Longevity / Hormesis Is the Quiet Signal Behind Longevity
Longevity science often gets reduced to names of molecules. Metformin. Resveratrol. NAD. The more useful question is what these interventions are trying to imitate: the body’s response to small, well-timed stress.
Longevity / Hormesis Is the Quiet Signal Behind Longevity - Full Transcript
and now uh particularly in america and western society we spent an extended period of time uh in senescence in really getting old so what's happening in your opinion well it it's what i call whack-a - mole medicine that most doctors are not all but most doctors treat diseases and you know if you take diabetes as an example most people will have increased blood sugar levels the older they get and that's actually a very good sign of aging and how long they will live but if you were to go to a typical doctor in most western countries they would say well you need to pass a certain threshold to be a diabetic and only when you have a disease i will treat you you know go home and don't eat so many potato chips and get off the couch but i'm not going to help you with medicine until you actually have a disease whereas we know that a drug like metformin which is as far as drugs go relatively safe will delay type 2 diabetes if you prescribe it earlier it's a very cheap drug as drugs go and so i i'm encouraging people doctors to think about prescribing metformin before diabetes actually occurs and it's a lot easier to prevent a disease than to try to reverse it yeah i think that's a a very good point and i want to i think we'll come back and talk about metformin a little bit later because it has as you and i both know a number of pluses and there are some people who feel it does have some minuses particularly in mitochondrial function and you're one of the world's experts on how to make your mitochondrial function better so i'm interested in that take in fact what the heck i was going to talk about later but let's talk about it right now okay uh
okay uh you i know take metformin yes yes and i don't and i maybe should convince me come on david you and i are sitting around having a coffee uh right well you know i i don't want you to live a day longer than you want to steve but uh so i'm not going to try my hardest to literally convince you but scientifically i'll tell you what i think and why i chose to and that is that i looked at the data in let's start with with animal studies it's not always the best but with animal studies i was on a paper with raphael de cabo down at nih the national institutes of health and we showed that metformin delays many diseases in those animals and they they do live slightly longer that's good it's obviously not doing them a lot of harm and then when i looked at the literature of other people who did studies on one study was over 10 000 patients veterans that took metformin others um now hundred thousand plus patients who have taken metformin when they look at the risk factors and the at the actually the incidence of diseases of aging not just diabetes but other diseases cancer heart disease frailty alzheimer's their chance of getting those diseases went down as well which is what you'd expect from a true longevity or what some would call an anti-aging drug and here's the striking thing those patients were healthier having diabetes than people who didn't have diabetes and that's remarkable so what does that mean for people who don't yet have diabetes i think it should be even more effective than those people who have been studied now the other thing is i i'm doing a risk reward ratio always with with myself what's the risk of not doing anything pretty high right i know what i'm going to be doing 20 years from now it's not
to be doing 20 years from now it's not going to be fun i'm 50 i'll be 70 in 20 years and but what's the risk of taking metformin well it does have side effects that can be severe but for most people the most you'll experience as an upset stomach which i'm prepared to tolerate and mitigate with the benefit of potentially having a much healthier older age you know you and i are probably both aware a recent placebo placebo-controlled trial in older adults uh using metformin to see if it would actually improve uh exercise building more muscle mass and i think theory behind it was excellent and i think it was a well-designed study and yet metformin failed to improve muscle mass generation to exercise any thoughts on that subject yeah a lot i get asked about it every day and i've talked to the people who ran that study and so i'm pretty qualified now to speak about it what the study showed there are now two studies and if i were to summarize it would be this that the patients the elderly patients that exercised whether they had a drug or not metformin or not all gained muscle mass and strength there was a slight difference in the muscle mass of those who took metformin they were generally had smaller muscles but they were just as strong as the other group that didn't take metformin and so i've jokingly said that it's a question of vanity versus longevity but but really what i mean is that we're we're trying to eke out the differences but the benefits were still there even in the metformin group because we don't know really what's going on and there might be some negative effects on the muscle um even though they were just as strong
even though they were just as strong i have decided to see what happens if i don't take metformin on the days that i exercise and recover from exercise which is generally sunday monday tuesday for me um and you know that's that's my little experiment it's not a clinical trial by any means but i think in the absence of more information i think that's a reasonable approach that sounds like a fun thing to do you know you and i have an n of one at all times and you of course have added your father uh to the end of one and let me we've talked about your dad and you talk about your dad in the book uh your your dad talk about your dad and tell me the effects of some of your crazy ideas on your father yeah right uh so yeah full disclosure full disclaimer here this again is not a clinical trial and it's not going to be published in a journal anytime soon but my family are a bunch of scientists my wife's a scientist from mit my father's a biochemist and we can read scientific papers my father believe it or not at age 80 is an independent individual and he has chosen uh to take my research uh seriously and has been convinced by himself not by me to try things because he knows what the odds are in his old age of things going wrong by age 80 most people have at least two or three major diseases that are being treated um he started taking resveratrol early uh one of the first people in the world uh this is now going back 13 years ago and so far so good he takes a gram or so a day and the reason i say steve also is we in my family of powder we just spoon it into yogurt and mix it around it's important to dissolve it in something for it to be absorbed we know that from human studies and just to dwell on resveratrol for a little bit
