175 - The biology of aging, rapamycin, and other interventions that target the aging process
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- เผยแพร่เมื่อ 7 มิ.ย. 2024
- Matt Kaeberlein is globally recognized for his research on the biology of aging and is a previous guest on The Drive. In this episode, Matt defines aging, the relationship between aging, chronic inflammation, and the immune system, and talks extensively about the most exciting molecules for extending lifespan. He discusses the current state of the literature of testing rapamycin (and rapalogs) in animals and humans, including Matt’s Dog Aging Project, and provides insights into how we can improve future trials by conceptualizing risk, choosing better endpoints, and working with regulators to approve such trials. He also examines the connection between aging and periodontal disease, biomarkers of aging, and epigenetic clocks. Finally, they explore some of the biological pathways involved in aging, including mTOR and its complexes, sirtuins, NAD, and NAD precursors.
We discuss:
00:00:00 - intro
00:00:10 - The various definitions of aging
00:14:08 - The relationship between disease and the biology of aging
00:20:55 - Potential for lifespan extension when targeting diseases compared to targeting biological aging
00:31:30 - Rapamycin as a longevity agent and the challenges of targeting the biology of aging with molecules
00:38:56 - Human studies using rapalogs for enhanced immune function
00:51:22 - The role of inflammation in functional declines and diseases of aging
00:56:56 - Study showing rapalogs may improve the immune response to a vaccine
01:02:26 - Roadblocks to studying gero-protective molecules in humans
01:14:44 - Potential benefits of rapamycin for age-related diseases-periodontal, reproductive function, and more
01:24:40 - Debating the ideal length and frequency of rapamycin treatment for various indications like inflammation and longevity
01:32:38 - Biomarkers of aging and epigenetic clocks
01:41:05 - Prospects of a test that could calculate biological age
01:47:28 - The Dog Aging Project testing rapamycin in pet dogs
02:05:00 - The role of the mTOR complexes
02:16:53 - mTor inhibitor called Torin2, mitochondrial disease and other potential pathways
02:27:24 - Catalytic inhibitors, sirtuins, and NAD
02:36:47 - NAD precursors: help or hype?
Show notes page: peterattiamd.com/mattkaeberle...
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About:
The Peter Attia Drive is a weekly, ultra-deep-dive podcast focusing on maximizing health, longevity, critical thinking…and a few other things. With over 30 million episodes downloaded, it features topics including fasting, ketosis, Alzheimer’s disease, cancer, mental health, and much more.
Peter is a physician focusing on the applied science of longevity. His practice deals extensively with nutritional interventions, exercise physiology, sleep physiology, emotional and mental health, and pharmacology to increase lifespan (delay the onset of chronic disease), while simultaneously improving healthspan (quality of life).
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In this episode, we discuss:
00:00:00 - intro
00:00:10 - The various definitions of aging
00:14:08 - The relationship between disease and the biology of aging
00:20:55 - Potential for lifespan extension when targeting diseases compared to targeting biological aging
00:31:30 - Rapamycin as a longevity agent and the challenges of targeting the biology of aging with molecules
00:38:56 - Human studies using rapalogs for enhanced immune function
00:51:22 - The role of inflammation in functional declines and diseases of aging
00:56:56 - Study showing rapalogs may improve the immune response to a vaccine
01:02:26 - Roadblocks to studying gero-protective molecules in humans
01:14:44 - Potential benefits of rapamycin for age-related diseases-periodontal, reproductive function, and more
01:24:40 - Debating the ideal length and frequency of rapamycin treatment for various indications like inflammation and longevity
01:32:38 - Biomarkers of aging and epigenetic clocks
01:41:05 - Prospects of a test that could calculate biological age
01:47:28 - The Dog Aging Project testing rapamycin in pet dogs
02:05:00 - The role of the mTOR complexes
02:16:53 - mTor inhibitor called Torin2, mitochondrial disease and other potential pathways
02:27:24 - Catalytic inhibitors, sirtuins, and NAD
02:36:47 - NAD precursors: help or hype?
p
Hello, and what about side-effects? I read, that there´s irreversible damage to male fertility, found in animal studies with rapamycin. Is that fully researched for humans? Thanks for the videos.
