204 - Centenarians, metformin, and longevity | Nir Barzilai, M.D.

[@PeterAttiaMD]

In this episode, we discuss: 0:00:00 - Intro 0:00:08 - Insights from genetic studies of centenarians and twins 0:11:13 - Genes with protective variants that aid longevity 0:22:23 - The relationship between growth hormone and IGF-1 0:35:37 - Use of growth hormone as a longevity tool 0:44:29 - Longevity genotypes: the role of APOE e2, Lp(a), Klotho, and CETP 0:50:04 - The correlation between high TSH and longevity 0:56:30 - Important pathways for longevity 1:04:38 - Insights from centenarian studies, nature vs. nurture, and more 1:14:56 - The contraction of morbidity that comes with improved healthspan 1:20:56 - Defining healthspan 1:26:14 - Unique perspectives and positive attitudes of centenarians 1:33:32 - Lessons to take away from centenarians 1:38:48 - Metformin overview: history, studies, and potential for gero-protection 1:50:07 - The TAME trial (Targeting Aging with Metformin) 1:59:29 - The challenge of studying metformin in animals models 2:07:27 - How data from the TAME trial could provide insights into biomarkers of aging and facilitate a future study on proteomics 2:14:54 - The search for biomarkers to identify who can benefit from treatment 2:26:29 - The impact of metformin on exercise, and finding the right indication for the use of metformin 2:39:36 - Are NAD precursors geroprotective?

[@ingridcarolina264]

aK

[@MrSmajgaard]

Very complicated But also very interesting

[@bettykennedy6858]

Lll lol l LL

[@JasonCunliffe]

Wow

[@sylviachrucky6416]

4:40

[@livehealthyfinishstrong]

I personally have no interest in living to 100, BUT strongly desire to be as healthy as possible until I die at 80-85. Reducing carbohydrates to a minimum and some intermittent fasting has transformed my health. I started this at age 62. I turn 66 next month. I lost a lot of weight, came off ALL medications (2 for hypertension), reduced my HbA1c from 9.9 to 4.9 (without medication). I was also able to give up my CPAP for sleep apnea.

[@denasharpe2393]

I did a similar turnaround but l was 73 at the time...at 75 now.. Off all meds and doing well!! Left behind almost all white foods...although l must confess...not vanilla ice cream ( occasionally )

[@gregorycollins3096]

I started taking Metformin in after hearing a talk by Dr. David Sinclair and starting to research the area of health-span and longevity.

[@rospez1763]

Wow, congratulations!

[@gloriasaliba3395]

@@gregorycollins3096 what dosage do you take?

[@gloriasaliba3395]

I’ve done the same Bill lost 22 kilos in 5 months reduced significantly high inflammatory cortisol and glucose levels - AIC at 5.9 hoping to reduce it further

[@coronadentalarts]

Peter , Thank you so much for kicking "educational podcasts" in the balls and showing them the path forward to what the laymen like myself are craving . Long format educational podcasts done right are cocaine for the new kind of learning addicts like myself . Im 54 years old and just beginning to appreciate the information i choose to gather equals a better me . I love the variety of great guests and most importantly how you steer the conversations with your questions , which i believe is what makes these kind of high end podcasts so informative . Granted , I am just a regular guy and constantly have to rewind these talks to try and keep up and absorb these kinds of talks and most of the time I find myself lost in trying to track the scent trail of understanding . I wish that my brain could have a more sponging attitude with your podcasts but i am grateful what i can retain and that you are taking my health understanding to a higher level . Cheers to you for your free to all educational services you have provided and carry on with .

[@Aileen-68]

😢

[@jellybeanvinkler4878]

I'm glad I'm not the only one who has to rerun parts, or all of Peter's podcasts. I am thankful that I don't have to stop to skip ads. Often multitasking while listening and The Drive is my go to, while doing busy work, even if I heard it before. I always have a better understanding of things I may not have gotten out of the first time through!

[@jtschury2025]

Repetition is the only way to learn I think I heard that in a podcast

[@vaughanmoody]

I just “liked” your KZbin comment then noticed your channel/account is called CoronaDentalArts. I live in Corona, CA. Is that where you live?

[@javadhashtroudian5740]

My academic background is organic chemistry, biochemistry, and neurochemistry. In my 20s I abused my brain and body through alcohol tobacco and cannabis. I have been a software engineer for 40 years. I still would read biology papers and started intermittent fasting around 2000. In 2012 my GP informed me that tests showed that I was pre-diabetic and pre-hypertensive. Since I don't like drugs that don't get you high I refused pills. I said if I can't control my blood pressure and sugar in 6 months through diet and exercise I'll talk about pharmaceutical intervention. Both my A1C and blood pressure are good now. Now at 75 I don't take any pharmaceuticals while every one of my siblings and cousins take at least one pill a day, some as much as six different pills each day. I do take supplements, intermittent fasting 5 days a week, exercise every day averaging burning 2500 kcals a day, meditate, and have peace and fun. I look much younger than my 75 years and smile a huge amount. I laugh a lot at myself. I believe my attitude keeps me young. My only health concerns are aching knees and peeing many times a night. I discovered that THC-O acetate helps me with urination but gets me high and very tired next day. If I was still a biochemist and had the funding I would do research on THC and TBD derivatives for too much urination. Last point I wish metamorfin was available without prescription. In the meanwhile I have started Berberine and NMN.

