Dr. David Sinclair on Informational Theory of Aging, Nicotinamide Mononucleotide, Resveratrol & More

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The Plant Paradox

David A. Sinclair, PhD, is a professor in the Division of Genes at Harvard Medical Institution and co-director of the Paul F. Glenn Facility for the Organic Mechanisms of Aging.

Dr. Sinclair's work focuses on comprehending the mechanisms that drive human aging as well as recognizing methods to reduce or turn around aging's impacts. Particularly, he has examined the duty of sirtuins in disease as well as aging, with unique focus on exactly how sirtuin activity is regulated by substances produced by the body in addition to those eaten in the diet plan, such as resveratrol. His job has ramifications for human metabolism, mitochondrial as well as neurological health, and also cancer.

▶ Get the episode's program notes, timeline, as well as transcript.

▶ Detailed summary of NAD+.

▶ Thorough summary of nicotinamide riboside.

▶ In-depth subject page on nicotinamide mononucleotide.

▶ Adhere To Dr. David Sinclair on Twitter.

▶ BOOK: Life expectancy: Why We Age and Why We Don't Need to.

▶ Go To the Sinclair Laboratory.

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  1. My two favorite people talking about the topic aging <3

  2. *00:00:36* – Landmark moments in longevity research with the discovery of genes that control the aging process and how these genes can be activated by lifestyle factors such as fasting and exercise.
    *00:01:06* – Altering the insulin/IGF-1 signaling pathway in earthworms can extend their lifespan by 100%.
    *00:01:45* – Slowly ageing by design: the rise of NAD+ and sirtuin-activating compounds.
    *00:05:02* – How resveratrol may delay aging by activating a class of enzymes called sirtuins.
    *00:06:15* – How the addition of an extra copy of the SIR2 gene in S. cerevisiae (yeast) can extend yeast lifespan by 30%.
    *00:06:40* – How having high levels of sirtuins may give organisms the benefit of caloric restriction or other stressors such as heat stress or amino acid restriction without actually engaging in those activities.
    *00:07:50* – How fasting for one or two days per week, a type of intermittent fasting, may activate sirtuins sufficiently to recapitulate the benefits of long-term caloric restriction. Review on caloric restriction and sirtuin biology.
    *00:08:15* – How the metabolic switch into ketosis may be an important differentiator between ongoing caloric restriction and finite periodic fasts.
    *00:08:50* – How caloric restriction potently increases sirtuins, as measured by SIRT1 levels, by as much as 5- to 10-fold in the liver and muscle of rats, but this beneficial activity is immediately dampened by the introduction of IGF-1 and insulin.
    *00:10:13* – How several pathways, including those involving sirtuins, insulin/IGF-1, and mTOR, all interact as components of a highly conserved holistic network to create the benefits of caloric restriction.
    *00:10:56* – Caloric restriction, fasting, and exercise increase levels of NAD+, and this activates sirtuins.
    *00:12:20* – NAD+ may regulate circadian rhythm though its control of sirtuins, which in turn regulate both the circadian clock in the brain as well as peripheral clocks, such as the liver.
    *00:13:00* – In addition to activating sirtuins, NAD+ is essential for mitochondrial metabolism and function but it is also required for repairing damage to DNA by activating an enzyme called PARP.
    *00:13:30* – How organisms have developed nutrient-sensing genetic pathways such as sirtuins, AMPK, and mTOR in order to understand what is going on in the environment.
    *00:14:44* – Although NAD+ levels and sirtuin activities decrease with age, animal studies suggest that raising cellular NAD+ levels can trick the body into thinking it is younger.
    *00:16:00* – Resveratrol enhances the binding of sirtuins to NAD+ thus making sirtuins more easily activated for a longer period.
    *00:17:28* – How DNA damage consumes NAD+ through the activation of PARP, a major DNA repair protein, leaving less NAD+ available to activate sirtuins and distracting sirtuins from fulfilling their other roles.
    *00:20:00* – Dr. Sinclair’s informational theory of aging posits that aging is due to a loss of cellular identity, a type of epigenetic signal noise, that has parallels in biology with the signal correction capabilities of the TCP/IP protocol.
    *00:20:33* – Steve Horvath’s epigenetic aging clock, which measures DNA methylation groups, may play a role in widespread gene regulation, including sirtuin genes, and how NAD+ may participate in resetting the clock.
    *00:22:56* – How the epigenetic clock can predict your chronological age and how long you have to live.
    *00:23:47* – How epigenetic reprogramming in old mice can restore youthful gene activity patterns, reverse the DNA methylation aging clock, and restore the function and regenerative capacity of the aging retina.
    *00:24:51* – The signal that resets the epigenetic clock in mice involves Yamanaka factors — a group of four transcription factors that can reprogram an adult cell to become a pluripotent stem cell that can form any cell type.
    *00:26:24* – How short term treatment with the Yamanaka factors can reverse cellular and physiological hallmarks of aging and prolong lifespan in mice with a premature aging phenotype.
