The Two New Highest Ranked Compounds For Lifespan Extension According to the ITP (The Optispan Podcast with Matt Kaeberlein)

The Two New Highest Ranked Compounds For Lifespan Extension According to the ITP | 40 - LTW #7 The Optispan Podcast with Matt Kaeberlein 6.43K subscribers 5,582 views Jun 11, 2024 The Optispan Podcast with Matt Kaeberlein Subscribe to our channel: / @optispan Related episodes: These 14 Medications are linked to lower death rates in humans: • These 14 Medications are linked to lo... DON'T Take Resveratrol Until You Watch This Video: • DON'T Take Resveratrol Until You Watc... How do scientists decide which interventions are worth testing in humans for potential health- and/or lifespan benefits? One way to start is to examine how interventions perform in model organisms such as mice. The Interventions Testing Program (ITP), a federally-funded initiative that began in 2002, tests drugs that may delay mouse aging, with the hope of eventually identifying new longevity interventions for humans. The program aims to take an unbiased approach to interventions testing as possible and to make all data publicly available. In this episode, Matt goes over recent ITP tests of a broad range of interventions that includes a vasodilator, a beta-blocker, a drug to reverse cyanide poisoning, and more. The drugs are alpha-ketoglutarate, 2,4-dinitrophenol, hydralazine, nebivolol, 16α-hydroxyestriol, sodium thiosulfate, and canagliflozin. He discusses which of these interventions produces lifespan benefits in mice, gender differences in effects, results from previous studies of the interventions, and the importance of examining the life expectancy of controls when evaluating the results of lifespan experiments. Matt has served on the ITP steering committee since 2012. 0:00 Trailer 0:46 Introduction 1:33 A primer on the ITP 9:31 Abstract: Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin 12:44 Looking at the details 15:10 Alpha-ketoglutarate 18:18 2,4-dinitrophenol 24:42 Hydralazine 26:06 Nebivolol 27:25 Sodium thiosulfate 28:32 Canagliflozin 35:20 16α-hydroxyestriol 40:47 What we need next 41:42 Wrapping up Producers: Tara Mei, Nicholas Arapis Video Editor: Jacob Keliikoa DISCLAIMER: The information provided on the Optispan podcast is intended solely for general educational purposes and is not meant to be, nor should it be construed as, personalized medical advice. No doctor-patient relationship is established by your use of this channel. The information and materials presented are for informational purposes only and are not a substitute for professional medical advice, diagnosis, or treatment. We strongly advise that you consult with a licensed healthcare professional for all matters concerning your health, especially before undertaking any changes based on content provided by this channel. The hosts and guests on this channel are not liable for any direct, indirect, or other damages or adverse effects that may arise from the application of the information discussed. Medical knowledge is constantly evolving; therefore, the information provided should be verified against current medical standards and practices. More places to find us: Twitter: / optispanpodcast Twitter: / optispan Twitter: / mkaeberlein Linkedin: / optispan https://www.optispan.life/ Hi, I'm Matt Kaeberlein. I spent the first few decades of my career doing scientific research into the biology of aging, trying to understand the finer details of how humans age in order to facilitate translational interventions that promote healthspan and improve quality of life. Now I want to take some of that knowledge out of the lab and into the hands of people who can really use it. On this podcast I talk about all things aging and healthspan, from supplements and nutrition to the latest discoveries in longevity research. My goal is to lift the veil on the geroscience and longevity world and help you apply what we know to your own personal health trajectory. I care about quality science and will always be honest about what I don't know. I hope you'll find these episodes helpful! Chapters View all Explore the podcast 46 episodes The Optispan Podcast with Matt Kaeberlein The Optispan Podcast with Matt Kaeberlein Podcasts Transcript Follow along using the transcript. Show transcript Transcript Trailer 0:00 the ITP is a federally funded program with the sole purpose of identifying new 0:06 drugs that increase lifespan in mice the gold standard for validating new longevity interventions the 2020 cohort 0:14 of the ni interventions testing program we had two winners out of eight new interventions tested Alpha estral has 0:22 been tested three times by the intervention testing program and in every case there was this male specific 0:29 increase in lifespan that brings to eight the number of unique drugs with at least a 10% effect on lifespan in either 0:35 males or females my name is Matt cabine and welcome to the optisan YouTube 0:45 channel hey everyone welcome to the opto span podcast on today's episode we're going to cover the latest paper to come Introduction 0:51 out of the National Institute on Aging interventions testing program the title of the paper published in geroscience uh 0:59 is lifespan effects in male um3 mice treated with sodium tho sufate 16 1:05 hydroxy estriol and late start kega floen so as many of you know I'm sure 1:11 the ITP is a federally funded program with the sole purpose of identifying new 1:18 drugs that increase lifespan in mice it was started in 2004 uh and over the past 1:24 couple of decades I would say has really risen to become the gold standard for validating or in some cases not 1:30 validating new longevity interventions um I'm going to actually start this episode by reading the description of A primer on the ITP 1:38 the ITP from the Nia website it says the interventions testing program is a 1:44 peer-reviewed program designed to identify agents that extend lifespan and healthspan in mice investigators at any 1:51 University Institute company or other organization are invited to recommend interventions for testing by submitting 1:58 an application before the February deadline each year testing is carried out in the genetically heterogeneous um3 2:05 Mouse stock at three sites the Jackson laboratory the University of Michigan