[@redbull9554]

Thanks Dr. Attia! I’m 54 year old male. Last 2 years; 500 mg metformin X2 daily. 200 mg Test Cyp per week. I train almost every day. I’ve put on muscle, lost fat. Now on peptides for more GH release and I’m visibly turning the clock back no matter which clock you use. My experience with metformin has been great!

[@fredbranson2791]

Peter is right about metformin for those focused on maximal performance or maximal hypertrophy (bodybuilders). You're growing because your test dose and gh are out pacing the blunting of metformin. No surprises there. I'm not against metformin but Peter's observations are backed up and also observed anecdotally.

[@denmar355]

What dose of metformin do you take?

[@redbull9554]

@@denmar355 500mg once before bed 500mg in the morning. I’ve dropped 10-15 lbs

[@sandrasweeney798]

I'm so sensitive to metformin that within minutes of taking it I am violently ill.

[@redbull9554]

@@denmar355 500 mg at night and the same in the morning. I lost approximately 20 lbs just doing this!

[@timmulder9112]

Like I've said before and I would like to say it again. In order to challenge yourself in the pursuit of physical fitness you need to do something that you enjoy. Improving the quality of your life not necessarily prolonging your life needs to be the primary motivation. One of the greatest benefits of regular vigorous exercise is you gain the strength to do the things that you want to do. I mean just a normal everyday activities are one thing but to do things like going for a hike bowling on a bowling league or even playing ice hockey again after the age of 60. One of the great lies that we've heard over and over all of our lives is your too old to do this and you're too old to do that. But we all need to start somewhere. In my own experience after retiring early at 62 is I decided to start rollerblading and ice skating. Then I began to start in calisthenics and then from there I went into high intensity interval training. Now I play hockey 3 to 4 times a week I play roller hockey ice hockey and street hockey just day before yesterday I had three on three hockey at the local inline roller rink against teenage boys and Young 20-year-olds. I play twice a week at the local ice rink scrimmage hockey against men half my age. But I said all that just to say this that in order to enjoy what you are doing you need to get better at it and so that became a motivation not so much to be better than the other guy but to be the very best that I can be!!

[@suzanbak1]

Excellent testimonial!! Role model! I love lifting heavy feed bags and tossing them into my truck.. at 59 people are amazed. I’m tempted to over share … my panties stay dry everyday 👍🏼💃 MANY benefits oI enjoy my 4th year low/carb carnivore lifestyle

[@HannahIm]

Very inspiring! I'm 42 and I would like to try roller skating again.

[@pramujisinggihriyanto6901]

I love how the interviewer asks the questions.... Critical, polite n straight-forward n has ample background knowledge.

[@chrispurdue5762]

Very interesting. My wife was put on Metformin and felt absolutely miserable the entire year that she took it. She was tired all the time which negatively affected her mental health. As soon as she stopped, it went away.

[@sandor1969r]

There are two minerals that helps with sugar metabolism: Chromium and Vanadium few people ever mention this and many not even knows it.

[@karmatseringstar]

GLP-1 alternative to metformin

[@vibhaspalding6457]

@@sandor1969r tried chromium before, waa ok. For me berberine works better. In UK, metformin is not easily available, not sold over the counter or anywhere. You can get it in US. So berberine is best for me.

[@donadams3313]

I have a friend who was put on metformin...he went from a person in very good shape...muscle structure was good...when he first started taking metformin he was complaining about pain in his thighs....Doctor keep taking it. 10 years later he looks like he is 9 months pregnant. eating salads. His heart has 30 percent calcium built up thanks to the statins. The statins destroy muscle and keep calcium from going into there bones. What metformin does it forces glucose into the cells. The cells regulate the amount of glucose they need. By forcing the glucose into the cells it builds up a toxicity and fucks you up at the cellular level. Of course by forcing the glucose into the cells...there is less in the blood so they soh it is good no glucose shows up on the blood test. See Bart Kay you tube...scientist presents it in a very simple fashion. He says fuck the statins and the metformin.

[@mirellamatotek4294]

@chrispurdue5762 Perhaps it has to do with being female because it seems the blokes do well on it but being 65 yro female, I was absolutely miserable and complained to my Endo who thought I was being hysterical. Of course I was hysterical because I was exhausted trying to walk and had absolutely no energy. Males have higher testosterone than females and perhaps the impact is not so evident than a female with declining testosterone. Also males have higher muscle mass. I am not happy about the decline in my muscle strength. I now feel like a baby learning to walk from scratch. They need to study females like your wife and me and make sure it is never prescribed to outliers like us. 😢 Who wants to live to 100 feeling invalid, decrepit and depressed?

[@Youtubedisco]

According to 23&Me, I'm Ashkenazi. Also, if you look at what the state of my health should be according to 23&Me, I should be a total, overweight mess. It may be "in the genes," but it's mostly up to you. I'm in great shape in spite of what the gene report looks like because of food control. All my immediate family have passed, so I'm doing what i can to see if i can make it to 150 y/o!

[@timmclaughlin1787]

Well I did not make it through the whole pod cast but tried to hang with you guys. My Mom who I care for is 101.Her Father lived to be 100. I am 67. I take no prescribed meds. I am an active Triathelete and compete regularly in Age group USAT racing. I believe my diet is my medicine. We are plant based 98% although I will eat Eggs at times. So, I find the topic very interesting. I am 138 lbs and can out run out cycle and swim many people 1/2 my age. Staying active is key and eating well. Live well and hey if it goes long then fine.

