Fasting has always carried a simple idea: the body can repair when digestion quiets down. Valter Longo's fasting mimicking diet adds a modern layer to that ancient pattern, using periodic, carefully structured nutrition to create some of fasting's signals while still providing food.
welcome to the metabolic link a medical and science focused podcast that explores the common thread of metabolism in health and disease this is where science meets Society welcome back to another episode of the metabolic link I'm your host Dr Angela PFF and I'm a scientist who studies the role of metabolism in health and disease I'm also co-founder of metabolic Health Initiative an education organization dedicated to sharing evidence-based information on metabolic health and therapies if you love learning about metabolic health check out our medical education platform the metabolic initiative where you can find a huge library of incredible lectures panel discussions q & as interviews and more all from the leading experts in our field visit membership. metabolic initiative. com to get started your first seven days are free and right now we're running a special offer use Code Black Friday at signup to get 50% off your first three months of membership the offer is valid through November 29th 2024 so on today's episode we're sharing a presentation by Dr wter Longo that was filmed this year at metabolic C Summit wter Longo PhD is a professor of gerentology and biological sciences and director of the Longevity Institute at the University of Southern California one of the leading centers for research on aging and age related disease his laboratory studies fundamental mechanisms of Aging by using genetics and biochemistry techniques with a focus on the nutrient response signal transction Pathways that regulate disease and Longevity this work has led to the discovery of the effects of periodic fasting and fasting mimicking diets on multi-stem Stem Cell Activation and regeneration in mice and to clinical trials on a range of age related diseases before we dive in I want to say a quick thank you to our sponsors please know that these Partners help us Contin to provide you with free quality content so when you listen to these ads and
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so that's what I'm going to talk about today this this fasting making diet and the idea that maybe you can intervene periodically and maybe as little as once every three or four months for five days and that can have long lasting effects and some of these effects are are very much uh surprising so these are uh my uh disclosure statements and um because of my interest in aging I always often start with this uh slide and and these are the risk factor for cancer heart disease and Alzheimer's uh and you see smoking and obesity keep coming up as the major risk factors for these diseases and of course there are major risk factors for all kinds of diseases and then uh I was struck by this slide that a friend of mine Matt kimberland gave to me uh which is is look at what happens this smoking and obesity compared to 30 years of Aging right so almost disappear and if you think about smoking and obesity in terms of a building imagine a four story building and being smoking in obesity and the Aging 30 years of Aging are the Empire State Building right so they almost completely disappear it doesn't mean that obesity and smoking are not important and we should eliminate them but just to uh put in in uh in comparison with how powerful the aging process is in driving lots and lots of diseases and so since um many years ago um we uh search for the uh genes the genetics of Aging the genes that control the aging process and if you look at the um the figure at the bottom left you see those those round uh dots and um and that's on the left is yeast is a unicellular ukar in its normal form what's called wild type and on the right that dot you see that's a
lot smaller that's a mutated one right so we we mutated the r genes the Tauruses kindes genes and then we mutated both and we starve them right and when we did that they live 10 times longer right so so this it took starvation plus two mutation one in the sugar pathway and one in the amino acid that way to get this complete reprogramming of the lifespan of a simple organism so of course 10 fold is very difficult to do for anything but a simple organism but this has been achieved for both yeast and worms right so now is it possible that we can at least have a partial success with with people and of course we know it's possible and I think most of you agree here nutrition is probably by far the best way to go short term let's say in the next 20 years if eventually we will have all kinds of crazy uh possibilities um and maybe those will work much much better but I would say in the next 20 years because of safety and efficacy already demonstrated the nutrition and uh and in part also exercise would be um will be the ones dominating but I don't think it's the nutrition that we've always heard about I think it's a major evolution of what we always heard about okay so then the the yeast is on the left and then you see the Flies and then you see the mice and and they're all dwarfs right and what does it mean it means that it doesn't mean that you need to be a dwarf to live longer it just means there is a big there's a major connection between the growth genes and the uh aging genes right so the growth genes are also controlling growth and reproduction are there's a trade-off between growth and reproduction and protection right and this is why we see this there are also all kinds of organisms that are not smaller and they live longer right so but but again I think this this record longevity you see in the dwarf jeans and and on the right you see this little mice and the little mice are growth
orone receptor deficient or growth orone deficient and now the um this deficiency is is switching them into this long live modality right the Long Live modality where they're again focusing much more on protection and repair than they are Focus in and um and growth and and so now at the top of it you see the people and this a long long lasting collaboration with haime kavara and endocrinologist down in keto Ecuador and haime have been following the human equivalent of these little PE these little mice the growth orone receptor deficient people for many many years and so uh not surprisingly uh they these people turn out to be S for the mice live 40% longer they have lless cancer the cancers most of the the tumors are actually benign versus malignant and they they get them later in life right so they get they're protected from diabetes they protected from cognitive decline and uh and so help with these little mice that I showed you earlier get to this very long lifespan without any diseases versus less than 10% for the wild type right so not only they live a lot longer but they get there with no diseases um so what about the people and here you see the um on the left cancer dats they're they rarely die of cancer they rarely develop diabetes cognitively I'm not showing it but we actually brought them to Los Angeles did fmis and they are they have a younger um cognitive function phenotype and maybe similar to those to that of somebody 20 years younger uh than they are so those that lack the gron receptor seem to have all these uh all these effects just like like uh what we had seen in in the mice so so if you look at this network and this is a very much a simplification of the network