and the University of Texas Health 2:11 Science Center at San Antonio those whose proposed interventions are accepted for testing by the ITP sponsors 2:19 will collaborate with the ITP principal investigators to develop the test protocol and interpret the data and will 2:27 be asked to serve as co-authors on resulting Publications all data will be 2:32 made freely available to sponsors for use in their Grant applications research talks Etc so there are a few key points 2:40 here that I want to emphasize the first is that anyone can submit a proposal anyone in the community can submit a 2:47 specific intervention to be tested by the ITP this is not just for academics in fact many of the proposals that are 2:54 submitted actually come from companies or Physicians or interested lay people 2:59 uh second is that every proposal is peer-reviewed and the way this works there are actually two committees 3:04 involved in selecting which interventions are tested by the ITP the first is the access uh panel so the way 3:12 this works is every proposal goes to the access panel there are three members of the access panel that score each 3:19 proposal and then the panel gets together to talk about the proposals and rank them and then there's a second 3:25 committee and this is the committee that I've been on for the past 15 or so years called the steering committee the 3:30 steering committee looks at the recommendations of the access panel and then makes the decision about which 3:36 interventions actually get tested every year usually there are between six to eight slots available and so six to 3:42 eight proposals can be selected for testing within each cohort each year um 3:48 second point I want to make is that this is in the umet 3 background this is 3:54 important because umet 3 is what's called a genetically heterogeneous background it's actually a four Way 4:00 Cross of four different strains and so that's important because this provides 4:06 something that we think is closer to the human situation where not each every animal is genetically identical to its 4:14 sibling or its cagemate these are genetically Unique Individuals it's 4:19 still somewhat Limited in genetic diversity but it's probably better than the common inbred strains like c-57 4:24 black 6 uh another Point that's worth recognizing is there's kind of built in triplicate replication to the ITP 4:32 because every intervention is tested independently at each of the three sites again Michigan San Antonio Jackson 4:39 Laboratories and Bar Harbor Maine um that builds in independent replication 4:44 especially if you see the same effects across each of the three sites um 4:50 another really important point is that this is about as unbiased an approach the intervention testing is you can take 4:57 the sponsors who are the ones who recommend the interventions um and who write the proposals can play a role in 5:03 helping to design the experiment but they don't have any role in the execution that's done at the three ITP 5:09 sites the ITP Labs have no real interest or incentive in getting a particular 5:14 result so we can be pretty confident that at least there was no bias due to 5:20 uh an interest in getting a lifespan extension or failing to get a lifespan extension uh being introduced into the 5:27 experiment so I think that's one of the reasons combined with triplicate replication that really the ITP has 5:33 become the gold standard for rigor and reproducibility um in the field uh additionally I think it's worth 5:40 mentioning that all of the data and bio samples are made available to the community so as an example we used 5:47 banked samples from the ITP in our publication on periodontal disease and 5:52 aging in mice the first paper we put out so um I had an interview with Jonathan on on the podcast where we talked about 5:59 that work and some of those samples where we showed that with age mice developed periodontal disease and that 6:04 Rapa and treated mice showed less periodon disease those actually came from the interventions testing program 6:10 an example of how the program has made samples available to the field there are many of those examples so I've got a 6:17 pretty long history with the ITP I'm a I'm a large supporter of the program I think it's a very important resource for 6:22 the field I actually first began serving on the steering committee in 2012 um and I can tell you it's not a 6:30 perfect system but it's really in my experience about as close as you're going to come in Academia um it's really 6:37 among the two best review committees that I've served on and I've been on a lot of review panels in my day and I 6:44 feel like the committee really makes the call nine out of 10 times that makes the right the right call so it functions 6:50 really well it's a really good group of individuals and and I've been very very pleased and I feel fortunate to have 6:56 been able to participate in that um committee I will say one of the things I've noticed in the past few years is that 7:02 the number of really good proposals is getting bigger and bigger every year and it's really swamping what the ITP system 7:10 can handle again there's really only six to eight slots available each year that wasn't always the case definitely in the 7:16 last few years uh there are probably two to three times as many really good proposals as can be tested through the 7:24 ITP and I think that we really need a significant expansion of the capacity 7:30 for rigorous intervention testing in in the field I there may be something that's worth coming back to in a future 7:35 episode but um I'd really just like to see some of the larger funders step up 7:41 and help build this infrastructure uh for the these sort of big idea really 7:46 important projects for the field um so hopefully that can that can happen um 7:51 okay so back to the ITP uh so and maybe this will help illustrate you know the limited capacity 7:59 over the past 20 years now 2004 I think was the first cohort um the ITP has 8:05 published results on 54 unique drugs along with two pairwise combinations and 8:11 how these things impact lifespan in myice some of the drugs have been tested at more than one dose or tested at 8:17 different starting ages but there are 54 I think unique drugs that have been