Dr Brad Stanfield om Resveratrol, NAD & Healthspan -

Resveratrol, NAD & Healthspan - Dr Glorioso & Dr Brenner Dr Brad Stanfield 207K subscribers 17,808 views Streamed live on Apr 13, 2022 #Resveratrol #Healthspan Livesteam to discuss the resveratrol, NAD+, and sirtuin research with Dr Christin Glorioso & Dr Charles Brenner. Timestamps: 0:00 Intro 1:30 Sirtuin Research 34:30 Resveratrol 1:15:00 NAD Research tro 0:01 hello everyone and welcome to this live stream where we will be discussing the resveratrol saturn and nad research and 0:08 how they relate to our health now the goal of this discussion is to have an open and honest and respectful look at 0:13 the differing viewpoints and controversies around resveratrol and situants so we're going to be moving through the timeline of research 0:19 starting from 1997 and working our way up to the present and i do want to stress before we begin this discussion 0:25 that before thinking about any supplements or interesting research in terms of your health it's diet exercise 0:32 sleep and meditation that always come first so joining me today we've got dr kristen 0:37 glorioso who's an md and phd and post-doc from mit she's worked in the guaranty lab and 0:43 that was the lab that was heavily involved in the 1990s and 2000s on the research around activating the cer2 gene 0:50 and how that might affect lifespan it's also the lab where dr matt cableline and dr brian kennedy previously worked 0:57 we've also got dr charles brenner with us who's an expert on nad metabolism and its roles in health and in 2004 he 1:04 discovered the nicotinamide ribside pathway to nad so welcome both of you hi 1:10 hi thanks for having us so yeah the original excitement around resveratrol was somewhat to do with the 1:17 idea that we could activate the enzyme cer2 and yeast and 31 in mammals which 1:22 was hopefully going to provide these lifespan benefits so i think let's start by going through the research on 1:28 saturn's and if over activating them is actually a good idea in the first place so i believe charles there's a 97 paper Sirtuin Research 1:34 that you wanted to start this discussion off with yeah um i think we could start with everybody 1:40 in agreement that um you know in the 90s uh 1:46 in uh dr grunty's lab there was a lot of excitement and activity of using yeast 1:54 so saccharomyces cerevisiae as a model for aging and um 2:00 so this is a paper for sinclair and guarantee and uh in the previous couple of years 2:08 they had shown that extra copies of a gene called sir2cer2 2:15 extend lifespan in this particular model and let me just take a minute to explain 2:22 this model because how do you use yeast to figure out uh how long cells or an 2:28 organism lives right it turns out there's two ways uh one way 2:34 is you can grow the cells all to exhaustion basically 2:40 right so you you grow them in a culture until they divide and use 2:45 up all of the resources and then you can keep that test tube or flask for days or weeks or months and 2:53 you can plate for viability right that's called chronological aging chronological lifespan 2:59 and then there's the other kind that was being done in this paper for example by sinclair and guaranty and 3:06 that's where you sort of install a graduate student or a postdoc 3:12 in front of a dissecting microscope and you look at how many times the 3:17 mother cell can produce a bud a daughter cell and you remove those daughter cells 3:24 and then you score the number of times the mothers can divide and in this paper 3:31 sinclair and that's that that's the model that was being used in this paper sinclair and grunty 3:37 acknowledged that those old mother cells basically don't 3:43 exist they're i mean they're incredibly hard to find in a culture before there's a 3:50 mother that has 20 bud scars there's literally two million cells in the culture 3:57 and so the type of aging that they were looking at is the old mother whether she 4:03 can she she doesn't really have a sex but we call them she the old whether the old mother 4:09 um can divide a 21st time but that's literally one out of two million cells 4:15 so there's no selective advantage for this type of aging of the old you know 4:21 mothers because any cell in the culture can regenerate a whole nother culture 4:27 but you know people study yeast because they study yeast i've done i did yeast for more than two decades 4:34 and so i know this paper well and essentially what uh sinclair and garente showed is that the old mothers 4:42 can use sir2 to divide a 21st to 22nd and 23rd time 4:48 because something called ribosomal dna circles stays in the mother cell 4:54 and so they they figured out that mechanism and but they knew 4:59 that ribosomal dna circles don't exist in other forms of life 5:05 um they knew and acknowledged in this paper that there are very few of these old mothers and that they didn't claim 5:12 that it was a selective advantage but this is a great paper from yeast but 5:17 what was extrapolated from this paper was that maybe sir two 5:22 would somehow anticipate causes of it of death or aging in animals 5:28 and it it generated kind of more excitement potentially than than it was warranted 5:35 it was certainly reasonable to test the hypothesis that animals with more copies of sir two 5:40 would live longer and and the guarantee and sinclair labs and others tested that hypothesis 5:47 but given that there's no selective advantage for that old mother to divide 5:53 a 21st time when 50 of the cells have never even been a mother one time 5:59 um there's obvious limitations of this study so what would i be correct in saying 6:04 that it's it's great for yeast but but exactly not not exactly something that you can extrapolate to to mammals for 6:11 example well it's actually even a little worse than that because in 2004 i think and i think you probably 6:17 have the paper brad walter longo who's a very uh well-known 6:23 and well-regarded um aging scientist um here in 6:29 in in los angeles at usc showed that deletion of sir two not 6:34 extra copies but deletion of sir two will extend lifespan in the other model 6:41 of yeast aging right that chronological model of east aging and this is selective right so if 6:48 yeast has been around for a billion years and yeast was here before there were any animals and we're talking about 6:54 conserved genes so genes that are in yeast that are also in animals that might have a conserved function 7:01 here if you don't have sir two you have a certain deletion those cells all of them in the culture 7:08 can live longer and one would assume that all yeast are descendant of 7:14 yeast strains that are resistant to desiccation and resistant to using up 7:20 all of their uh nutrients so here it's not one out of a two million cells that 7:25 has an advantage it's every cell in the culture 7:31 will have a longer chronological life span if it doesn't have sir two 7:37 so that makes sirtu not a gene that fights aging 7:43 um that if you have certain sir two activity that you're better ager 7:48 this indicates that if you don't have sir two you're you're a better ager in yeast and 7:54 this as i said is selective trait but this wasn't known until 2005 8:00 right and in the meantime there was so much excitement to test whether 8:06 you know extra copies of sir to extend lifespan that people reported 8:12 that it extends life span in worms and flies and it wasn't until 2011 8:18 that we learned that individuals from nine different institutions led by linda partridge and david gems 8:25 showed that you can't reproduce those results then in flies and worms that 8:30 when you back cross those flies and worms the extra copies of sir two don't 8:36 provide a longevity advantage so that's really where the whole sir two 8:41 story got off off the rails so i think thanks charles i think i'll turn it over to you kristen um about 8:48 that uh original uh sort of cer2 research so is there anything that you'd like to to add or comment on from what 8:55 charles has said and any other papers that you wanted to go through yourself yeah so i just so i just want to say i i 9:01 study human so this is this is far from my area of expertise yeast um but you 9:07 know um and also was in the grunty lab many many years after this paper was 9:13 published but you know in thinking about this i mean i think this is kind of an 9:18 interesting dichotomy in science right you know and something that's extending lifespan you know in 9:25 replicative east and and possibly not extending going the opposite direction 9:30 in in um uh chronological uh lifespan in yeast and and how do you 9:38 how do scientists go in in and figure out who's right or what the nuance is or you know how do you resolve 9:45 that discrepancy and how do you move forward and you know i think just for the audience 9:52 to put this in a big picture context right the read the real reason we're doing all of this or i mean there's 9:57 multiple reasons people people do things but one reason that i think is what the audience is probably interested 10:03 in is how do you go from there to drugs that are going to help people 10:08 live a healthy life right what is what is the role of resveratrol right what is what so so the reason people start in 10:15 yeast and start in lower organisms is because they're easy to screen so right surgery was found by a screen for 10:21 lifespan originally because how do you do something high throughput to find even a starting point right so 10:29 so that's where we started and then there was this all right well if it works in yeast or there's some 10:35 controversy in use that's still being resolved obviously you know maybe you know charles dr brenner can can 10:42 can talk a little bit about how where that controversy is now and and what's happened in yeast since then with sir 10:49 too um but yeah there was then people tried this in flies and in worms and 10:54 there was a 2000 so granty lab showed that there was ex 11:00 extension with over expression of sir two and worms and then there was this 2011 paper right where 11:06 um partridge group uh came out and said there was an extension of flies and worms and then 11:12 guarantee lab came back out and said okay we did this 20 times there was a little bit of a background error in that 11:17 first paper but here we've done an extra good job showing that it does extend lifespan to a lesser degree than the 11:24 original paper said but still extends it so there's this back and forth right 11:30 as we get we as we go up and as we go up the phylogenetic tree and as we uh try to work our way towards finding 11:36 drugs that are going to help people so a lot a lot of this um you know sort 11:42 of comes back to the premise right and and uh you know kristin i think we agreed yesterday we're all going to call 11:48 each other first names so um so so so kristen said you know there's a 11:54 discrepancy in yeast i would say not really discrepancy so um 11:59 you know it's two different models right so chronological aging where it's all of 12:06 the cells grown to stationary phase and how long do they survive right so then 12:12 sir two is bad so if you have sir two you have a short life span and cannot be 12:17 extended by calorie restriction in the 12:22 replicative model where it's this one out of two million cells for which there's not really a selective advantage 12:29 sir two is good the those two things can both be true right 12:35 here but the premise this is important the premise was 12:41 that there there might be genes that are conserved between 12:48 yeast cells and animals control the process of 12:54 lifespan extension with you know in response to calorie restriction 12:59 and that premise has basically been defeated because 13:04 um when you say a conserved gene it means that a gene that has to stay 13:10 doing that function in other organisms so for example you know citrate synthase 13:16 in yeast is there to catalyze a reaction between 13:22 