because different cells have different network but there some of the usual susp suspects are these so grone igf1 Tor ases on one side responding to the protein proteins and specifically to um to certain amino acids and on the other side the sugars and the insulin signaling and Ras PKA signaling and so how do you control these um in the calor restriction field that I was telling you earlier uh in Roy Walford for a 100 years they've been looking at something called calorie restriction so what if you just reduce the all the calories um by about 25% right so you reduce the proteins the amino acids the sugars the fats equally and and in fact there's a lot of data in uh from from mice and rats and that showing that um the this extend lifespan but this is very difficult and also there's data when eventually they did the study the color restriction study monkeys the monkeys lived a little bit longer but uh probably uh were showing the evidence for tradeoffs right so they were weaker uh they're living longer more frail at least from some point of view maybe the IM the immune system certainly muscle loss Etc so um so is it possible then that you can intervene uh periodically um and generate a u you know starvation response state for just a few days and is it possible that that will last a long time um and of course they will control all these Pathways but it will control them not just acutely but long term right so growth ormon gf1 T PKA is it possible that the short intervention is causing long-term effects on all these markers the holiday season is starting and it can be easy to fall out of my routine a bit around this time of year which is one of the many reasons why I decided to
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activating what Pathways um we know enough to fold the system and create a fasting mimicking diet that will generate so they'll allow patients to eat and yet get the effects of fasting so that was the idea of course it's a low calorie low sugar low protein high fat um diet and uh um and the what we were looking for was lowering of igf1 insulin like growth factor one lowering of glucose increase of igfbp1 which is an inhibitor of igf-1 and increasing Ketone bodies these were the the four things that we felt were representative of a full fasting response and uh and so I'm today I wanted to talk about a recent paper um which by by Amanda in the lab and in Amanda what we wanted to do for a long time I mean most people don't want to change your diet right and and of course we we we're going to keep saying change your diet and have much healthier diet but most people are not going to do that so we always wanted to do a study about what happens what if you just allow somebody to have the whatever diet they had before and you just intervene once a month for 5 days of course uh this is a mouse study because in M we get to do a lifespan and we get to look at everything like so a lifelong study of a high calorie Western diet high sugar high fat Western diet um versus the same diet but with five days a month fasting mimicking diet so 25 days of this bad diet five days of the fasting mimicking diet and uh and so interestingly it takes a while for this bad diet if you look at the top it takes a while for this bad diet to get cholesterol to be higher but eventually after middle age you start seeing where
it says hfcd high fat and high calorie diet you see that cholesterol goes up and then eventually after uh you know a 23 Cycles when the mice are older uh the cholesterol is very high but you see the AG h c hfcd plus fmd is able the fmd Cycles once a month for only five days are able to reverse the effect of uh U this Western diet on cholesterol are able to reverse the effect on on leptin and also able to reverse the effect uh of the western diet and glycemia and insulin resistance and and so there you see on the left is the The Mouse and the high fat diet uh and then next just next to it of course the DI the control diet on the left and then in the middle the same high fat diet but just five days a month of the fasting mimicking diet and U and and to the right the effect on fat right so the the just the five days amount are able to completely reverse the the fat accumulation uh that these mice undergo on the western diet so what happens well there's I think in nutrition there is a lot of oversimplifications right so and and remember earlier I talked about calorie restriction and so there's the assumption that calorie restriction is going to somehow um you know increase the the insulin sensitization and the burning of calories um but it turns out that color restriction also eventually and this is some New England Journal medicine papers eventually color restriction can also slow down metabolism and reduce energy expenditure right so so then the fasting and probably lots of types of fasting if
they're long enough they're going to get this effect right they're going to get the organism eventually into energy saving in a Thrifty mode where the energy the organism is going to try to save as much energy uh as possible because it thinks it's going to eventually start and so here if you look at so we did RNA sick in the fat cells and we looked after the mice accident so the the there's a temporary fasting Ming diet and then we wait and then we look at what happens in the uh in the fat cells and basically metabol the fat cells kept on you know working very hard even after the exit from the fasting wiing diet and if you look at the Ketone bodies on the right you see that uh four days after the return to a high fat diet only the fmd group is still B breaking down fat right so instead of building fat is breaking down fat um and so this is what we want when I have a a long enough fasting period to cause catabolism breakdown of fat and but we want to avoid this entry into a Thrifty mode where life energy expenditure is is reduced another interesting thing is that you see that again the fat uh is reversed the fat accumulation is reversed but the lean body mess is not affected right so so the the fast mimicking diet even this lifelong uh intervention is protecting the lean body mass and is protecting the H absolute lean body mass not just the relative mass okay so and then the ultimate of course is Lipan what happens to Lipan you see the a dramatic effect that the Western diet has in shortening the lifespan of of even a mouse and uh and then you see the in the the green survival curve showing that um you know most of the great majority of this
shortening effect is reversed by just this five days a month of the fasting mimicking diet okay so these are um the the more expected results and and here we continue these results with a type two diabetes Model A genetic model dbdb mice lack in the Lapin receptor and U and these mice um eventually become obese and uh and they develop hypoglycemia as you see there on the right blood glucose level go Sky High and then on the left you see they start dying because of this hypoglycemia right so then if we start the cycles of the fast mimicking diet after the hypoglycemia has been developed you see that the glucose levels drop and and the death the this hyper glima dependent dats are are eliminated so this part is consistent with what I just showed you in lots of papers now we publish and others the publish are showing that fine the more uh surprising part is the type one diabetes part right so because now um we're we're looking at we're using a a toxin called strep strepto stoin which is specifically damaging the P pancreatic cells you see the red cells at the bottom those insulin producing beta cells so we we treat the ice with SZ and most of those cells most of those red cells are gone and then and this is permanent you see what it says stz D5 day5 stz D50 D50 after 50 days that's it they're type one diabetic they're no longer making insulin but if we start after they're already type one diabetic if we start the fast diet Cycles you see that the glucose level start coming coming down and eventually they go back to normal and if you look at stz plus fmd D50 now they've restore the ability to make insulin right so so what happened there but what happened is if you look at these are are the expression