tested in 20 years we really need to do 8:24 better than that um and so they make a point in the abstract here to say that with this current paper there are now 8:31 seven individual drugs that increase lifespan by at least 10% in either male 8:37 or female mice we'll come back to this point that most of the drugs really with 8:42 the exception of Rapa mice and that robustly increase lifespan in the ITP increased lifespan either in male or in 8:49 female but not in both sexes we don't understand that um so I actually counted seven before this paper I'm not really 8:56 sure what the discrepancy is but the seven prior one winners that I've come up with of at least a 10% effect on 9:02 lifespan are rapy clearly the the most robust uh of the group acaros canag lloan which we'll 9:11 talk more about today 17 Alpha estrad which is related to one of the drugs that were tested in this paper um ndga 9:19 captopril and aaz anthon and then the two combinations that had robust effects on lifespan are carbos plus Romy and 9:26 Metformin plus Romy so that is all public data um but without further Ado Abstract: Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin 9:32 let's jump into the 2020 cohort results so again title of the paper if you're interested in looking at the primary 9:39 research is lifespan effects in male um3 mice treated with sodium thiosulfate 16 9:44 hydroxy estriol and late start kagaoan um okay so I will read the abstract and 9:51 kind of comment on it as as I go through it so again genetically heterogeneous um3 mice born in 2020 so this is what we 9:58 call the 2020 cohort uh but of course it takes a few years for the mice to age 10:04 out so that's why the paper is being published in 2024 you will often see this that the publication lags the 10:10 cohort year by about four years so mice born in 2020 we're used to test possible 10:16 lifespan effects of and here are so here's the collection of drugs that were tested Alpha ketoglutarate AKG two4 10:25 dinitrophenol hydrazine nebivolol 16 Alpha hydroxy estriol and sodium thos 10:32 sulfate okay and to evaluate the effects of kagin when started at 16 months of 10:39 age so recall kagin had been previously shown to extend lifespan when started at a young age okay so uh 16 Alpha hydroxy 10:48 estral produced a 15% increase in median lifespan in males but led to a 10:53 significant 7% decline in female lifespan so interesting sex dimorphism 10:59 there canag laflan started at 16 months also led to a significant increase 14% 11:05 in males and a significant decline 6% in females we'll come back to this uh 11:11 canaga floen given to mice at six months LED as in our previous study to an increase in male lifespan without any 11:18 change in female lifespan okay so that's reproducing what they'd seen in a previous cohort suggesting that this 11:25 agent may lead to female specific late life harm so again I'll come back to this but the fact that when kosm was 11:31 started late in life there was a shortening of female lifespan when it was started early in life there was no effect on female lifespan is consistent 11:38 with the idea that there's a late life detriment to kagin that might be offsetting an early life benefit 11:45 specifically in female mice okay um we found that blood levels of canagan were 11:52 approximately 2old higher in aged females than in young males suggesting a 11:58 possible mechanism for the sex specific disparities in its effects so maybe it's 12:03 reaching toxic levels in the Aged females uh nebivolol was also found to produce a female specific decline 4% in 12:11 lifespan none of the other tested drugs provided a lifespan benefit in either sex these data bring to seven or eight 12:19 by my count the list of ITP tested drugs that induce at least a 10% lifespan 12:24 increase in one or both sexes they also add a fourth drug with demon at midlife 12:30 benefits on lifespan that's the Kegan and provide a testable hypothesis that 12:35 might explain the sexual dimorphism in lifespan effects of the sglt2 inhibitor 12:40 kic leosin okay so that's the abstract got through that now let's um take a little bit closer look so this table Looking at the details 12:47 shows you the list of interventions tested in the 2020 cohort the dose and 12:54 the starting ages um I don't think it's really worth getting into the doses at 12:59 at this point uh um suffice it to say that for every intervention tested the 13:04 proposer has to make a case for what dose should be tested and when the dose 13:10 should be started in terms of the age of the mice at the time the experiment is 13:15 initiated okay so let's start with the things that didn't work um and again it's important to keep in mind a 13:21 negative result from the ITP doesn't mean necessarily that the drug can't 13:26 increase lifespan at some dose or in certain strain backgrounds in mice it just means that at the dose that was 13:32 tested in um 3 they did not deser detect a statistically significant effect on 13:38 lifespan um it also doesn't mean that this drug won't work to impact healthspan or lifespan in humans at some 13:43 dose or in certain individuals but I think it is fair to say that this is viewed as a compelling result if it's a 13:51 negative result that significantly reduces enthusiasm for an intervention 13:57 within the field for better worse I think that is the case when a drug fails 14:02 to show an effect in the interventions testing program that reduces enthusiasm across the field for that drug as a 14:09 potential longevity intervention okay so in this regard it is perhaps worth mentioning some of the notable prior 14:16 failures to come out of the ITP these are all drugs that people were pretty excited about that completely failed to 14:23 show any benefits in the ITP and these include Resveratrol met foran nicotinoid 14:29 riboside and fisinin and so it's beyond the scope I think of this episode to really get into the details of each of 14:35 these drugs I actually just did an episode on Resveratrol for those who are interested um I think it's just fair to 14:42 say that you should be skeptical of people who tout any of these things as longevity drugs given that they failed 14:51 to show lifespan extension in the most unbiased and well-controlled studies um 14:56 that have