oxaloacetate and acetyl-coa to make citrate right it's same in e coli same 13:27 in yeast same in in humans right and so the idea is sir two is is a 13:32 longevity gene and it's conserved meaning that organisms 13:39 would have dropped off of the face of the earth if they didn't have this gene and that's why it's so fundamental that's why it 13:45 was in the yeast gene set and that's why it's in the worm and fly gene set and the mouse and the human gene set that's 13:51 what a conserved gene is right but longo's 13:56 experiment in 2005 shows that it's not conserved as a longevity 14:04 gene if yeast still has cer2 genes it must be 14:09 because of some other property of the sur2 gene actually sur2 is also required for haploid cells to 14:16 mate with each other but if it was all about survival right if it was all about survival 14:23 yeast would have lost the sur2 gene and by the way that mechanism that was described so 14:28 beautifully by sinclair and guaranty of repressing ribosomal dna circles is not a conserved 14:34 process so the premise that it was a conserved process 14:40 and that and that it's it's it's a gene there that is in other forms of life to 14:46 mediate the effects of calorie restriction has been debunked dozens of ways right 14:52 and and and and i think that we're both interested in human now right you and i as well as 14:58 brad who's a physician and i it doesn't seem like sirtuins add 15:05 a lot of value in terms of human medicine they there was a company formed 15:11 in initially to test whether srt 501 which is a 15:18 formulation of resveratrol could activate cert 1 and maybe that's going to be a drug and 15:23 folks were in the new york times claiming that it's going to treat diabetes and as a side effect 15:29 people were going to live longer right and that and other compounds were clinically 15:34 tested there were some safety problems they don't extend lifespan you know in in 15:41 model organisms they don't look like promising drugs and i think that we've kind of you know 15:46 tested the premise and the premise and the hypotheses have been falsified and 15:52 you know now it's claimed that certains mediate the effects of nad and 15:58 as a professional nad researcher i can tell you that they don't um 16:03 and so you know that's i think where the where the story stands at that that it's 16:09 a it's a it's a nice story but um there's not any scientific 16:15 validity to the idea that sirtuins are longevity genes 16:21 well so i mean i think there's kind there's kind of a lot there and we we jumped ahead a little bit but you know i 16:27 think um our sir two wins longevity jeans if that you know if that's the question i mean i 16:33 think part of what you're saying is that they don't have just one function that's 16:38 meeting mediating caloric restriction well lots of genes don't have just one function right i don't think that 16:44 that is makes them not doing the other function so an example of this rate is cell cycle so 16:51 cell cycle genes were found to you know be involved with cells dividing right in 16:56 peripheral tissues and in tissue culture and but then what is the cell cycle genes doing in non-dividing neurons they 17:03 have a different function right um so i i think the sir two and five and 17:08 by the way right there's there's ones are two in an east but but that turns into 17:14 seven sirtuins in humans right so they divide and have a whole family of certains each one of them has a 17:21 different place in the cell and each one has a different function and so you know it gets quite 17:27 complicated in terms of of what they do um so 17:32 uh are they extending lifespan um in higher 17:38 organisms i think you know in male mice um it was shown that strategics 17:43 is possibly mediating lifespan there's been a lot of papers showing health span 17:49 benefits to over expressing your twins and in some cases knocking them out so 17:55 right um so and that's but that's not just troops of sirtuins right that's true of a lot of 18:00 these longitude i was still called longevity genes i don't know that i would say that to be called a longevity 18:07 gene it needs to have only one purpose and that purpose no no i agree it doesn't have to have to have one purpose 18:14 i i said that the premise um that 18:21 they were conserved to extend lifespan doesn't hold up 18:27 that but and and and we've really known that since 2005 because 18:33 where there's selection for chronological aging and there's not a selection 18:38 for one out of two million cells to divide a 21st time right we we can agree on that 18:45 right that that literally the oldest cell out of 2 million whether that divides one more 18:52 time or not the yeast culture doesn't care about that but in chronological lifespan 18:57 um it's the survival of the cells over time right that's clearly a selective trait 19:03 so by 2005 we know that even in yeast sir two can't be conserved as a longevity gene 19:11 because deletion of it has a longer lifespan right and and then we know 19:18 that um you know like cert one is essential in some mouse strains it's 19:24 not essential in other mouse strains basically as a bone growth phenotype right 19:30 and and you know but the cell the cell can i mean the the mice you can make the mouse right 19:37 and it lives a normal life span and then you overexpress cert one and they did not get you know extended lifespan 19:45 now i the thing that is important though is that the amount of attention and 19:52 expectation that arose out of this amazing story because um 19:58 you know the principles are are excellent scientists and amazing 20:04 storytellers right and so the the story was that we have found the central uh 20:10 mediators of lifespan and the central mediators of caloric restriction which i think that 20:17 we all everyone involved in this debate if it's a debate or discussion i think we all agree that these are not 20:25 the central mediators of caloric restriction and lifespan would you agree with that kristen 20:30 um i mean i what what is what does that even mean well who who what process is the central 20:37 mediator yeah so so right so so but you wouldn't if someone if someone said is 20:44 there a single mediator of of lifespan or caloric restriction we might not even like the premise of 20:51 the question but we certainly wouldn't nominate any gene in the sirtuin family where was 20:58 that though is that was said hundreds of times it was said 21:04 uh you know in promoting uh circus it was said in 21:09 um hundreds of nih abstracts it was said in hundreds or thousands of 21:15 um review articles conclusions of papers that these are the central 21:22 players in lifespan and that there's an activator namely resertral 21:27 of a certain one that is going to allow people to live to 150 it was said thousands of 21:34 times it's it's well recorded it's in a best-selling book today right right 21:42 so i don't know i don't i don't have the book memorized actually i i actually 21:47 sadly have not read that book i probably should but you know um 21:52 uh i think this is a question of language and this is one that i think we're trying on a high level to deal 21:58 with yeah general and science communication right well i think scientists 22:04 maybe most scientists write are very careful about the words they choose and the way they describe things for to try 22:10 to be precise to try to not overstate conclusions to try to be very 22:16 accurate it's a matter of scientific integrity right um then you get into the world of what's 22:22 printed in a newspaper headline right and it's very different most scientists are upset about that you know yeah 22:29 yeah but but not all cancer right so for example for example 22:34 you know in 2007 so our lab discovered the at our kinase pathway is as brad 22:40 said in 2004 and um you know we knew from the work in the grunty lab that sir two is an 22:48 important mediator of um this replicative lifespan in yeast 22:53 right so we we put nr into that assay and the reason why i know it's the old mother cell is that you know it's done 23:00 in in my lab by peter bolenki and we reported in 2007 that despite high 23:06 glucose so not calorie restricted conditions we could get we could double yeast lifespan with nr 23:14 and that it depended upon the nr kinase gene and the other genes 23:20 that take nr to to nad so we we showed that we could extend yeast lifespan with 23:26 nr in 2007. but i never got out ahead of my skis and said that 23:32 because you know sir two and its homologues are the central mediators of lifespan in 23:39 humans that nr is going to be a human longevity drug and um and i i won't say that today 23:47 because you know human aging is different than than yeast aging human aging is different than mouse aging 23:54 human aging is different than macaque aging you know in in in primates um 24:01 males and females are fertile throughout their lifespan 24:06 in humans there's a really really interesting exception to the reproductive capacity going along with 24:14 lifespan with women right so women have menopause you know usually in their 24:19 fifth decade and men to a certain extent i will say that well no men have a declining sperm production capacity 24:26 throughout their life but it doesn't fall off a cliff right so so human women 24:34 are an exception to a very wide broad rule that says that animals 24:42 live as long as they can reproduce right and i don't i in 2007 nor do i think 24:50 today that any gene and yeast can anticipate the causes of aging 24:56 in an animal and especially not in a human right because even 25:02 uh even primate gene sets don't anticipate the delta between 25:09 female reproductive capacity and female longevity in a human being there's some 25:14 human specific genes that confer that that involves you know the roles of 25:20 grand mothers in in in the 300 25:26 000 years of human evolution so biology is complicated and storytellers 25:32 and it's not only you know newspaper headline writers that take things and hype them up it's some 25:40 individuals in science that hype things up and say that because 25:45 we found it in in yeast we're going to find it in worms and then publish things 25:51 prematurely that turn out to be not reproducible 25:56 and then there's other people that don't even ever retract or say things or or admit that things aren't true so 26:04 research all doesn't actually you know activate cert one it doesn't 26:09 activate east sir two it doesn't extend yeast lifespan um 26:14 matt caberline showed that it doesn't activate cert one it doesn't extend yeast lifespan 26:22 and um you know they're they're folks today that are saying oh no research hall is a certain one activator and 26:28 there's a huge global market for research all for exactly that reason and there are people that are still 26:34 saying that cert genes are conserved as longevity genes despite the fact that even in 26:41 yeast that chronological lifespan is longer without it so it's not only headline 26:47 writers that do hype it's you know it's it's folks in the scientific community 26:52 and i would argue that hype hurts right so okay so that's that's really 26:58 like you know i think this is a version of always punished right but there's there's there's two different ways of 27:04 communicating there's the way that scientists communicate with with each other right 27:10 and then there's the way that people that are not in science communicate about the science 27:16 and so there's pros and cons of both right i'm an academic i'm currently 27:22 right trying to learn how to communicate in a way that is going to resonate and not wear the pants out of 27:29 you know people that are non-scientists and and have them actually be excited about what we're doing be excited about 27:35 the future of science we have decreasing science funding in this country you know if we're increasingly 27:42 siloed so how do you communicate both