of genes in the pancreas right so so if you look at the left they say Al right El libidum right the mice are eting normally and green means they're all off and These Are embryonic developmental G genes the genes that are turned down when the pancreas is first generated at Birth so as expected they're all off then if you look at the central uh Lane fmd you see all red right including several yamanaka Factor right so o four socks 2 and lots of these genes like nanog that are associated with cellular reprogramming so now we already have shown in in hematopoetic cells that the f Ming diet is causing lthsc which are long-term emetic stem cells so the the bone marrow cells is reprogramming them and making them accelerate increase the level of emat totic stem cells that are able to self renew but here now we're showing something different which is reprogramming and not necessarily turning on stem cells but they're reprogramming cells within the pancreas to be functional beta cells right so this is um a little bit of a you know holy gra in the Aging field can we reprogram cells to make him younger right so can you take a cell that is damaged that is old and reprogram it without without changing it without substituting it a reprogram and reset the cellular age into a much younger uh cell right so this is suggesting that this is an opportunity to do it in a very coordinated way um that is now able to uh turn reprogram the cells and then making beta insulin producing again right damage beta cells nonfunctional cycles of the fmd and now they're functional beta insulin producing beta cells okay this is we shown this for human cells and for we
did it in Vivo mice but also with human cells from type 1 diabetics and you see there PKA the usual supect T and PKA they keep coming up as a negative regular of this process right so counterintuitively the nourishment the high nourishment proteins the amino acids and the sugars are blocking this regenerative effect and I'll tell you why in in a second or probably why okay so human mice we see this reprogramming this factors reprogramming factors are turned down and then um after some Cycles the beta cell regeneration is restored and the normal insulin secretion is restored okay so what about people now we've done many trials and luckily uh we basically our philosophy has been anybody that wants to do a trial I'll uh will provide the fasting making diet that comes in a box and uh you know it's very risky right because they could come back and say it didn't work or it made it worse for the patient but this has been our philosophy like hey you test it and you let us know what happens but the first trial we did it and so there was 20 17 and there was uh five days fasting mimicking diet once a month for three months right so and the patient were asked to don't change anything in your kind of like the mice that I showed you earlier don't change anything in your lifestyle uh just do the fmd and then go back to the exercise and nutrition routine that you had before so three Cycles once a month for three months and then uh we compare Baseline with um one week after the cycle three and mon three okay so we compared that when people had returned to the normal diet for at least a week before we we looked at the blood and so you see effects on body weight abdominal fat weight circumference and lean body mass just like for the mice now that's relative lean body mass is actually going up after fmd Cycles but the
absolute stays the same right and that's what we are hoping for uh that you know we will see these major effects on fat um but uh without uh reducing Lim body mass uh and then differently or very differently from chronic calorie restriction we see these differential effects right so if you look at blood glucose people that started with a normal glucose stay there right so if somebody started with 85 fasting glucose didn't change very much uh but the pre-diabetic most of them return to the normal state right uh if you look at igf-1 which I just told you it's very Central sort of marker for for aging and diseases uh those that had igf1 lower than 200 stay there decreased a little bit but those that the igf1 ined over 200 there's a much larger uh drop cat protein the same those had normal uh didn't change and and the ones that had moderate to high levels of CRP um were CRP was reduced cholesterol same uh less than 200 not much and higher than 200 uh it was reduce much more uh systolic blood pressure and the same again this is small effects again these are not hypertensive patients they're normal so most of them had a relatively normal blood pressure but if it was above 120 on average this was decreased uh to a healthier level so this is is telling you that um it's resetting and this is probably why we go back to this you know yamanaka factors and this reprogramming because it seems like it knows how to put back the system into being younger and more functional rather than just changing things and blocking things um okay so this we just published in collaboration with Mark Houston in
Tennessee this 84 patient and this was four fmd Cycles against four months of the Mediterranean diet and uh and so uh you know some things very similar the Lapin reduction so probably reversal of Lapin resistance or reduction of Lapin resistance happen equally in the Mediterranean diet continues for four months or in four five day cycles of the fmd but if you look at a Depon for example which is a insulin sensitizer uh for the Mediterranean diet is going down and for the fmd Cycles is going up right so so um some difference at least between the two A1C normal again nothing happens the pre-diabetic we're starting to see a drop in A1C and the diabetic we see a larger drop in A1C in this trial and um but the biggest change difference with the Mediterranean diet was uh this is four months of the Mediterranean diet three pounds and these were uh o overweight or patients that had BMI over 28 so um for four months of Mediterranean diet three pounds of of muscle mass loss nothing for the fmd and then three month follow up after the four months five pounds of Lian body mass loss right and uh and again no significant difference in the fmd group and now we just finished another trial which I'm not going to talk about and again we saw the same effects on the lean body mass love a good night's sleep me too but I don't always get it did you know that sometimes poor sleep is associated with magnesium deficiency and research suggests that as many as 75% of American adults might be deficient it's no wonder that so many of us struggle to get consistent quality sleep but sleep is so important experts say that sleep can be as important to your metabolic Health as things like diet and exercise so that's why I wanted
