol around what it means to get stem cells

The lack of such a randomized clinical trial is what has been hampering this field

To be clear, the FDA does not authorize the use of stem cells

So all of this is existing either outside of the United States where it’s not regulated by the FDA or there’s some sort of gray areas where it can be done, but it’s obviously not covered by insurance or any of these other things
If you’re presumably using, Peter’s not sure how much these protocols are using autologous stem cells versus the stem cells of others
The total lack of consistency in what the actual agent is, the actual stem cell is a big part of what makes this very challenging
Peter asks, “ Who do I trust? ” It’s not like he can look at someone’s data and draw conclusions You’re basically looking at a bunch of marketing material, not actual data.
It’s not like he can look at someone’s data and draw conclusions
You’re basically looking at a bunch of marketing material, not actual data.

When we talk about osteoarthritis , at least we have the advantage that there are canine models of osteoarthritis where they’ve looked at stem cells

They have mixed results
Some of them have shown that dogs with osteoarthritis, when injected with stem cells do tend to improve their gait, do tend to see a reduction in lameness (partially assessed by gait, partially assessed by pain relief through medications)
Other studies have found no benefits whatsoever
It’s hard to tease out what that means Does it mean that the methodologies are flawed and that in some of these studies, they’re not actually using the right stem cells? What is the concentration of stem cells? What’s the protocol? How many injections do you need? All of this stuff is still unclear
Does it mean that the methodologies are flawed and that in some of these studies, they’re not actually using the right stem cells?
What is the concentration of stem cells?
What’s the protocol? How many injections do you need?
All of this stuff is still unclear

Again, stem cells is a very broad term

Are we talking about a pluripotent stem cell?
Are we talking about a donor derived stem cell?
Are we talking about a fetal derived stem cell?

“ We have a cottage industry that is the absolute wild west. ”‒ Peter Attia

Peter wishes there was greater financial incentive to study for what the answer is as opposed to just say, “ Yeah, we know the answer. It works ,” or “ We know the answer. This is a total sham. It shouldn’t be done .”

It’s very hard to have this above noise right now because of a total absence of data, not because there isn’t biological plausibility

There is biological plausibility, but it’s just there’s no data
Peter is clearly am not going to call this nonsense, but this is not going to rise to the level of promising in his mind yet

Fasting as a tool for longevity (and why Peter stopped his fasting protocol) [55:45]

How do you think about long-term fasting as it relates to longevity?

Peter hates talking about nutrition even though he is knowledgeable on the subject

Peter is going to call this fuzzy

This is an area where Peter has seen an enormous change in his point of view over the past 300 episodes

Disclosure: some people listening to this podcast might know of Peter’s work in the fasting space
For Peter, fasting has historically been a very important part of his thinking about how to live longer, how to use fasting as a geroprotective tool
A little bit of historical context is relevant here We spoke earlier about rapamycin, which stands alone in the pantheon of molecules as the only molecule that has universally extended life across all model systems of eukaryotes (which span 1 billion years of evolution) That’s a big deal But we shouldn’t forget that there is one non-drug intervention that has also done that: fasting or caloric restriction (and it did it long before rapamycin)
We spoke earlier about rapamycin, which stands alone in the pantheon of molecules as the only molecule that has universally extended life across all model systems of eukaryotes (which span 1 billion years of evolution) That’s a big deal
But we shouldn’t forget that there is one non-drug intervention that has also done that: fasting or caloric restriction (and it did it long before rapamycin)
That’s a big deal

So there’s clearly something magical going on with caloric restriction when it comes to elongating life

But the question is, can we extend that into humans?

Perhaps the more important question is, what would the fasting protocol be?

Peter wrote a piece on this a long time ago about: How long should you fast? To what extent should you fast, and how frequently should you repeat the fast? Those are basically your 3 variables And there are obviously so many combinations of those You can do it for 1 day, 3, days, or 5 days You could do it once a year, once a quarter, or once a month
Those are basically your 3 variables
And there are obviously so many combinations of those
You can do it for 1 day, 3, days, or 5 days
You could do it once a year, once a quarter, or once a month

Even if you took reasonable spots, it quickly becomes impossible to test all of these, and so instead, what we’re left with is a cult of personalities where people tell you what they do

Peter has been guilty of that, although he hopes he has always been clear about saying, “ I have no clue if this is ‘right’. ”
Peter was doing 7-10 days of water only fasting once a quarter
And then 3 days once a month on the alternative So 2 months, a short fast, and 1 month, a long fast; repeat
What data could he point to for that protocol? None. Absolutely none. He made it up And was very transparently that he made that up
So 2 months, a short fast, and 1 month, a long fast; repeat
None. Absolutely none. He made it up And was very transparently that he made that up
And was very transparently that he made that up

Were things happening in his body from a cellular level that were beneficial?

Probably

Did he have great biomarkers to show that?

No, because he was relying on very standard biomarkers
Fortunately, his standard biomarkers are generally quite good, so it’s not like, “ Yes, your glucose is going to go down, your ketones go up, your insulin goes down a little bit ,” but those things are transient
And by the way, a lot of things got really bad when you fasted: your thyroid function completely deteriorated, your androgen function completely deteriorated

But what was really interesting is the thing we couldn’t measure: what was actually happening to those hallmarks of aging?