effectively and with passion and to 27:48 show the excitement behind science while at the same time not saying things that are overblown or inaccurate right 100 27:56 agree you know and except that except that science funding is increasing uh 28:02 federally as well as privately now well not as a percentage of r d i can 28:07 show you those figures but anyway it's uh so 28:12 you know i some of the best speakers right that i've seen so if you go to the big 28:18 society for neuroscience and watch the keynotes which i sometimes do and they're amazing right and they're some 28:23 of the most science famous scientists in the world we are able to take a field that's not my field 28:29 right and tell me a story that is both scientifically accurate and simple 28:35 enough for me to follow being not in my field and inspiring right that's that's 28:41 that's that's what we all aspire to right so that's that's what we hope for and i completely hear you that like some 28:48 of those claims may have been too simplistic right they're made for investors they're made for the general 28:54 public possibly even you know a lot of times people that are writing stories they 29:00 don't want a complicated science headline you know such and such may have a role in 29:07 you know a specific time type of yeast lifespan extension 29:13 and this part of caloric restrict like that's not a headline right so it's like how do you how do you make a headline 29:19 that is something that people are going to understand and be exchanged you want to join to know something really really 29:24 funny there's there's something called betterage's law and betterage's law states 29:30 that any headline that is stated as a question has an answer and the answer is no so 29:37 for example if the headline is could certuan genes be the key to human 29:44 lifespan and there have been innumerable headlines such as that the answer to 29:50 that question is no you know could this phytochemical 29:56 um eliminate fatty liver the answer is no um could we all live forever the answer 30:04 is no study that and look for outcomes on that stuff i don't know 30:10 is that is anyone uh proven better age is better no no no it's just it's it's an aphorism right but it but it it's 30:18 generally it's generally uh true that when when 30:23 the when the headline writer knows that they have to state it as a question rather 30:29 than saying um you know harvard university city of hope ucsf 30:35 scientists um have have shown that a phytochemical 30:40 is the key to fighting fatty liver right they won't write it as a declarative sentence so 30:47 they write it as a question and you know 99 of the time the answer is no 30:54 yeah so so i think you know i think to bring it back to bring it back to you 31:01 know what we're interested in which is how do you move forward with human health span extending 31:07 um drugs or interventions right you know i i whether or not sirtuins are activated 31:13 right by resveratrol right whether so there's been a big back and 31:20 forth in the literature i don't know there's i read a bunch of uh review papers there's this you know there was a 31:25 stuff about a fluorophore and then amino acids and then you want me to cover that as a biochemist you want you want to go 31:31 through that as a because that's sort of what brad um promised out of out of this hour we could do that 31:38 i think that that would be a good um segway into that whether so i think there is um 31:44 i think there is still some debate uh from from what i'm gathering from youtube about about saturn and the merits of whether 31:50 we should be over activating them or not um i i think yeah charles 31:56 in my correct in saying that there's that we probably um there's probably no benefit of over activating the the cert 32:02 the sir two or also two and genes and mammals and kristin saying well that the literature is still open 32:08 is that where is that where we're at with this stage of the discussion it sounds like we have we have a we have a 32:14 disagree we have an agreement let's see if if i can summarize we have an agreement that um scientists should not 32:21 over hype their studies right um we have agreement that um i think 32:27 they should hype them appropriately but find a way to stay in a way that's not going to bore people and decrease 32:33 science i have a problem with with hype um there there's a way to 32:40 rate doesn't well excitement i mean to con conveying the excitement is good 32:46 right but to me hype means to um 32:53 amplify something in a non-evidence-based way so that that that's why i can't get 33:00 behind things that are hyped okay yeah i mean i don't think it should be a non-evidence-based way but it 33:06 should convey the excitement and also all of these journals are behind pay walls how are people supposed to know what we're doing 33:12 at all right and then you read them and even experts in the field can't follow them sometimes yeah okay 33:18 okay so so we we agree is it okay if i say hype hertz then if 33:23 we've so hype being defined as non-evidence-based 33:29 statements that um are 33:34 you know you know likely to get people to think that a problem has been solved or that 33:41 a right that so we agree on that um we agree that 33:47 um even in yeast um cells live longer if they don't have cer2 so it's kind of a head scratcher 33:54 why you would look in why you would expect you know animals 34:00 to live longer if they have more copies of sir two um but we we haven't talked about 34:05 resveratrol yet so um caberline actually you know and and he had some uh 34:12 impressive co-authors on these papers uh stanfield's and uh brian kennedy um 34:20 they were interested in yeast right and they were interested in uh the sir two gene and they were i mean 34:28 kennedy and caroline were both in the grunty lab and they both worked on Resveratrol 34:33 claire by the way and dave dave sinclair of course and um and so they 34:40 want to see whether um resveratrol extended lifespan in 34:45 yeast and they reported it doesn't so they're using the same assay that 34:51 that david did of replicative lifespan this old mother thing 34:57 and um so that's in this paper jbc paper and then further 35:03 um and and now i don't want to get too geeky as a biochemist but you see in 35:08 this in this abstract it says floor delice um 35:14 lice is a amino acid lysine so there's a particular peptide that was synthesized 35:20 by conrad hoets it was in um david sinclair's first paper on 35:25 resveratrol as a as a sirtuin activator and basically this paper cable line 35:32 showed that that that fluorescent dye is the thing 35:37 that sir two is interacting with that human cir sir two and yeast sir two 35:44 interact and that the the resveratrol 35:49 uh effect is something that occurs in the test tube and it doesn't actually involve 35:57 and a physical interaction with a certain gene or so two and gene product then years 36:03 later so years later david came back sinclair 36:08 came back and said no i've mapped the amino acids in human cert 1 that you need these 36:16 amino acids in human cert 1 to interact with resveratrol and the resveratrol 36:21 thing is real because if i mutate these amino acids i 36:27 don't get the activation of residual right right so that's hubbard 36:33 thank you um brad is like right there with all these papers so um 36:39 so according to hubbard it's these particular amino acids that are specific to human 36:45 and the problem is you go look for those amino acids that hubbard and sinclair found in 36:53 cert one they're not in yeast sir two so then something's gotta be wrong 36:59 david could not have found resveratrol the way he describes resveratrol 37:05 according to his current explanation of how reservatrol works so it's it's 37:10 constant gold post shifting it's first saying that reserve troll extends lifespan to yeast that can't be 37:16 reproduced then resvertrol activates uh assert one enzyme that 37:22 can't be reproduced then he says well no it does activate human cert one and 37:28 here's how but now he's moved the goalpost around that it couldn't have been where it initially was so something 37:35 multiple bodies of this research really should have been retracted and 37:41 um i think that that would be a much more straightforward and honest way of dealing with 37:47 the facts as we now understand them well i think somehow this has turned into become like a moratorium on david right 37:54 and and i think like it's you know there has i i don't know what to say because i i wasn't there at the 38:01 time when all this was happening but you know there's a back and forth of papers you know where 38:07 there'll be a paper published by david sinclair and then there'll be a response from camberlin and and this back and 38:13 forth and back and forth where are we with where resveratrol is in terms of activating the sirtuin genes 38:20 i'm not sure that's even resolved yet you know from what i was reading last night just in the review papers that 38:26 brad sent around you know there's now there's this question well maybe you need multiple copies of resveratrol 38:32 maybe in vitro you need the in internment terminus is not there and that's why people aren't seeing 38:37 activation and you know and so i don't i don't know where the state of this is but it 38:43 where it was left did not look clear for me in in my view there's sort of like three 38:48 invalidated premises one is that you'd want to activate cert 38:53 one two is that resveratrol is an activator absurd one and three that resvertrol 39:01 would be available to a human being when taken orally and all three of those things are wrong i don't know though 39:07 from what i don't know brad in in that review paper it looked like people were saying it was bio-available 39:14 it's not bio-available it's bio-available to a mouse a very very high-dose resveratrol 39:21 has effects on overfed mice we we know that that's been that's been 39:28 reproduced in in other laboratories by the time that uh johan alex who i i know you sent 39:35 me some papers from johann uh was working on that um the the last papers from from johann 39:43 showed that it doesn't depend on cert one it goes through the ampk 39:48 uh pathway because reserve troll is a stressor and doesn't depend on cert one and so 39:56 ours is basically consistent with all the other stuff saying that resveratrol 40:01 has a totally indirect mechanism of action that doesn't depend on 40:07 uncert one and and and again the activities were in overfed 40:13 mice and you know yeah overfed people i just want to point yes but but 40:20 but resvertrol bioavailability is nil in people which is why 40:26 um which is why circus you know made a form microcrystalline formulation of 40:32 resveratrol to increase its oral uh bioavailability and which is 40:37 why they uh looked for novel compositions of matter that would potentially activate 40:44 cert one and the pfizer group in 2009 showed that 40:50 neither resvertrol nor the other uh proposed sirtuin activating compounds 40:57 from circus are direct activators of cert one that when you knock out 41:02 um the cert one gene in mammalian tissue culture you still get the effects of these compounds 41:09 they don't depend upon certain one they don't bind directly to assert one and so the whole thing has been falsified 41:16 i mean i i i've been hearing this story for a long time i mean this is there there's a point of view that 41:24 uh and wants to paint david and his research as as a as 41:30 uh as all wrong but i don't think the literature bear bears a more complicated picture in which there's this back and 41:37 forth other people are publishing on aspects of it the brunei lab the alex lab chinamai's group showing 41:43 you know positive results in in specific subclasses of neurons and and there's a 41:49 whole body of research on this and i think what i think is that it's become this 41:54 personal battle you