[@caribbeangtr8077]

Get Liquid Biocell which is a supplement of Collagen 2, Hyualaronic Acid and Chondrorin Sulfate. Antiages you from the inside out, joint and connective tissue health; eye health; hair and nail health. You can't see your internal organs, but the suffer shrinkage just like your shin. Therefore stands to reason that a supplement that promotes younger healthy skin will promote healthy internal organs too.

[@caribbeangtr8077]

Collagen and hyaluronic acid has Bern known to keep the brain hydrated and prevents loss of cognitive functions

[@timmothyburke]

I've come to the conclusion that this stuff is super complicated and I'm too stupid to understand it all. I'm still gana exercise though.

[@bartrobinson2103]

My thoughts exactly

[@merlingeikie]

Just get familiar with the medical lingo

[@808ionman]

Same

[@Nando_lifts2021]

Right on Tim Burke. We can excersize and do it hard lol

[@christinelatham213]

Yeah, that and the life force of the individual that motivates and operates the body is the factor, and the rest of this is of low consequence.

[@robertstancliffsr9575]

I began taking metformin for type 2 diabetes when I was 45. I have been taking it 35 years and have had no noticeable side effects. Most of that time 2x1000mgs daily. I will be 80 in August of 2023. The metformin has helped me control my blood sugar and my A1C stays around 5.8. I am also 5 years older than the oldest member of my immediate family lived to be. I don't know if that has anything to do with the metformin. I also have regular kidney function test and they show no kidney damage. I had my B-12 checked and it was not low but I am taking a B-12 supplement anyway because it's not going to hurt anything. Never even had a hint of the diarrhea people often mention.....Metformin works great for me and with my insurance, it's free......Of course I am going to keep on taking it..........maybe the only side-effect I will have is longevity, and I can live with that one.......

[@freedominsteadof1984]

Very interesting podcast! On somatropin & longevity: Did you read Dr. Fahy’s work? The TRIIM trial indicated a correlation of not a causation of somatropin and epigenetic age markers. He used Vit D, DHEA, Zinc & somatropin and showed that his healthy patients are 2.5 years epigenetically younger than before. Now TRIIM X is currently conducted with a larger cohort of healthy patients.

[@DoloresGeyer]

Great interview. You are both comfortable having a very interesting conversation. I would love to be in these aging studies. I am 80 years old, in good health, look younger than my years. My Dad lived to 93, died from a fall. Mother died from lung cancer at 68, was a heavy smoker. Why aren’t these studies looking at someone like me?

[@lannguyen-pu1db]

If mum smoked while breastfeeding or changing diapers, then baby is heavy smoker at a very very young age.

[@muveefan]

Your parents are proof that pasive smoking doesn't cause harm 🤔

[@caw383325]

I am a certified forensic pathologist. It is my opinion that the problem with growth hormone is it’s impact on myocardium. Hypertrophic myocardium is very bed for longevity. Shiping Bao, MD.

[@Nilsosmar]

1) Interesting podcast; thanks for posting. 2) Genes clearly play a role in longevity. But our lifestyles... what we eat, how much we exercise... can influence the expression of our genes.

[@Joseph1NJ]

And happiness. I believe there's been at least one study showing meditation can lengthen telomeres.

[@londonmm]

@@Joseph1NJ Telomeres are most likely not a great marker of longevity or healthspan. They change too often and don't always correlate as expected.

[@leoswoyer8348]

I agree more inputs are needed in the analysis of genetic consequences including diet, exercise, environment, location, and socioeconomic factors.

[@annierocks8620]

And infections my dad died of COVID at 76 he wasn't sick or I'll at all. All his family lived passed 90. COVID ended his and my uncle life too soon.

[@simonmojarad4806]

I love it and it’s refreshing, Peter for the first time started challenging his guest when they refer to flawed studies.

[@pramujisinggihriyanto6901]

This is the best podcast on Metformin n biomarkers. I love it.

[@DrTomMD]

Questions missed: 1. B12 monitoring and/or prophylaxis protocol for TAME? 2. Deeper dive into preliminary data that metformin may also come overtime particularly in older individuals I suspect, increased risk for other vitamin deficiency such as riboflavin and folate (happened to be personally)? 3. Dosing formula for TAME - immediate release (like DPP) or more convenient, lower side effect, ER (extended release) formula?

[@robynhope219]

Yes, there should be a spokesperson answering our qs.

[@GreyBeard_Fit]

This channel is a treasure trove of valuable health information. Really enjoyed the segment on Metformin as I’m currently taking Berberine and moving to dihydroberberine this week to evaluate its efficacy. Researching Metformin now. Planning to binge watch several podcasts/videos over the next month or so.

[@dralexbrothers]

Have you ever sat with an "average 95-102" year old? I have and most of them can hardly move and have had enough. Keep your body moving, exercise, ideal body weight and love what you do.

[@dralexbrothers]

Thanks awesome!! Lucky man. But he is an outlier. Most don't want to be here. I see 5-10 a week in my profession.

[@outofchips]

Excellent insight!

[@robynhope219]

Yeah, it's ridiculous...most extremely old ppl have miserable lives.

[@ChessMasterNate]

The reason Centenarians are upbeat is because their Amygdala has atrophied. That is the part of our brain that is constantly preparing us to react to negative or dangerous things.

