281 ‒ Longevity drugs, aging biomarkers, and updated findings from the Interventions Testing Program

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Richard Miller is a professor of pathology and the Director of the Center for Aging Research at the University of Michigan, as wells as a previous guest on The Drive. In this episode, Rich provides an update on the exciting work of the Interventions Testing Program (ITP), an initiative designed to assess potential life-extending interventions in mice. Rich covers the notable successes like rapamycin, 17⍺-estradiol, and acarbose as well as notable failures like nicotinamide riboside, metformin, and resveratrol, providing valuable lessons about the intricacies of the aging process. Rich delves deep into aging biomarkers and aging rate indicators, unraveling crucial insights into the science of geroprotective molecules. Additionally, Rich discusses some surprising successes of recent molecules tested by the ITP and concludes with an optimistic look at future frontiers, including bridging the gap from mice to humans.
We discuss:
0:00:00 - Intro
0:00:50 - An overview of the Interventions Testing Program (ITP)
0:08:51 - How the mice used by the ITP are superior for research relative to mouse models used in most research
0:17:11 - Design of ITP studies, outcomes tested, and metrics of interest
0:29:00 - The process and challenges of drug formulation for mice
0:36:11 - Four drugs identified by the ITP that extends the lifespan of mice
0:43:32 - The success of rapamycin and what it tells us about the biology of aging
0:51:49 - Other measures of healthspan evaluated by the ITP in stage 2 studies
0:59:18 - Distinguishing aging rate indicators from biomarkers of aging
1:01:16 - Aging rate indicators identified through the examination of slow-aging mice
1:15:36 - Why proteomics are essential to understand changes in the cell
1:25:30 - Unraveling aging rate indicators: dose-effect, duration, and future frontiers
1:31:54 - A closer look at aging rate indicators: bridging the gap from mice to humans
1:44:32 - What do laboratory mice die from?
1:48:09 - Distinguishing between a drug that improves an age-sensitive outcome and a drug that improves all aspects of aging
1:48:48 - The ITP study of 17⍺-estradiol: mechanisms of life extension and surprising sex differences
1:58:34 - Unsuccessful drugs studied by the ITP: resveratrol, metformin, and nicotinamide riboside
2:09:13 - Over-the-counter successes in the ITP: meclizine and astaxanthin
2:16:00 - A senolytic drug, fisetin, fails to extend lifespan
2:22:30 - Optimism about future findings
--------
About:
The Peter Attia Drive is a deep-dive podcast focusing on maximizing longevity, and all that goes into that from physical to cognitive to emotional health. With over 70 million episodes downloaded, it features topics including exercise, nutritional biochemistry, cardiovascular disease, Alzheimer’s disease, cancer, mental health, and much more.
Peter Attia is the founder of Early Medical, a medical practice that applies the principles of Medicine 3.0 to patients with the goal of lengthening their lifespan and simultaneously improving their healthspan.
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[@PeterAttiaMD]

In this episode, we discuss: 0:00:50 - An overview of the Interventions Testing Program (ITP) 0:08:51 - How the mice used by the ITP are superior for research relative to mouse models used in most research 0:17:11 - Design of ITP studies, outcomes tested, and metrics of interest 0:29:00 - The process and challenges of drug formulation for mice 0:36:11 - Four drugs identified by the ITP that extends the lifespan of mice 0:43:32 - The success of rapamycin and what it tells us about the biology of aging 0:51:49 - Other measures of healthspan evaluated by the ITP in stage 2 studies 0:59:18 - Distinguishing aging rate indicators from biomarkers of aging 1:01:16 - Aging rate indicators identified through the examination of slow-aging mice 1:15:36 - Why proteomics are essential to understand changes in the cell 1:25:30 - Unraveling aging rate indicators: dose-effect, duration, and future frontiers 1:31:54 - A closer look at aging rate indicators: bridging the gap from mice to humans 1:44:32 - What do laboratory mice die from? 1:48:09 - Distinguishing between a drug that improves an age-sensitive outcome and a drug that improves all aspects of aging 1:48:48 - The ITP study of 17⍺-estradiol: mechanisms of life extension and surprising sex differences 1:58:34 - Unsuccessful drugs studied by the ITP: resveratrol, metformin, and nicotinamide riboside 2:09:13 - Over-the-counter successes in the ITP: meclizine and astaxanthin 2:16:00 - A senolytic drug, fisetin, fails to extend lifespan 2:22:30 - Optimism about future findings

[@nicolelittle6429]

Wow. This podcast is so generous in its sharing of real knowledge. What a gift.