been carried out to date so again doesn't mean they can't have any possible benefits but the best standard 15:03 of data that we've got these drugs failed to show any effect positive effect on lifespan from the ITP okay so Alpha-ketoglutarate 15:10 who could we add to the 2020 list of disappointments um probably the highest 15:16 on this list has to be Alpha ketoglutarate so uh Alpha ketoglutarate is a metabolite that is endogenously 15:23 produced in mitochondria as part of the tricarboxylic acid or TCA cycle um work 15:29 from Gordon Lithgow and my good friend Brian Kennedy that was published in 2020 reported that alph ketoglutarate could 15:35 extend lifespan in celegans and in mice um and so that was the study I think 15:41 that laid a lot of the groundwork for the incentive to test AKG through the interventions testing program I've got 15:48 to say personally I was never really convinced by the lifespan data in that 15:53 study um it wasn't a big effect and uh and so I ever really I I guess I should 16:01 say I wasn't a strong believer that AKG is a potent longevity drug in mice based 16:06 on that one study I did find the Frailty and health span data in that paper to be 16:11 more convincing and both the published and some unpublished data that I've seen here look more compelling to me and so 16:19 um I think it's also probably worth mentioning there is one human study that's been published uh that reported 16:26 an 8-year reduction in the the epigenetic clock for people taking 16:33 calcium Alpha ketoglutarate they also saw a change in the placebo group so again little bit hard to tell how robust 16:40 or real that result is but I'd have to say for me especially given the failure 16:45 in the ITP AKG Falls pretty solidly in the towards the bottom of the second 16:51 tier of longevity interventions um that I'm enthusiastic about I don't 16:58 personally take calcium Al ketoglutarate I don't think that the bulk of evidence at this point really suggests that this 17:04 is a robust intervention for modulating the biology of Aging in either 17:09 laboratory animals or people again having said that the Frailty data in mice looks pretty interesting to me so 17:16 it may be one of these cases where for certain individuals it could have a benefit in terms of some metrics of 17:22 Health span even if it's not a potent modulator of biological aging or longevity on the positive side I think 17:30 there's not much risk from alpha ketoglutarate so it's been used as a nutritional supplement for many decades 17:37 in the form of calcium Alpha ketoglutarate in fact it was first marketed for calcium supplementation not 17:43 the alpha ketoglutarate um side particularly for bone density and so you 17:48 know there may be some benefit from calcium Alpha ketoglutarate independent of the AL ketoglutarate part through the 17:55 calcium supplementation but again it's been used widely as a suppl as far as I know really nothing in the way of side 18:01 effects so the risk profile here is very low again I think the question really is 18:06 just you know how good is the evidence for healthspan and again given the most recent result from the ITP not very good 18:14 evidence for longevity at this point okay so the second failure that I was 2,4-dinitrophenol 18:19 actually more disappointed by was uh two4 dinitrol phenol I actually remember 18:25 reviewing this um as part of the steering committee being pretty excited about this um so dinitrophenol is a 18:33 really interesting molecule it's something called an uncoupler um and it's called that because it can uncouple 18:39 the proton motive force of the mitochondria from energy generation and 18:45 basically it does this by allowing protons to flow across the mitochondrial 18:50 membrane and so what this kind of you can you can think of it as uh if your 18:56 body was a car like running the Transmission in neutral so you're burning fuel but you're not going 19:02 anywhere that's kind of what the the uncouplers do is they kind of burn 19:08 energy without creating ATP or burn fuel burn carbon without creating ATP by 19:15 uncoupling the mitochondrial electron transport chain and so in the 1930s 19:20 there was actually quite a bit of interest in dnp as a weight loss drug because it actually works really well 19:26 because what you're doing basically is burning through the carbon in the food 19:31 that you're eating um to uh burn energy and so people will absolutely lose 19:37 weight if they take dinitro phenol um so it works really well as a weight loss drug the problem is that if you push it 19:44 just a little bit too far it rapidly causes major problems and actually several people died from dinitrol phenol 19:52 um and so the FDA pulled it off the market in the late 1930s because people were dying from this weight loss drug 19:59 um but in recent years there's been a whole body of literature on sort of lowd 20:04 do levels of uncouplers and potential health benefits associated with lowd 20:10 dose levels of of dinitrophenol in terms of obesity and metabolic Fitness and um 20:16 uh other potential effects uh from just kind of burning the mitochondrial engine 20:22 at a at a low level um some people have suggested that this may actually mimic some of the effects of caloric 20:28 restriction because one of the things that we see with caloric restriction is an upregulation of uh endogenous 20:34 uncoupling proteins that actually have a similar effect to dinitro phenol so the 20:41 thought is that this might reduce oxygenative stress a little bit or mimic caloric restriction in other ways in 20:46 addition to preventing obesity so it was proposed and accepted uh as uh an intervention to be 20:54 tested by the interventions testing program in part the evidence to support this proposal was a 2008 publication 21:02 reporting that low levels of dnp could increase lifespan um in mice and so I 21:10 think it's worth maybe taking a look at the data from that paper because again this illustrates one of the points that 21:16 I've made before about short-lived controls in these Mouse experiments and 21:22 getting fooled sometimes by results that seem promising but then don't replicate when they're tested in strains where the 21:28 controls are longer lived so if we actually look at the graph from this