Understanding Longevity: Research, Substances, Genetics, Diet, and Implications

Substances 1:55 0
“certainly with respect to the podcasts around rapamycin and metformin”

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Substances 3:18 0
“one around an sglt2 inhibitor and another one around nicotinamide riboside”

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Immunizations 6:50 0
“the lab i worked at at harvard was an immunology lab and the one at sloan kettering was an immunology lab too then when i set up my own lab at boston university it was principally to study immunology and how aging modified the immune system”

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Genetics 10:07 0
“then when it later became established that the limitation of growth the hayflick limit was actually due to shortening of telomeres a very important finding and certainly true people convinced themselves because they thought it was like aging the telomeres were something to do with aging too”

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Substances 12:02 0
“it's entirely possible that hyperbaric oxygen could well have health benefits under certain circumstances”

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Genetics 13:22 0
“telomere biology is a critical element in cancer biology and the amazing work that several people including blackburn did to work out the telomere story is i think really a fundamental advance in our understanding of cancer in people”

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Genetics 13:51 0
“Vera Gorbunava at Rochester has done some lovely work on the ways in which different species with different body size and different life spans differ in their ways of stopping the cancer process some relying like people do on the telomere alarm clock where the tillers get too short that this puts a whole lot of anti-cancer defenses into play and others like mice where this does not happen.”

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Nutrition 21:14 0
“obviously there was the vast literature on caloric restriction so almost without exception and there are some very notable exceptions but almost without exception some form of caloric restriction”

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Genetics 21:44 0
“cynthia kenyon's work which i think was probably early 90s right that was 1993. and if i recall her first observation was with was it daft 16 was the first one or was it the first paper the critical paper made two big discoveries one was the mutants of death to extended lifespan and that mutants of daf-16 blocked when combined”

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Genetics 23:15 0
“linda partridge and her colleagues proving that there could never be a single gene mutation that extended lifespan aging was too complicated too many feedback circuits it could never ever be done”

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Genetics 25:36 0
“whether or not it's a single gene or multiple genes is probably less the point, the bigger point at least for me as an outsider is aging malleable yes or no”

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Genetics 26:28 0
“my own current sort of philosophical framework is that aging is caused by an awful lot of different things some cells die some cells become mutant some tissue structures get cross-linked or heavy metals accumulate in a key cell”

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Genetics 26:53 0
“there are biological processes that can postpone all of that stuff together that can postpone it for five decades and people or almost a year in a mouse or 25 years in a chimp”

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Genetics 27:10 0
“what i care about is what is the process that can postpone all the different aspects of aging”

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Genetics 32:36 0
“the next point that makes this pretty special is you are using genetically heterogeneous mice these are not homogeneous so explain to folks why using these genetically heterogeneous mice is an important feature of the ITPs.”

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Genetics 33:46 0
“about 90 percent of the work in aging with mice and actually of medical research with mice uses a single inbred genotype where every mouse is the same there's no variation from mouse to mouse in their genetics.”

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Genetics 34:25 0
“what we wanted to do in developing a genetically heterogeneous stock was avoid that we did not want to trick ourselves into picking a drug that only worked on black six mice and conversely we did not want to miss a really good drug that just happened not to work on black six mice.”

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Substances 38:34 0
“one of them was aspirin one of them was a molecule called ndga which is nor dihydro guyaretic acid which actually does work it's worked three times in a row although it works only in males”

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Substances 39:12 0
“the initial dose of aspirin was very low that is 1 100th of the dose a person would take even if adjusted for mouse body weight and it gave only an sort of an 8 or 10 increase and it was in males only”

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Substances 39:54 0
“maybe it would have worked even better if we'd used a higher dose maybe it would have worked even better maybe even in females if we used a dose that approximates the sort of 83 milligrams a day thing that i used to take to prevent heart attacks”

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Substances 44:58 0
“rapamycin is one of the candidate drugs who brought that to the committee dave sharp dave sharp was a colleague of randy strong's at texas he's an expert on tor the target of rapamycin”

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Substances 45:30 0
“rapamycin is that drug and it's actually safe enough that you can use it in certain high-risk situations in people.”

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Substances 45:43 0
“randy strong noticed first of all that when you gave it to mice in the usual form 90 95 percent of it was eaten up in the stomach so randy and dave and their collaborators then spent a year trying to successfully trying to reformulate the rapamycin by coating it in a kind of a shell that would get it through the stomach into the small intestine where it would be absorbed”

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Substances 46:22 0
“the first drug that gave a very strong signal in both males and females and it's still the only drug that we've tested so far which gives a very strong signal in females”

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Immunizations 51:29 0
“that's why a lot of people get immunized and don't want to have their kids smoke etc but it hasn't worked on the aging process”

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Disease prevention 51:29 0
“that's why a lot of people get immunized and don't want to have their kids smoke etc but it hasn't worked on the aging process”

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Substances 53:12 0
“when you give the same dose of rapamycin in chow, the blood levels in the females are three times higher than the males”

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Substances 57:52 0
“so that means of the drugs that we've tested for late start rapamycin works perfectly, acarbose works about half as well as an early start and 17 alpha estradiol seems to work just as well in late middle age.”