    *00:27:45* – Dr. Sinclair’s hope that we may eventually find a way to induce Yamanaka factors in a way that is more safe and applicable to humans than current genetic engineering and viral techniques used in animal research.
    *00:28:25* – How fasting, exercise, and other lifestyle factors may slow the rate of epigenetic aging but may not be sufficient to reverse it like some of the powerful Yamanka factors may be able to.
    *00:29:51* – How Dr. Sinclair’s lab and others are trying to find safe ways to reset the epigenetic aging clock with Yamanaka factors without causing tumors and other safety issues.
    *00:32:46* – How Dr. Sinclair thinks Claude Shannon’s theory on mathematical theory communication may also explain the aging process.
    *00:34:02* – Dr. Sinclair’s take on who some of the top scientists to follow in the field of aging epigenetics are, which includes Drs. Juan Carlos Izpisua Belmonte, Steve Horvath, Manuel Serrano, Anne Brunet, Shelley Berger, and Jessica Tyler.
    *00:36:00* – How nobel-prize winning biologist John Gurdon put an adult cell nucleus from a tadpole into a frog’s egg, producing a new tadpole, suggesting that the genome can be reset to a very early stage in an organism’s lifespan. Review on nuclear reprogramming.
    *00:36:22* – How cellular NAD+ is made from a variety of precursors including tryptophan, nicotinic acid, nicotinamide riboside, nicotinamide mononucleotide, and nicotinamide. Nicotinamide riboside gets converted into nicotinamide mononucleotide, which is then converted to NAD+.
    *00:37:33* – How NAD+ is a large molecule that does not get taken up in animals as efficiently as the NAD+ boosters nicotinamide riboside and nicotinamide mononucleotide, the latter of which is transported by a recently discovered transporter.
    *00:38:18* – How NAMPT, an enzyme in yeast that is activated by exercise and calorie restriction, is key for NAD+ production and longevity benefits.
    *00:39:45* – Plants produce compounds that activate sirtuin pathways in plants in response to stress and, in turn, the compounds activate beneficial pathways like the sirtuin pathway in humans, a phenomenon called xenohormesis. Resveratrol is one such compound and is produced when grape plants are stressed either in response to fungus or a lack of water.
    *00:41:11* – How small stressors such as exercise, calorie restriction, and ingestion of plant polyphenol compounds activate various stress response pathways in the body that help slow aging, but calorie excess and a sedentary lifestyle have the opposite effect, signaling the body to reproduce and continue aging, a concept known as the disposable soma theory of aging.
    *00:41:56* – When rhesus monkeys were fed a diet high in refined sugar (sucrose) and fat for two years, they experienced a 40% increase in arterial stiffness and inflammation but this was completely reversed if they were given 80 mg of resveratrol per day for one year then 480 mg/day for a second year.
    *00:44:26* – How resveratrol is a very insoluble molecule but its bioavailability can be increased if it is taken with food that contains a moderate amount of fat.
    *00:45:38* – Mice that were fed an obesogenic diet but were also given a low dose of resveratrol lived longer and had organs that were healthier and younger looking compared to mice fed the obesogenic diet alone.
    *00:48:32* – How a phase 2 clinical trial involving people with Alzheimer’s disease showed resveratrol improved mental examination status scores, induced marker changes that might suggest reduced accumulation of amyloid-beta in the brain, lowered markers of activated microglia, and more.
    *00:49:28* – How resveratrol has been shown to induce autophagy by directly inhibiting mTOR through ATP competition in mice.
    *00:51:00* – How both nicotinamide riboside and nicotinamide mononucleotide have been shown to improve cognitive function and brain pathology in mice that have been engineered to get a disease similar to Alzheimer’s disease.
    0:51:29 – How treating mice with nicotinamide mononucleotide can prevent age-related endurance losses by promoting new blood vessel growth.
    *00:52:30* – How an NAD+ isotope tracer study revealed that orally administered precursors of NAD+ such as nicotinamide riboside and nicotinamide mononucleotide do not form NAD+ in any other tissues other than the liver, but that dose was half the amount used in animal studies that showed benefits in the brain and muscle.
    *00:53:37* – How there may be a threshold dose of nicotinamide riboside and nicotinamide mononucleotide that needs to be crossed in order to override the liver’s first pass clearance mechanisms so that nicotinamide riboside and nicotinamide mononucleotide NAD+ levels rise in other tissues like skeletal muscle, and this is why almost all animal studies use very high doses.
    *00:54:13* – How there may be challenges in translating animal studies on nicotinamide riboside and nicotinamide mononucleotide to humans particularly due to the need to determine the dose required to promote health benefits.
    *00:56:33* – How a couple of clinical trials are underway to test safety with a molecule called MIB-626, which is a potential strong NAD+ booster.
    *00:59:16* – Older mice that were given NMN (300 mg/kg/day) experienced delayed aging in the liver, muscle, immune cells, eyes, and bones, but those that took a lower dose of NMN (100mg/kg/day or human equivalent of 8mg/kg/day) had improved mitochondrial function and enhanced physical performance.
    *01:00:05* – How fragmented sleep consistently leads to higher fasting and postprandial blood glucose levels.