paper um we can use the rule of thumb 21:35 remember now the idea here is to just quickly estimate what the median lifespan is for the control and treated 21:42 groups from these kinds of lifespan experiments and the way we do this is we look at 50% or 05 on the Y AIS which is 21:50 survival um go straight across to the control group curve and then go straight 21:56 down and see where that hits the x-axis so in this case that 50% Mark which is median lifespan is about 102 weeks or 22:03 that's about 716 days okay now we do the same thing for the treated group the 22:08 group that got dnp start at 50% go over to the treated line and then go down to 22:15 the x-axis that puts us at about 110 weeks or 770 days so this is shorter 22:22 than what we would hope to see for a really solid Mouse longevity experiment 22:28 in fact um we recently published a paper uh with Brian Kennedy and and Camille 22:36 pus at uh National University of Singapore uh making a sort of rule of 22:41 thumb that we call the 900 day rule so we would really like to see the longlived intervention group be above 22:48 900 days in order to have a lot of confidence in a in a result and so in 22:53 this case the long lived long lived intervention group coming at it 770 days 22:59 is actually less than where we would really like to see the controls between 850 and 900 days this is a common 23:06 pattern this was the case with nicotin anded riboside it was the case with metformin that the studies reporting 23:13 lifespan extension were done in short-lived uh experiments where the controls were short-lived then when they 23:20 were tested in the interventions testing program they failed to extend lifespan so the literature is full of examples 23:26 where short-lived control RS appear to have led to potentially artifactual 23:32 lifespan extension that hasn't been reproducible again just because an experiment has short-lived controls if 23:38 you see a lifespan extension it doesn't mean it's not a real result but I take a 23:44 degree of skepticism higher skepticism when the controls are short-lived and 23:49 the longlived group isn't even as long lived as where the controls should have 23:54 been which was the case in this experiment okay now if we compare this to to the controls for the ITP 2020 24:01 cohort using our same method start at the 50% or 0.5 on the Y AIS go across to 24:07 the controls and then go down to the x-axis you can see the ITP controls in both males and females were well above 24:14 800 days in fact around 900 days for the females again the long lived group in 24:20 the original study with dnp was only 770 days so the long lived group in that 24:26 study aren't even as long lived as the untreated controls from the ITP so again 24:31 rule of thumb but it's a good rule of thumb and I think it works pretty well um so if you're looking at lifespan 24:37 Curves in mice just remember the 900 day rule okay so we'll move on to Hydralazine 24:43 hydrazine this uh is an FDA approved drug as an anti-hypertensive it was 24:48 approved in 1953 it works as a very strong vasod dilator so it relaxes the 24:54 arterial smooth muscle um it's a pretty potent vasod Di 24:59 probably more potent than ACE inhibitors at least that's my understanding uh used to treat high blood pressure acutely and 25:05 also for heart failure and in 2021 this was actually the 106th most prescribed 25:11 drug in the United States so it's a very important medication I would say the 25:16 evidence here for longevity was pretty weak probably weaker than many of the interventions that get tested by the ITP 25:23 so there were two worm papers reporting lifespan extension in s rapitis elegans they came from the same lab um 25:30 personally I wasn't really in favor of testing this one um one of the papers suggested that the mechanism was through 25:37 Sirin and those of you who have kind of followed me you'll know that I tend to 25:43 be very skeptical of papers that make connections to cerin as the mechanism of 25:48 action regardless there wasn't a ton of evidence supporting the idea that this 25:53 drug was a potent longevity drug but was FDA approved um clearly has some medical 25:59 uses and people was tested did not show a benefit in the ITP uh nebivolol is Nebivolol 26:06 another drug in the FDA approved category this one is a beta blocker FDA 26:11 approved in 2007 so relatively recently um this one was tested based on the idea 26:18 that it is a novel class of mtor inhibitor so again I'm not really aware of any longevity data for this drug but 26:24 of course we know that rapy which is the most effective to come out of the ITP is 26:30 a specific inhibitor of mtor complex one uh uh nebivolol was identified from 26:38 a high throughput screening assay to bind to mtor uh by Goo copasi and 26:44 colleagues and then some evidence was provided in cell culture models that this drug could inhibit mtor complex one 26:51 so that was really the rationale for testing it um the rationale makes sense 26:57 uh uh again I don't know how convincing it is that this is really a potent 27:03 inhibitor of mtor in Vivo in animals but regardless it did not show a lifespan 27:09 extension in the ITP at the dose tested again I don't think we can really 27:14 conclude much from that because I'm not really convinced that it actually effectively inhibited mtor in the 27:20 animals that were treated so little bit hard to know what that means um the next Sodium thiosulfate 27:25 drug that did not show an effect was sodium thos sufate this is a sulfide donor molecule this is again an 27:32 interesting drug it's used clinically um I think its most common use is to reverse cyanide poisoning and this is 27:38 actually on the World Health organization's list of essential medicines this drug was tested by the 27:45 ITP based on the idea that sulfide donors can reverse certain chemical 27:51 modifications in proteins that happen with aging and restore the function of those proteins and there's a pretty good 27:57 body of literature mostly in seans that hydrogen sulfide um can have an impact 28:04 on longevity that caloric restriction can increase hydrogen sulfide which can act as a sulfide donor so the idea here 28:11 was that this might be a more potent sulfide donor that could have an effect 28:17 on