know between scientists and and but you know what what me what 42:00 should be conveyed to the public i think i think it's a disservice to say that respiratory has no good effects whether 42:06 or not it works through you know um sirtuins or not i'm not sure that even 42:12 really matters it works through m kinase it works through all kinds of other pathways who care it does matter because because 42:19 premise matters right so for example so again the if the idea is that 42:25 um you know cert one is a longevity gene is is is is 42:31 what you know is is stated over and over again and therefore activating cert one will 42:38 promote longevity pathways that you know the the headline 42:43 story and you know it's in like i say it's in a book um says that you know we discovered 42:50 longevity genes that are conserved all the way from from yeast to humans and we have activators of 42:57 these longevity genes and they they work in humans and if you look on page 304 of 43:03 my book you can see what my practices are um which involve a gram of reservetrol 43:10 in the morning you know with yogurt in order to activate my cert one gene and 43:16 if you go go back you know further you you see claims that you know 43:21 uh we're gonna live to over 150 by by doing this and so if it turns out that 43:29 then that cert one is not a longevity gene then why would you be looking for 43:37 activators of cert one and if it turns out that residual is not orally bioavailable or even worse 43:44 that it causes substantial toxicity such that gsk which paid a lot of money 43:51 for this technology and tested it clinically had to suspend clinical testing because of adverse events and no 43:59 signal in any of the things that they were looking for you'd have to say that this is a falsified hypothesis well i 44:06 don't know so okay so there were a compound right made by a company 44:12 called surgis which was a company started by david sinclair that was meant to make 44:17 activators right of the sirtuins in order to treat health health span 44:23 basically age-related diseases right and those compounds were patentable and 44:29 uh they went into a clinical trial now was did gsk buy 44:35 or after uh the multiple myeloma trial that i don't i don't know 44:41 right there was a multiple myeloma trial where there was toxicity yeah i thought it was um i think they 44:47 bought it before yeah they conducted that they conducted the trial so they bought it so 44:52 so there was a small trial rate of less than 50 people i don't know how many people that had some side effects right 44:58 including there was um diarrhea and vomiting and that led to 45:04 renal failure and people that were already pretty sick right they had cancer so um and they stopped the trial does that 45:12 i mean that's terrible right but does that equal sirtuins aren't it was 45:19 largely a leap the thing is that um they had 45:25 many therapeutic you know you know areas at gsk that you know they 45:32 thought that these sirtuin activating compounds were going to 45:38 address right so pre-diabetes diabetes cardiovascular health ocular health 45:45 you know and other things and uh basically none of it panned out 45:50 and um you know mice with extra copies of cert one don't have supervision 45:56 um super hyphen vision um they don't um live 46:01 longer they don't have improved cardiovascular health um when 46:08 um dr grunty you know knocked out the cert one gene he said the thing is 46:14 very highly expressed in the pancreas and um and that uh what you what happens in the 46:21 pancreas of the cert one knockout is overexpressed ucp2 with an uncoupling 46:27 protein so how is it that when you know that loss of cert one 46:33 gives you higher mitochondrial activity because you have higher expression of uncoupling 46:39 protein how is it that people can still go around saying that there's going to be 46:44 um higher mitochondrial activity if you activate cert one when it's actually 46:49 deletion of certain one that gives you higher mitochondrial activity 46:54 so there's just it's all the problem is it's all story you know um 47:00 there's a saying you know sort of all hat and no cattle and i i think that's 47:05 what the the sirtuin story is um right now i think that 47:11 i i think you know i think it's it's their separate issues right all of these are separate issues that we're weaving 47:17 into like a narrative here but i i think whether or not resveratrol works or it has benefit is a separate 47:24 issue from ucp5 and mitochondrial function i mean that could be cell type specific we 47:29 could go on forever why sometimes that's up and sometimes sets down right so i don't know that these 47:35 are a linear story i think you know if if we hang it in whether or not people should take 47:41 respiration off that's the bottom line right i personally don't take her spiritual i eat blueberries and grapes 47:47 and stuff and try to increase my consumption of foods that i think probably could have some benefit right but 47:54 it you know should that should that be a line of research that's pursued i think that's that's the bottom line and i 48:00 think one trial with one drug that had bad side effects doesn't definitively answer that question yeah we could get 48:07 some people from gsk that would potentially talk about the amount of research that 48:12 was done and the degree of disappointment in uh sirtuins as 48:20 you know uh activation targets um well i wish i wish that was published so 48:27 that we would could see that right because well so that okay so let's talk about that so let's talk about um you 48:34 know confirmation bias and model bias right because you're you're interested 48:39 in science communications and you know so what happens when someone publishes an exciting result what 48:46 happens when someone publishes an overhyped result right 48:51 so um when it was claimed that uh certains are conserved as 48:57 longevity genes which i think we've established that they're not you know even conserved in yeast as longevity 49:04 genes because deletion of that gene gives a longer lived yeast and that's a 49:10 selected trait but when you claim that they're conserved as 49:15 longevity genes and you make the story around it then you shine this huge light of okay 49:22 these this gene or like you said seven sirtuin genes these are the 49:28 these they were promised as the central mediators of calorie restriction 49:34 benefits of calorie restriction they were promised as the central mediators of longevity right so that means 49:39 resources went to those genes right and those targets that could have 49:45 been you know looked at all other things right you you said that a lot of 49:50 resources went to tour as well right and other gene logged on sure sure but 49:55 and um but when you when something becomes hot um you know scientists use the term sexy 50:03 i don't know whether it's really sexy but um it becomes you know it's it's hot it's 50:09 considered exciting it's hyped and then people start looking at it right and then um like for example the you 50:16 know cert one gene was simply over expressed in a mouse didn't extend lifespan and then somebody said oh well 50:24 you know maybe you have to just express it in one cell type and then like dozens of different groups 50:30 expressed it in different cell types and it didn't extend life span in you know like nine of those cell 50:37 types and those results don't even get published and then somebody finds oh there's one particular neuron 50:44 that if you have extra copies of of cert one in that neuron then it extends 50:49 lifespan so that's confirmation bias means because it's an exciting result you can publish that 50:55 positive result but most of the negative stuff doesn't even get published like you said you don't know we don't know 51:01 exactly what gsk did we know that they spent billions of dollars after they 51:07 you know invested 720 million in this program but we don't we don't have a lot of 51:14 output from that right because pretty much everything was negative to the point that they and and for full 51:20 disclosure um because i you know developed the nicotinamide riboside 51:25 technology when i was at dartmouth i was on the scientific advisory board of searchers so i saw this stuff pretty 51:33 pretty close i mean i was you know an expert biochemist there was a available 51:39 to evaluate whether or not they could find um compounds that activated you know 51:46 cert one without the presence of the flourgenic reporter group john denu was on the board uh 51:53 um um and you guys also i mean being on the board also means there's equity right so 51:59 you guys lost money when when searchers tanked right uh i i 52:05 i searches was considered to have succeeded because circus 52:11 was able to sell itself to gsk so 52:17 searchers as far as search was concerned as a biotech startup 52:23 they feel like they succeeded now when pharma took that on right and pharma 52:29 made 720 million dollar worth investment and then invested billions of dollars 52:35 after that gsk feels like they got burned because 52:40 um they frankly they didn't really do their due diligence and they 52:46 should have you know paid more attention to uh to to critics and the and the 52:53 substantive problems of whether or not the compounds hit their targets and by 52:58 the way when i was an advisor of searchers and like i say very capable of 53:04 determining and helping their scientists determine whether they have direct activators they 53:10 were actually having meetings where they were keeping uh advisors like 53:15 myself from seeing the actual data okay so the play of circus largely 53:22 seemed like let's create a hyped story and that's why i say hi perts 53:28 and let's promote the heck out of this thing it was constantly um in new york times newsweek uh time 53:36 magazine washington post and and other places as you know a startup company that was 53:43 going to develop longevity drugs and then gsk is a big traditional pharma 53:49 that made this radical you know uh play into you know years 53:56 before altos a radical play into the uh 54:02 longevity medicine if you will right and um they feel like they got burned 54:09 because um the things just broke down like the 54:15 non-reproducibility of of the even the worm and the fly uh life extension results the the 54:24 non-reproducibility of resveratrol is a direct activator the non-cert one dependence of the 54:33 srt 1720 which is a circus composition composition matter 54:38 um that that that the pfizer group showed that oh i mean 54:43 first of all i can't i can't comment on what happened at gsk right um you have some inside knowledge of that that i i 54:50 can't deny or verify because that's that this is part of what happens at pharmaceutical companies right we don't 54:56 know what's going on because it is behind um ndas and everything else and people 55:03 don't talk about what's happening so and it's not published so we i can't really 55:08 confirm or deny any of that um but you know i can say from a high level 55:14 you know how many drugs work right very few how many drugs work right there 55:20 there are you go in to these companies with the knowledge that there's a low success rate right sometimes things 55:26 don't work out is that necessarily the fault of the investigators i don't 55:32 know i mean i is that mean that this entire class of genes or class of drugs 55:37 is a total red herring i i wouldn't go that far i mean i think there's there's promise 55:43 still in this in this stuff from what i can see from what other groups are publishing you know from what's out 55:49 there in the literature um you know should we throw out bottom-up approaches entirely for 55:54 screening for for for drugs uh i personally take a top-down approach 56:00 i start in human for that reason but i i think there's a lot of scientists out there that start in worms or east or 56:07 screening for drugs