    • Family Betancourt

      @Re3iRtH I’m not sure why you brought up centenarians. Just because those people lived to that age w/o fasting and taking pills that have a hormetic effect does not mean that fasting and introducing a hormetic effect will not have a significant benefit to longevity.

      If you wanted to learn more, there is PLENTY of research papers you can review. There’s also tons of additional interviews with these leading scientists. You could also just wait another 5-10 years to see what we’ve learned through more clinical trials.

      In the meantime, I’ll continue to take sulforaphane (aka the good thing about broccoli), maybe resveratrol and follow this science closely.

    • @Family Betancourt That was one thing among many that I brought up.
      I will also add. There is evidence that a lot of molecules have zero effect of they are taken in a pill.. ie. as opposed to eating the actual food containing it. Lots of vitamins are this way. I think eating sprouts like Rhonda does is probably better. But like I said, an affluent person that will already live to 90.. I’m not buying it will add even 1 year to your lifespan. No evidence, just hope and speculation.

    • Family Betancourt

      @Re3iRtH I think you’re reducing a bit much here. The convo was specific to resveratrol, though I added sulforaphane. There’s been plenty of studies showing efficacy on resveratrol, but not enough human clinical trials. I’m not aware of any of them using something other than a prepared pill. For sulforaphane, there’s over four completed clinical trials using Avmacol & six in the recruiting phase. If you read through the other studies, most show ‘broccoli extract’ which is essentially what Avamacol is. The point that pills have zero efficacy for these molecules is false based on existing studies.

      Using the affluent people live to 90 statistic will not help you as an individual. It’s like using BMI to evaluate a member of a population. The evaluative measure BMI was designed to look at a population, not individuals, just like the affluent people living to 90 statistic.

      Longevity research is kind of in it’s infancy because of how it is regarded. I feel there are only general guidelines with overwhelming evidence such as Mediterranean diets, exercise, metformin and sulforaphane are pretty well established. I’m still on the fence regarding resveratrol.

    • @Family Betancourt I’m not convinced sulfurophane will help improve life or extend life when you are 90. Strong joints, mobility, and muscle mass WILL. But you’ve peaked my interest and convinced me so I’ll try it! Do you recommend any specific brands on Amazon?

    • Hello, I did not have biology in school nor chemistry, but after the Veritasium video and seeing David Sinclair on the JRE. I became very intrested in this topic, because who does not want to live healty and increase their longevity right? So my knowledge on the subject is very very limited and i have no idea were to start. So my question was how do i figure out a good diet for me and how do i become more knowledgeble in this subject to make informed decions?