[@binathere2574]

That's interesting

[@timmothyburke]

Seems like we are better off talking about berberine instead of metformin

[@gregorycollins3096]

Please explain why you came to this conclusion.

[@robertstancliffsr9575]

I can't say because I have never taken berberine. But the 2000mgs daily of metformin I have taken for the last 35 years have never caused any of the side effects many people say they have with metformin. I just turned 80, and plan to continue with the metformin......

[@DrTomMD]

No. We shouldn’t.

[@thehealthychefri]

Metformin has many great properties, but you don’t want to be on in while you’re building muscle! It promotes AMPK, muscle growth is all about MTor..

[@jimwilliams3333]

That's my picture at 77 and I'm 80 now 6ft. 170lbs. I stopped drinking and smoking at 35 of which I never particularly liked drinking or smoking anyway. I had started both at about 20years old before stopping. My father was born in 1894 and bootlegged whisky at one time and smoked even unfiltered Lucky Strikes to death at 91, and his brother not smoking but drinking lived to 100. We did grow up on a farm by a river with lots of fish and vegetables from the farm, and so I'm a believer that if you have good genetics and take care of your health you could live to 110 or 120. However, by listening and following Dr. David Sinclair of Harvard anti-aging research's health care methods could live even longer, and with coming developments with OSK genes, live very long continuance. Another thing being missed in this interview is called coming AI. We will be something vastly different when we merge with AI to survive AI. We will be it and it will be us...than what. How many grams of NMN did you take can make a difference also.

[@chillerhr3804]

it would bi nice to know, if one wants to experiment a little, what to check prior to taking Metformin for a spin, and how often and what to check during taking it (in terms of possible negative effects I mean), how much to take and how often, and what type of symptoms or effects to be mindful about while on a drug…that would be nice

[@persistenthomology]

its called asking your doctor lol, this is a prescription medication (in the US). these folks can't provide specific medical advice over a podcast.

[@chillerhr3804]

@@persistenthomology maybe you can tho…beeing so smart?

[@lannguyen-pu1db]

Maybe pop one whenever feeling the need and a couple or more when feeling not OK at all?😬🔫 oops. but gun does look 😂 in context.

[@robertstancliffsr9575]

I have been taking metformin for over 25 years for type 2 dainties. I take 2x1000mgs daily and have no known side effects. No liver or kidney damage verified by regular test and no reduced B-12 level. My A1C in normal for a non-diabetic and I can eat some things I probably would not eat if I was not taking metformin. I'm 78 and healthy, and hopefully I will be able to enjoy increased longevity, at least partly because of the metformin. Metformin is free with my insurance, works great for me and I see no reason to fear taking it...

[@user-nz6xd5cu4n]

Thanks for introducing video to the podcast.

[@BorjeLindh]

Metformin seems to lower inflammation but also testosterone, growth hormone, mTOR response etc. These things are really good if you for example have cancer. But the same effects also blunt the effects from exercise. So my current understanding is that though metformin is good if you want to get old, but be aware of the side effects. Comments?

[@binathere2574]

I have also read Metformin depletes B12

[@rickg24]

You would just have to supplement some B12

[@jeanpeuplue4012]

hello Peter, I was interested in this interview, because I am affected by acromegaly, and as you probably know, it is a benign tumor of the pituitary gland that causes an endless production of Gh, at the beginning my Gh levels were at 1500ng / ml, for an IGF-1 level at about 750 ng / ml, after two surgeries 10 years apart, the tumor has been reduced by more than 90%, Gh levels have decreased, but IGF-1 still remains around between 285 and 550. After informing about Ladron's disease, person having a problem dimerizing Gh in the liver, receptor problem, I come to think that it is possible that some receptor acromegalic people is too sensitive, or works too much to the production of IGF-1. Finally, it is true that with my high growth hormone level, I heal very quickly from my injuries, whether orthopedic or other, and I am rarely, if ever, sick but i develop some type of tumeur, begnin for the moment.

[@AdAm-cw3gi]

’As useful as a warm bucket of hamster vomit’ Peter Attia MD Interesting and entertaining as always! Grateful to you, your team, and all the interesting guests!

[@mpoharper]

My aunt is a centenarian. She is highly educated and she is mentally tough!

[@jamesgordon8867]

What's their insulin resistance?

[@gregoryludkovsky5185]

Long time no see ! Nice to have you back , Peter

[@robynhope219]

I had a suggestion: why not interview 103 yr old holistic physician, Dr. Gladys McGarey, who is still working, btw. I am reading her lovely book A Well-Lived Life. This woman is awesome, and has a lot to say about love, wisdom, and longevity.

[@1wasavi]

Makes me kinda fell glad a bit, at least on my mother's side, dying of old age is a thing. And what he mentioned people dying in like less than a year as soon as things start to go bad is absolutely true.