Were we improving at the cellular level, things like senescence, autophagy, all of those things? We can’t measure those things, so we don’t know
Peter had some rationale, extrapolating from mouse studies So many hours of fasting in a mouse produces cellular changes that are incredibly beneficial to disease prevention Given what we know about the relationship between mice fasting and human fasting, it should be that by about 5 days to experience some of those benefits
Even if that were true, the question remains: how often do you need to do that? No idea
We can’t measure those things, so we don’t know
So many hours of fasting in a mouse produces cellular changes that are incredibly beneficial to disease prevention
Given what we know about the relationship between mice fasting and human fasting, it should be that by about 5 days to experience some of those benefits
No idea

Why Peter stopped his fasting protocol

It came down to 2 things
The most important was that he took a look at the bigger data of himself and realized that over the course of 3 years he had lost close to 20 lbs of muscle (it might have been 16 lbs) It’s very difficult to gain back the lean muscle you keep losing You lose a ton and you regain some of it
It’s very difficult to gain back the lean muscle you keep losing You lose a ton and you regain some of it
You lose a ton and you regain some of it

Around 2021 he stopped fasting and focused on gaining back the 20 lbs of muscle he lost

Is fasting a viable tool for weight loss?

Yes, it’s one of the tools in the CR/ DR/ TR kit
Peter is still a TR (time-restricted eating) guy for caloric restriction purposes He drinks a coffee in the morning He will have a protein shake in the morning that is very low in calories (120-150 calories) He doesn’t eat a male until 2:00 in the afternoon He has dinner at 6 or 7 He does this to manage total caloric intake, not because there’s some magical benefit to not having meals spread throughout the day
He drinks a coffee in the morning
He will have a protein shake in the morning that is very low in calories (120-150 calories)
He doesn’t eat a male until 2:00 in the afternoon
He has dinner at 6 or 7
He does this to manage total caloric intake, not because there’s some magical benefit to not having meals spread throughout the day

Why is this fuzzy?

In many ways, this suffers the same problem in terms of getting into much more dispositive clinical trials Which is, we’re clearly never going to do the experiment that asks people to undergo different fasting protocols for the entirety of their life to determine if indeed they live longer
Which is, we’re clearly never going to do the experiment that asks people to undergo different fasting protocols for the entirety of their life to determine if indeed they live longer

So we are going to have to come up with better proxies, meaningful biomarkers of the hallmarks of aging

If we can do that, then maybe we can start to get a sense of whether or not rapamycin and fasting should be important parts of our armamentarium as we think about ways to impact those hallmarks of aging

You mentioned there were 2 things that caused you to change your mind [about fasting]. The first was muscle loss, what was the second?

The second one was more of a social issue

Peter happened to be traveling a lot during the time he was fasting
It’s very easy for him to fast when he is away from home
All of these fasts were done while he was in New York and lived in San Diego So he didn’t have to be fasting around anybody He was just fasting in his apartment alone Even if he went out to dinner with friends, he would just drink soda water while they were eating dinner
Once he stopped traveling it meant all those fasts were going to have to be done at home, and he didn’t want to do it He didn’t want his kids to wonder why daddy is never eating
So he didn’t have to be fasting around anybody
He was just fasting in his apartment alone
Even if he went out to dinner with friends, he would just drink soda water while they were eating dinner
He didn’t want his kids to wonder why daddy is never eating

Back to biomarkers to know if fasting is working. What would have to be true or what would have to change outside of that to cause you to start fasting again long-term?

Peter doesn’t know
He would need to see something incredibly compelling in a higher order model Maybe in a dog model or something like that
This is a great example of where he thinks companion dogs are a great model to study things, because he thinks most people find binary fasting far easier than caloric restriction And there’s already a lot of controversy around caloric restriction
Peter has an entire chapter on this in Outlive where he talks about the Wisconsin/ NIA monkey studies
But for most people, if you told them they just had to reduce calories by 25% for the rest of their life to live longer, most people would say, “ I don’t want to live longer. That’s torture. ”
It’s actually easier to periodically do these big fasts
Peter would like to see an experiment of that done in a better model than just mice
Maybe in a dog model or something like that
And there’s already a lot of controversy around caloric restriction

The energy balance theory [1:06:30]

Historically since the podcast started, we’ve had tons of guests on who have different opinions on this
This is something that Peter has written about a lot

How do you think about the energy balance theory right now as it relates to the ranking system?

Peter puts this right between promising and proven

To summarize the energy balance theory

Energy balance is determined solely by the caloric density of the foods consumed, less the energy expenditure And that the net available caloric density of a food is its contribution to energy balance
This is where Peter feels a little bit bad talking about this because he hasn’t been as diligent as maybe he should be in staying up on this world Over the past decade, he’s largely not paid attention to it Because in many ways, he’s seen what he believes is a reasonable answer
For folks who don’t know part of the history here, Peter was once running an organization that funded research directly to try to answer this question He went into that thinking the answer was going to be one thing, but actually very excited to see regardless
That study , while it had some flaws, actually came out and showed something else, which was if indeed isocaloric manipulations of macronutrients change energy expenditure, it’s not an enormous difference
What does that mean in English? If you give 2 people equally caloric diets that are radically different in macronutrients, do you have a significant difference in energy expenditure? That’s what was being tested by that theory
And that the net available caloric density of a food is its contribution to energy balance
Over the past decade, he’s largely not paid attention to it
Because in many ways, he’s seen what he believes is a reasonable answer
He went into that thinking the answer was going to be one thing, but actually very excited to see regardless
If you give 2 people equally caloric diets that are radically different in macronutrients, do you have a significant difference in energy expenditure? That’s what was being tested by that theory
That’s what was being tested by that theory