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Substances 58:22 0
“they found that the muscles got stronger, their glucose tolerance got better, muscle structure changed for the better.”

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Substances 59:12 0
“what we've learned about rapamycin since that time is it inhibits two complexes of TOR complex one and complex two.”

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Substances 1:02:23 0
“the basic idea that knocking down TOR complex one might be a good thing and that knocking down TOR complex two might be a bad thing.”

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Substances 1:05:18 0
“randy strong and marty javers and their colleagues at the university of texas did a really useful study they gave rapamycin for a short period of time to male and female mice and then took blood samples every i don't know every hour every two hours or something and the rapamycin blood content in the female mice was two or three times higher than it was in the male mice.”

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Substances 1:06:56 0
“the study that was most informative for rapamycin was to take fresh virgin mice and give them the drug at a defined date at a defined amount and then quickly measure the blood levels after that.”

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Substances 1:07:50 0
“the a carbos application came in from david allison and a colleague of his daniel smith. this is an off-the-shelf drug typically used in people with diabetes and it basically blocks the absorption of glucose in the gut.”

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Metabolic health 1:10:10 0
“my current interpretation is that it probably is operating by blocking very highest levels of glucose it in the mice did not lead to a change in the integrated glucose level there's a clinically useful measure which is used in human diabetics too hemoglobin a1c which gives you a measure of over the last few weeks how much average glucose has been in the serum”

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Metabolic health 1:10:31 0
“if a person with diabetes takes a carbos that hemoglobin a1c goes down that's one of the ways in which you know it's working in a person”

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Metabolic health 1:11:45 0
“it's a reasonable guess that both acarbose and canagliflozin are working by eliminating the huge peak of glucose you get after you eat a meal with a lot of starch in it”

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Body weight 1:12:53 0
“a carbos led to weight loss or a lack of weight gain we don't understand it we see that in some populations but not all”

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Nutrition 1:17:05 0
“the mice in question were being given a diet consisting of 60% coconut oil”

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Nutrition 1:17:17 0
“the mice that were dying because they were on 60% coconut oil were dying because their livers got so big, so filled with fat that it compresses the chest cavity and crushes the lungs and the mice cannot breathe.”

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Substances 1:18:49 0
“resveratrol did not go through our usual screening process. This was a directive from the top.”

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Substances 1:20:15 0
“resveratrol given to mice on a normal diet does not extend their lifespan.”

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Substances 1:23:38 0
“I went to circus I gave my talk on rapamycin which is what they wanted to hear.”

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Substances 1:23:50 0
“I'm going to work for a company that works on torrid hitters.”

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Substances 1:25:06 0
“Green tea extract, many people have said it's good for you, traditional Chinese medicine etc.”

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Substances 1:26:24 0
“Methylene blue, curcumin, many of these other things that have been tested.”

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Substances 1:27:57 0
“17 alpha estradiol, which is very much the same compound except for one of the bonds tilts up instead of tilting down.”

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Hormone balance 1:29:54 0
“now if i'm looking at my table correctly the 17 alpha estradiol in cohort 5 extended median survival in males but not maximum and of course no it doesn't well that was used at a low dose at a low dose when we went back and we did it at a three times higher dose it extends our measure of maximum longevity as well as median longevity and at all three sites”

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Hormone balance 1:31:46 0
“there is one obscure paper by a swedish or finnish group maybe 15 years ago that said they had detected 17 alfastradiol but only in the brain and in fact they said that they had isolated in the brain a receptor which they called the estrogen x receptor that was relatively specific for 17 alpha estradiol the one that's working in our tests”

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Substances 1:34:41 0
“hydrogen sulfide might be an important controlling element in the aging process and had published a long and really impressive series of papers uh on that so he suggested that we give to mice a drug that would it would break down to produce hydrogen sulfide a drug called sg1002”

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Metabolic health 1:37:19 0
“something about aging in the male mice depends a lot on staying away from really high glucose levels”

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Disease prevention 1:37:39 0
“the mice are mostly dying of cancer both the males and females about 80 percent of the deaths are due to some form of cancer”

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Metabolic health 1:38:14 0
“why high glucose is bad for cancer is a relatively straightforward question at least compared to why disproportionately for males and females”

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Substances 1:43:27 0
“there are all sorts of reasons in which metformin failure is unsurprising one is it might be really good for people and not good for mice.”

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Substances 1:43:38 0
“it might have been great or if we had given it for a few months and then taking it away for a month and then given it for a few months that might have worked as well.”

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Substances 1:44:08 0
“it's been published twice once by rafa to cabo once by us in our study it led to no significant lifespan extension in either males or in females.”

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Substances 1:46:34 0
“in metformin we have this undeniable data of diabetics that take it versus diabetics that don't and you know you can slice that 10 ways to sunday it always seems to favor metformin in that diabetic group.”

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Substances 1:47:13 0
“the tame study was a paper doubtless familiar to you an epidemiological paper the point of the paper was not so much that metformin was good for diabetics which everybody knew it was it was that the mortality risk of diabetics on metformin was actually better than non-diabetics of the same age and sex.”