[@capcomfan82]

Gotta love this free education. Its great.

[@marksimard3532]

Meet Maria she will help you recover ITP losses

[@Ivika06_09]

She's on telegrams.

[@Ivika06_09]

Makis55 The username

[@vaughanmoody]

Man, Dr Miller sure knows his stuff! I’m always impressed by how much some people know about a complex subject such as this. Kudos to him and Peter Attia.

[@ASAPRocky619]

You should add the name of the people you’re speaking with either in the title or thumbnail.

[@Ivika06_09]

Meet Maria she will help you recover ITP losses..

[@marksimard3532]

She's on telegrams..

[@marksimard3532]

Makis55 The username..

[@zacwarnest-knowles9139]

Agreed

[@traciallen6822]

Why did you make him go through such specific details of the experimental design? As a listener, I was really turned off by this.

[@SilverFan21k]

Ty Peter for covering Longevity. Just found this video

[@riceexperiment]

The details in this podcast are fantastic.

[@marksimard3532]

Meet Maria she will help you recover ITP losses

[@Ivika06_09]

She's on telegrams

[@Ivika06_09]

Makis55 The username.

[@edouarddebonneuil149]

Bravo - this is life-changing for next generations obviously, and perhaps current ones too

[@barbaraarzooni6919]

So much great info. w/Dr. Rich Miller...thank you.

[@Ivika06_09]

Meet Maria she will help you recover ITP losses.

[@marksimard3532]

She's on telegrams.

[@marksimard3532]

Makis55 The username.

[@Funymoney010]

Very exited to watch this! Thank you!!

[@marksimard3532]

Meet Maria she will help you recover ITP losses.

[@Ivika06_09]

She's on telegrams.

[@Ivika06_09]

Makis55 The username.

[@PartTimePermies]

Interesting studies in the cancer genetics realm: there is a study on rapamyacin in people with Lynch syndrome to see if it reduces LS related cancers and a study looking at effects of metformin on cancers related to Li-Fraumeni syndrome. Both were presented at this year's NSGC conference. Really interesting potential off label uses.

[@carrievanderhoff]

I sure hope there is no pop quiz after the lecture! This is interesting, what I was able to grasp of it that is. Pre-requisites or deeper understanding of science and medicine would have made it more relateable. Great respect for guest, so accomplished.6: 1:46:50

[@DeletedDenizen]

The word you are looking for is: propedeutics

[@carrievanderhoff]

​@@DeletedDenizen I thought he was referencing drugs: Psychedelics? Don't trust telemarketer who are so vague and cannot even spell properly!?

[@Ivika06_09]

Meet Maria she will help you recover ITP withdrawal pending

[@marksimard3532]

She's on telegrams

[@marksimard3532]

Makis55 The username..

[@larrycobb7073]

A wonderful & very informative podcast. I hope Rich's biomarker testing is productive in determining future testing candidates. ITP is doing great work !

[@goraneriksen9461]

Thanks for this video! Hope they will test OTC compounds that has shown results in other labs soon such as GLYNAC, I know they tested Glycine with positive results, but other labs has combined NAC with Glycine with better results, would love for ITP to test and confirm the other labs results.

[@stephen6155]

Awesome and informative. I wonder if they have tried Omega-3's? Or just combine astaxanthin, Meclizine, Acarbose, 17a-estradiol, and rapamycin :)

[@Ivika06_09]

Meet Maria she will help you recover ITP losses..

[@marksimard3532]

She's on telegrams

[@marksimard3532]

Makis55 The username.

[@kennyprice5017]

the ITP did test fish oil and it did not have an effect on increased lifespan.

[@bneymanov]

Just fantastic!

[@Ivika06_09]

Meet Maria she will help you recover ITP losses.

[@marksimard3532]

She's on telegrams.

[@marksimard3532]

Makis55 The username..

[@shus5787]

Thanks for the info

[@Ivika06_09]

Meet Maria she will help you recover ITP withdrawal pending..