  3. OMG I’m excited to listen to this!! The whole time listening to him on JRE I was dreaming of a convo between you two.

  4. In a few weeks from turning 71 . All this info is interesting.

  5. I’m really hoping we start using these genetic treatments within the next decade, in the 2020s, and not just still talking about it.
    Life Code. It’s more exciting than computer code.

    • Hell yeah! I’m quite surprised by how much they seem to have uncovered about the dynamics of the methylation clock of aging! And with AI and more data and research from more labs in the field, it’s looking more hopeful than ever right now!

      And till then, we have time-tested (fasting, cold-water therapy, heat-exposure, exercise, phytochemicals and good diet) and emerging methods of managing aging personally, as shown on this channel.

    • I’m trying not to be too optimistic about the timeline. NAD precursors, senolytics, healthy diet, exercise and quality sleep may help me live long enough to undergo these types of treatments.

    • depends who we are using it on lol

    • As a little kid, I always wondered why not cure aging and you won’t have to worry about 80% of diseases. Microsoft and Apple should be working on aging like they work on I.A., code, and digital advances.

  6. He’s been studying this for 30 years ? Yet he only looks like 35…i guess he found a cure ?!?

    • Gregory Ludkovsky

      D .S .is a VERY SICK MAN !! He has terrible genes He talks about it freely. He HAS TO TAKE MEDS TO STAY A LIFE. And yet he does look sickly

    • @Gregory Ludkovsky He looks thin because he says, the way to keep your body from aging is to essentially starve yourself so that your cells go into a survival mode.. that’s the secret to not aging as fast.

    • This man DOES look 15 years younger…there is no way you would think he is 50…stop hating n start replicating whatever the hell he’s doing?

    • Arunava chakraborty

      @Dexter Lacroy nr or nmn is not same lol…nmn has a pospate group witch is help the main nad compound to go to the pathway to make nad+…nr just don’t go like that…..and dna repair ment is not happened in nr..

    • @Arunava chakraborty Did your “lol”-dropping make you feel extra sciency? Didn’t mean they’re literally the same but they are similar in the sense that they are nad+ boosters meant to accomplish the same thing

  7. Another great video from Rhonda “studies have shown” Patrick ?

  8. I suspect the 5 thumbs down people in the first 9 hours didn’t actually listen to this or all of it.

    • Niagen groupies

    • J. Boogie I had to google that, it’s expensive. I didn’t hear them mention that, are they paid by them?

    • @James Phillips Niagen is NR. NR that has been researched extensively, human/animal trials etc. There’s a lot of money behind it. Dr. Sinclair takes NMN but he’s very careful not to recommend it over NR. I’m not certain what’s going on, could be that because Dr. Sinclair is an inventor of the patent Elysium uses for their NR and has an NMN based supplement he’s working on which will likely financially benefit him. Like most companies, Niagen will try to protect their product/image against competitors. All speculation on my part but there’s something there and thought it would be funny to joke about.

    • Anon Bianco thanks I agree

    • J. Boogie thanks I agree

  9. Appreciate all the editing you do for your videos Rhonda!

  10. Excellent; it gives someone with no background in biochemistry; a fair chance of grasping the concepts you’re excited by Rhonda.

    Those notes on the screen and the time stamps; brilliant! I’ve heard David Sinclair several times now, but this was the most plausible presentation by far – now I want that book! Thanlyou

    • Thanks so much, Ron! One thing we’ve started doing is taking the on-screen notes and breaking them out into a powerpoint presentation for members. This episode alone yielded over 150 slides! Anyone reading this that thinks that might be interesting, please make sure to check out our membership program that offers some great bonuses on our free content, like a monthly Q&A and more. foundmyfitness.com/premium

  11. Very well done! This discussion illustrates why its so helpful to have an interviewer (Patrick) who actually knows the subject matter well enough to keep it at level which is truly informative for reasonably well informed laypeople instead of the boringly simplistic repetitive level of so many others.

  12. It’s sort of strange that two people this smart chose to sit down for an extended time in the most uncomfortable simple chairs I’ve ever seen. Couldn’t they chose a comfortable chair?