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Substances 1:50:01 0
“nad and its chemical derivatives would surely be on that list”

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Substances 1:50:14 0
“there's a great deal of pretty strong data suggesting that aspects of aging and age sensitive diseases can be altered by making nad more or less available”

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Substances 1:51:01 0
“the reason that nr nicotinamide riboside was recommended to us by a company that wants to sell it is that it's orally bioavailable and more stable than some of the other ways that have been proposed”

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Substances 1:51:32 0
“we tested it it's a bioavailable form we used a dose that they suggested and the paper that will have come out by the time this podcast becomes available suggested that in our did not extend life span in our mice”

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Nutrition 1:56:24 0
“you actually can put something in the food that extends healthy lifespan and it's an enormous effect 10 times better than a cure for cancer.”

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Substances 1:57:25 0
“two drugs that we've tested so far work just as well in middle age and one works half as well.”

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Substances 1:57:50 0
“we have two drugs rapamycin and one we didn't mention the amino acid glycine which have equally strong effects in males and females.”

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Nutrition 2:02:22 0
“one profound difference is herbivores versus omnivores now that might pose a lot less of a difference for the itps than it does for one of my pet peeves which is the never-ending nutritional studies of mice which i find generally unhelpful for that reason.”

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Disease prevention 2:03:18 0
“any effort to thwart human aging must be able to punch atherosclerosis squarely between the eyes.”

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Substances 2:03:29 0
“we gave them a lot of my some rapamycin and then instead of letting them die we euthanized them at 22 months of age when most of them were still alive and fairly healthy and then with the aid of a pathologist j irby wilkinson irby looked at dozens of different organs and sue brooks also looked at their tendons so their tendons were youthful their kidneys were youthful they did not have changes in the heart they did not have changes in the endometrium they did not have changes in the liver they did not have changes in the adrenal that were characteristic of 22-month old control mice.”

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Purpose 1:30:31 0
“you're grounded in reality and you don't buy into this idea that immortality is in our future and you view it as an enormous win if there's a drug out there that can extend human life by 25”

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Most important takeaways of the video

  1. Rapamycin and metformin are substances discussed in relation to longevity, with studies conducted by the Interventions Testing Programs (ITPs) which are considered the gold standard for testing longevity molecules in mice.
  2. SGLT2 inhibitors and nicotinamide riboside are being studied for their effects on longevity, with nicotinamide riboside being popular as a supplement for NAD precursor.
  3. The Hayflick limit, linked to telomere shortening, is crucial for understanding aging, with some associating telomere length with aging.
  4. Hyperbaric oxygen therapy is speculated to have potential health benefits under certain circumstances, with ongoing investigations into its efficacy.
  5. Telomere biology is critical for understanding cancer

Overview of Topics Discussed

The discussion encapsulates a wide array of themes predominantly linked to aging, substances that may influence longevity, and the genetics of aging. The prominent speaker, Peter Attia, focuses greatly on the molecular aspects that potentially extend lifespan, mentioning substances such as rapamycin, metformin, and NAD.

Significance of Telomere Research

Research on telomeres plays a crucial role in understanding aging and cancer. There’s debate on how telomere length impacts aging, yet research by Blackburn and others has advanced our understanding of how telomeres contribute to cellular aging and cancer. Different species employ varied strategies involving telomeres to stave off cancer, offering insights into potential anti-cancer mechanisms.

Emerging Substances in Longevity Research

Various substances are under scrutiny for their roles in promoting health and extending life, such as SGLT2 inhibitors and nicotinamide riboside, along with interest in compounds like 17 alpha estradiol and hydrogen sulfide. The unique formulation of drugs, like the reformulation of rapamycin for effective absorption, underscores the innovation in drug delivery targeted at enhancing effectiveness.

Role of Diet and Metabolic Health

Much emphasis was placed on the impact of dietary interventions like caloric restriction, noted extensively across longevity studies, and its varied effects on health. Moreover, drugs like acarbose have been highlighted, which influence glucose metabolism and potentially impact aging and weight management. The diet used in studies (like a high coconut oil diet) can significantly affect health outcomes.

Use of Genetically Diverse Models

The discourse also delves into the methodology of using genetically heterogeneous mouse models used in research to avoid biases that arise from using genetically homogeneous models. This highlights a shift towards a more robust and generalizable form of data that can potentially traverse across different genetic backgrounds.

Insights into Specific Substance Effects

Detailed discussions about the biological effects of substances like rapamycin, which impacts TOR pathways integral to aging, and metformin, particularly noted for its benefits in diabetic patients, were notable. The drug rapamycin, despite its initial digestion challenges, has been reformulated for improved efficacy highlighting the ongoing optimization in drug therapy targeted at aging.

Broader Implications for Aging Research

The conversation tailors around not just tackling the symptoms or markers of aging but understanding and potentially manipulating the underpinning processes that lead to aging. This paradigm shift focuses on not just extending lifespan but enhancing life quality, indicating an optimistic but measured view on the future of longevity research. The discussions narrate both the complexities and potential of targeted molecular interventions, alongside dietary and genetic strategies, to modulate aging processes effectively.