The Drive remains amongst the very best longevity podcasts, and this was one of the best episodes.
Attia has reach elite levels of Erik Weinstein
Glad Dr A talked about his own self-regimen - at the 38 min mark.
By far one of your best pods. Aside from the wellspring of interesting info that is Matt K, your skills as an interviewer are dramatically improved, compared to the earlier pods. Namely, you seem to be honing in on the ideal balance between being inquisitive and conversational, on the one hand, vs being patient and letting the guest elaborate, on the other. This podcast was also the ideal ratio of depth and breadth. Seems like you're really getting the knack of knowing when you'v reached sufficient depth that it's time to segue into the next topic. Bravo sir.
What an awesome pod ! I am Looking forward to more. Thank you.
Thanks Peter and Matt. I have listened completely thru this podcast while traveling 4-times. Seriously! I never get tired of it. Such a nice balance of information, research and personal input. You really understand and can explain this difficult subject matter. I keep picking up a bit more (this covers such a breadth of material on aging). FYI - I am going on 2-years of rapamycin use once a week 6mg - precribed by my personal physician and blood monitored every 3 months. He and I can't believe the amazing results in pushing back on the biological age in all my organs. I will be 64 years young in 1 week. But, feeling more like my TRuMe epegentic 50 year biological age reading. BTW - Matt's comment there is no such thing as a healthy 65 year old. Ouch. I guess I have one more year of health. Hahaha. Proof of Rapa effectiveness! Jason
Thank you. Another great show.
Excellent interview
Great interviewee
Great podcast. Great to hear what they do know, what they don't know, self experimentation, and speculation.
Also nice to see Peter mention senolytics and voice an opinion on epigentic clocks.
Western diet supports magic like Tesla. Cancer is a tiny price worth paying for all the innovation and giant leap forward for Humanity. Let's give respect where it is due - the food industry that's supported all this progress for all these years on Earth.
The context, timing and dose are interesting and very important. Naltrexone is another very good example. In low dosage (up to 4.5mg) the effects are massively different, as well as the timing in many cases.
Great conversation 🔥
I ( a female, then 74 years old ) had two infections within three weeks’ period in spring of 2020, probably the second could have been COVID since it was pretty severe with very high fever but I put out fever within four days, the second one after sweating profusely and not eating, just drinking and resting but not taking any medicine just some antimicrobial ointment for the nostrils and throat. I was completely well after a week!
Hi Paula, I hope you are still well. I assume there was no Dr intervention? Sounds like you weren't too worried. I had covid last year and joined a Facebook group for vaccinated, covid positive. I only stayed with that group briefly, but was struck at how scared and stressed out these people were. Half the battle is educating yourself, taking care of yourself with healthy lifestyle, and staying calm! I think so many get very ill, and have lasting effects because of stress and panic.
thanks for sharing this whole episode with even us freeloaders :) much appreciated !! This is probably the most valuable info I've received in my entire life :)))
Can't find the link to the 2009 UMich paper where older mice on rapamycin had their immune system restored to that of young mice?
Amazing
Protein and carbs stimulate mTor via different pathways. Does it mean it's beneficial to switch to fat metabolism(low carb, keto) to receive the benefits rapamycin gives?
How soon can we start seeing rejuvenation centers instead of hospitals?
Have you released your book for mental consumption? I am ready to feast. I do not see any hits on Amazon. Peace, health and blessings...
I'm still very surprised why Prof. Valter Longo has not been in the show yet! Please invite him! I imagine your chat with him to be fascinating!
Thanks Peter! Amazing episode!
Longo will never be invited. Longo favors a diet very high in carb, low fat with olive oil and low animal products.
@@cutabove9046 Yeah, but he has key research on fasting. Which is in the core of Peter an his audience interests.
@@cutabove9046 not very high on carbs, he actually advises avoiding bread, pasta rice etc..
@@YoavHillel Read his book. His diet is 10% protein, 20% fat (mostly olive oil) and 70 percent carbs. He calls it his longevity diet. The only exception is when getting above 65 years of age. He recommends upping protein to at leas 15% to prevent muscle loss as you age. And yes, he advises against "processed carbs" like sugar, white flour and products made from them like too much bread and too much pasta, but not brown rice. You are therefor never going to see him invited on this channel. In his opinion low carb, keto and carnivore lead to illness and early death.