longevity um it turns out it did not increase lifespan uh in the ITP there 28:23 are at least one other drug that was previously tested by the ITP again through the model of a sulfide donor 28:28 mechanism that also did not extend lifespan in the ITP okay so those are the drugs that didn't work now let's Canagliflozin 28:34 talk about the winners for uh 2024 so the first up is kagin super Interesting 28:40 Drug this is part of a class of drugs called the sglt2 Inhibitors or sodium glucose Cod Transporter 2 inhibitors for 28:48 those of you who watched the episode I did on the study from epna that looked 28:54 at prescription medications in the United Kingdom and their association with all cause mortality 29:01 this is one of the drugs that when prescribed to people again at least in the UK data set was associated with 29:07 lower all cause mortality these drugs are anti-diabetes drugs and they work 29:14 primarily by blocking the reabsorption of glucose by the kidney so basically you just pee out more glucose and that 29:21 reduces blood glucose uh levels so clearly beneficial for diabetes and 29:27 there's growing evidence in people that these drugs may be beneficial for blood pressure kidney disease heart disease 29:33 weight loss and I'm sure other things will um will come down uh the Pike in 29:38 future um research so again this molecule was also associated with lower 29:46 all cause mortality and the episode I'd refer you to is uh these 14 medications 29:52 are linked to lower death rates in humans uh longevity this week number four um so so KAG laflen was first 29:59 tested by the ITP in the 2016 cohort uh published in 2020 again remember the 30:05 foure lag from the cohort to the year of publication where it was reported to extend lifespan when started at seven 30:13 months of age so in young mice in that study it was male specific so it 30:19 increased lifespan in male mice had no effect on lifespan when started in female mice so it was tested here as 30:26 part of what is called The Phase 2 study in the ITP where a drug that has shown a positive effect in phase one can be 30:32 selected for further testing either at a different dose or at a different age of onset or both um and so here it was 30:40 tested uh starting at a later age 16 months at two of the three sites at one 30:47 of the sites it was tested H starting at six months I'm not sure I I probably 30:52 knew I don't recall why this difference in sites um uh happened but this did 30:59 break the sort of triplicate replication model of the ITP in the sense that only two of the sites did the 16-month onset 31:07 okay so um in both groups the six and 16mon groups the male mice showed 31:15 lifespan extension in the six-month group there was no effect on lifespan but in the 16-month group the female 31:23 mice showed a significant reduction in lifespan which is pretty interesting and not that typical actually to see 31:30 lifespan shortening from the interventions testing program so we can take a look at the actual data again the 31:36 lifespan extension looks pretty robust the lifespan shortening is you know it's 31:42 not huge right so again is this is statistically significant is it something where I would really hang my 31:48 hat on it I don't I don't know it's probably real but it's not a very large effect um 31:55 so again lifespan shortening is pretty uncommon in the ITP I don't I don't know what the total number is but it's it's 32:02 probably less than five of drugs that have showed a negative effect on 32:07 lifespan interestingly we had two this year so um so that's kind of it's kind of interesting and not something that's 32:14 seen commonly um it does raise the possibility as suggested in the paper 32:20 that conaglen in females specifically has a detrimental effect late in life 32:27 and that that may actually be offsetting a benefit in the females from early life treatment which is why the lifelong 32:34 treatment in the females basically has no effect it's like you're cancelling the effects out now that's pure 32:40 speculation may or may not be the case but it is sort of interesting to think about and I think this idea that uh 32:48 higher levels of drugs specifically in aged mice or certain drugs at the levels 32:54 that could increase lifespan in young mice can actually cause problems in aged mice is interesting and we're seeing 33:02 evidence for this with with potentially other molecules like nicoti-namid mononucleotide as well that specifically 33:08 in aged mice you can get toxicities due to metabolism of these drugs that that 33:14 may be beneficial early in life so that might be What's Happening Here specifically in the female mice was also 33:21 interesting that in the female mice there was about 20 fold higher levels of kagin specifically in the age females 33:28 compared to young males so maybe some drug metabolism leading to toxicity 33:34 effects there but I think a lot more research really needs to be done to really tease this out I do think it's 33:39 important here though to be careful that we don't over interpret the data from 33:46 the ITP specifically in these sex specific effects that we don't really understand for their relevance in humans 33:53 so I mentioned earlier a carbos a carbos shows a similar sex specific effect on 34:00 longevity in the ITP as does 17 Alpha 34:05 estradiol and the estradiol uh molecule that we'll talk about in a minute all show this sex 34:12 specific effect in males that may or may not actually tell us anything about the 34:19 potential impact in humans and so in the case of the sglt2 Inhibitors um if we go 34:25 back to this study from from the UK population looking at all cause 34:31 mortality there I don't recall any sex specific difference between males and 34:39 females in other words this association with sglt2 Inhibitors and 34:44 lower all cause mortality did not appear to be male specific in that study so 34:50 again given that we don't really understand what's going on with the sex spe specificity in the ITP and whether 34:57 it's a 3 unique feature I just want to be a 35:02 little bit careful that we don't assume that the same sex specificity is going to apply in humans and so for now I 35:10 think we just have to accept that this mechanism underlying the sex specificity 35:15 