and and sometimes they don't make it all the way up the phylogenetic tree right 56:12 um but i don't think that means there have been nobel prize given up and given out for discovering genes for diseases 56:20 right that they that have been discovered in c elegans that have been discovered in other organisms so i don't 56:27 think we throw out that approach entirely no i i wouldn't throw out that approach so you know 56:32 i just wonder if i can just interject here i just wonder if we can see if we can get a little bit of agreement so 56:38 coming back to the idea of trying to over express or over activate saturn's 56:44 so it i think we can i think we can agree that there's certainly debate within the literature and from what 56:49 kristen you've been saying if if you read um and and for the for the viewers if you read uh different 56:56 review articles that are published and and peer reviewed some of them will say yes 57:01 resveratrol does activate so two and one and that by activating saturn one you can get these lifespan extension uh 57:09 effects whereas if you it seems that if you go through the data yourself and and that charles 57:14 that's what um i think you've been doing uh trying to explain that story is that 57:20 and if if you look at it it does seem that the hypothesis that if you over activate so 57:26 two and one um you probably won't be seeing these lifespan extension uh effects 57:32 is that something that we can is that something that we can agree on and then we can hopefully move more towards resveratrol 57:39 and whether possibly the other targets of resveratrol might be worth uh further investigation 57:46 i'm not even completely sold on that because the last i was reading last night was 2015 papers and it was saying that you need 57:53 three different molecules of resveratrol plus the internals and then it activates circums 57:59 so i that's the last i i heard i don't know what the state of that is now but so so what what about coming to the to 58:06 the idea though of activating saturn one so where at the moment 58:12 kristin after this discussion where do you sit with trying to activate the two-in-one in terms of how that relates 58:17 to human health activating sir two in one in human health yeah so do you think that that would be 58:24 saying if if you had a better compound that what that was for sure orally bioavailable 58:30 and um 58:36 and would activate cert one do you still see the value of that as a 58:44 potential human right i think that's unlikely to work i mean i you know the the 58:51 as was mentioned over expression of 31 has not has not extended mouse lifespan my 58:57 certain people right there is some some work with other sirtuins that doesn't i 59:03 you know certainty fives or g6 maybe activators of those would be helpful there's a lot more that needs to be done 59:09 to understand the roles of all of these things right right sure so so overall can can 59:17 can we agree that activating or over expressing situation one in humans is unlikely to give 59:24 lifespan or health span benefits would would that be a fair thing uh to say kristin 59:32 so i feel kind of like that questionable about that i mean i don't i i that would not be approach i 59:38 would take i think that's lowered down on the things that are likely to work but for me to say that definitively i'd 59:44 have to see a 31 activator in primates showing no benefit 59:51 because i i you know how else are we going to answer that question my certain people right 59:56 there's back and forth on cell type specific specificity but if it's already failed in a mouse would you 1:00:02 spend you know hundreds of thousands of dollars millions of dollars to test it 1:00:08 in in primates i i wouldn't start there right but here's the thing mice are mice are 1:00:15 not people right so human brain aging and mouse brain aging 1:00:20 are have if you look at the transcriptome changes between the two with age you know there's a correlation of less 1:00:27 than you know 0.2 so you know humans aren't my 1:00:32 so right so so to me it's it sounds like um and and by the way you know 1:00:40 i think that we we could probably also agree that aging is very polygenic right 1:00:46 there's thousands of right so there's thousands of genes involved in the function of our brains and our liver and 1:00:53 our musculoskeletal system or respiratory system or circulatory system right and so the idea that activating or 1:01:02 inhibiting a single gene would promote um human health span or longevity 1:01:09 is pretty much a long shot right well i do think that there are probably 1:01:15 upstream genes right probably more than one upstream gene there's probably i don't 1:01:21 know so so we're working on this in human brain right and so we've found regulators of that are upstream of of 1:01:28 uh human brain transcriptome changes with age and so we do think that there are genes that are functioning as master 1:01:34 regulators not one gene right but i think that's possible 1:01:40 they do i think you have to affect the whole program or part of it you have to affect the whole program yeah and i 1:01:46 think that that would i think be a nice segue into resveratrol because i think many people would agree that resveratrol 1:01:52 is a so-called dirty molecule and that it it affects a lot of different things and i'm i'm not sure if we can get it 1:01:59 dirty well it's often referred to as a dirty molecule because it it's not it doesn't 1:02:06 just have one clear target um that that it does affect a lot of different uh a lot of different 1:02:12 things within uh within the cell and within the body so i i was hoping that we could get a little 1:02:18 bit of agreement around the merits or or lack thereof of zotuan one but i think 1:02:24 um i think it will be good to move the discussion forward to more what the potential benefits or or lack 1:02:30 thereof of resveratrol supplementation might be um because you know there is there is certainly 1:02:36 some debate and and i probably said in the camp that resveratrol isn't a direct activator officer two and one but given 1:02:42 that we can't agree whether activating saturn one is a good idea or not i think let's move the discussion 1:02:48 forward to possibly the other targets that resveratrol may have and i think charles you mentioned that it might 1:02:53 activate ampk um similar to what uh what metformin does so um that's possibly where we can pick up 1:03:01 the conversation but the problem is that it's not orally available in in humans so to me it's 1:03:10 um you know not much of a useful conversation i'm i'm 1:03:16 really surprised that um you know research all 1:03:21 you know advocates are still um talking about it um 1:03:27 it to me it's been as i said disproven 1:03:33 in terms of all of the premises that would that made it interesting it's not 1:03:39 humanly available it doesn't activate cert one and then to me there's no evidence that 1:03:45 activation of certain one is something that you'd want to do so i don't 1:03:50 even fully understand why people are interested in in it 1:03:56 kristen what do you think well i think bruce verital has it does have i mean it it targets ampk and a bunch of other 1:04:03 things i don't know if you can pull up that review there was one of the review papers you had on reservation towards 1:04:09 the end it had a paragraph that said that um that it is bioavailable so 1:04:17 you know i don't know you know well terra snowbean was developed because it's more uh human bioavailable 1:04:25 than residual but um there are published status saying that 1:04:32 terrastillbean gives a time and dose-dependent increase in low-density 1:04:37 lipoprotein cholesterol which is bad for human health so and and contrary to the 1:04:43 idea that uh terra still being is a certain one activator so 1:04:49 you know i i don't understand why people you know yeah pterosaur being i don't think was 1:04:55 was it was not made it it's it's naturally occurring 1:05:01 blueberry skins no one made it right right but it's um you know it's 1:05:08 sold as supplement and um you know the company that that that i 1:05:13 consult for um chromadex on chief scientific advisor used had a proprietary formulation of 1:05:20 pterostelabine and you know when when we looked at uh human literature 1:05:27 that was coming out and uh saw that terror still being was increasing 1:05:33 low density lipoprotein cholesterol you know we shut down our business because we thought that this is a potentially 1:05:40 harmful compound there's no reason that people should be taking this 1:05:46 yeah um okay i mean i'm just looking at the wiki page on terra still bean so it's found 1:05:52 in almonds fairies blueberries grapes and vines um 1:05:57 a randomized double blind placebo control styled up uh trial of healthy human subjects given 1:06:03 terror still being for 68 weeks showed terror still being safe uh for use at dosages up to 250 1:06:09 milligrams per day resveratrol fda status in 2007 1:06:17 approved synthetic there are two papers showing that it 1:06:22 increases low density lipoprotein cholesterol in people like they didn't have adverse events in 1:06:29 you know six to eight weeks whatever it was but uh we know the association between low density 1:06:36 lipoprotein cholesterol and atherosclerosis and you know future cardiovascular events so 1:06:42 um you know it's not healthy to take 1:06:49 yeah i don't i don't know i mean i think i think it's 1:06:56 uh we you know we can go and i i don't know how to comment on that because we can go 1:07:01 into the weeds of each of these papers um could be a battle 1:07:06 like forever right in in terms of of what you want to cite this i think this is the problem is that there's there's 1:07:14 a body of literature for and against each of these things if you read the reviews they're not coming out with a 1:07:19 consensus right and so if you only talk about one side of the literature and ignore 1:07:25 all the other side of the literature then you can support a conclusion but that's cherry picking so 1:07:32 you know i don't feel comfortable coming down on one side of this or another at this point i mean there's 1:07:38 things that are clear to me in literature and there's things that are unclear and this story to me is still 1:07:43 unclear i suppose that's the um that's the thing that kristen when i see patients in the 1:07:50 clinic so say if i'm seeing a newly diagnosed type 2 diabetic you know that the first line of treatment is always 1:07:56 diet and exercise and then we start them on metformin that's the first line medication and then we move into second 1:08:02 line medications you know say with glp1 agonist has a bunch of literature against it 1:08:08 right i mean that's not clear sorry kristen i missed that even metformin you 1:08:13 know there's a body of literature saying it's unsafe that's not even clear well for type 2 diabetics that there's a 1:08:20 reason why that's the first line medication that we prescribe um it's it's been used for 1:08:27 decades and the data on that is quite clear that for type 2 diabetics it does 1:08:32 seem to reduce cardiovascular disease in those type 2 diabetes right much more controversial for healthy people right 1:08:39 yeah to take to take metformin right so there's where you see that it can impair 1:08:45 the benefits of exercise right and you know metformin 1:08:50 has multiple targets as well but one of the things that metformin does is 1:08:56 inhibit gluconeogenesis right so that's why you would take it as a type 2 diabetic 1:09:02 but you don't want to inhibit you know complex one when you know you're 1:09:09 fit and and healthy and exercising yeah my my overall point is that in in type 2 1:09:15 diabetics i want to be prescribing medications that i know will be beneficial for them um 1:09:21 and and that the benefits will vastly outweigh any negative effects and when it comes to 1:09:29 resveratrol you know i'm not a