[@marksimard3532]

She's on telegrams..

[@marksimard3532]

Makis55 The username.

[@wendyvg1225]

I'm just so baffled my the enormous sex differences in the effects of various drugs. It's seems like such an important outcome, potentially also holding information about the pathways if not posing important implications for numerous of other drugs. I wish someone would dive into the nitty gritty here and hopefully shed some light in these findings!

[@Nilsosmar]

Re: both the controls and the animals being given the drugs always living longer when tested in Michigan, I wonder if they've looked at the level of lithium in the water in Michigan as compared to other test cities; it could explain the difference.

[@goraneriksen9461]

Got to say that Mr. Attia looks incredibly healthy and glowing skin. He got to be doing something correct,

[@MichaelMerritt]

Was thinking the same. Beyond Rapa I'd love to know what's working for him.

[@videoagogo1]

Maui Nui Venison stick protein, for one ;-)

[@marksimard3532]

Meet Maria she will help you recover ITP losses

[@Ivika06_09]

She's on telegrams l..

[@Ivika06_09]

Makis55 The username..

[@weiminyang7206]

Great!

[@supralogical]

About Meclizine: "Meclizine should not be given to children under 12 years old without medical advice, and its use should be discussed with a doctor if you have certain medical conditions like liver or kidney disease, asthma, glaucoma, an enlarged prostate, or urination problems. Also, consuming alcohol while taking Meclizine can increase side effects. Possible side effects include drowsiness, dry mouth, headache, and sometimes vomiting.

[@digitalmiked]

Re: discussion at 26:00 - unexplained inter-site differences in survival curves in male controls, have you checked to see if cages are electrically grounded differently? Maybe Michigan cages are being grounded somehow and other two are not?

[@PartTimePermies]

I'd like to add another post-transcription process that might impact the mRNA protein discrepancy: differences in post trascription mRNA processing (spicing). This can be impacted by the original DNA code and mutations, but sometimes there are alternative splice donor or acceptor locations that would alter the protein product that is translated.

[@marksimard3532]

Meet Maria she will help you recover ITP losses.

[@Ivika06_09]

She's on telegrams.

[@Ivika06_09]

Makis55 The username.

[@zibtihaj3213]

Mr Attia , what about this new Crispa technology ?

[@milenabellotti9771]

Does Rapamycin cause thrush in women like other antibiotics?

[@user-wz9pu7ty9z]

How can I get rapamycin???

[@Brucesama]

Does anyone know if Dr. Attia does some live workshops where we can ask questions

[@DeletedDenizen]

He has a practice so you could just hire him

[@Ivika06_09]

Meet Maria she will help you recover ITP losses...

[@marksimard3532]

She's on telegrams.

[@marksimard3532]

Makis55 The username..

[@Erwin_AMS]

Does this mean the TAME research will not continue anymore?

[@Magamomma22245]

1st .Have a happy day all!

[@marksimard3532]

Meet Maria she will help you recover ITP withdrawal pending

[@Ivika06_09]

She's on telegrams..

[@Ivika06_09]

Makis55 The username.

[@PartTimePermies]

Lol, advantages of living in Michigan. Another reason to have Mivhigan pride?? (Go Blue! lol)

[@marksimard3532]

Meet Maria she will help you recover ITP losses

[@Ivika06_09]

She's on telegrams..

[@Ivika06_09]

Makis55 The username..

[@steven871]

Could anyone kindly post a summary? Unfortunately, I don’t have a 150 minutes to spare to get through it all.

[@DeletedDenizen]

Summary is that good research is being conducted at the ITP. The submission process, the current trials. And that the compounds that have demonstrated extension of lifespan in mice are: Astaxanthine (being the only OTC compound here) 17-alpha-estradiol Acarbose Meclizinw Rapamycin Also that resveratrol has nothing to show for lifespan improvement and David Sinclair is a charlatan.

[@marksimard3532]

Meet Maria she will help you recover ITP losses.

[@Ivika06_09]

She's on telegrams..

[@Ivika06_09]

Makis55 The username..

[@edouarddebonneuil149]

Would it make sense to test in rats? Mice are a great model but mouse populations die quite more from cancer than human populations so rats might be better

[@DadOmega]

What is the human dosage of 17⍺-estradiol for life extension in men?