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after the six Cycles the other very important things which we keep seen are is the effect of the fmd and the drug use right so these were combined in this Tri it was fmd together with any drug that was prescribed to the patient and you see that at the Mediterranean diet after six months um six Cycles uh 20% of the patient had the increased use of drugs 50% the same and 30% reduced and if you look at the fmd group instead nobody increased uh 30% stay the same and 70% re reduce drug use and now this is the third trial where we see this meaning that they're slowly moving into uh remission right regression remission of diabetes and eventually about 15% already after six months uh we're able to uh be drug - free the other interesting thing is hypertensive therapy right so you see again these were not hypertense patient but a lot of them did have hypertension and you see Mediterranean diet uh some of them increase very few decrease drug use in the six Cycles but the fmd nobody increases use of hypertensive drug and and two to three times larger group decreases uh hypertension drugs okay so then uh this is about to be published uh this is universal Laden 100 patients 12 Cycles the fast making diet and these again are diabetic patients um and there receiving monthly uh fasting mimicking diet uh um cycles and so here they look at um on the left is A1C in the center um medication and in the and c is either dropping A1C success in either dropping A1C or dropping drug use right and you see that in all cases you see a the fast
mimicking diet group having a larger percentage of patient reducing A1C a much larger percent of patient reducing A1C a but a Eightfold higher portion of patient reducing uh glucose lowering medications and um and again similar drop in uh succeeding in either dropping the glucose lower medication or the um A1C okay so this is just a summary you know so four trials there is another one there going to be published very soon 100 patient randomized crossover confirming all these results so I think we're now getting hundreds of patients is getting closer to be fairly conclusive I mean it'd be nice to have we're running now a large large study in southern Italy with 500 patients three arms with longevity diet Plus or fmd alone longevity diet Plus fmd or control so I think that you know that will be truly conclusive uh and the big difference we're doing with that trial is that we're only doing it once every three months right so we we sort of took our chances and said well instead of once a month is it possible they could still work if we do it every 90 days so five days every 90 days could could still have some of these uh similar effects we don't know but we'll know I think in about a year but so far all these trials are are showing you see A1C reduction uh very consistent and diabetes drug reduction very consistent and also evidence for for effects on hypertension and U and other cardiovascular uh markers or risk vectors okay so this is an incomplete network but the idea is the fmd is affecting uh igf1 is affecting ID pontin insulin fasting glucose level obesity Ketone bodies and a lot of these are
long-term effects they're not just acute but for example igf-1 the effect of lowering igf1 can last for months and now multiple trials have shown that right so somehow is reprogramming maybe the liver probably the liver and lots of different organs and is keeping uh this some of these factors uh insulin included leptin leptin is another one of the factors that is long-term affected by the uh fasting mimicking diet Cycles okay so then I switch to to cancer um and um so um in the um at the beginning as I mentioned we were more focused on what is the effect of the fasting mimicking diet in protecting cancer patients uh but then right after we turn into what is the effect of the fasting Mak D making the the all kinds of therapies more effective against cancer so this is an example the lung cancer um slide is now from my lab is from a Swiss lab and the breast cancer is ours but the point is chemotherapy alone I mean this is showing cancer-free survive right so can you take a mouse and cure it from cancer even though they're metastatic Mals and chemotherapy alone doesn't cure anything fasting psychos alone doesn't cure anything and and this is true for lung cancer multiple lung Cancers and it's true for breast cancer okay so it's very difficult to have a nutritional intervention Alone um er curing even a mouse from any cancer uh but if you combine the fasting and the chemotherapy now you're starting to see 40 to 60% in lots of different models of cancer-free survival right so it's it's this true synergism between the fasting conditions and the um and the uh therapy and usually is the therapy whatever therapy is the research pointed
to being very effective for that particular cancer right so in this case is we use the chemo that was effective treating that particular cancer and it works very well okay so then the idea is um yeah chemotherapy and radiotherapy they kill a lot of cancer cells but they also kill a lot of normal cells and we want to protect the normal cells and make it worse for the cancer cells right then you want to separate the two as as much as possible and um and so we started thinking about how to use technology ology to do this and so um and I have a lab in in Italy that focuses on cancer and um and so Julia in that lab Julia Salvador in the lab uh took on something that we had shown a long time ago which was normally if you starve a normal cells akt signaling and and tour signaling goes down right but it turned out if you starve breast cancer triple negative breast cancer cells the uh akt went up and tour went up right so and and we did this in 2012 and I sort of like didn't didn't think about it for a while but then we um we started you know um working on it and so Julia showed by doing what's called RNA seek and also single cell RNA seek started looking at the network so what happened in cancer cells as after you starve them and what happens in these cancer cells uh not surprisingly it they turn on pi3 kise and they turn on all kinds of other genes but there's not very many Pathways that they turn on right um and so we started thinking about Escape pathway blockade right so can we use techniques that eventually be fairly straightforward to use in a cancer patient you look at out the you you use the fasting making diet the system requires in a differential way so normal cells they know what to do with fasting and they go one way and they can
cancer cells get confused and they go exactly in the opposite way they start turning on pi3 can they do what they shouldn't do right they Rebel but now because we know that we can intervene and and look how how powerful it is in this case she's using she sees the pi3 canes Tor and akt are all uppr regulated so now she uses three drugs Romy ptil and oser um and you see what happens to the tumor now tumor is going very fast is triple negative very aggressive and now it goes the other way right so now you have tumor regression and if combined with the fmd starting even um before the treatment with the drugs you see this long-term you see that that those reverse Square the reverse triangles so after a long long time the tum more is still under control right they don't they are not able to become resistant and so why is that well it turns out the story is is more complicated than we appreciate why because you see under the right the fasting making diet is making is doing something which we call reducing redundancy Pathways metabolic pathway so usually a cell has many many ways to stay alive right and the fmd the starvation condition are reducing this to a very very few and one of them is pi3 canes in this case one is T and one is cdk46 right so so now um the by a combination of the drugs blocking these Pathways and the fasting um we can uh sort of go after let's say the differentiated cancer cells but on the other side the cancer stem cells don't care right and this is what makes cancer so so difficult to treat the cancer cells the cancer stem cells now are depending on glucose they don't care about this pi3 akt and Tor they care about glucose and PKA right Usual