The evidence is much more clearly in favor of the fact that no, you do not [have a significant change in energy expenditure]

A couple of caveats

There are clearly differences in the thermogenesis of food 1000 calories of protein, 1000 calories of fat, and 1000 calories of carbohydrates are going to have different processing amounts of energy that will result in different amounts of net available energy
Furthermore, different types of foods are going to differentially impact appetite
Therefore in a free living environment, this isn’t to say that macronutrients don’t matter, but what we’re really trying to tease out is there truly a scenario under which a person who’s eating 3000 calories of a balanced diet can switch to 3000 calories of a ketogenic diet and have weight melt off them? Just because they’re on a ketogenic diet, they somehow magically start burning a lot more energy Peter believes the answer to that question is no He does not see any evidence to support that
1000 calories of protein, 1000 calories of fat, and 1000 calories of carbohydrates are going to have different processing amounts of energy that will result in different amounts of net available energy
Just because they’re on a ketogenic diet, they somehow magically start burning a lot more energy
Peter believes the answer to that question is no He does not see any evidence to support that
He does not see any evidence to support that

Peter thinks that if a person is on 3000 calories a day of a balanced diet and they switch over to what they believe is 3000 calories a day of a ketogenic diet and the weight starts pounding off them, they’re either moving more or eating less than they realize

How would you respond to people who maybe get frustrated at your ability to change your mind if new data comes out?

In general,there may be at times in science, a resentment if you do change your mind, and that leads to potentially people sticking with their beliefs maybe longer than they should
First of all, this is news to Peter that people are upset about that He would bet it’s not scientists who are upset Any scientist who doesn’t do that needs to be questioned
He would bet it’s not scientists who are upset
Any scientist who doesn’t do that needs to be questioned

“ If you can’t change your mind in the presence of new data, I think by definition, you’re not a scientist. You’re an advocate. ”‒ Peter Attia

Advocacy has its place, but not without science
The only thing Peter would ask of those people that are upset with him is, “ What would you propose as the alternative? ”
Is it vexing that Peter changes his mind on things Yes, if it means that it impacts your belief about what is good to do and what is not good to do
Look at the alternative: Peter is confronted with new data but ignores it? Or he pays attention to it and lies about it? How is this better than simply being uncomfortable with the fact that he used to believe this thing and now he doesn’t anymore?
Yes, if it means that it impacts your belief about what is good to do and what is not good to do
Or he pays attention to it and lies about it?
How is this better than simply being uncomfortable with the fact that he used to believe this thing and now he doesn’t anymore?

The idea that sugar is poison [1:12:00]

Is sugar poison?

This is a very loaded question
Peter would argue, is the premise of the question even logical? What is a poison? Poison is a word that speaks to a dose, speaks to a frequency, speaks to chronicity, acuteness, all of these things
Broadly thinking, is something chronically a poison? Is it acutely a poison?
What is a poison? Poison is a word that speaks to a dose, speaks to a frequency, speaks to chronicity, acuteness, all of these things
Poison is a word that speaks to a dose, speaks to a frequency, speaks to chronicity, acuteness, all of these things

Let’s start with something everybody has in their house: acetaminophen (Tylenol)

Is it a poison? It doesn’t have a skeleton on the cover with bones through it, right? It doesn’t look like the Drano you have under your sink that is clearly marked as a poison
What happens if you took 20 grams (20x the dose)? You would be dead of liver failure in 3 days if someone wasn’t able to pump your stomach in time or get you a liver transplant So that sounds like a poison That’s actually acutely quite toxic
It doesn’t have a skeleton on the cover with bones through it, right?
It doesn’t look like the Drano you have under your sink that is clearly marked as a poison
You would be dead of liver failure in 3 days if someone wasn’t able to pump your stomach in time or get you a liver transplant
So that sounds like a poison
That’s actually acutely quite toxic

Is alcohol a poison?

It depends on the dose
There are clearly doses at which alcohol is quite toxic (it’s neurotoxic)
And there’s certainly a scenario where you have a glass of wine a few times a week and it would be almost impossible to measure a negative effect of that
Peter says all of those things to anchor people in what we’re talking about

The phrase sugar is poison is not helpful: it’s loaded, it’s emotional, it’s sort of nonsensical

What we should really be asking

What are the biochemical effects of sucrose or high fructose corn syrup (or fructose in general) at different doses and under different metabolic conditions?

This is an area where Peter’s view has changed quite a bit, and it’s changed because of the data

He just doesn’t see the data to demonstrate that an isocaloric substitution of fructose for glucose is demonstrably worse for health outcomes if total energy intake is preserved

Now, does that mean that eating sugar in an unrestricted manner in a free living environment is of no consequence?