dwell on resveratrol for a little bit um people go back and forth on resveratrol uh i can tell you in my lab we've we've definitely proven how it works uh we have new results that i haven't published but we we have had a science paper that that was very positive and show that it's working through the the two and pathway that we work on and we have new results that really nail it you know i don't i very rarely say we proved anything but this experiment that we've done has proven that it works the way we said it did but also what's it really encouraging is that there are human studies that are now showing that resveratrol does many of the things that we saw in mice many years ago protects people from high high fat diet and reduces blood sugar levels uh which is is great you know part of the reason that there were negative results i think in people is that though the researchers didn't realize that you need to dissolve resveratrol into something that allows it to be absorbed and when you do that you get five-fold higher levels in the blood um so getting back to my father uh he's been on resveratrol he's now on metformin he's been i've met foreman for probably six years now because he had high blood sugar everyone in my family dies early from diabetes related complications or heart disease and he's now the longest lived person in our family at least in on the male side uh and then he started adding nmn which is an nad boosting molecule the same one i take uh he did started that about three years ago and those are the main things now if people want to learn exactly what we do and it's a long list uh page 304 you can skip to that in my book but you'll miss all the good sin here yeah yeah thanks steve but the but also in part two of the book the middle section it's about things you can do with your daily life about what to eat when to eat what to do with exercise the science backs up and steve you and i have a lot in common in how we approach our daily
in common in how we approach our daily lives and what we think will improve health anyway i'll just finish to say that my father is 80. he has no illnesses he has no aches or pains he's got as much energy as he did when he was in his 20s and 30s and mentally and physically he he can outpace me um and so yeah so far so good he's a big kind of hope for all of us now you bring up resveratrol and i can't leave that without talking about hormesis because one of the theories of how resveratrol works is hormesis so what the heck is hormesis and why is it so important right well hormesis is essentially what doesn't kill you makes you stronger uh you could possibly say what what doesn't kill you makes you live longer as well because what we discovered first in yeast cells that you know you can make beer and bread out of and eventually in animals and now in humans we found that these enzymes that i mentioned earlier called the sirtuins these are protectors in the body and they do a lot of good things they protect cell identity they repair dna they boost energy in the mitochondria which you mentioned earlier so we discovered that but then what we realized in the 2000s was that these genes and the enzymes that are produced from them are turned on by hormesis and what that means is any anything that puts the body in a state of perceived adversity right you don't want to actually damage the body to be able to live longer and be healthy you want to give the impression that times are going to be tough so being hungry uh during the day exercising these are all things that tell the sertuan genes to come on and to protect the body there are some other things that i do such as go to the sauna and jump in cold water buds to try and stimulate and get my body out of its complacency
my body out of its complacency when we sit around all day i'm at a standing desk by the way of for that reason uh if we sit around all day and we don't exercise and we eat constantly our defenses don't get turned on we don't have hormesis and resveratrol which we talked about i've called a xeno hermetic molecule which means hormesis that you get from other species such as plants so when plants are stressed they make resveratrol and other molecules like it and i have this theory and some evidence that when we eat those stress plants our body thinks that our food supply is running out and it will also have the benefits of dieting and exercise as well i love that so uh the more stressed plants i eat the less exercise i have to do is that what i'm hearing here today right let your food be stressed so you don't have to be well yeah you know an interesting aside um uh this is not to talk about i happen to have an olive oil that has 30 times more polyphenols of any olive oil and the person who developed it is in the moroccan desert and he knew that great wines come from vines that are stressed they're planted in rocks they're underwatered horrible conditions and he says you know i bet you could do that with olives so he found a rocky part of the moroccan desert underwatered them and planted the vines right next to each of the trees right next to each other so they had to compete and when he finally made the olive oil uh the french government found it had 30 times more polyphenols than any olive oil they had ever tested and so you're right a a stressed plant gives more polyphenols and resveratrol is certainly one of those polyphenols so i think you're absolutely right on this so yeah so we're all going to go out and eat stressed plants or stress plant by-products