[@mame5023]

🎯 Key Takeaways for quick navigation: 02:08 🧬 *Genes play a significant role in individuals living to 100, especially when comparing lifespans between 90 and 100.* 08:03 🧬 *Centenarians don't have a perfect genome; they have a few disease-causing variants, but not as many as expected.* 09:53 🧬 *Centenarians have fewer disease-causing variants, suggesting some genetic protection against age-related diseases.* 13:16 🧬 *High levels of HDL cholesterol, controlled by specific genotypes like CTP and APOC3, are observed in centenarians.* 19:08 🧬 *Growth hormone and IGF signaling pathways, including the FOXO3A genotype, are common in centenarians, impacting longevity.* 22:48 🧬 *The growth hormone and IGF pathways play a crucial role in growth, with hundreds of genes influencing height and longevity.* 25:18 🧬 *Dwarfs, little dogs, and ponies show better longevity, indicating the potential influence of growth hormone-related pathways on lifespan.* 27:36 📉 *Growth hormone deletion in centenarians led to lower IGF-1, but they were taller, revealing a complex relationship between growth hormone, IGF-1, and height.* 28:42 🔄 *Lymphoblast incubation showed an amplifying switch; when not incubated with growth hormone, receptor activity was lower, but with growth hormone, it increased, indicating a unique mechanism.* 32:10 🔄 *Antagonistic Pleiotrophy Hypothesis: Things beneficial in youth can turn against you in old age; growth hormone's role changes with age, impacting health outcomes.* 35:55 🩹 *Growth hormone has shown positive effects in healing orthopedic injuries, fostering rehabilitation, and making patients feel better, but its role in overall longevity remains uncertain.* 39:12 🤔 *Uncertainty about when to start gero protectors like metformin or synolytics; the age for optimal initiation is unclear, and individual biological age assessment may be crucial.* 42:13 🧬 *ApoE2 genotype is associated with longevity, despite its links to certain diseases, indicating a complex relationship between genes and longevity.* 47:20 🔄 *Centenarians with high Lp(a) also have CTEP homozygosity, suggesting a protective mechanism that counters the potential negatives of elevated Lp(a).* 49:11 🔄 *A potential explanation for the protective role of ApoE2 in centenarians, amplifying the longevity genotype's effects, allowing certain populations to reach extreme ages.* 51:44 🧠 *Long-lived individuals and their offspring may exhibit subclinical or clinical low thyroid function, challenging traditional TSH thresholds.* 57:49 🧬 *Ongoing efforts aim to recruit 10,000 centenarians for whole exome sequencing to accelerate understanding of longevity genes and potential drug development.* 01:11:55 🔄 *Environmental factors, lifestyle choices, and resilience genes play significant roles in the interplay between genetics and longevity.* 01:16:46 🧠 *Centenarians experience a compression of morbidity, being sick for months at the end of their lives, unlike non-centenarians who are often sick for years.* 01:18:10 📉 *The idea is presented that if we replicate the contraction of morbidity in non-centenarians by promptly addressing diseases, it could dramatically truncate lifespan.* 01:19:19 ⚕️ *The challenge in discussing health span is the lack of precise definitions and metrics in medicine, especially regarding physical health in aging individuals.* 01:21:39 🤔 *Questions arise about whether centenarians genuinely have better health span or if they simply live longer and experience a compressed period of morbidity.* 01:23:41 🧠 *Aging centenarians often have a positive outlook and focus on the good aspects of life, potentially influenced by changes in both environment and physiology.* 01:25:47 💰 *Economic considerations of increased health span include reduced medical costs in the last two years of life and the overall value individuals bring to society through continued productivity.* 01:27:13 👵 *Centenarians may compartmentalize grief and negative experiences, allowing them to maintain a positive outlook, emphasizing the complexity of aging and mindset changes.* 01:34:12 🚴‍♂️ *The key takeaway from centenarians for longevity is not to avoid exercise and healthy practices but to focus on identifying longevity genes that could be translated into drugs.* 01:36:17 🔄 *Centenarians' superpower seems to be delaying the onset of diseases, experiencing bad events 20 to 25 years later than the average population.* 01:40:41 🧪 *Nir Barzilai emphasizes he's leading a metformin study but doesn't personally prescribe it, highlighting the distinction between being an advocate and a scientist.* 01:41:20 📄 *Metformin hits all hallmarks of aging, supported by papers from 2016 and 2020, showcasing its potential benefits in age-related processes.* 01:42:31 🌿 *Metformin, derived from the French lilac, has a rich history, initially used for treating the flu, malaria, and inflammatory diseases in the 1950s and 60s.* 01:43:12 🌐 *Metformin's mechanisms were initially studied at Yale in the 1990s, with a focus on its impact on hepatic glucose production and its potential anti-aging effects.* 01:44:10 ⚖️ *Metformin boasts a remarkable safety record, with side effects typically occurring in the first week and being manageable, making it a generally safe drug.* 01:48:22 📊 *Nir Barzilai discusses the challenges and considerations in designing the TAME (Targeting Aging with Metformin) study, focusing on the cluster of cardiovascular, cancer, cognitive, and mortality outcomes.* 01:51:22 🧠 *TAME aims to be agnostic to specific diseases, targeting aging as the driver of multiple conditions, with mortality serving as a key endpoint for study continuation.* 01:58:58 💡 *Nir Barzilai explains the rationale behind assigning equal weight to various outcomes in the TAME study, emphasizing that all represent significant health events.* 02:01:56 🐭 *Discussion on the challenges of translating results from animal studies, particularly the inconsistency in metformin's effects when tested at different dosages, raising questions about the relevance of certain models.* 02:04:15 📊 *Metformin in animal studies showed a consistent 7-10% increase in longevity, with potential health span effects including cancer prevention.* 02:05:10 🧪 *Metformin studies in animals and centenarians present challenges due to cancer-related deaths, making it difficult to determine if they die with or from cancer.* 02:05:52 📈 *Metformin administration to animals in the ITP showed varied results in longevity, with one center reporting a 10% increase and another reporting a -2% change, raising questions about dosages and consistency.* 02:06:33 🤔 *The relevance of animal studies, especially with metformin, might decrease as human clinical trials like TAME (Targeting Aging with Metformin) progress.* 02:07:00 💼 *Preliminary human data on metformin shows a consistent 20-30% positive effect on various studies, supporting its potential as an anti-aging intervention.* 02:08:18 🧬 *TAME (Targeting Aging with Metformin) aims to collect biomarkers, including plasma, DNA, and cells, for omics studies to understand aging mechanisms and treatment effects.* 02:09:55 🧩 *Large research teams are crucial for handling big data in aging studies, ensuring the right questions are asked to yield meaningful insights from diverse datasets.* 02:10:50 🔄 *Key questions in aging research focus on identifying biomarkers for aging and assessing biomarkers that change with treatment, providing immediate feedback on the effectiveness of interventions.* 02:13:20 🔄 *Assessing health span requires considering functional outcomes, such as the ability to climb stairs with groceries, rather than focusing solely on disease prevention or remission.* 02:29:59 🧠 *Exercise not only benefits muscles but also improves brain function, decreases cancer risks, and has various effects, highlighting the multifaceted impact of exercise.* 02:30:57 💪 *Muscle growth requires the activation of mTOR, impacted by metformin, but trade-offs include healthier muscles with decreased hypertrophy.* 02:32:45 🔄 *Aging-related transcriptome changes can be reversed by interventions like exercise and metformin, indicating potential benefits in maintaining a more youthful biological state.* 02:34:22 ⚖️ *The potential blunting of cardiorespiratory fitness by metformin is attributed to its mitochondrial inhibitory effects, prompting considerations for personalized use based on age and health status.* 02:40:10 ❓ *NAD precursors' efficacy is questioned due to challenges in understanding their biology, and skepticism is expressed about their impact on health despite personal experiments.* 02:45:42 🎙️ *The episode concludes with a discussion on the challenges and potential outcomes of aging-related interventions, highlighting the importance of continued research and individualized approaches.* Made with HARPA AI