[@Ivika06_09]

Meet Maria she will help you recover ITP losses.

[@marksimard3532]

She's on telegrams.

[@marksimard3532]

Makis55 The username

[@sindhujabheesette5981]

I think these are all mouse studies and are preclinical. It would be wise to wait for the clinical studies to proceed to test safety and efficacy before using it for lifespan benefits

[@DadOmega]

@@sindhujabheesette5981 If one were to conduct the studies in humans what would the human dose be?

[@StandUpChuck]

This where our belief in any of you falls apart. Hubeman had a guest that was saying the complete opposite about these very same supplements metformin, resveratrol etc...

[@kerrynmckay5273]

3rd!

[@Magamomma22245]

The early bird gets the worm, the second mouse gets the cheese and the third place, I'm not sure…;) Have a happy day!

[@marksimard3532]

Meet Maria she will help you recover ITP withdrawal pending

[@Ivika06_09]

She's on telegrams

[@Ivika06_09]

Makis55 The username..

[@intuitivesean443]

Trim -x study?

[@videoagogo1]

Thymus Regeneration, Immunorestoration, and Insulin Mitigation trial ?

[@Ivika06_09]

Meet Maria she will help you recover ITP withdrawal pending

[@marksimard3532]

She's on telegrams..

[@marksimard3532]

Makis55 The username..

[@mikespector2]

Are any human males taking 17 alpha estradiol?

[@vadimfedenko]

yea. bryan johnson is one example

[@jennakericson]

Richard Dawkins was going to go with the title "The Immortal Gene" but decided on "The Selfish Gene". I wonder Y

[@Cikflipp180]

Admittedly I skimmed over this while biking, but it sounded like he missed a key Attia dimension, which is whether despite not extending lifespan, something like NMN extends healthspan. I make this distinction as Rich continually talks about how gullible people are for believing in "snake oil", but seemed to gloss over this consideration entirely (at least based on what I heard).

[@DeletedDenizen]

They talk about it some 45 minutes before the end, as Dr Attia specifically asked about if they test for healthspan. Dr Miller said they don't test specifically for function until stage II trials (i.e. after a compound demonstrates a lifespan improvement). He says he doesn't think there is much utility in looking for that specifically because when a lifespan impact is achieved it is precisely through the mechanism of delaying (offsetting) the onset of the decline in function.

[@Cikflipp180]

@@DeletedDenizen thanks! I was too immersed in zone 2…

[@Ivika06_09]

Meet Maria she will help you recover ITP withdrawal pending

[@marksimard3532]

She's on telegrams..

[@marksimard3532]

Makis55 The username

[@gondwana6303]

Except for rapamycin, very little insight into mechanism of action and rationale for drug choices. Not informative and more like two guys glad handing each other.

[@sandybayes]

I had to unsubscribe because Dr Attia ignores the research oni ngesting red meat. I will not follow someone who is going to recommend things that will shorten my and other's lives.

[@nichtsistkostenlos6565]

He has gone over this probably hundreds of times at this point. Nutrition data is HIGHLY confounded, particularly the studies around red meat mostly due to healthy user bias. It's very, very difficult to pick out whether red meat is actually bad or if the multitude of other habits baked into the average person who consumes or does not consume red meat are the contributors. Just because somebody disagrees with you, doesn't mean you shouldn't listen to them either.

[@marksimard3532]

Meet Maria she will help you recover ITP losses.

[@Ivika06_09]

She's on telegrams.

[@Ivika06_09]

Makis55 The username.

[@greggbambu411]

You are getting triggered by the meat issue. This is just silly. Unless you hear exactly what you want to hear, you knock all the pieces off the chess board and go home to your safe space where meat eating won't be accepted.

[@AFFANYC]

Honestly, who cares about the type of mice you use. Can you get down to the point? You making your podcast boring. Unless your target audience are scientists. 😂

[@family.hackers]

Lipofuscin is a potential ageing biomarker @peter

[@rayquaza6791]

lipofuscin is a symptoms of retinoids poisoning.