we really don't understand very well and it's a mystery that remains to be solved okay so now let's talk about the last 16α-hydroxyestriol 35:21 molecule uh that was tested in 2020 also showed a positive effect on lifespan 35:27 this is 16 Alpha hydroxy estriol so this is also known as estriol so you if 35:33 you'll see it sometimes referred to that um this is a weak estrogen and it only has about 10 to 20% of The Binding 35:40 Affinity of estrogen for the estrogen receptor and it's used primarily clinically as part of hormone 35:47 replacement therapy for menopausal symptoms in women okay so this is this 35:52 is part of uh HRT for some women so again this is super interesting to to me 35:58 because like the sglt2 Inhibitors estriol came out as a winner in the 36:04 study from the UK population as a drug that was associated with lower all cause 36:11 mortality um and again i' refer you to the episode where we really do a deep 36:16 dive into that paper if you want to get a closer look at this but um but it was interesting to me that estriol and I 36:23 think five other estrogens out of the 16 molecules that were associated with lower all cause 36:29 mortality uh were these were in the class of the estrogens so that was probably the strongest signal to me that 36:36 came out of that study interestingly there that was only in women because it was only in women where enough people 36:42 had been prescribed these estrogen molecules so again in that study there 36:48 was a strong correlation between estrogens including this molecule and 36:53 lower all cause mortality in women specifically okay so why I was 16 Alpha 36:59 hydroxy estriol tested by the ITP and this goes back to 17 Alpha estradi which 37:05 I previously mentioned which had been shown by the ITP to increase lifespan 37:10 specifically in male but not female mice so this was seen in the 2009 cohort 37:17 started at 10 months of age and then again in the 2011 cohort at a higher 37:23 dose and then 17 Alpha estrad was also tested again in the 2016 cohort at a 37:30 higher dose but beginning late in life at 20 months of age and in every case there was this male specific increase in 37:37 lifespan so again let me just say that again because was a little bit complicated so 17 Alpha estrad has been 37:45 tested three times by the intervention testing program starting at 10 months of age starting at young age but at a 37:52 higher dose and then starting at 20 months of age which is about the mouse equivalent of a 60-year-old person in 37:59 every case it increased lifespan in males but not in female mice okay so 38:05 again a very very robust and reproducible effect but sex specific in 38:11 its effect from 177 Alpha estradi so it was also observed in a 38:17 metabolomic study uh that the um3 mice treated with 17 Alpha estral had 38:25 elevated level levels of two specific spe ific metabolites in their livers estriol 3 sulfate and 16 Oxo estradiol 3 38:34 sulfate okay so the names don't really matter just appreciate that these are two molecules that are um intermediates 38:43 in the conversion of 17 Alpha estradi to 38:48 16 Alpha hydroxy estriol and so the hypothesis was that 16 Alpha hydroxy 38:55 estriol may be a downstream component of the mechanism by which 17 Alpha 39:03 estradiol was increasing Lipan specifically in male mice and that the 39:10 16 Alpha hydroxy estriol might increase lifespan in both male and female mice 39:17 okay so hopefully that was clear again short answer is this molecule was tested 39:23 because the thought was this might be Downstream in the life fan extension pathway for 17 Alpha estrad and that it 39:32 might give both male and female effects rather than the male specific effects that had been previously seen and that 39:39 appears to be half correct so it did in fact increase lifespan but again it was only in male mice interestingly here 39:48 there appeared to be a small but statistically significant lifespan shortening effect in female mice I don't 39:55 know what that shortening effect means um but it does appear to be the case 40:01 that this metabolite is in the pathway for how 17 Alpha estradi is increasing 40:09 lifespan in male mice so um so that's 40:14 interesting now again I want to come back to that UK study because there these estrogens including estriol and 40:23 estradiol were associated with lower all cause mortality specifically in females 40:28 in humans so again just reemphasizing the idea that I don't want to draw too much from this sex specific male 40:36 specific effect in the um 3 mice to conclude that the same sex specific effect is going to be present in humans 40:43 we just don't we just don't know okay so I think what we really need at this point obviously is a mechanistic What we need next 40:50 understanding for what's underlying these sex specific effects and whether these sex specific effects are somehow 40:56 spe specific to um 3 um and so again I I alluded to earlier that um 3 is 41:03 genetically mixed which probably makes it a better strain background for longevity testing than a very inbred 41:10 strain like c-57 black 6 but it would be interesting to know of these 41:16 interventions that have a sex specific effect in um 3 do they also have a sex 41:21 specific effect in something like c-57 black 6 in mice because if they 41:27 increased lifespan in both males and females in a different strain background that might tell us that there's 41:32 something here about females in umet 3 or males I suppose that are leading to 41:38 this sex specific effect I think we just really don't know at this point okay so that wraps the 2020 cohort of the Nia Wrapping up 41:45 interventions testing program we had two winners out of eight new interventions tested estriol and late life canag 41:52 liosen so again by my count that brings to eight the number of unique drugs with at least at least a 10% effect on 41:58 lifespan in either males or females and four now that show late life benefits 42:04 those would be rap ay a carbos 17 Alpha estrad and now kagaoan and finally for 42:12 at least one more year rapy remains as the ITP world champion and gold standard 42:18 longevity drug we'll see if somebody from the 21 cohort can unseat 42:23 Rapa um and as always thanks for watching if you have any comments or