[@jamisellepalacios8099]

I am new to your podcast, very interesting subjects and totally new concepts for me. Grandma lived to 95 but my mom died at 64. I am in my 40’s with rapidly hormone changes and not to mentioned had gray hair since my 20’s. Would like to know more about visible aging components and their impact to longevity.

[@DrTomMD]

1:46:55 DPP was an intention to treat analysis. Seems like Peter was saying it wasn’t. If so, he’s wrong. Also to be clear, DPP had 3 arms (not just two mentioned): Metformin, placebo & therapeutic lifestyle change with ~7% weight loss (on average) resulting in 30% reduced T2D conversion in Metformin group vs almost 60% in therapeutic lifestyle group. Not 30% each.

[@beepbeepnj2658]

Forget the complicated stuff as famous NYC investor Irving Kahn who lived to age 109 thought his long life was due to his love of work and a good diet. He had 3 other siblings all who lived past 100 including 1 sister who thought a fun life was drinking, smoking, eating rich foods and nightlife. It was found out all 4 had high levels of HDL cholesterol and a slightly underactive thyroid or what would be a slightly elevated TSH in their genetics.

[@zack_120]

2:33:34 - no, 4 months is a rather short time window of one's life. It is a major short coming of many if not most/all intervention studies in humans or animals. In other words it's just a snap shot of a life span, hence it's extrapolability to overall benefits of health especially longevity is small. Sometimes it can even be mistaken when the short effect is transient and the longer effects are just the opposite!

[@jayalanlife5926]

Nir is looking younger with every podcast, maybe he should include skin health.

[@denasharpe2393]

Yes indeed!! Love his skin !!!

[@espinosalexis]

Will you ever interview Prof. Valter Longo?

[@methodtraining]

💯!!!

[@elizabethk3238]

Couldn't take METFORMIN, so switched to BERBERINE. Works similarly.

[@zeeparnas7454]

Which berberine are you taking? Thanks for the advice

[@beepbeepnj2658]

Nir must be right because famous NYC investor Irving Kahn who lived to age 109 thought his long life was due to his love of work and a good diet. He had 3 other siblings all who lived past 100 including 1 sister who thought a fun life was drinking, smoking, eating rich foods and nightlife. It was found out all 4 had high levels of HDL cholesterol and a slightly underactive thyroid or what would be a slightly elevated TSH in their genetics.

[@bill9989]

One question and one comment: Q. I've looked here for the two metformin articles Dr Barzilai referenced to show to our primary care Dr's but can't find them. Any help? Comment: I don't think the Dr's prescribing metformin after reading the articles is still true. I suspect that off label prescriptions for anything are mostly a thing of the past because of the hysteria generated over covid off-labels and the restrictions placed on individual physicians by their practice groups and their malpractice insurers. Fear of malpractice lawsuits has chilled the practice of medicine into paralysis.

[@pamlovell9125]

My great aunt who was the eldest child and obese the majority of her adult life lived to 100. Her youngest sibling -- my grandmother the baby of the family-- was thin her entire life died from Alzheimers at age 74. Go figure.

[@lannguyen-pu1db]

Fat is good for the brain, which is 90% fat, so you might be on to something there. Are there many fat people with Alzheimer's?

[@scottymackay1801]

My grandmother was overweight her whole life and didn't exercise other than short slow walks. Lived to 103 and died just a few months ago from complications due to falling and breaking her hip. When the doctor was evaluating her for surgery, he said her organs like heart, lungs etc were like a 20 year old.