  13. Intermittent fasting is one of the most effective yet cheapest anti-aging strategy you have

    • @Charles Patrick Judging on rat studies, it could be more like 20 years added.

    • ​@Commodore Grayum Nah. If not carbs, then what you eat?? David Sinclair is telling in almost every interview how large quantities of protein intake signals our genome through mTOR (one of the 3 biggest pathways to DNA damage) – the more protein, the faster the aging. Fat cannot be healthy either (for long term, and unless with developed cancer (Warburg effect related)).
      Best is slow-carbs – complex carbs, more usually in whole foods, even more in old plant varieties.

    • @musaire “large quantities of protein intake signals our genome through mTOR”

      It’s not just the amount though, is it. It’s the timing. If you spend a lot of time fasting, then mTOR spends less time being stimulated.

      “Fat cannot be healthy either”

      Wrong. This is just mainstream demonisation of fat, which was based on literally fraudulent research in the first place. There’s no evidence that ketogenic diets cause any disease. The only studies “showing” that “high fat low carb” diets cause negative effects use diets that still have a lot of carbs and are not ketogenic.

      “Best is slow-carbs”

      “Slow” carbs are not slow. They raise your blood sugar almost as much, and almost as quickly, as sugar or any other carbs.

    • Autophagy with fastin can only activate if you follow a good ketogenic diet and fast for at least 18h a day. Remember that 40% 50% protein a day is NOT a keto diet. So a diet like Slim Land follows can give u benefits on the daily. But for the average person who eats carbs here and there, it’s 3 days to raise autophagy, and another 3 days to get any benefits from the process. So a 5-6day waterfast is neccessary and I.F. can be beneficial to help your gut/colon and aids in more beneficial microbiome.
      Best would be to be in ketosis even prior starting a 5 day waterfast. Autophagy drops after 3/4days and you boost some stem cells without stressing your body too much. 4x a year if you’re unhealthy, 2x a year to maintain and aid health. Eating a normal diet and doing IF, you’re not fasting. You’re just eating in a time restricted window, that’s not fasting lol.
      Btw carbs are good, fats are good, protein is good. This bs with this is bad this is good is long gone. Everything has it’s place, if you follow a high carb diet, you keep fats lower, and protein probably lower aswell, BUT YOU KEEP THOSE IN. Same time a very high fat diet can work with a low amount of carbs, not even keto. It get’s complicated if you want to pound tons of healthy fats and eat fruits. Like Ray Peat does, then you suddenly need thyroid hormones, and testosterone, cuz otherwise everything gets fucked since you try to trick your body into beliving it has to move a lot while not moving LOL.
      That’s why in the end no matter what you eat, so long it’s not processed and whole food like it’s good, but you have to move, daily, restress the body with cold/heat/gym/hiit and same time give time to rest and regenrate.

  14. This the best David Sinclair interview that I have seen or heard. It really helps when the interviewer has so much knowledge on the subject.

    • @billytheweasel Rhonda Patrick sits at home or in the office for 6 hours reading research papers. Do you think any MD has six hours or even one hour a day to devote to reading research papers? Doctors actually have to see patients and save lives.

    • @Re3iRtH I agree 100% It’s so unfair that we get to see the nut graph of endless hours of cutting edge research then just walk into our Dr’s office. But it IS the damn job so they need buck up like everyone else. I work and still stay informed. And it isn’t even my damn job.

    • @billytheweasel Yup. Think of litigation lawyers. They can’t get away with applying only the law they learned during law school or clerking. They are expected to go to court with the latest case law and the current version of the statute. Or they get sued by their clients.

    • He is such an inspiration! I bought his book and am trying to buy his supplements. Am so in awe how the company he cofounded sold for $720 million!!!

    • I was going to comment the same thing. And I watched at least 10 interviews to D. Sinclair and read his latest book.

  15. Rhonda thank you for doing these podcasts they are invaluable.

  16. This should be required watching in all high school science class.

  17. This is the only YouTube channel I’m scared of missing out.

  18. This is like anti-aging avengers!

  19. Rhonda is so freakin funny ?..together with incredible knowledge, always makes these interviews even better than most.

  20. 1:01:13 : Sinclair says “And I take a gram of NMN every morning”

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