No, it doesn’t mean that at all
And it certainly appears that in at least a susceptible individual, that a high consumption of fructose (and it seems even more clear in liquid fructose) can drive appetitive behavior To put that in English, if you’re drinking a lot of sugar, it makes you want to eat more calories Now, we can debate how many calories, and Peter believes that these data have been misrepresented and overstated
To put that in English, if you’re drinking a lot of sugar, it makes you want to eat more calories Now, we can debate how many calories, and Peter believes that these data have been misrepresented and overstated
Now, we can debate how many calories, and Peter believes that these data have been misrepresented and overstated

Peter thinks that in a free living environment, people will consume more energy if they have more access to sugar

Peter had this discussion on the podcast with Rick Johnson [ episode #194 ] using one of the most robust experiments on this topic

To his recollection it was 9 months in mice (an eternity)
Under isocaloric conditions, when these mice were fed, when their total calories were controlled and you had high fructose versus low fructose groups, you did not see a statistically significant difference in body weight (That’s a big deal)
Now, would you see a statistically significant difference in metabolic parameters? Peter thinks you might if the fructose dose gets high enough
This comes back to something Peter said at the outset, “ The dose makes the poison. ”
Peter thinks you might if the fructose dose gets high enough

We don’t know yet what that does looks like as a function of the other parameters

For example, when Peter was a teenager, he trained 6 hours a day and never ran less than 8 miles in the morning, and there was no way he was eating fewer than 200 g of sugar a day He would drink 2 L of orange juice as a snack He didn’t eat bowls of cereal, he at them a box at a time Was he unhealthy? No chance He probably had 4% body fat
He would drink 2 L of orange juice as a snack
He didn’t eat bowls of cereal, he at them a box at a time
Was he unhealthy? No chance
He probably had 4% body fat

The point is, the context matters

If he ate that much food today (nevermind sugar), he’d be dead

Peter’s takeaway : everything about this is problematic because people want to focus on just 1 macronutrient (in this case, fructose or sugar as a molecule), and we don’t want to focus on the overall dietary pattern that accompanies it

When Peter consumes fructose , it’s generally in the form of fruit He doesn’t restrict his consumption of fruit (he eats it all the time) He generally doesn’t drink calories outside of protein shakes These are artificially sweetened with sucralose and things like that If he drinks a carbonated beverage that’s sweet it’s a diet Dr. Pepper once or twice a month Would the regular Dr. Pepper kill him? No, but he’s choosing diet because of his teeth
He doesn’t restrict his consumption of fruit (he eats it all the time)
He generally doesn’t drink calories outside of protein shakes These are artificially sweetened with sucralose and things like that If he drinks a carbonated beverage that’s sweet it’s a diet Dr. Pepper once or twice a month Would the regular Dr. Pepper kill him? No, but he’s choosing diet because of his teeth
These are artificially sweetened with sucralose and things like that
If he drinks a carbonated beverage that’s sweet it’s a diet Dr. Pepper once or twice a month
Would the regular Dr. Pepper kill him? No, but he’s choosing diet because of his teeth

“ What you’re hearing me kind of react to is not because I think sugar is poison. I think a high sugar diet is just a dietary pattern that is incongruent with eating the right kinds of foods that I generally want to eat anyway .”‒ Peter Attia

Give your quick 2×2 framework of metabolically healthy, unhealthy

Nick thinks this paints a bigger picture of why Peter doesn’t look at sugar as being toxic, but how he looks at it more holistically
For metabolically unhealthy patients, who need to lose weight and need to increase their muscle mass, Peter might not be so liberal with sugar for them
Peter adds, “ There’s definitely an area where I’m still actively trying to investigate this. ”

We will do a podcast on this topic: Is there a unique role that fructose plays in the development of NAFLD (non-alcoholic fatty liver disease) ?

NAFLD is running rampant right now in the world
1 hypothesis is that it’s not just energy imbalance (which is clearly associated with NAFLD) In other words, you take a person with NAFLD and they lose 20 pounds, their fatty liver is going to get better no matter what
In other words, you take a person with NAFLD and they lose 20 pounds, their fatty liver is going to get better no matter what

But then the question is, should those people be restricting fructose?

And again, lots of great mechanistic data for why fructose rather than glucose would disproportionately play a role in the development of NAFLD
There’s even more compelling evidence for why liquid fructose is potentially playing a greater role
Peter hasn’t yet seen a compelling clinical trial that can that independent of weight loss, isocaloric substitution of fructose for glucose results in an improvement of NAFLD
For his patients with NAFLD, he tells them not to drink alcohol and not to consume fructose (outside of mild amounts of fruit) This is a recommendation for which they don’t have incredible evidence, but if nothing else, that change in behavior reduces caloric intake, which results in weight loss (what we care about)
This is a recommendation for which they don’t have incredible evidence, but if nothing else, that change in behavior reduces caloric intake, which results in weight loss (what we care about)

Peter’s 2×2 framework involves 3 questions

1 – Is the person overnourished or undernourished? That is determined by the total amount of body fat and visceral fat
2 – Are they adequately muscled or under-muscled? This can be determined by looking at the fat-free mass index or appendicular lean mass index (ALM)
3 – Are they metabolically healthy or not
That is determined by the total amount of body fat and visceral fat
This can be determined by looking at the fat-free mass index or appendicular lean mass index (ALM)

Understanding the answer to those questions, you pretty quickly can come up with a point of view on how a person needs to train and how a person needs to eat and maybe even in some cases, how you want to tweak their macronutrients

The idea that sugar substitutes are dangerous [1:22:15]

How do you think about the idea of sugar substitutes and if they are dangerous?