pre-clinical scientist when i'm hearing that there's a lot of conflicting data 1:09:35 on on both sides and that the human data is not conclusive that it's not going to be you know resveratrol is not going to 1:09:42 be a medication that i'm going to recommend to my type 2 diabetics to take when when the it sounds at the 1:09:48 preclinical world um you know just in this discussion we can clearly see that there is um that there are 1:09:55 different viewpoints so i i just i don't know where where to 1:10:00 take the the conversation around resveratrol at this point because it has been studied for such a long time um 1:10:08 and and billions of dollars as charles has mentioned has been pumped into resveratrol research and 1:10:14 you know that it's still not not coming through as a clear even type 2 diabetic medication well 1:10:20 part of the problem right is it so so i agree with you i don't take resveratrol i mean i don't take any of these 1:10:26 supplements because i it is unclear to me but that doesn't mean i think i'm a hundred percent that it's bad or or 1:10:33 right i just don't know enough yet and i you know the same could be said for these other supplements that are 1:10:40 happening right now right so i don't take them either um and i don't think 1:10:45 it's that much clearer for them metformin being one rapamycin being one 1:10:51 right even nad supplementation i don't think any of this stuff because i think it's unclear how i'd say i'd say the data's clear on 1:10:57 metformin for type 2 diabetics and that's why again it's the first line medication that i prescribe well i mean 1:11:03 that then you talk you talk about the resveratrol literature is pretty supportive in 1:11:08 in type 2 diabetes as well right like it's coming down on the side of supportive 1:11:13 um there's no there's no guideline that that suggests using 1:11:19 um resveratrol in type 2 diabetics okay so i i don't i don't think that we can 1:11:24 say that resveratrol is beneficial at this point for type 2 diabetics we can't say that because more research 1:11:31 needs to be done but it's it's also not patentable so how do you how 1:11:37 how do you go forward in getting those trials off the ground you know um 1:11:43 so it's i think it's unclear i think more research needs to be done 1:11:50 but you know it's also a matter of the system that we're in you know and and a lot of those molecules are not fda 1:11:56 regulated in the u.s right so you can get anything that that could that claims to be respiratory 1:12:03 and take it who knows what it is so you know it's complicated what you i 1:12:09 don't i don't think as physicians which i'm not practicing right into residency but i'm a physician right i i wouldn't 1:12:16 prescribe anything that i wasn't 100 sure that is going to have an effect i 1:12:22 wouldn't recommend things that aren't approved right besides exercise diet and sleep 1:12:29 and and low stress and and meditation like you were saying right so 1:12:34 so i don't know if we should be even making recommendations to people like that 1:12:39 well i suppose it's my job right when when a patient comes to see me in the clinic with type 2 diabetes i'm i'm 1:12:45 going to treat them because they're my patient um right and i couldn't recommend stuff that's not approved 1:12:50 right yeah yeah absolutely and and i think that's that's kind of the the point that i wanted to try and get 1:12:56 across that you know billions of dollars have been spent on resveratrol research and 1:13:03 of resveratrol and despite that that body of work it it's 1:13:08 it's still unclear as to whether there are true benefits for type 2 diabetes the same you could say the same thing 1:13:15 for a lot of other drugs i i don't know what the point of that is 1:13:20 well not for the not for the drugs that are approved for type 2 diabetes that we commonly prescribe a little 1:13:27 unclear even statins are a little unclear i don't know i mean yes they're approved 1:13:32 metformin for type 2 diabetes that's that there's a reason why that's the first line medication that we prescribe 1:13:38 it's it's been well studied and that the evidence is overwhelmingly supportive to use metformin and type 2 diabetes and 1:13:44 then the second line drugs come in with you know the glp-1 agonists with the sglt2 um inhibitors 1:13:52 you know those are the the body of evidence is quite clear on that and and that's why they're part of clinical 1:13:57 guidelines and my concern is that you know again despite and this is just me 1:14:03 speaking as a clinician despite all of this research that's gone on into resveratrol and resveratrol analogues 1:14:09 there there doesn't seem to be a clear consensus from the preclinical world let alone into the clinical world 1:14:16 i don't know i mean has there been more money pumped into resveratrol um 1:14:21 than other drugs that are approved i don't know that that's a true statement 1:14:27 well i mean you could say sirtuin activation had uh you know multi-billion dollar we 1:14:33 already said that certain activation respiratory are not the same thing right okay well that's breaking some 1:14:39 some ground for youtube vid uh uh viewers today well not necessarily 1:14:45 the same thing right so um i i want to you know maybe you 1:14:50 know pivot a little bit and and talk about nad so 1:14:56 nad coenzymes four of them are the central catalyst of metabolism and NAD Research 1:15:02 our research has shown that the nad system comes under attack in many different 1:15:08 conditions of metabolic stress probably you know 10 different conditions 1:15:14 dna damage reactive oxygen species generation in animal models of obesity type 2 1:15:19 diabetes diabetic neuropathy chemotherapeutic neuropathy central brain injury 1:15:25 inflammation infection and um you know through the use through our our 1:15:32 research into the nr pathway we found that the nr 1:15:37 pathway gets upregulated in a number of these conditions of metabolic stress so like at heart failure 1:15:43 a cardiac nad goes down in a mouse looks like the same thing happens in 1:15:50 human heart failure and we can show that in the mouse model of heart failure that 1:15:55 oral nr will restore nad to the failing heart nicotinamide 1:16:01 won't because the nr pathway gets upregulated nicotinamide pathway gets down regulated in a failing heart so we 1:16:08 think that there's a use case for nr um in wellness 1:16:14 as well as potentially in disease and conditions of metabolic stress in which nad comes 1:16:19 under attack and nr has a great safety profile 1:16:25 um there are placebo-controlled uh trials that consistently show safety of nr up to 1:16:31 two grams a day and there are increasingly some positive results showing 1:16:37 anti-inflammatory effects of oral nr combination trials where 1:16:43 time to recovery from covid was accelerated cerebral blood flow in a small 1:16:49 parkinson's trial and so forth so i'm pretty excited about that and but again i don't get out ahead of 1:16:55 my skis and claim that you know people are gonna live to 150 1:17:00 with it but i think that the use case is building uh repair and resiliency as we age 1:17:07 because all of these attacks on our nad system occur over time 1:17:14 yeah i think overall i'd i'd agree with that i'm quite excited about the the promise or hope um of nad precursors in 1:17:22 particular i'm excited about their effects with diseased states so in particular heart failure i think that 1:17:28 would be a fantastic trial to run if you could do a randomized placebo-controlled study in you know class three or class 1:17:34 four heart failure patients um i think that that would be uh a very interesting study i'm 1:17:40 i must admit i'm less uh certain or less bullish about the 1:17:45 effects that it might have for otherwise healthy people but for disease states um i'm i'm very curious to see the research 1:17:52 kristin what do you think about the the nad precursor research so i mean i 1:17:59 i think that in general i mean it's it's just like everything else it needs to go through trials and we'll see what the 1:18:04 results are right so um i think anything 1:18:10 sort of promoted uh off label we should be very careful about hype and and um you know i think 1:18:18 people should be careful and know that there's controversy in the literature and and to 1:18:24 read papers for and against and to read reviews and to read meta-analyses and to make decisions with eyes wide open and 1:18:31 and not think there's just one version of any story which is why i think it's important to have these kinds of conversations you 1:18:38 know um and yeah i mean i look forward to seeing 1:18:43 what happens with these with these drugs and to see where we get i do think it's going to be very exciting i think 1:18:50 a lot of you know there's been the reason there's so much controversy 1:18:55 and in all of this is because it's so exciting you know for for the future i do think we're gonna have drugs that 1:19:02 work i think that we're gonna you know extend a health span at least a 1:19:08 lot and that people when they do die are gonna die healthier and you know with better quality of life 1:19:14 at the end of life and i'm very excited for that you know i'm not gonna i'm gonna wait and see 1:19:21 for myself and for what i tell other people you know in terms of i'm not going to make a claim that something is 1:19:26 definitely going to work or not work and i think we should all go in eyes wide open to to what we're taking and what we 1:19:32 put in our bodies and and make sure that we do our own diligence in in investigating that 1:19:38 and be careful about what we say right so i agree 1:19:46 um charles if i may there's one particular question i wanted to ask you around nad 1:19:52 there was a recent paper that came out it was an observational trial that took muscle biopsies from 1:19:59 older adults who exercised and compared it to those that don't exercise and took muscle biopsies from 1:20:05 younger people and what they could see is that there did seem to be a correlation with with age and lower nad 1:20:12 particularly if the older adults weren't exercising so what so if an and and this is one of the 1:20:20 the things that i've been trying to grapple with if people are exercising and leading an otherwise healthy life in terms of 1:20:26 you know diet and meditation and things that's where i'm a little bit confused as to where nad precursor 1:20:33 supplementation may further improve the health of those otherwise healthy people well you know we 1:20:40 we all are exposed to some sunlight right so sunlight damages dna 1:20:45 when dna is damaged parp 1 and part 2 get activated and 1:20:51 consume nad in order to facilitate dna repair when we all live in oxygen at the inner 1:20:59 mitochondrial membrane there's reactive oxygen species that are generated that churns nadph so the nad system is is 1:21:07 challenged constantly through our life and 1:21:13 when we see um you know double-stranded rna are like coronavirus 1:21:20 or um zika you know other other viral pathogens 1:21:26 we have an interferon system the interferon system turns on five members of the parp 1:21:31 super family that consume nad and that at that lower nad state 1:21:39 um our defenses against coronaviruses are impaired that's something that i'm 1:21:45 extrapolating that from from model studies from from our laboratory 1:21:50 so i would say that the nad system is sort of constantly under attack as well as 1:21:56 is under challenge as we age and that's the use case for for nr 1:22:03 yeah i i i hear that and and that's one of the big reasons why i'm excited about 1:22:08 using these precursors um in in diseased states but from that and again i'm 1:22:14 extrapolating from this human observational study if if people are exercising and having a healthy diet it 1:22:21 seems that they can maintain good levels of nad and the muscle at least um as as 1:22:27 they get older um so so