Suspects come back around but now in a very different way so now because the fasting is also reducing glucose is able to control PKA control stemness and reduce the level of cancer stem cells and so on one side is blocking is killing differentiated cancer cells on the other side is killing cancer stem cells and that's and only in this combination now you see things working okay but then we started thinking okay um these drugs um yeah this is very promising but very difficult to to navigate the cancer uh field because it's very expensive clinical trials hundreds of millions of dollars and and to convince companies these all these drugs are not ours right so you have to go and and convince the pharmaceutical companies to to you know participate in the trial it's a nightmare so we started thinking can you can we come up with a set of of non-toxic drugs right that anybody can take and could we make them um together with the fasting making diet as effective as this very toxic or some of these toxic drugs of course rapamycin is not because rapamycin is used for as an anti-aging drug that's the exception right the other two you know they're they have lot of side effects the one going after pi3 canes and cdk46 okay so then um for a long time linos polling back in the 50 years ago started talking about vitamin C high do injectable vitamin C and cancer treatment and then L kentley um had revived this some years ago showed that with coloral cancer that is K mutated so this have this R constitutively active it showed that vitamin C was was toxic to cancer cells and you see it says CTR control STS is fasting CTR vitamin C is just vitamin C you see the toxicity do CRC is coloral cancer the toxicity goes
up when you use vitamin C right it's a little bit more toxic and then you see lung not very much uh but pancreatic cancer yeah there is a big increase but then look at what happens when you add the the fasting and fasting miming diet to the Vitamin C right so now there again synergism between vitamin C and fmd and this is in vitro but you also see in inv Vio uh you see the fmd plus vitamin C the tum more volume inv Vivo stays the lowest and this is multiple uh system that we use so it's working very well and very consistently this is just three cycles of the fast Ming diet um plus plus vitamin C okay so now it's are completely nontoxic in fact we're using two anti-aging intervention right two intervention that you could do for your entire life I mean poing used to take seven grams a day of of vitamin C uh and um so uh yeah so these are are very very much nontoxic and so uh now we're saying how can we expand this can we add other drugs that are non-toxic and have Co non-toxic cocktails that will be as effective as what I showed you earlier with these very expensive drugs uh plus the fmd okay so why does it work well it turns out that um normally vitamin C is stop produces free radicals and free radical damage the cell but What vitamin c does also is turn on something called e hem oxygenase one so hem oxygenase One controls fertin and high levels of fertin are protecting are basically Scavenging the iron away from what's called Phantom chemistry so what does it mean so the the vitamin C can be toxic but it needs iron to be toxic and if ftin is a high level the iron is scavenged and and not toxicity now the fmd in a fasting mimicking diet in a differential way is causing an increase of ftin in normal cells and a decrease of ftin in cancer cells right
and it's it's almost it knows what to do and the reason that it knows what to do is because it's probably um is the fasting period is probably always had that role of getting rid of damaged cells right so it was a we used to starve all the time and the starvation period may have very well been an opportunity to get rid of autoimmune cells insulin resistant cells precancerous cells cancer cells etc etc right so that's what we starting to think because just too many examples of knowing what to do and in some cases opposite effects right so making the immune system more aggressive against cancer but making the immune system less aggressive in an autoimmune situation how can it be right I doesn't know to go in completely opposite directions and the same immun T cells for example right so something is EV is evolved for that purpose right so it's start ation condition probably being that opportunity now nobody start no nobody fast anymore and so we lost this opportunity to sort of reset the system okay so what about um what about uh hormone therapy now this is combined with Palos Li and fulvestrant standard care for ER positive for hormone therapy for hormone dependent uh breast cancer and you see the green line is the growth of uh the tumor um when the mice are treated with fulvestrant and Palos estrogen receptor blocker and cdk46 blocker right so it works for a while then just like in women the cancer becomes resistant and then you got a problem right um so so now if you see the purple when you add the fmd that never happens and if you look at the and so even after you know I year and a year or so uh you have 100% survival and the
tumor is actually regressing right so the two drugs plus the fmd now we go from tumor adapting and growing to tumor regressing and eventually lots of the mice become cancer free and even if you look at the right panel you see the tumor is growing very fast then we had the fmd um and and now the tumor goes the other way right so it's it's causing it's able to also uh reverse the cause for a a resist a drug resistant tumor and why is doing that well it's doing that because and this is what makes it so difficult to do this with drugs because it's lowering igf-1 is lowering insulin and it's lowering leptin and all three are necessary so now you have two drugs bosp and fulvestrant and then you will have to add you will have to know and then add another three drugs lowering leptin insulin and igf-1 to get this effect right and this is why the fast iming D acting a little bit as a wild card is is making the environment so difficult and by lowering all three now the cancer cells does not know a rewire anymore there's nowhere to go and this is why slowly you know and this is a very long experiment for Mouse uh it the tumor goes down until you get to cancer-free survival okay so then what about the immune system uh was Stefan a long time ago had already shown that if he combines chemo with fast mimicking diet uh you see the CDH cells the tumor infiltra lymphocytes go way up so you see it on the bottom left fmd alone doesn't do anything dxor rubis and chem alone doesn't do anything now you combine as I showed you earlier doxorubicin and fmd and now the t - cells are moving in right they're they're attacking the the tumor and um and this is true for breast cancer is also true for melanoma same thing you see there fmd alone not much and um and doo alone not much okay