See one of our premium newsletters on this topic Peter thinks it’s one of our best premium newsletters ever (it may be a bit long)
Sugar substitutes have been around for a long time
In the ‘70s and last 20 years there have been concerns around the toxicity of them (especially aspartame and saccharin )
Peter thinks it’s one of our best premium newsletters ever (it may be a bit long)

If you want to talk toxicity, the doses of sugar substitutes [used in toxicity studies] are literally orders of magnitudes greater than what would be consumed by humans

Even though there were maybe flaws in some of those studies, even if you were to take them at face value, it’s hard to imagine

The rat study that got everybody worried about saccharin

The rats that developed tumors were being fed the equivalent of 800 diet sodas for every day of their life That’s how much saccharin those rats were being fed to develop these liver tumors
It’s a very slippery slope to then say, “ Oh, well then these things are poisonous .” By that logic, if you took 20x the dose of Tylenol, you’d be dead And you’d be dead much quicker than you would die from this cancer
Here we’re talking about 800 times the dose over the entire duration of a life At that level (just to be glib) oxygen is toxic to people We have 21% oxygen in the air that we’re breathing If you are in a 100% oxygen environment indefinitely, the amount of free radicals you would develop would kill you
That’s how much saccharin those rats were being fed to develop these liver tumors
By that logic, if you took 20x the dose of Tylenol, you’d be dead And you’d be dead much quicker than you would die from this cancer
And you’d be dead much quicker than you would die from this cancer
At that level (just to be glib) oxygen is toxic to people We have 21% oxygen in the air that we’re breathing If you are in a 100% oxygen environment indefinitely, the amount of free radicals you would develop would kill you
We have 21% oxygen in the air that we’re breathing
If you are in a 100% oxygen environment indefinitely, the amount of free radicals you would develop would kill you

Everything becomes toxic at some point

The aspartame data was a little less extreme

A paper in 2007 looked at higher rates of cancer in rats that consumed pretty high amounts of aspartame from the day they were born right on to the duration of their life They were still consuming the equivalent of 20 cans of diet soda every single day to get to some of those outcomes
They were still consuming the equivalent of 20 cans of diet soda every single day to get to some of those outcomes

Is it possible that these things are cancer causing at normal doses?

It is possible, but Peter doesn’t think it’s that probable, and therefore when he thinks about sugar substitutes, he’s less concerned with the cancer stuff and more concerned with the metabolic stuff (the impact on gut health and those other things)

The 2 biggest areas to talk about with non-sugar sweeteners

What is the impact on body weight and what is the impact on glycemic control or metabolic health?

The 1st generation versions of these ( saccharin , aspartame , sucralose ) seem to have a slightly negative effect on those parameters when calories are controlled
Conversely, the newer ones ( xylitol , erythritol , stevia , and allulose ) appear to have less detrimental effects Some of them that are not even what we would consider non-nutritive Allulose may even have slightly beneficial effects on glycemic control due to SGLT1 signaling, but it’s a little too soon to say that
This now comes back to a heuristic, “ How do I behave around these things? ” Peter is clearly consuming some of them Even the cleanest protein drink has some amounts of these products in them The ones Peter generally uses have sucralose in them
Peter doesn’t usually drink diet sodas because he mostly drinks sparkling water
He doesn’t add sweeteners to anything he consumes If he’s drinking coffee, he puts a little cream in it
He does chew gum with xylitol in it, and that’s more around some of the potential benefits of xylitol on the enamel of teeth
Some of them that are not even what we would consider non-nutritive
Allulose may even have slightly beneficial effects on glycemic control due to SGLT1 signaling, but it’s a little too soon to say that
Peter is clearly consuming some of them Even the cleanest protein drink has some amounts of these products in them The ones Peter generally uses have sucralose in them
Even the cleanest protein drink has some amounts of these products in them
The ones Peter generally uses have sucralose in them
If he’s drinking coffee, he puts a little cream in it

Peter’s advice to people who are consuming lots of artificial sweeteners who are struggling with glycemic control, body weight or things like that is: substitute them out, but don’t substitute sugar in, just get rid of it period

For example, go from drinking diet Coke to drinking water, bubbly water Not drinking Coke, because that’s probably a worse outcome if no other reason just from more calories coming in
If you’re struggling on that front, getting rid of those things might matter
Not drinking Coke, because that’s probably a worse outcome if no other reason just from more calories coming in

The area where we are most interested in understanding things is what is the impact of these things on the gut, and how foreign are these things to the bacteria in our gut?

Are they being provided in a high enough quantity to even materially impact the guts?
There are some animal studies that suggest that this is a big issue
Peter thinks it’s a bit too soon to say that

The debate on red meat and cancer [1:28:45]

Does red meat give you cancer?