in those in that instance what would be the use case to 1:22:33 to take nr or any of any other of the nadp well you're you know metabolism is trying to do a lot of things at the same 1:22:39 time right and so if you're repairing if cells are repairing their dna their their nad is for sure compromised 1:22:47 um when cells are dealing with uh activation of the innate immune system 1:22:54 through uh interferon their local nad system is is compromised so um 1:23:02 you know the the athletes 20 year old athletes that you know take 1:23:07 take and are you know are doing it because they can see a performance increase 1:23:14 uh time to recovery from you know hard workouts and you know 1:23:20 seeing seeing benefits almost everybody um observationally sees um anabolic 1:23:28 effects like fingernails and hair growing faster i shave my head these days 1:23:33 but you you see more um you know on the razor or or you know your hair 1:23:39 dresser will see um more hair between haircuts that's observed by almost everybody and 1:23:46 um how do you quantify that though i mean that's that's not yeah so that's not like i i qualify that by saying that we 1:23:54 don't have placebo-controlled data on that but that's that's literally every 1:23:59 person that you know it virtually every person notices that 1:24:05 because it's so it's so clear when you're cutting your fingernails 1:24:11 no that's not that's not that's not that's an observation pipe would have hype would have been if 1:24:18 i said that you know it'll you know regrow baldness or that you'll 1:24:23 live longer or that your mild time would would be faster and i don't i mean a lot of people want more hair growth right so 1:24:30 i i mean i it would be great if it did but you know 1:24:35 just based on hearsay i mean i don't know i'm just trying to hold you to what you're saying earlier oh i'm i'm very 1:24:42 comfortable with people holding me to to what i say but um yeah hair the rate of 1:24:48 hair growth is it's not going to grow hair where you like um i have male pattern baldness like a 1:24:56 lot of 60 year old guys but um you know uh it doesn't grow hair where 1:25:01 you don't have hair but the rate of of hair and fingernail growth is 1:25:06 seen by virtually everybody benching to see if that if that stacks 1:25:12 up with the placebo control trial as you say um yeah yeah 1:25:17 um kristen is there any other topics that you wanted to to cover during this live 1:25:22 stream no i mean i think we got to i think we got to most of it i mean i feel i i hope 1:25:29 that people uh can see it maybe some feel good about seeing a more 1:25:34 well-rounded picture of why there's so much controversy in this right of how complicated the back and forth of the 1:25:40 literature is and you know how to be careful and what they take and looking 1:25:46 into it you know i recommend going to pubmed this is how scientists figure things out 1:25:52 right go to pubmed and don't listen to other people but just type in review articles or two in a review article 1:25:59 nad review article rapamycin whatever it is and just and and read the high level literature you 1:26:07 know or ask ask someone else about it i think we should be wise consumers of of the things that we put in our bodies 1:26:14 and and know the full story you know i think it's great to to have us on here and and try to give the full picture but 1:26:21 even here you see that you know we're not fully in consensus on all of this stuff and i think 1:26:27 that's because me you know that's maybe appropriate for where we are with these stories at this point 1:26:33 so um that's all and and i want to i you know i want to thank thank you guys a 1:26:38 lot for having me on here it's been really fun you know i want to thank you kristen for 1:26:43 coming on um it's great to have someone to offer the other side of the story um and 1:26:49 and to have an open and honest conversation about it so i really appreciate you coming on yeah and and to 1:26:54 be clear i mean i don't consider myself to be the other side i consider myself to be sort of you know 1:27:00 a third-party mutual observer of what's happening but yes yeah i appreciate it 1:27:07 charles is anything that you wanted to leave us with or any other papers you wanted to go through yeah well i i tend 1:27:12 to think that you know expert analysis is you know is valuable i try to be available to to people on 1:27:21 on twitter at charles m brenner to try to explain experiments in in my view 1:27:28 um going through figure by figure is important and um 1:27:34 not getting ahead of our skis is really important and i think metabolism is really exciting 1:27:41 and i want to you know convey the excitement of that and um 1:27:47 and i'm grateful to you brad for bringing people together and trying to promote 1:27:54 science communication thanks to kristin as well it's really nice to to meet you 1:27:59 and um i hope that we can continue to um educate people in the future 1:28:05 yeah for sure i'm i'm super excited about that too oh you can find me on twitter as well at dr glorioso 1:28:12 awesome well i think we'll leave it there but once again thank you to both of you um and chat i really hope you 1:28:18 found this conversation useful um overall again can't stress this enough diet exercise sleep always come first 1:28:24 and always have a healthy skepticism about anything that you may hear from anyone online including myself so just 1:28:31 wanted to leave everyone with that okay yeah okay bye bradstanfieldmd #Resveratrol #Healthspan The links above are affiliate links, so I receive a small commission every time you use them to purchase a product. The content contained in this video, and its accompanying description, is not intended to replace viewers’ relationships with their own medical practitioner. Always speak with your doctor regarding the content of this channel, and especially before using any products, services, or devices discussed on this channel. Chapters View all Transcript Follow along using the transcript. Show transcript Dr Brad Stanfield 207K subscribers Videos About 206 Comments rongmaw lin Add a comment... @DrBradStanfield Pinned by Dr Brad Stanfield @DrBradStanfield 1 year ago Timestamps: 0:00 Intro 1:30 Sirtuin Research 34:30 Resveratrol 1:15:00 NAD Research 14 Reply @itsdangeroustobeweakboii9045 @itsdangeroustobeweakboii9045 1 year ago Thank you Dr. Brenner for clear and direct communication with strong evidence based arguments. Very refreshing in the longevity space. 11 Reply @ltsiros @ltsiros 1 year ago I'm on camp Sinclair in general but I want to thank Charles Brenner for holding the contrarian view, as it's essential to keeping science healthy. Thanks Brad also for hosting! 13 Dr Brad Stanfield Reply 1 reply @kurtv6736 @kurtv6736 8 months ago Brenner speaks in facts. Hopefully, more interviews like this will safe people a lot of money. 2 Reply 1 reply @jnsmeets @jnsmeets 1 year ago Thank you Brad. This was quite an accomplishment! Many of the claims made in this area appear to get stuck in quicksand. As you point out in your opening and closing statements, nothing trumps a healthy diet, regular exercise, meditation and a good night’s sleep. Ethical standards in scientific research must never be compromised. 26 Dr Brad Stanfield Reply Dr Brad Stanfield · 1 reply @ats89117 @ats89117 1 year ago I LOVE the fact that Dr. Brenner doesn't feel the need to be nice to his fellow researchers. We need this honesty desperately. Too many researchers seem to be influenced by selling products or books or feeding their ego at the expense of having the best science being promoted to the general public... 40 Dr Brad Stanfield Reply 9 replies @BizAutomation4U @BizAutomation4U 1 year ago (edited) Appreciate Dr Stanfield's effort here, and am appreciating Dr Brenner (why no title ?) more and more with each interview. He appears sincere in his effort to help educate his peers and is such a smart subject matter expert. I used to consider him arrogant and Dr Sinclair humble, but now I have the exact opposite opinion, interesting. 30 Dr Brad Stanfield Reply 6 replies @guiadelapielblog1918 @guiadelapielblog1918 1 year ago Thank you Brad, and well done the three of you for giving different opinions in a really good debate (a shame that David Sinclair doesn't want to participate in this sort of debates) . A good conclusion is that none of these supplements should be recommended while there is not consensus. Some scientists should not be afraid of recognizing that were wrong or not enough is known. 3 Reply @emittfuller6348 @emittfuller6348 1 year ago every interview I watch with DR Charles Brenner my respect for him grows both as a scientist and as a human 5 Dr Brad Stanfield Reply @TheBiffsterLife @TheBiffsterLife 1 year ago Real science, and understandable to real people. Two thumbs up! 6 Dr Brad Stanfield Reply @danielcraver859 @danielcraver859 1 year ago Absolutely brilliant interview. Dr. Brenner's explanation of the human female menopause being distinct amongst primates with regards to longevity really does help explain why human genes are unique and and thus using other animal.models in longevity research is ultimately flawed to an extent. I would suggest though that editing human genes to prolong fecundity would be advantageous for healthspan in humans. 3 Reply @RXP91 @RXP91 1 year ago Excellent discussion. Thankful Dr Glorioso and Dr Brenner gave their time for this. The argument that we don't know because research hasn't been done or is going strikes me as a little extreme. It's an argument that we don't know anything because not every molecule has been tested or studied forever. Making claims like living to 150 and Yoghurt/Olive oil solve the bioavailabilty issue are clear falsehoods and need to be described as such. Thank you Brad for bringing this to my attention. 6 Reply @RobertNaik @RobertNaik 1 year ago Maybe it’s just me. But I feel like Dr Brenner made the points and explained them very well. 31 Dr Brad Stanfield Reply Dr Brad Stanfield · 3 replies @ats89117 @ats89117 1 year ago Brian Kennedy and Matt Kaeberlein are good examples of really smart guys who are never rude. Dr. Brenner is more aggressive in going after people he doesn't agree with. This approach has some rough edges but it brings out contrasts that might otherwise be missed... 3 Reply 1 reply @gabewb @gabewb 1 year ago Thank you for your contribution, Dr Christin Glorioso! Really appreciate your push-back and fact-checks. 5 Reply @baileystruss7319 @baileystruss7319 1 year ago (edited) Can you please elaborate on when NADH supplement might be more preferable than an NAD precursor? There are some efficacy studies with it in CFS/ME and a couple other conditions. Surprisingly it's never talked about in the NAD circles. 4 Reply @pelegbahat6216 @pelegbahat6216 1 year ago (edited) Two people on completely different levels of intellect and integrity. Reply @melodielumley6450 @melodielumley6450 1 year ago Thank you Dr Stanfield. Excellent discussion. Reply @matt3006 @matt3006 1 year ago We need conversation and thought, not 1 person being right and 1 person being wrong, to grow. We're not static, nor are Christin or Charles. You may go down the road of 1 hypothesis ending up not having a valid outcome, but that doesn't make you invalid for going down that road. If anything, it's good not to write things off too quickly, before traversing the full narrative. 