so then uh we were actually scooped by this group in in Spain that um got there before us so I say what if you combine immunotherapy with fasting fasting mimicking that that's what they did with lung cancer and it worked very well and they were able to show a very strong effect of the combination of fasting with uh with immunotherapy and in this case they use pd1 checkpoint Inhibitors okay so then salvator in my lab in Milan instead looked at pdl1 antagonist and ox4 Agonist po of them immunotherapy drugs used the PD pdl1 of course a lot more than the anti The al40 Agonist um but this is a single cell RNA SE so we look at single cells and then um using this we can figure out that the the compared to the immunotherapy alone the fmd plus immunotherapy is able to increase multiple population of CD4 cells activated CDA cells and also these tcf7 positive T cells so they is very aggressive turning of the immune system against the cancer and in Vivo you see this you know very strong effect and by the way interestingly immunotherapy doesn't do much in almost any Mouse Malo cancer Moda even melanoma and so um and but when you combine it with the fasting making diet it it does so the fmd does more than immunotherapy in a mouse so uh but but together they're very very powerful okay so the other thing is very interesting was side effects of the immunotherapy and here you showing in the triple negative breast cancer any immunotherapy caused was little to the mouse right and it was little you see that the the survival curve coming down either either with pdl1 drugs Ox 40 or both and it comes the their what's killing them is this
very this anaphylactic uh shock and you see aops and Bas basophils and Granulos sites go skyh high and the fmd brings it back down right so again it knows how to regulate this um resp immune responses okay so um you know so this is what I told you so far why does it work is because it affect glucose it affects igf-1 affect insulin autophagy hem oxygen A1 fertin and and so it can have this this very wide regulatory effects on so many different system but I I think the take on point is this differential effects in normal cells protect and in cancer cells is making it very difficult for the cancer cells to survive because this changes everything okay what about clinical trials in the last four minutes that I have um the uh the first one was leaden uh showing this 125 patient uh randomized trial uh breast cancer patient before surgery uh and you see the uh the fmd um those in the fmd group are having um improved clinical response and there there's about a third uh three times Less non-responders in the fmd group um compared to the regular Di group um and also the pathological response Miller pain looks at active cancer cells within the tumor there's a do response in the compliant uh so the compliant are responding so those that did lots of TR lots of uh cycles of chemotherapy with the fast making diet are showing a much stronger pathological response uh compared to the compliant to none of the Cycles or regular diet compliant uh the problem with this TR was compliance to the MD was law or because they were not followed by dietitians or nutritionists they were specialized in in fasting type therapies
this is very important right that to have Personnel that knows what they're doing not that the dieticians were not competent it's just that they didn't know about any of this and they sometimes go against it right and we've seen this at our own hospital they may say well you know the patient should be fat more uh and so I disagree with this trial and and they may you know actually interfere with it um okay so then vernieri did a 100 patient trial uh at University of Milan and then the N lab did another 100 patient trial at University of Genova and the the um the one in Milan at the top showed consistent with the mouse data activation mean a rewiring of metabolism in the cancers but more so the immune system attacking the cancer cells much more when the fmd when the fasting making diet was used and and then this is very interesting they took out of the 20 stage four metastatic patient five of them actually they publish a follow-up paper in the European Journal cancer showing the five out of the 20 they had cancers Advanced stage stage four lung cancer stage four coloral cancer breast cancer they were actually went into remission right so it's very and they published this because it was so unusual for five patients in a trial like this going into remission after you know being at such an advanced stage so you know still uh early but very promising and then uh the verer group just published this is the fouryear survival or so uh showing that big difference between patients that were uh do chemotherapy plus fmd this is triple negative breast cancer so very aggressive very high mortality uh those that do uh fmd plus chemotherapy there is about 50% survival uh versus less than 20% uh for the chemotherapy alone and then um the um I just want to show
uh this um yeah this basically this slide is showing that there was no uh side effects in the in in terms of muscle there was no muscle loss in the patient receiving many cycles of the fasting making diet so the my end slide um we think on one side is this multistem regeneration is occurring very clear in mice and rats in people we see evidence for this for stem cells circulating stem cells go up but you know it's hard to to demonstrate it uh so on one side the multistem Regeneration and on the other side I think the you know this effect that the fasting making diet has an an risk factors for diabetes cancer cardiovascular disease Alzheimer and so um I think together uh this makes the uh this you know intervention very promising I think for the prevention and treatment of lots of diseases and that's all I have I want to thank all the people I think I thank most thank [Applause] you wonderful we have some time for questions so if you have a question please make your way to one of the aisles where the um microphones are set up and uh to get us started uh Dr Longo I actually wanted to ask you a question myself if you don't mind so some of the Synergy that you're reporting here between fasting mimicking diets and um other cancer therapies we see similar at least preclinical reports with ketogenic diet even when fed ad libidum um what role do you think ketones themselves are playing well there's a number of paper showing down the ketones uh can can have anti-cancer effects right so yeah certainly the ketones they they get pretty high in these diets and so an experiment that we've been thinking about which we haven't done yet is uh you know if we block the ketones um you
know what happens do we still see this uh these effects uh certainly I reviewed some papers looking at the ketones in activating the immune system uh so that's certainly one of the potential mechanisms you know the the fasting inde dependent Ketone body increase is signaling to the immune system uh to attack cancer cells right so yeah yeah great all right we can start with over here hi thank you so much um I'm Dr Json forign from Canada Nova Scotia Canada I think this is fantastic and it's you know there's no drug better than this in many ways I am curious what's you know has there been have there been trials that have looked at a 5day f MD compared to like a standard water fast uh and what's the long-term compliance it's great to have these results but we people be able to continue it for a year or five years or 10 years down the road yeah so uh the comparison I mean we started we were only fasting right then that's how we started in a formal clinical trial and we did and leaden did the same and then we both abandoned it because I think the doctors were worried and the patient and we were surprised we thought cancer patient are going to be highly motivated they're going to do water only fasting they didn't and so and this is why um this is why we we asked the National Cancer Institute for funding uh for this so yeah so I think that the the fasting making diet is probably the way to go also for regulatory reasons right the and so for safety reasons right so the now we've have thousands of patients that have been through trials with the fasting making diet and you know at some point I think the the FDA and lots of regulatory agencies will will see it as very safe uh whereas what only fasting um I think it's uh I mean it's possible but uh I think we uh involuntarily abandon that