Peter begins by saying, “ This is going to sound bold, but I would actually put this in the nonsense category . ”
Which is not to say that a dietary pattern high in red meat could not play a role in the development of cancer, but that’s very different than the question
If the question is, “ Does red meat cause cancer? ” That’s not correct and there’s plenty of evidence that that is not correct
That’s not correct and there’s plenty of evidence that that is not correct

If the question is, “ Do people who eat a lot of red meat or do people who eat a lot of processed red meat have a higher risk of getting cancer? ”

The answer to that question is yes, but it’s probably less because of the meat

Although in the case of certain processing, it may be the case
But it’s probably much more because of what they’re not eating Their diets tend to be much lower in vegetables and specifically much lower in insoluble fiber (which plays a very important role in the prevention of colorectal cancer)
Their diets tend to be much lower in vegetables and specifically much lower in insoluble fiber (which plays a very important role in the prevention of colorectal cancer)

The debate on red meat and cancer goes back for long periods of time

It suffers from all of the usual trappings of nutritional epidemiology, which is why John Ioannidis famously said, “ All nutritional epidemiology belongs in the wastebasket .”

The 2 most obvious problems with nutritional epidemiology in this regard are

1 – It’s very difficult to get an accurate reflection of what people consume using food frequency questionnaires (almost impossible)
2 – It’s very difficult to disentangle the variable of interest from the other lifestyle variables that are covariates within the problem and that speak to what we refer to as the “ healthy user bias ”
Peter doesn’t dispute for one moment that every time you do an epidemiologic survey and you compare people who live on hot dogs and pepperoni to vegetarians, the epidemiology will always tell you that the vegetarians are going to live longer While that might be an extreme example, you do appreciate that on average those vegetarians have a much higher socioeconomic status, they are much more health conscious They are exercising much more, they’re much less likely to be smoking, doing yoga, all these other things
While that might be an extreme example, you do appreciate that on average those vegetarians have a much higher socioeconomic status, they are much more health conscious They are exercising much more, they’re much less likely to be smoking, doing yoga, all these other things
They are exercising much more, they’re much less likely to be smoking, doing yoga, all these other things

Therefore, how can we disentangle the variable from the effect?

When you look at the most compelling case for people who eat the highest amount of meat and their risk of cancer, there was a study that was done in Europe that looked at nearly half a million people It divided them into a cohort that were eating more than 160 grams per day of protein from red meat and processed meat. It compared them to people that were eating virtually none, 20 grams per day They’re comparing the extremes, and indeed there was a difference (but it was relatively small) The difference between a 1.7% increase in the risk of cancer versus a 1.3% absolute risk for colorectal cancer over the period of study
So just again, what does that mean? It means that the difference in risk between the super high protein consuming meat group and the low group was 0.4% of actual percentage points That means basically you have to put 250 people on a low meat diet to reduce 1 case of colorectal cancer
Again, that’s assuming that you arrived at this through randomization, which you didn’t
There was another study , it was a 10-year observational study that looked at about 150,000 people with the highest tertile of red meat consumption They had a 50% increase in relative risk to those in the lowest tertile The error bar on this study was so big that it barely made statistical significance despite the sample size there This just speaks to the heterogeneity of this
It divided them into a cohort that were eating more than 160 grams per day of protein from red meat and processed meat. It compared them to people that were eating virtually none, 20 grams per day They’re comparing the extremes, and indeed there was a difference (but it was relatively small)
The difference between a 1.7% increase in the risk of cancer versus a 1.3% absolute risk for colorectal cancer over the period of study
They’re comparing the extremes, and indeed there was a difference (but it was relatively small)
It means that the difference in risk between the super high protein consuming meat group and the low group was 0.4% of actual percentage points
That means basically you have to put 250 people on a low meat diet to reduce 1 case of colorectal cancer
They had a 50% increase in relative risk to those in the lowest tertile
The error bar on this study was so big that it barely made statistical significance despite the sample size there This just speaks to the heterogeneity of this
This just speaks to the heterogeneity of this

Peter’s takeaway:

Every one of these studies basically ends up having the same issue: when you look at the details, you realize it is very difficult to come up with a meaningful view that it’s red meat specifically that is driving cancer As opposed to the absence of vegetables, the absence of fiber, or maybe the presence of some of the ultra processing things that go into consuming certain patterns of meat (like gas station bought jerky and stuff like that)
As opposed to the absence of vegetables, the absence of fiber, or maybe the presence of some of the ultra processing things that go into consuming certain patterns of meat (like gas station bought jerky and stuff like that)

Peter thinks the ill health effects for red meat consumption are incredibly weak; the hazard ratios themselves for this are very, very small, even with all of the limitations that he mentioned

Therefore, if you go back to the Austin Bradford Hill criteria of epidemiology (which Peter outlines in great detail in the book ), it’s very hard to imagine that there is causality here
The epidemiology here is so underwhelming that it almost draws the opposite conclusion It’s almost hard to believe there is a signal given how underwhelming the epidemiology is
Whereas conversely, when you look at the epidemiology of smoking or the epidemiology of exercise, those are so overwhelming that it factors into what we see as the overall causality narrative
It’s almost hard to believe there is a signal given how underwhelming the epidemiology is

Give us feedback

If you like the theme of going through and ranking these things let us know We have a huge list of items we can hit moving forward
Normally, we do super deep dives, but once in a while we do a summary synthesis of evolving positions on things Let us know if you like these and we’ll look to do that more
We have a huge list of items we can hit moving forward
Let us know if you like these and we’ll look to do that more

Selected Links / Related Material

Peter’s book : Outlive: The Science and Art of Longevity by Peter Attia with Bill Gifford (March 2023) | [3:45, 1:34:30]

Previous episodes of The Drive that discuss rapamycin : [11:00]