@@cutabove9046 Attia is VERY clearly not a low-carb purist in spite of his personal history with a ketogenic diet. He advocates the benefits of keto in certain cases, especially in metabolically deranged and neurologically impaired individuals, but he constantly stresses “not one size fits all” when it comes to nutrition. Also, he doesn’t shrink from controversial topics or from discussion with other scientists with whom he might not currently see eye to eye.
Can ketone measurement be a bio marker for Autophagy?
People always talk about rapamycin, metformin, resveratrol and NMN in a slower aging sense. But if you dont even know the exact dose and are flying blind. What makes you think to high doses cannot result in accelerated aging?
Since both of you take Rapamycin, curious about your oral health now. Just basic answer - is it SAME, BETTER, WORSE?
I'm a dentist and just took my first dose. I can update you in a few months but man I can see those first 2mg are hitting me hard. Feeling very tired weak and light headed ....
@@arhu74 age?
@@jellybeanvinkler4878 47 and each subsequent dose came with less side effects. I am up to 30mg effectively now (10mg with grapefruit juice a cyp3a4 inhibitor) with no noticeable effects
Man, if I were rich enough, I would fund that periodontal study yesterday...
The Glycome is a very interesting test of biological age. GlycanAge run by Prof Gordon Lauc in Zagreb.
In response to the Understanding of aging vis a vis the Treatment of it in health or disease states - which mirrors the epistemic opacity in many fields - I’ll drop the title to one of my favorite papers by Nassim Taleb: “**Understanding is a Poor Substitute for Convexity (Antifragility**)“. The heuristic is that when you detect acceleration of harm (fragility) then it’s safe to avoid something instead of over intervening (iatrogenics). Like the health-seeker avoiding sugar and starchy carbohydrate instead of waiting for a miracle drug to fix aging in health and disease states. You may not understand why it works but you can detect the acceleration of harm by adding those things back in. So you eliminate fragility.
The studies showing rapalogs' improving immune response to vaccines in older adults is particularly of interest right now as I'm following the very detailed data on the Israeli Ministry of Health's data dashboard on covid. They show that while people 60 or over are a relatively small fraction of those infected, they constitute the vast majority of those seriously ill and this includes people vaccinated fully and even with a booster. At this point in time, finding any way to improve immune response in older adults could have a significant impact on a number of issues: the rates at which older adults become seriously ill and die, the pressure on the health care system, and through this, alleviate the overall pressure on society that comes with dealing with this disease.
Where does Matt and Peter source their Rapamycin from? Looking for the highest quality.
pfizer
They can write themselves scripts. Try all day chemist.
What are, your thoughts, on Metformin?
Longevity certainly have some genetic aspects to it. All of my grandparents lived over 96+ years. My maternal great grandfather lived to be 106. I checked my genetic SNPs I have most of the longevity markers.
Tell us which SNP's are you talking about specifically...
You say we can't measure autophagy, but aren't there a bunch of proteins used to measure autophagy flux? How are they not biomarkers of autophagy? What am I missing? I was talking to a guy researching mtor and muscle breakdown and much of his research revolves around measuring autophagy.
Wish they'd have expounded upon the dosing in the dog trial. .15mg/kg = 11.25mg /week for a 75kg human. With Peter/most taking 6-8mg/week, this is much higher. Why? He talks abt being conservative for sides in dogs, but this is a high dose. With mice trials showing males do better on higher dose, I'm wondering if 6-8m is too low for maximum efficacy?
He actually mentioned in this video that his dose is mostly based on Joan Mannick's trial of everolimus in humans (an mTOR inhibitor very similar to rapamycin), which showed that at 5mg, everolimus was effective in improving the immune system of aged individuals such that they had a better response to an influenza vaccine.
I had a severe toxic reaction to Metformin. And it depletes CoQ10 & B12
Ok, so where can I buy rapamycin from?
Search on "Sirolimus", the generic name for Rapamycin, on IndiaMart. Cost is typically about $1/1mg tablet. No prescription required. Have shipped via IndiaPost EMS / Speedpost. At University of Washington they use the Zydus Sirolimus version in their clinical studies.