[@danmcqueen5295]

@lan nguyen Just anecdote but I'm a retired professional nurse who worked in geriatrics for 2/3 of my career. It seemed to me a definite majority of demented individuals are "normal" weight, probably around 75%. On the other hand it seemed, obese individuals who live past about 68 tend to have dementia as well.

[@Daniel-hh8od]

Maybe we should look into studying taking low-dose methimazole or propylthiouracil in healthy, non-hyperthyorid individuals to see if there is a longevity benefit.

[@michaeldomansky8497]

Between taking my Metformin, NAC, Benfotiamine, and Ivermectin I am completely inflammation free! No arthritic limp, no back pain, no bursitis. I take no NSAIDs or Tylenol !

[@nakiabrown1976]

Any of your organs being damaged by these meds? Ivermectin 🤔

[@lannguyen-pu1db]

Sure invermectin not killing gut bacteria?

[@denmar355]

I have taken ivermectin many times and experienced zero digestive changes. Strangely though after taking it I experience a couple of days of less sinus issues and less typical arthritis aches.

[@michaeldomansky8497]

@@lannguyen-pu1db no effect on gut!

[@gloriaspau8994]

I am 81 on metformin for one year, lost 15 lb, 5ft 7in , 134, 1000 mil a day, at one time my liver numbers were high, after taking metformin normal, fasting sugar 5.6, not so good rising from sitting position....muscle strength not so good.

[@TheSpikyCantelope]

Do some light weight training! You can make it to 100! You got this :)

[@binathere2574]

I have read Metformin depletes B12. You might like to check your Active B12

[@claudettesechler149]

So great! Wonderful guest! Gives me such a perspective on metformin

[@blaney6591]

Episode was confusing and difficult to follow. Can someone post a layman's summary of conclusions drawn? (The link to show notes above only review topics covered, not conclusions). Thanks in advance.

[@persistenthomology]

you can either use a lot of googling, or find detailed shownotes with references if you become a member of the podcast.

[@IanPChase]

@Ken M, You seem to go out of your way to find and negatively respond to people looking for a summary.

[@luckyi2]

What about fertility issues in men taking metformin. Also I feel some of these things talked about could be possibly helped out by doing a carnivore diet.

[@bjarnetungland4544]

Solid podcasting there. Good question about the evidence of metformin, nmn. Ect.

[@KevinGilbertDC]

Great interview Peter! Good timing just read Nir's book "Age Later". Good read. Looking forward to further research data from TAME. On a side note, I hope I fall somewhere between a patient and "just" a social media follower! LOL!

[@valerietromble581]

Pvt

[@maudmuller2031]

My mom lived to 104 1/2. Too bad you couldn’t have studied her!

[@drbravinderreddy]

Looks like the host is speaking to the expert just to clarify his own thoughts or to reiterate his familiarity with the nuances of genetics in longevity! Goes without saying that this recording is not for non-geneticists!

[@zazzleman]

I get an uneasy feeling Peter is conducting a passive-aggressive campaign against David Sinclair. A lot of what I have seen over the past 12 months is pointed and silly nonsense.

[@askingwhy123]

I have a hard time understanding Dr. Barzilai's response to, as he put it, hundred-year-olds who come to him and "want something"; he refuses because he doesn't want to cause harm. But he also reports centenarians as having a 30% annual mortality rate! Every year! Facing such odds, an oncologist would probably be requesting compassionate use exemptions to throw in the kitchen sink to help a patient. Informed consent is everything for me under such circumstances: HGH, anabolics, literally anything else I thought might help. Risky case studies can also be an amazing source of new research approaches. For the very aged with a strong will to self-experiment, I see almost no moral limits on trying combinations of existing compounds. The asymmetrical risk of inevitable death makes the calculus clear.

[@angelar3625]

Ggreat great information, excelent interviewer!! Thank you so much for your time 🙏🙏

[@dlbdlb3919]

I feel like this path of investigation is a merry go round

[@tampa1342]

Yes, Peter, really great job, your knowledge and effort to convey new knowledge to people, but first of all, more types of genetic homogeneity should be included in any research regarding longevity. not only Ashkenazis..!

[@ParanoidBishop]

Can you link the metformin studies, so I can send them to my GP?

[@Yiayia3]

What about metformin causing severe lactic acid build up and causing many deaths?

[@robertstancliffsr9575]

Not true, extremely rare, almost nonexistent ...........it was mentioned and "boom" all of a sudden metformin causes death from lactic acid was everywhere...just pure BS...

[@jaswantkhalsa2849]

Are you saying that if we have a chronic disease at 72, forget the things to prolong life to old.

[@esmeraldacole8936]

Thanks for the information , very useful!

[@peterg5251]

Maybe I'm just missing them but are the article about Metformin linked somewhere?

[@jaynepower4330]

Cannot find links either but there might be something linked to the TAME Trial. (I haven’t had a chance to check it yet)

[@mbnto3135]

Question. I’m at minute 12 and 3 hypotheses are suggested: environment, good genes, bad genes. What about the role of stochastic processes in disease, which I understand to be formidable? Maybe centenarians are lucky?

[@PattyRichardson1]

A great video!

[@johnegan6803]

Has any research been done concerning people with accelerated aging and comparing their genomes and gene expression with the centenarians?I once had a Dental patient with precocious puberty and her condition seemed to suggest accelerated aging and reduced life expectancy.