Rapamycin is one of the bigger hits in the ITP study : Rapamycin fed late in life extends lifespan in genetically heterogeneous mice | Nature (D Harrison et al. 2009) | [13:00]

Previous episodes of the Drive that discuss metformin :

Large epidemiological studies on metformin : [17:30]

Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study | International Journal of Epidemiology (M Keys et al. 2022)
Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls | Diabetes, Obesity & Metabolism (C Bannister et al. 2014)

Previous episodes of The Drive with Nir Barzilai : [20:00]

#204 – Centenarians, metformin, and longevity | Nir Barzilai, M.D. (April 25, 2022)
#35 – Nir Barzilai, M.D.: How to tame aging (January 7, 2019)

Previous episodes of The Drive with Rich Miller : [23:30]

TAME trial : The TAME Trial: Targeting the Biology of Aging. Ushering a New Era of Interventions . | afar: american federation for aging research (2024) | [24:00]

Previous episodes of The Drive that discuss NAD : [24:30]

Newsletter about NAD : Separating substance from nonsense in a study on NMN supplements | PeterAttiaMD.com (A Misic, K Birkenbach, & P Attia 2023) | [24:30]

Small studies supplementing with NAD in patients with neurodegenerative disease : [28:15]

The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease | Cell Metabolism ( B Brakedal et al 2022)
Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study | Amyotrophic lateral sclerosis & frontotemporal degeneration (J de la Rubina et al 2019)

NAD supplementation and MCI : Results from a pilot study: The effects of nicotinamide riboside on mild cognitive impairment | Alzheimer’s Association (M Orr et al 2020) | [31:30]

2006 mouse study on resveratrol : Resveratrol improves health and survival of mice on a high-calorie diet | Nature (J Baur et al 2006) | [34:00]

Previous episodes of The Drive that discuss resveratrol : [34:45]

Newsletter about resveratrol : Is low-to-moderate alcohol consumption beneficial for longevity? | PeterAttiaMD.com (A Misic, K Birkenbach, & P Attia 2024) | [34:45]

ITP study of resveratrol : Evaluation of Resveratrol, Green Tea Extract, Curcumin, Oxaloacetic Acid, and Medium-Chain Triglyceride Oil on Life Span of Genetically Heterogeneous Mice | The Journal so Gerontology Series A (R Strong et al 2012) | [36:30]

Previous episodes of The Drive that discuss the importance of muscle mass and strength : [38:15]

#285 – AMA #55: Exercise: longevity-focused training, goal setting, improving deficiencies, managing emotional stress, and more (January 15, 2024)
#242 – AMA #44: Peter’s historical changes in body composition with his evolving dietary, fasting, and training protocols (February 13, 2023)
#235 ‒ Training principles for mass and strength, changing views on nutrition, creatine supplementation, and more | Layne Norton, Ph.D. (December 19, 2022)
#227 – AMA #40: Body composition, protein, time-restricted feeding, fasting, DEXA scans, and more (October 17, 2022)
#206 – Exercising for longevity: strength, stability, zone 2, zone 5, and more (May 9, 2022)
#205 – Energy balance, nutrition, & building muscle | Layne Norton, Ph.D. (Pt.2) (May 2, 2022)
#176 – AMA #27: The importance of muscle mass, strength, and cardiorespiratory fitness for longevity (September 20, 2021)
#163 – Layne Norton, Ph.D.: Building muscle, losing fat, and the importance of resistance training (May 24, 2021)
#151 – Alex Hutchinson, Ph.D.: Translating the science of endurance and extreme human performance (March 1, 2021)

Newsletters about muscle mass : [38:15]

Can a new drug mimic the effects of exercise on bone and muscle? | PeterAttiaMD.com (S Lipman, K Birkenbach, & P Attia 2023)
Muscle Mass and Cognitive Function | PeterAttiaMD.com (A Misic, K Birkenbach, & P Attia 2022)

Previous episodes of The Drive that discuss VO 2 max : [38:15]

#261 ‒ Training for The Centenarian Decathlon: zone 2, VO2 max, stability, and strength | Peter Attia, M.D. (July 10, 2023)
#223 – AMA #39: The Centenarian Decathlon, zone 2, VO2 max, and more (September 19, 2022)
#217 ‒ Exercise, VO2 max, and longevity | Mike Joyner, M.D. (August 8, 2022)
#206 – Exercising for longevity: strength, stability, zone 2, zone 5, and more (May 9, 2022)
#201 – Deep dive back into Zone 2 | Iñigo San-Millán, Ph.D. (Pt. 2) (March 28, 2022)
#176 – AMA #27: The importance of muscle mass, strength, and cardiorespiratory fitness for longevity (September 20, 2021)
#151 – Alex Hutchinson, Ph.D.: Translating the science of endurance and extreme human performance (March 1, 2021)

Newsletter about VO 2 max : The [almost] unbelievable effects of a high maximal aerobic capacity on all-cause mortality | PeterAttiaMD.com (S Lipman, K Birkenbach, & P Attia 2024) | [38:15]

Previous episode of The Drive with Jeremy Loenneke : #179 – Jeremy Loenneke, Ph.D.: The science of blood flow restriction—benefits, uses, and what it teaches us about the relationship between muscle size and strength (October 11, 2021) | [44:15]

Other episodes of The Drive about BFR : [44:15]