by-products by-products and that includes really good uh red wine is that true or is that french paradox a total myth uh i don't think it's a total myth but the amounts of resveratrol that we find we have to give people uh would be the equivalent of hundreds of glasses of red wine every day uh work yeah the news just just keeps getting better and better right but please don't don't over drink the alcohol is of course not not helpful and there's a lot of calories that said i'm happy to entertain the possibility and there's some evidence from looking at populations that drinking a glass or two of red wine over 40 years can be beneficial and there's not just resveratrol in red wine there's quercetin and other things as you know steve and so that cocktail with a bit of alcohol may be responsible for some of those health benefits that we call the french paradox where the french can eat a lot of cheese and fat and they don't have high rates of heart disease no yeah i think that's very true and like you say and i say in all my books look if you don't drink don't start it's uh rule number one i think what's one thing that my listeners can do to stimulate or mises for themselves you've mentioned several of them come on give us an easy one all right well so so having read tens of thousands of papers and read your books uh and studied this for my whole life if there's one thing that i could say that everybody needs to do it's eat less often yeah so that's not malnutrition not starvation please nobody become underweight but what this means is the three big meals a day with snacks in between in my view is ludicrous and has led us into a world of obesity so i've recently well actually most of my life i've
well actually most of my life i've skipped breakfast but more recently tried to even skip lunch and then have a normal dinner and it's been great for me and we know in mice if you here's something that i'll leave everyone with before we take the break uh i mentioned rafa de cabo down at uh nih my good colleague down in bethesda he did a study that i think is a landmark he mixed different types of different amounts of protein fat carbohydrate and gave 10 000 mice different versions of a diet and they all lived the same life span the group that lived the longest was the group that gave that had access to the food only two hours a day which argues that it's not just what you eat but when you eat that's important yeah i think that's so important and and whether we call it intermittent fasted or i like time restricted feeding which is kind of what you and i do uh you're you know you're an expert in this field would you please tell people why breakfast is not the most important meal of the day uh well so i found at least for myself and i assume i'm an average person uh when i measure my blood sugar so steve i started measuring my my blood sugar with a patch you can buy it's prescription only but still it's i managed to convince one of my friends to let me try it what i found is that i and i've heard many others their blood sugar goes up in the morning and people like me are not hungry at all when we wake up um and so it's it's really force-feeding for many of us and i can do quite well without breakfast and i don't need it i'm actually i do much better physically and psychologically mentally without breakfast so i think for many people having a breakfast is not just um a waste of money it's actually it's dangerous because it adds up the calories adds add up fast
calories adds add up fast yeah that's a really good point uh you know both our cortisol and our adrenaline levels rise in the morning and that of course both kick up blood sugar and i take care of a large number of diabetics many of whom have been on insulin and one of the things they don't quite get is they always wake up with an elevated blood sugar and they think it's because of what they ate the night before and most of them unfortunately then say oh my gosh you know i've got to eat some food and that will bring my blood sugar down well in fact when they measure it again at 11 their blood sugar is down and they make this connection that the food brought it down well it didn't their cortisol and adrenaline fell normally yeah and as you know for the last now this will be my 18th year from january through june i not only don't eat breakfast but i don't eat lunch uh so i i'm a mouse at the nih uh i eat all my calories in a two-hour window and so far so good you know as i say i'll let you know when i'm 150 if the experiment worked right
Transcript auto-generated by YouTube. Verbatim — duplicates intentionally preserved.
In this conversation with David Sinclair, the thread worth keeping is hormesis (as explored in this deep dive). The body adapts when it receives a signal strong enough to notice, but not so strong that it overwhelms repair.
Hormesis describes the adaptive response to manageable challenge. Exercise, heat, cold, fasting, and certain plant compounds all create signals that ask the body to become more efficient and resilient.
The benefit is not the stress itself. It is the recovery response that follows. That distinction matters, because more stress is not always better.
Fasting and nutrient timing can support metabolic flexibility: the ability to move between fuel sources and maintain steadier energy. In plain language, the body becomes less dependent on constant intake and more capable of using stored energy when needed.
That can feel like cleaner energy, steadier appetite, and a calmer relationship with food when the practice is built gradually.
Compounds such as metformin or resveratrol are often discussed as longevity tools, but they sit inside a larger context. Sleep, movement, food quality, muscle, and recovery remain the foundation.
The most grounded approach is to treat supplements and medications as medical conversations, not identity markers. The ritual comes first.
"Longevity begins when stress is precise enough to build adaptation, not constant enough to become depletion."
"Hormesis is the body learning from a manageable signal."
"The recovery response is where the adaptation lives."
"No compound replaces the daily architecture of sleep, movement, and food."
Use hormetic practices in measured doses: strength training, sauna, cold, or fasting should leave you more resilient over time.
Prioritize metabolic fundamentals before chasing compounds.
Discuss medications and supplements with a qualified clinician, especially when they affect glucose, appetite, or cardiovascular markers.