questions please leave them below um and 42:30 specifically if you like this kind of Deep dive into the ITP let us know we can absolutely do more episodes looking 42:37 at prior years upcoming interventions being tested hopefully some interviews with the folks involved in the ITP if 42:44 you're not yet a subscriber please hit that subscribe button and I hope to see you next time on the optis span podcast The Optispan Podcast with Matt Kaeberlein 6.43K subscribers Videos About 1:13:13 Dentist Reveals Exciting Research Findings Involving Rapamycin on Oral Health | 5 - Jon An, DDS, PhD by The Optispan Podcast with Matt Kaeberlein 50:59 These 14 Medications are linked to lower death rates in humans | 23 - Longevity this Week #4 by The Optispan Podcast with Matt Kaeberlein 37 Comments @jonathonmills3563 13 hours ago Highlighting Astaxanthin and glycine would be more viewer useful since both met statistical significance and are readily available to the average person 8 Reply @BarryBPruett 15 hours ago I like the deep dive into ITP and other robust testing. Would be nice to see summary of which protocols are likely to work for humans i.e. maybe look at human testing results that confirms some of the ITP results which are associated with mean and/or max life extension. 4 Reply @bill9989 16 hours ago Matt, thanks for all your videos. You are my goto guy for longevity. Today, you spared me the expense of AKG. I already spend a significant amount on other interventions, specifically rapamycin, metformin, taurine, astaxanthin, gly-nac, and others. 4 Reply 2 replies @bob-ss4wx 4 hours ago Matt; Excellent! Really helpful when you describe having "the engine burning energy and the car not moving"! Reply @peterz53 15 hours ago Matt. ITP results could be of more useful if human equivalent dose would be published with results. Also, for positive results, it would help to have test run again using a feasible dose. If I recall correctly this was a problem with the 2019 astaxanthin study in that dose used was very high in human terms, being a lot higher than typical supplements or what can be obtained in diet. So we really don't know if lifespan needle will move in humans taking in normal supplement amounts. 5 Reply 1 reply @epigeneticnerd4244 16 hours ago Hello Matt and his crew. I have patients on rapamycin and wondering if you guys are still collecting data on rapamycin users and if so, where would I direct these patients to help contribute? 6 Reply 1 reply @Samucacamilo 12 hours ago This is awesome. I have been using ITP data as my guiding light for any experimentation decision and the deep dive on this years/2020 findings was great. MOAR. Reply @ryan_the_red_4907 5 hours ago Great detailed explanation of ITP Reply @supermanman6460 14 hours ago It’d be be cool if there was a clips channel for the podcast. I don’t have time to listen to the fullbroadcast. 3 Reply The Optispan Podcast with Matt Kaeberlein · 2 replies @Tron-Jockey 13 hours ago Many of us on Metoprolol were intrigued by recent information on Rilmenidine and would like to switch. Can you address Rilmenidine in the future? 1 Reply @kaceeboxers3580 4 hours ago Watched your video earlier on the UK data concerning estradiol, if I recall , 5 different variations of estrogen were in the top 10. So, puzzling to me, and I had to listen twice to fully understand, why these mice studies showed no additional longevity in female mice and even slightly shortened lifespan. It is understood not all mice studies correlate to humans, as for instance, rapamycin has demonstrated. All very intriguing. You explain this data in such detail and it is fully appreciated. Reply @orion9k 13 hours ago 21:50 that looks like the exact same grapth they used, for the Tourine mouse experiment Reply @workingTchr 8 hours ago Keep in mind that longevity isn't the only valid metric. There are supplements that can improve this or that condition and make like more pleasant (or bearable, depending on your POV) for the time you have. Reply @wpmitra7251 3 hours ago I think Acarbose works better than canagliflozin. ITP also said it extends lifespan. Fewer complications too. Reply @bob-ss4wx 4 hours ago Does 16a-hydroxyestriol follow pathway of Rapamycin? Does anyone take both? 1 Reply @FatherGorgony 10 hours ago Thank you very much. Very interesting. And what about Taurine? Reply @newyorkskier 7 hours ago I sense a hint of disapproval of the data coming out of Sinclair lab although I agree that his method of disseminating scientific data can raise an eyebrow even though it increases awareness of the potential of health span augmentation. Also, there is a huge body of data liming sirtuins to improving healthspan (at least mechanistically) and probably lifespan although one can criticize the therapeutic compounds used to modulate sirtuins Reply @bob-ss4wx 4 hours ago Are the Names and Organizations of the Access Panel Review Public information? Reply @HvdHaghen 8 hours ago I'm very interested in an ITP test of rosemary acid because it is consumed in high amounts in Acciaroli in Italy and also on Ikaria in Greece, both known because of the longevity of the inhabitants. This could be caused by the effect of rosemary acid on vascularisation. Does anybody know how the necessary request for the ITP test has to be done? 1 Reply @Dr_Mandler 11 hours ago We know that finasteride in males increases estradiol levels, could this be a benefit of finasteride without having to add exogenous estradiol or estriol? Reply @bob-ss4wx 4 hours ago Would using mice kept in cages skew the results of mice used? Would using mice from the wild provide better results? Reply @davidwoods1622 12 hours ago Has the ITP tested C60 or methanol Blue? 1 Reply @y.g.1313 9 hours ago Noise. Reply @SoulDelSol 8 hours ago Are people similar to mice Reply @bobbobson4030 15 hours ago Hi Matt, read your paper recommending the comparison of intervention Vs best case control (900 days median) in lifespan studies. What would be the equivalent best case number for 90% survival for control mice? Reply @arthurmario5996 9 hours ago will people never stop buying snake oil? Reply @europaeuropa3673 13 hours ago Not for me. bye. Reply @roanaur7518 15 hours ago What is your opinion on Sinclairs information theory of aging? DOI: 10.1038/s43587-023-00527-6 1 Reply 1 reply