#242 – AMA #44: Peter’s historical changes in body composition with his evolving dietary, fasting, and training protocols (February 13, 2023)
#196 – AMA #32: Exercise, squats, deadlifts, BFR, and TRT (February 21, 2022)

Meta-analysis of blood flow restriction training : Low intensity blood flow restriction training: a meta-analysis | European Journal of Applied Physiology (J P Loenneke et al. 2011) | [47:30]

Brand of BFR cuff Peter uses : KAATSU | [50:00]

| [51:30]

Previous episode of The Drive with Alton Barron : #232 ‒ Shoulder, elbow, wrist, and hand: diagnosis, treatment, and surgery of the upper extremities | Alton Barron, M.D. (November 28, 2022) | [51:30]

Previous episode of The Drive with Adam Cohen : #264 ‒ Hip, knee, ankle, and foot: diagnosis, treatment, and surgery of the lower extremities | Adam Cohen, M.D. (July 31, 2023) | [51:30]

Newsletter on variables involved in fasting : Wanna know what keeps me up at night? (2019) | [59:00]

Other newsletters about fasting :

Wisconsin/NIA monkey studies of caloric restriction : [1:06:00]

Caloric restriction improves health and survival of rhesus monkeys | Nature Communications (JA Mattison et al. 2017)
Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys | Nature Communications (RJ Colman et al. 2014)
Impact of caloric restriction on health and survival in rhesus monkeys : the NIA study | Nature (JA Mattison et al. 2012)
Caloric restriction delays disease onset and mortality in rhesus monkeys | Science (RJ Colman et al. 2009)

Do diets that differ in macronutrient content result in differences in energy expenditure? : Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men | The American Journal of Clinical Nutrition (K Hall et al 2016) | [1:08:00]

Previous episodes of The Drive with Rick Johnson : [1:16:00]

#194 – How fructose drives metabolic disease | Rick Johnson, M.D. (February 7, 2022)
#87 – Rick Johnson, M.D.: Metabolic Effects of Fructose (January 6, 2020)

Mouse study comparing high-fructose and low-fructose diets : Sucrose induces Fatty Liver and Pancreatic Inflammation in Male Breeder Rats Independent of Excess Energy Intake | Metabolism (C Roncal-Jimenez et al 2011) | [1:16:00]

Previous episode of The Drive on sugar and sugar substitute s: #141 – AMA #18: Deep dive: sugar and sugar substitutes (December 14, 2020) | [1:19:15]

Newsletters on sugar substitutes : [1:19:15, 1:22:15]

Sugar substitutes: deep dive into the pros, cons, available options, and impact on metabolic health | PeterAttiaMD.com (K Birkenbach & P Attia 2023)
Silencing the alarm on aspartame and cancer | PeterAttiaMD.com (K Birkenbach & P Attia 2023)
Replacing sugar with allulose (P Attia 2020)

Newsletter explaining Peter’s framework for viewing nutrition : My nutritional framework | PeterAttiaMD.com (P Attia 2020) | [1:19:15]

Rat studies on the ability of saccharin to cause cancer : [1:23:30]

Ruminations on a Rat – Saccharin and Human Risk | AEI (W Havender 1979)
Bladder tumors in rats fed cyclohexylamine or high doses of a mixture of cyclamate and saccharin | Science (J Price et al 1970)

Data on the ability of aspartame to cause cancer : | [1:24:30]

Life-Span Exposure to Low Doses of Aspartame Beginning during Prenatal Life Increases Cancer Effects in Rats | Environmental Health Perspectives (M Soffritti et al 2007)
First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats | Environmental Health Perspectives (M Soffritti et al 2006)

Studies comparing cancer risk in people who eat the most processed meat to people who eat the least processed meat : [1:32:00]

Meat, Fish, and Colorectal Cancer Risk: The European Prospective Investigation into Cancer and Nutrition | Journal of the National Cancer Institute (T Norat et al 2005)
Meat Consumption and Risk of Colorectal Cancer | JAMA (A Chao et al 2005)

Newsletters about red meat :

The red meat and plant-based recommendation war (2020)
Is ditching meat a “game-changer” for your health? (2019)
Is red meat killing us? (2018)

People Mentioned

Matt Kaeberlein (Professor of Pathology at the University of Washington, founder of the Dog Aging Project, and expert in longevity) [15:45]
Andrew Huberman (Associate Professor of Neurobiology at Stanford and host of the Huberman Lab podcast) [17:30]
Nir Barzilai (Professor of Medicine and of Genetics at Albert Einstein College of Medicine and PI of the TAME trial ) [20:00]
Rich Miller (Professor of Pathology at the University of Michigan, Director of the Paul Glenn Center for Biology of Aging, and expert in the Interventions Testing Program) [23:30, 34:45]
Jeremy Loenneke (Associate Professor of Exercise Science at the University of Mississippi and expert in blood flow restriction) [44:15]
Alton Barron (Orthopedic surgeon with expertise in shoulder, elbow, and hand) [51:30]
Adam Cohen (Orthopedic surgeon with expertise in sports medicine injuries of the shoulder, elbow, hip, knee and ankle) [51:30]
Richard (Rick) Johnson (Professor of Medicine in the Department of Nephrology at the University of Colorado and expert in fructose metabolism and metabolic disease) [1:16:00]

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