@@bchik9856 brillant, thank you! I can see some online sellers but keep on pondering if that is safe; btw it’s for my parents not for me, I am absolutely sure they would benefit from it; they swallow way too many pills, I’m trying to talk them into ditching some of them and embarking on some fasting from time to time
@@bchik9856 Thanks for this, had not come across Indiamart but looks good.
Push Health is another option, if you don't want to buy from India. Paid $60 (push health app fee) for 120mg (insurance covered the meds in my case, out of pocket max was met).
Enough chit-chat. Just give me a pill now.
Its available now - search on "doctors that prescribe rapamycin" and you'll find information on how to get rapamycin.
Regarding the 51m mark, on how the immune system malfunctions with age, not so much that it's weak.. how do you measure chronic-sterile inflammation.. P16, P21, markers of senescence? And is it possible that an immune system that responds incorrectly, may lead to the myriad of autoimmune disorders, YET, may be better at warding off cancer?
Regarding the known side-effect with Rapamycin (mouth-sores), any thoughts on Nir Barzilai's Aging paper,
"Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults",
where he says only muscle mass is negatively affected, not strength!
"The function of the muscle didn’t change. So if they have less muscle, and the function of the muscle didn’t change, it means that for a gram of muscle, the muscle was better. So I looked at it and took the muscle from those two trials because they had muscle biopsies, and we did a transcriptome. And we basically saw that all the work to get hypertrophy, you have to activate mTOR. And remember when you activate mTOR, it’s not good for aging. So the muscle growth was associated with mTOR, which Metformin blunted, because that’s part of what Metformin does. On the other hand, people on Metformin had a transcript that was a protective transcript for aging with genes for autophagy, against inflammation, and some other things. So there was a trade off. And for me, I’m exercising and I’m on Metformin, for me it’s not that important to bulge my muscles. For me, it’s more about aging. So if you want to show muscles, don’t take Metformin. But I think Metformin protects your muscle from the aging effects. And so if I were you, I would say do it together. And the question of timing, it depends. I’m on extended release Metformin. So it’s not that timing would have a huge effect. And I’m also exercising sometimes in the morning, sometimes in the evening."
Would love to hear Keith Baar take on whether PPAR gamma/delta signaling is affected. And where does strength come from, if it's independent of muscle size? For example, in Blood-Flow-Restriction (BFR) weight-training, ex. GoBstrong , KAATSU, would seem to fool the body to react as if heavy weights are being used.. yet without actual heavy tendon-loading, would strength and/or muscle size increase or neither?
Those of us with Myositis conditions, which are autoimmune, are highly prone to also developing cancer. I have Polymyositis and endometrial cancer.
My Grandparents lived to be 103 years old , without any brain or cardiovascular decline. They lived in CUBA.
Why don't start a clinical trial on Rapamycin in people, with periodic testing of GrimAge (the best predictor of time-to-death)?
These epigenetic clocks are much hyped but of questionable value as objective true markers of biological aging and the efficacy of various treatments as they pertain to true age reversal.
There is a rapamycin study going on right now - The PEARL rapamycin study. But there are thousands of people already using rapamycin for anti-aging, and we're getting some very good results on reductions in biological age measures... such as they are right now.
NMN questions are prevalent because we don't need an Rx. Don't you think?
Bringing @Nina Teicholz to the show is possible? Thanks.
who is downvoting? Must be Sinclair and his disciples.
NAD is the key, to reverse aging
Is it wise for me to go and get some rapomycin and take 1mg per week for 3 months. Im 62 and I think in good health
Lots of people are already taking rapamycin - most of us take 5mg to 10mg dosed once per week. Search on "rapamycin news" and you'll find the user group of people trying out rapamycin.
... hey one more thing. I think nr and nmn are great molecules, im convinced it works, and most important its SAFE!!! Its easy to jump on the rapamycine band wagon but its hard to find out later that the wagon has got no breaks. I personally only take niacin and its fantastic, from my own experience, i perform much better..... its great to hear about rapamycine but please not on the costs of the benefits of other safe remedies, at least for the time until rapamycine has been searched properly.... and by the way, no one claimed that nmn etc could extend lifespan
All the autophagy promoting drugs/supplements inhibit mTor and subsequently lower testosterone. How can this promote longevity if muscle building and cell division is inhibited?