um so and the other question was uh or can you yeah can can they do it for a long period yeah I mean in the late in trial um with obese patient itic we were surprised you know the compliance was pretty high around I think 80% or so 12 Cycles one year of uh monthly fasting making diet and so I think probably very feasible um because uh even for a diabetic patient we see that probably on year two it will go from once a month to maybe once every two months or once every three months and then on year three as they improve maybe even less right so that's the idea the two to to change it um progressively so that it's less of a burden but it still keeps the the patient in in this improved Stadium okay we have a question from our virtual attendees um someone has asked has the fasting Mimi mimicking diet been compared to time-restricted eating or one meal a day the fast miming diet has it been compared to Tim restricted eating patterns or one meal a day eating patterns um no I think that um I think the of course the the time res the eating can be very effective for lots of things but I just point to one study that just came out right so we had published a long time ago that if you do fasting prolonged fasting for three days or so and then you hit the mice with uh chemotherapy um then the heart is protected and it's a paper just came out in cell metabolism showing if you do alternate day fasting the heart is Damaged more right so chemo Plus alternative fasting and and yes so just tell you that this is not one big word like fasting and it works for everything and no matter how you do it I think you need to know the mechanisms you need to standardize it you need to combine it with the right type of drug and and you need to be very careful it's
always the same for that purpose you know the the FDA is not there by mistake you know you could argue that they're slow but it's also yeah so we we want to use that kind of uh standard and uh it doesn't mean that you know there's a a paper showing 14 hours of fasting uh you know prolong I think was overall survival in breast cancer patients right so the women that fasted for 14 hours or longer survive more than those that that they fasted nightly for Less right so it doesn't mean that you know timed eating is going to be bad for you but it just means that there's going to have to be dedicated trials to to figure out when it works and why it AB absolutely thank you very much I was uh particularly reassured to see the data on the maintenance of lean muscle mass with the fat mimicking diet I'm a pediatrician so I have a big interest in prevention and it looks like with cancer and with hyperglycemia the benefits are really clearly outweighing the risks and I'm just curious if there's either been a subgroup analysis based on age or if you have any speculation about whether for people using this more for prevention perhaps because they have a risk factor whether at either early age or elderly age whether there's a possibility that um the risk of sarcopenia might be different at different ages thank you yes so in my basically um if we keep it doing a LIF long very frequently we stop at the equivalent of let's say of an 80y old right uh we we see this the mice when the fat storage goes too l they suffer right they they it's not good for them to fast uh but we were surprised to see in we just finished an Alzheimer trial with very old patients and I thought for sure they were never going to be and this was monthly uh for a year and uh and at least the
preliminary data shows that potentially there was some Frailty delay in those did the fmd right I mean it's it's fairly small I think with 60 patients but uh very surprising right very surp I would have expected exactly the opposite even based on the mouse work right but uh yeah so we'll see but uh that's very interesting uh to see the early data showing Frailty potential Frailty delay and in the red model of caia we see a slight small some maybe not significant similar effect right they seem to be uh the KIA KIA seems to be delayed in a red model in a Kia red model yeah maybe I missed this but did you did anybody look at the synergistic effect with fmd with radiother therapy too yeah so we published on that a long time ago uh in 2012 and it worked very well radiation plus uh fasting this was water only fasting in mice so the two uh they show I think it was additive effect um so yeah but that was the only only uh study we've ever done combining so no human studies um yet that I know of okay we'll come over here sorry you guys were in the light I couldn't see you I realize you're blinded uh good evening great talk Susan misso Trinity College um I've done a lot of work on adenosine and ketogenic diet so I was really excited to see adenosine on one of your slides and um I've often thought of adenosine as being a really key um opportunity to do that sort of reprogramming like dedifferentiate and redifferentiate in an Adaptive way and I just was wondering if you thought adenosine might be a key mechanism promoting some of the changes and epigenetic changes that are probably happening with this excellent approach with fmd yeah yeah so we we've been
meaning to look at epigenetic uh um changes for maybe 15 years and uh there almost for sure there are epigenetic changes um but we haven't gotten there yet so so you know that's one failure I think from from my group because we should have done it a long time ago and should have looked the mechanisms but uh yeah we haven't done yet thank you Dr Longo really wonderful presentation I appreciate all the great info um my question is about uh feron levels and the um the role of uh fertin and vitamin C and the fasting mimicking so in your um in the study that you cited do you have um the the doses of Vitamin C or how frequently the vitamin C was given and was that for longer periods than just during the fasting um yeah yeah so we this is very fre as frequent as possible right and we in the fmd we can only do it let say once a week for 3 Days in the mice and so we would give them the vitamin C high dose injected and the fmd at the same time as frequently as possible now there are um there are places that do vitamin C injections so for example I know that you see Irvine as a center that does vitamin C IV so um yeah so there I mean for somebody that that wanted to consider even though it's it's very premature I think you know because the trials haven't been done so now we're thinking of a trial with coloral cancer a USC immunotherapy vitamin C and fmd but um but there are ways now I mean in in by in the vitamin C levels have been published because there have been a number of trials that have looked at IV