[@evelynramos445]

Thank you Drs

[@hdoggett]

What is the effect of emotional and mental resilience on longevity?

[@richarddickson7522]

I often wondered what happened to Paul Simon after he dropped out of the music scene.

[@wilyinfidel1091]

@richard Dickson Read your comment and he magically morphed into Paul Simon! Definitely same wig shop.

[@erastvandoren]

The aging biomarker argument is stupid, IMHO. Yes, you can manipulate it. But maybe it is what it takes to delay aging - to do exactly those manipulations daily. Lower your glucose & LDL, keep albumin high and CRP low, and so on. Do it daily, and you stay young longer.

[@jessiedavenport775]

So many law suits against metformin stroke , heart attacks , dementia etc

[@binathere2574]

Metformin, I have read, depletes B12. Those issues you mention are symptoms of B12 deficiency/Pernicious Anemia.

[@evelynramos445]

Careful for regular exercise

[@coachpaul-vedicfitness]

What about Resveratrol ?

[@davidt3698]

Brilliant foodstuff. Red grape juice counters varicose veins by encouraging collagen production. Resvetatrol.

[@erwinrogers9470]

Great interview

[@Just_An_Idea_For_Consideration]

Excellent Info!!!

[@robynhope219]

Yes, but missing pieces

[@audreyhurley6248]

How do I sign up Nir ? I’m interested in getting into your test study, I live Austin, TX area? Is there a study here?

[@sandor1969r]

The people that lives longer happen to live in places where food is most natural no chemicals like the Hunza tribe for example. Costa Rica has ten times more centenarians than here in USA as Costa Rica food it is reach in nutrients and minerals as they use water that came down from rives near vulcans to irrigates their crops and probably never eat fried food or drink fluoride in water , just two very bad things for the gens.

[@thomaswipf7986]

5mg/day of mk677 is one of my favorites for recovery

[@fredbranson2791]

Peter please cover SGLT2 for longevity. Metformin is old news. Agree with you in regard to performance athletes or those that focus on exercise. SGLT2, however, extremely interesting for geroprotection (body composition, inflammation, cardio & renal protective).

[@Joseph1NJ]

So Peter asks If GH was so deadly, where are the bodies? He answered his own question, we just don't have the data.

[@rickg24]

Take a look at all of the professional bodybuilders and wrestlers dropping dead. Makes you 🤔

[@roseperozzi6730]

Great topics. Merry Christmas 🎄🎁

[@adhipmitra]

Very educative.

[@chickensandw1tch]

1:10:50 hell yeah🗣️💯 1:44:35 okay now this is epic 2:16:40 💀

[@timscannell1268]

Great work

[@nobodyatdrivingseat]

Hi Peter, what inhibitors do Nir and you talk about in 14:46 ? ctap inhibitors ? Thanks

[@gamblinguru33]

CETP Cholesteryl Ester Transfer Protein

[@vellyd.6165]

My grandma is 99 y old and nobody died in my family under 90 (or was killed by the communists), men and women. I am from Bulgaria, my grandgrandma died by incident with 95+ and ate 15 eggs for breakfast, healthy until she died

[@immers2410]

15 eggs a day. Do you mean fish eggs?

[@denisvoronin2048]

I only manage to eat 3 but I'm 110 kg guy. How can a woman eat 15 eggs in 1 sitting is beyond me. Your grandma were either a superhuman or a competitive world class eater

[@zandrarose2258]

Metformin had me seriously planning my suicide. I am so glad I realized it was the drug and not me.

[@peacewins3281]

Please share I have a problem when I take any diabetes medication I feel very agitated & high anxiety.So I have done ketogenic diet with great result,then I lose dicipline and go back to carbs....And doctors don't understand.

[@thomasg.hallal8950]

Is depression a side effect from metformin?

[@larrycobb7073]

Like Nir, upon taking NMN I experienced more REM sleep & more enhanced dream recall.

[@audreyhurley6248]

Drs I’ve asked my doctor about prescribing Metformin and rapamycin. Did blood work he stated no diabetes so no need for either. I explained and he knows I’m a care giver with no real caregiver support for myself. Still got no. So would either of you would you prescribe to me?

[@persistenthomology]

sounds about right, most doctors are very conservative. try another doctor, one who actually keeps up with research. doctors dont prescribe over youtube.

[@MargeSimpson-bn7lu]

Sure with ApoE$ folks looked in demented patients for index cases which how the RR was overestimated, today the E4/E4 has regressed to the mean maybe ~4

[@leadimentoobrien1221]

Metformin has a black box warning. U need to take mehlated b12 and b1 can't Take it if u have CKD low gfr

[@doriscastillo2232]

All the way from Republic of Ireland filipino

[@lookup912]

This conversation type is an official sport of the nerd-olympics🤣. A total matrix-brainiac-download for health nerds like myself... completely fanning out.😍🧠🤓

[@evelynramos445]

Had friend recently died at 97 yrs without his bride! Broke his hip !

[@jamesgordon8867]

The ages in the old testament: God never designed us to age

[@evelynramos445]

Side of Chub?

[@robynhope219]

I don't care to be a centenarian..I just want HEALTHSPAN while alive.

[@WorldsBestGuys]

You will know when the longevity research has actually become successful when all of this stuff is censored- the general population will not be allowed to live so long when there’s all these current population related issues, unless there is a need found for them such as slavery.