Normal human life is a balance -autophagy/anabolism sleep/exercise day/night yin/yang Daily rapamycin alone in my opinion would likely promote frailty. I suspect balancing resistance training and aerobic exercise is a better approach. Substituting pills for behavior change is popular but does not treat the cause. Exercise is an essential part of a healthy lifestyle.
I just took my first 2mg (genuine stuff from a pharmacy in western Europe) and I feel like trash. Oh well it's for the greater good later on....
NAD!!
What the ninth Dr Peter?
Epigenetic modulation
Epigenetic modulation
What contributes to brain damage are SEED OILS.first on foremost. I'm 70 and I don't have any declines. As a piano teacher over 50 years I'm sharper than when I was younger.❤
.... hmmm a lot of praising of Rapamycin, however the risks are still high. Who ever wants to heal a frozen shoulder, just go Keto for 4-8 weeks, and inflammation will b gone, and for anti aging and reducing mTor, just fasting and plant based diet reduced in protein (for times when not on keto). Should b safe and cheap and legal.
Risks of rapamycin are greatly overblown. We have hundreds of people in the Rapamycin Usergroup on the rapamycin news forums and people are doing great on it. Some side effects, but all minor. At the lower, pulsed doses used in anti-aging, side effects are almost always minor; a canker sore, a small rash, maybe a runny nose... and even here its only a small percent of people. People rely too much on the old research of extremely high doses used in organ transplant patients and extrapolate from that baseline. Its a different reality with weekly pulsed rapamycin. I encourage you to read up.
@@rapamycinnews... thx, i think it over,...... i hve an chronic infection, only found out recently, now i put myself on Metformin and Aspirin, it work to some extent. But if this is not removing the infection ill try and get Rapamycin..... the thing is, if u hve a condition u always have to take some risk when choosing a medication, even when taking M and A..... u just wanto get rid of the infection
@@mickmack9333 If you have an infection - don't take rapamycin. Better to get help for your chronic infection.
@@bchik9856..... i was mixing up infection and inflammation....... is rapamycin ok for inflammation? Sorry, it was a bit missleading
Sorry but I do not want to live too long.
Quality of life and health till the end is my goal .
But thats the point of rapamycin - please read the research. It reverses or slows aging in most organs of the body. Thats increasing both healthspan and lifespan. Many of us are already taking rapamycin with good results.
aging = lack of nutrition, lack of microbiome diversity...there are way to reload microbiome in ancinet societies
Sounds scary, testing drugs that may affect how egg chromosomes sort out during division. Thalidomide?
So you had inflammation in your shoulder that went away after 8 weeks. And you body couldn't have healed itself in 8 weeks, so it must have been rapamycin. Silly. My take away from this is. Poor studies, poor science, poor data. Silly. If you're going to serious with this subject you really need to get people who understand data involved. Your standards for data are just wrong -to put in nicely. You don't even have baselines and you speak as if you have real data. Come on.
Thanks for showing you and your guest have not definitive definition of aging.
There is no such reality of reversing ag
Revers aging is a myth, only moderate decline is in any way approachable
You want to know why we live ?
Read the Bible. God set our limit.
We have a sin nature.😊
All you need is an expensive mic to sound expertly.
Matt is far to conservative to be in medicine. The would never be any new drugs developed if he was in charge.
Are you kidding? Rapamycin is routinely dismissed by clinicians and scientists because of ignorance, and a seeming inability to understand basic pharmacology - the dose makes the poison.
Matt has been fighting that for years and is advocating for an apparently 'risky' drug for testing in clinical trials, that is very much not conservative.
I don't think he is conservative. I think he is sceptical.. as one should be. I actually agree with alot of things that he says.
Junk
Man boring ... same stuff over and over ... nothing new
Do something about it. Fund, research, advocate.
Then you weren’t really listening
This is an incredibly rude comnent for someone who's bringing us a goldmine of fascinating research and expert-level discussions (something usually not freely available)
So much positive help for individuals but what about the whole. We currently have a magnitude of world problems exacerbated by the huge human population. How does massive increasing of population help....?
Attia is woohoo self-absorbed.