um vitamin C treatment for cancer patient haven't worked very well because they you know they were not combined with the fmd or anything else so that may be the reason why they had limited limited efficacy so far but those those papers are published right so you can easily find what the dose the injected dose was in those trials you know so I think in in our trial we're going to use those that the standard uh injector levels per per square meter or whatever that they they used we have two more questions lined up so we'll take these and then we'll have to close the Q & A thank you Dr Longo uh we've been doing your diet program for quite a few years at the clinic and uh with great outcomes um great data on your solid tumors with the fastan diet can we extrapolate that into the blood cancers also or have you done any studies on blood cancers compared to Aha yeah so we just published two papers in this month right so one on all and one on CLL and the um and the CLL one which we just published in cancer coming out in cancer research also had two patients I mean it's very anecdotal case reports two case reports but in these two case reports just using this were patients that were in the pre treatment phase right so watch and wait and uh and for one patient for five or six years we've been able to keep the patient away from from chemo and other treatments right so very promising for espe especially for blood cancers because it may be one of the rare exceptions where the fasting mimicking diet and possibly ketogenic diet um will work along right and and in some patients now we're using a combination by the way of ketogenic diet and fmd especially G blastoma the very aggressive tumors um we're we're now
using this combination right so yeah for blood cancer I think it's be exciting to to uh to see a trial or several trials on um uh in the patient that have not yet been recommended a therapy but they're getting close can they be uh treated just with the diet wow excellent last question again than thank you Dr Longo marvelous work I uh I'm John chadborne I'm a former Professor retired Professor from Southern Methodist University I uh am curious about uh whyi days uh for fasting and uh how would that compare for example if you had someone fasting for 60 hours every week for weeks at a time uh would that be more effective UH 60 hours a week for two months or is it better to do five hours of fasting once a month for six months yeah this is similar to the the question before so I think my answer is again it needs to be standardized if we want this to to if you want fasting and ketogenic diet to move in to the mainstream I think it's going to have to be standardized and it's going to have to be repeatable so you know any any intervention could work theoretically but you know five days um allow the Ketone bodies to to get to pretty high levels it's a full ketogenic State um and low glucose low igf1 high igfbp1 low leptin etc etc autophagy is is uh occurring at pretty high levels by then you know if you look at much lower let's say 16 hours um most of these changes are not even beginning to occur uh so yeah so I think theoretically it shouldn't work if just because you do 16 hours or 14 hours but it doesn't mean like I said earlier they couldn't help
tremendously anyways for different reasons right so I mean for cancer what we're going after is remission right can we treat the patient for three months and get all the cancer cells that's what we're going after and for that I think we're going to need to have precise protocols and and follow them now for cancer prevention and uh you know a patient that may not do any of this and might do a standard let's say immunotherapy could they also do let's say 14 hours of fasting per day or 16 hours yeah absolutely I think uh it's probably a good idea um and yeah so we recommend that because it's also very safe yeah okay thank you perfect sorry oh oh he's back sorry well uh I I have actually been uh doing this uh 60 hours uh uh every week for uh weeks at a time and I do lose weight of course you know call a 6 or I have personally done this for a couple months at a time it gets my Beta hydroxy butyrate up to five Millar but then it it falls again uh when I'm starting to eat again and I'm eating a normal amount less than 2, 000 calories a day but still you know eating a reasonable amount so it's kind of a curious thing I've been trying to follow the dagostino safe read protocol uh for press pulse uh and as I say I cannot keep my my ratio of ketones to glucose uh anywhere close to one for an extended period of time but but uh but I can get my BHB up with a 60h hour fast to 5 molar it's just that it falls again yeah I mean the question is what are you trying to achieve right so and and also the other question is what are the long-term
consequences you know in my case I kept some levels of carbohydrates fairly High because I was worried about the long-term consequences of going back and forth from a highly ketogenic State and I'm not saying it because there is any evidence that that's bad sure sure but I was just worried that what if somebody does it for 20 years High ketogenic to not back and forth and back and forth could it be that after a thousand times you have a problem and that's how I was thinking right that so yeah so then again it it depends what you're going after and you know for different diseases and and purposes it's probably a completely so 60 hours it may be very work very well for you but you know what are you trying to achieve that's the question great thank you so much thank thank you Dr lunga thanks for listening to this episode of the metabolic link if you liked it please be sure to leave us a review share it or drop us a comment if you want more content like this including access to our private podcast feed that offers exclusive AdFree episodes that also provides continuing medical education please visit our medical education platform the metabolic initiative at membership. metabolic initiative. com your first seven days are free and right now we're running a special offer use Code Black Friday at signup to get 50% off your first three months of membership the offer is valid through November 29th 2024 thanks for tuning in
Transcript auto-generated by YouTube. Verbatim — duplicates intentionally preserved.
The fasting mimicking diet is built around nutrient-sensing pathways. When calories, protein, and certain growth signals drop for a defined period, the body shifts away from constant building and toward maintenance, cleanup, and repair.
In plain language, restraint becomes information. The body reads scarcity as a reason to conserve energy, clear damaged components, and prepare for renewal when normal nourishment returns.
Longo's work connects fasting cycles with insulin sensitivity, the science of inflammation, abdominal fat, and markers of biological aging. The promise is not that fasting replaces medical care. It is that metabolic flexibility can change the terrain on which aging and chronic disease unfold.
A body that can move gracefully between fed and fasted states tends to feel steadier: clearer energy, better appetite regulation, and less dependence on constant intake.
The important word is periodic. More fasting is not automatically better. The value comes from a defined protocol, adequate nourishment between cycles, and clinical caution for anyone managing illness, pregnancy, medication, or disordered eating history.
This is hormesis with boundaries. A measured stress creates adaptation. An excessive stress simply becomes strain.
Restraint becomes information. The body reads the pause as a reason to repair.
Think of fasting as a periodic signal, not a permanent identity.
Protect nourishment between fasts so repair has the materials it needs.
Use clinical guidance when fasting intersects with disease, medication, or frailty.
The useful lesson is not intensity for its own sake. It is designing a practice the body can absorb.