[@petercoderch589]

Rapamycin is the classic case of "much ado about nothing". The most powerful life-extending effect ever seen for rapamycin was 14% for male mice. In Human terms, since Human males live an average of 76 years(varying from country to country, with a range of 74-81), that would translate into about an extra 9 years of life. Seems signficant, right? the problem is that all these drugs are much, much more effective in short-lived species than in long-lived species. The reason for this goes back to Darwin's theory of Evolution and the evolution of "longevity pathways". From the point of view of Evolution, how long you live or even how healthy you are is 100% irrelevant. Evolution doesn't care about your health and longevity. What Evolution cares about is *reproduction* ,that is, leaving copies of your DNA. In fact, the only reason why the selfish replicators even create a body in the first place is to aid in their replication. You don't need to live long: you only need to live long *enough* to reproduce. You don't need to be super-healthy: you need to be only healthy *enough* to reproduce. Basically, you only need to be healthy "enough" to long "enough" to make babies, and then you are as good dead as alive for Evolution. It simply doesn't care. So why would we develop "longevity pathways" in the first place? Becase reproduction requires energy, which requires food, which is not always available. So we evolved to have mechanisms that prolong our lifespan during famines so that we can survive longer to reproduce. But here's the problem: famines in Nature have a fixed "X" amount of duration. It does not vary by species. So these "longevity pathways" boost the lifespan of long-lived species by the same *absolute* amount of time as for short-lived species. Even the longest famines do not go longer than about 1-2 years tops. Now, if you are a mouse, living an extra 2 years is huge because your total lifespan is only 2-3 years. This is why calorie-restriction mimetics boost the lifespan of short-lived species such as mice by a massive 50% to 65%. However, for a Human that lives 76 years, an extre 1 or 2 years of lifespan means like 2-4% lifespan. And yes, all this drugs that work on the "longevity pathways" can increase lifespan by a maximum of 1 or 2 years. This is all very well-understood and predicted by Evolutionary biologists that understand Darwin. But Peter Attia doesn't understand Darwin. Rapamycin is also a terrible drugs with horrible side effects. It carries a black box warning from the F.D.A regarding immusupression and the risk of severe infection and death. It also causes loss of protein synthesis which is needed to sustain life. I know a girl that underwent organ transplant and takes rapamycin, and she lost all her teeth as her kaw bone necrotized. MTOR activity is absolutely essential for maintining not only your muscles, but your bones as well. Worse, MTOR suppression has strong depressive effects. Now they are working on drugs to *induce* MTOR in the brain which has strong anti-depressant above and beyond what any antidepressant has. So basically, you risk losing all your muscles, your teeth and suffering severe bone fractures for "maybe" and extra 1-2 years of lifespan. no, thaks. Longevity is primarilly *genetic* . Teh Worl'd's largest longevity study was done by the New England Centenarian Study. At the cost of tens of millions of Dollars, they did full genome sequencing of over 2,000 centenarians, semi-supercentenarians and supercentenarians. You know what they found? They were hoping to find some "magical" genetic variants that could single-handedly boost longevity by years if not decades. What they found, instead is that centenarians and super-centenarians have *millions* of genetic modifications compared to average people. In fact, centenarians have modification on *entire chromosomes* comapred to average people. To gain the extra 29 average years of lifespan that semi-supercentenarians and supercentenarians have compared to average people, you need millions of genetic modifications across thousands of genes. This is exactly what Darwin's Theroy of Evolution predicts. There is a saying: "You are only as strong as your weakest link." To live 30 years more, it's not enough to have a better heart, or a better brain, or better bones . You need *all* these things to be enhanced in function, because having a weakness in just one of these things will kill you. If you have a fantastic lipoprotein profile but mutations in the LMNA gene that causes cardiopathies and arrythmias, you will die anyway. If you have a perfect heart but your brain starts to atrophy rapidly at 50, you won't live long either. If you have a perfect heart and brain, but your ribosomes don't work very well, you will accumulate lots of crosslinks protein in your cellular matrix and die young from arthritis and other infllmmatory dseases. If you have all these things perfect, but have defective mutations in your insul receptor gene and develop diabetes, you will die young from kidney failure and vascular disease Longevity requires *ALL* your organs and physiological processes to work better than average. To mimick these processes with small molecules like Attia wants to do would require hundreds if not thousands of small molecules a day. Even if your liver doesn't become foie grase in a week from having to metabolize all these drugs, Attia has no way of knowing how to dose and time so many different drugs to make them do more good than harm. This strategy of micro-managing metabolism with small molecules that Attia wants is *IMPOSSIBLE* to work. But that is what happens when an establishment doctor doesn't understand Darwin. Longevity is *polygenic* . In fact, it is probably the most polygenic trait known to science. If you see the works of Vera Gorbunova, Vadim Gladyshev and Guimarães, you'd understand that. But don't expect an establishment doctor like Attia to understand Darwin.

[@vadimfedenko]

first of all: response to rapamycin is very dose-specific. as you said, mtor is essential for maintaining health. so taking rapamycin daily in high doses, like patients with organ transpalnts do, is very dangerous. however, when you hear people talking about rapamycin for longevity, they mean a much smaller dose (10mg or lower) taken once in a week, not daily. it's a completely different story with a different safety-profile, it basically acts as a strong cr mimetic, and doesn't cause people any trouble (people taking rapamycin for years, with seemingly no side effects). regarding the rest of what you said, you're acting like you know the truth, but really you just explained a very niche theory of aging, currently not much supported by science. everything you said is probably wrong (evolution might as well care about age, there might be a single cause of aging that triggers the other hallmarks, etc)

[@petercoderch589]

​@@vadimfedenko First of all, 10 mg is a *huge* dose. Even 2 mg leads to complete suppression of MTOR. Also there is no evidence that intermitent rapamycin use gives lifespan extension to a greater degree than it gives side effects. And finally, there is no evidence that RM extends lifespan in Humans. It's all speculation. If you read studies carefully, the *maximum* lifespan extension that they got from RM ws 14% in mice. Putting adide the fact that all these drugs etend lifespan much more dramtically in short-lived animals such as mice, a 14% life extension is too optimistic. But even 15% means an extra 8 years of life. So basically, you risk shattering your bones, losing all your teeth and risking serious illness from infections from a compromised immune system for "maybe" an 8 extra years of life. No, thansl

[@petercoderch589]

@@vadimfedenko First of all, 10 mg is a *huge* dose. Even 2 mg leads to complete suppression of MTOR. Also there is no evidence that intermitent rapamycin use gives lifespan extension to a greater degree than it gives side effects. And finally, there is no evidence that RM extends lifespan in Humans. It's all speculation. If you read studies carefully, the *maximum* lifespan extension that they got from RM ws 14% in mice. Putting adide the fact that all these drugs etend lifespan much more dramtically in short-lived animals such as mice, a 14% life extension is too optimistic. But even 15% means an extra 8 years of life. So basically, you risk shattering your bones, losing all your teeth and risking serious illness from infections from a compromised immune system for "maybe" an 8 extra years of life. No, thanks.

[@petercoderch589]

@@vadimfedenko First of all, 10 mg is a *huge* dose. Even 2 mg leads to complete suppression of MTOR. Also there is no evidence that intermitent rapamycin use gives lifespan extension to a greater degree than it gives side effects. And finally, there is no evidence that RM extends lifespan in Humans. It's all speculation. If you read studies carefully, the *maximum* lifespan extension that they got from RM ws 14% in mice. Putting adide the fact that all these drugs etend lifespan much more dramtically in short-lived animals such as mice, a 14% life extension is too optimistic. But even 15% means an extra 8 years of life. So basically, you risk shattering your bones, losing all your teeth and risking serious illness from infections from a compromised immune system for "maybe" an 8 extra years of life. No, thansl

[@petercoderch589]

@@vadimfedenko First of all, 10 mg is a *huge* dose. Even 2 mg leads to complete suppression of MTOR. Also there is no evidence that intermitent rapamycin use gives lifespan extension to a greater degree than it gives side effects. And finally, there is no evidence that RM extends lifespan in Humans. It's all speculation. If you read studies carefully, the *maximum* lifespan extension that they got from RM ws 14% in mice. Putting adide the fact that all these drugs etend lifespan much more dramtically in short-lived animals such as mice, a 14% life extension is too optimistic. But even 15% means an extra 8 years of life. So basically, you risk shattering your bones, losing all your teeth and risking serious illness from infections from a compromised immune system for "maybe" an 8 extra years of life. No, thansl