1 Reply @g333z @g333z 1 year ago I have various thoughts on this, but one important thing should be highlighted, imo: It's essential to verify the summaries made in review articles by examining the data they're based on. I've read review articles in decent journals which misstate results from the papers they're citing. There's even papers which seem to conclude things which aren't necessarily supported by the data they report! Always examine the original data. To be clear: I don't know which review article Christin is referring to about the bioavailability of resveratrol here, and I'm not saying anyone is wrong. But clearly she and Brenner disagree on that point, and it needs to be investigated and clarified. The warning I've provided above could be the reason for this disagreement, or it could be something else instead. I just wanted to point out the potential pitfall here. 6 Dr Brad Stanfield Reply Dr Brad Stanfield · 2 replies @clarehazell2097 @clarehazell2097 1 year ago So good had to listen to this twice. Couldn’t give up my nmn. Maybe placebo but believe it’s contributing to my renewed energy and improved performance- yes toe nails do seem to need trimming more often! Reply @treewx @treewx 1 year ago So awesome, thanks to everyone involved. 3 Dr Brad Stanfield Reply Dr Brad Stanfield · 1 reply @stevenkocaj1573 @stevenkocaj1573 1 year ago That was a tad intense at times! Good in depth debate though. Seemed to perfectly reflect the real world controversy around resveratrol. Thanks Brad. Reply @alexmatheson6 @alexmatheson6 1 year ago This is juicy. Your Awsome man, some of the best presenting ability. Your format is really effective I hope you get some good gigs you deserve it. 1 Reply @samatoid @samatoid 1 year ago (edited) Just because Brenner appears to present his case well doesn't mean he is correct. The field is enormous and virtually anyone of competence can cherry pick papers that support their points. There are a large number papers that support some bioavailability of RSV and its efficacy in various situations - this is in direct opposition to what Dr Brenner was contending. This indicates to me that he has an axe to grind. Rivalry in research is nothing new. The jury is still out on sirtuins. The one paper that showed significant improvement in mouse lifespan via overexpression sirt6 is the one ray of hope - it needs to be explained and understood. Dr Brenner was silent on this and continued to harp away on Dr Sinclair rather than address the subject. He was doing exactly what he accuses Dr Sinclair of doing - opening his mouth wide without facts. I say neither Dr Brenner nor Dr Sinclair are pure researchers and both have a lot of ego in this game. I consider this discussion today to be a waste of time. Dr Glorioso was not well prepared for the debate, but she was at least fair. 28 Reply 6 replies @flogold6535 @flogold6535 1 year ago Dr. Brad, what are your thoughts on protein powders for maintaining muscle strength? Reply @sandymoran5077 @sandymoran5077 1 month ago Thank you Brad, appreciate other views & opinions Reply @GhostmanGus @GhostmanGus 1 year ago If we replaced Christin with David Sinclair you probably would have had the video of the decade. Christin offered barely any contribution, Brenner was an excellent contribution to this. Thank you Dr Stanfield, a new fan of your work. 11 Reply 6 replies @vario2664 @vario2664 1 year ago (edited) Brenner doesn't take any prisoners, and that's the way science has to be. Basically she offers nothing more than the hope there is a ray of sunshine somewhere in the 'bad' science Brenner exposes. 11 Reply 3 replies @burttheman3697 @burttheman3697 1 year ago Dr Brenner was a lot milder than in the first interview, which made it easier to listen to his knowledge. Even considering buying Tru Niagen now… 5 Reply 2 replies @itsdangeroustobeweakboii9045 @itsdangeroustobeweakboii9045 1 year ago As a researcher myself its simple: do not lie. That includes exaggeration of course. I am stunned their could be support of any kind for this type of language by Christine. Particularly in the context of gaining funding/support for research. If you want funding/support - do good research - not hyped research. Reply @johnthomas1294 @johnthomas1294 1 year ago Hmmm, Dr Brenner is very good at sticking to scientific facts when discussing other's work but is more than happy to resort to anecdotal evidence when discussing his own product. I've used NR and I have not noticed the hair and nail growth he mentioned or any other benefit for that matter either. 2 Reply @cryptscendence3421 @cryptscendence3421 1 year ago NAD is highly depleted with age and other conditions even if active and excercise is present 5 Reply @sebacatana @sebacatana 1 year ago (edited) Dr. Glorioso is such a politician. Absolutely transparent avoidance and denial. Her answers and attitude in this debate were so frustratingly blocking any constructive outcome. After the first 30min, when she felt the battle was not going well, she just stopped collaborating. The exact opposite of what scientific debate should be about. She was obviously protecting dr. Sinclair's past mistakes. If not clear to everyone from her weak ideas and come-backs, the passive-aggresive attitude right near the end, picking at the "hair growth" remark, should make it all clear. Anyway. Dr Sinclair's mistakes would not have even been such a problem if he were a man with some spine and if he would have accepted he was wrong. We would have all moved on. Of course Sinclair and his business would have lost some money, but so what? He still hold a valuable body of knowledge that is useful for longevity science and he would have kept his image intact. But with his attitude, I'm not so sure about him. And if his team is made up of people like dr. Glorioso, I'm not sure they can be trusted. PS. I am now a fan of dr Brenner :) his discouse and knowledge are quite convincing. 19 Reply @pakistanicecream7769 @pakistanicecream7769 1 year ago (edited) Good video with good guests selection. Reply @MiguelSanches5 @MiguelSanches5 1 year ago Tnx for great video! Could you please share a link to the resveratol review paper you are refering to in the video? Reply @user-rn6if3vl8p @user-rn6if3vl8p 1 year ago It is clear that Dr. Glorioso’s knowledge of the topic is cursory at best. Her default argument against Dr. Brenner appears to be along the lines of ‘well authors of these review papers conclude that sirtuins are conserved as longevity genes’ etc, rather than actually addressing the hard data and their merits/limitations. Her being a former Guarante lab member + being well-credentialed, I was hoping for an actual debate with insightful rebuttals to the points that Dr. Brenner regularly makes. But it is very clear that she was ill-prepared. Borderline painful to watch when she tried to refute the clinical consensus regarding the prescription of metformin for T2D. @Brad — would you be open to having Dr. shin-imai or Dr. Guarante on for a discussion with Dr. Brenner? 13 Reply Dr Brad Stanfield · 2 replies @bobheadzeek @bobheadzeek 1 year ago Brenner was too good. 2 Reply @Tagmeinllc @Tagmeinllc 1 year ago Charles Brenner is a Genius!!! 1 Reply 1 reply @ticketforlife2103 @ticketforlife2103 1 year ago there's something I don't understand here very well and if someone could please explain this: - we have the technology to create human cells in petri-dishes - we can design an Ai to build a model with different human cells interacting with each other. why no one is doing that? Reply @kamanashisroy @kamanashisroy 1 year ago Guys, we do not want to overexpress sirt all time to keep damaged cells alive, sometimes we need to allow old cells die and taken over by new cells if possible. 1 Reply @Jerry-zf3cn @Jerry-zf3cn 1 year ago When the resvertrol study flaws were first reported, I thought it amounted to nothing more than an embarrassingly simple lab error by an elite scientist. I expected Dr Sinclair to offer a humble , albeit red-faced, heartfelt apology, and then everybody would put this behind them and move on. However, Dr Sinclair's refusal to acknowledge, discuss, or debate this, along with his efforts to deflect attention with outdated studies and reports, has my cynical side wondering if there's not something horribly unethical or possibly even criminal yet to be discovered. He made sh*t-ton of money off of what turns out to be a faux 'discovery'. 1 Reply 2 replies @finnbruton7274 @finnbruton7274 1 year ago 1:05:52 Christin: “I’m just looking at the Wikipedia on pterostilbene” Charles: *Suppresses eye roll* 😂 Reply @JacksExoticReptiles @JacksExoticReptiles 1 year ago Charles didn’t mention that Resveratrol needs a fat to be taken along with it in order to make it absorbable. That’s like saying well you take a fat soluble vitamin on an empty stomach and so it’s not bioavailable. Reply @mattweiler971 @mattweiler971 11 days ago (edited) There is also lots of potential upside benefits with Pterostilbene but he cherry picks two studies that may increase LDL in some people.. yet ignoring multiple studies that show possible benefits in "Various studies have demonstrated the antioxidant, anti-inflammatory [6], and anticarcinogenic properties of pterostilbene, which has led to the improved function of healthy cells and the inhibition of malignant cells [7-9]." Reply @vario2664 @vario2664 1 year ago Regarding resveratrol, what would warrant further research of it as opposed, sarcastically, to the substance of fly wings, if the weight of the research thus far has smacked it down?? 2 Reply @alexzaykov4382 @alexzaykov4382 1 year ago Very interesting video, thanks to Dr. Brenner. Dr. Glorioso didn't supply much useful input. 2 Reply 1 reply @audreyhurley6248 @audreyhurley6248 1 year ago Hello. Off topic does quercetin work to help with inflammation and removal of dead cells? Reply 2 replies @nandoluislopes @nandoluislopes 1 year ago It seems exaggerate to say that caloric restriction is central to anti-aging. It really delivers some great results. But there still seems to have same ageing process going on with the monkeys. Delivering the CR results through drugs would still leave room for improvements it looks like. 1 Reply @markwilkinson9601 @markwilkinson9601 1 year ago So...what should I take with NMN if I don't take Resveratrol? 1 Reply 1 reply @KenOtwell @KenOtwell 1 year ago As soon as Dr. Glorioso said that she doesn't' know where resveratrol stands because there are so many papers going back and forth... that tells me she's not serious. You have to look at the CONTENT of the papers, not their number and sequence, which is what Dr. Brenner is doing. I'm at minuite 42 and I've yet to hear Dr. Glorioso discuss the actual science. 17 Reply 1 reply @michaela2634 @michaela2634 1 year ago With all due respect, Dr Glorioso devolved the argument into semantics which made this a snore to watch. Whereas Dr Brenner seemed to be a fountain of knowledge. 2 Reply @lrduff @lrduff 1 year ago The date the video aired should always be shown. Reply @talkeetna911ify @talkeetna911ify 1 year ago I'd like to see research into Peptides short chain amino acids Reply @lureup9973 @lureup9973 1 year ago When she poopooed met Forman, it became clear christin wanted to muddy the waters of what we know and don’t know....point... fact, nothing is 100 %, and every medicine has some variations of results and varying studies results....we just simply are looking for resonable proof or doubts to the value of a specific molecule and or study to judge wether it’s worth our interest...dang, I’d hate to have her advising me on medical decisions 🥴 1 Reply 1 reply @chris_1683 @chris_1683 1 year ago Why not upload this to spotify? 1 Reply @vario2664 @vario2664 1 year ago (edited) Brenner would probably have NO problem entering into a debate with Sinclair, but Sinclair knows he comes out of such beaten up and wouldn't touch it. HAHAHA.... 4 Reply @paulfiedler9128 @paulfiedler9128 1 year ago So calorie restriction doesn't extend life span? I've heard that so many times I thought that was fact. Reply @CarstenBornemann @CarstenBornemann 1 year ago (edited) Olive oil, two tablespoons a day, as a resveratrol substitute, good or bad? 5 Reply 4 replies @levondarratt787 @levondarratt787 1 year ago Great team-up! Widening the discussion, bringing parties to the table. 2 Reply @adamernster2471 @adamernster2471 9 months ago (edited) The question I have is: what is glaxo doing with their $720 million purchase? Nothing? Reply @sandymoran5077 @sandymoran5077 1 month ago PubMed March 18,2020 4.3 RESVERETROL CHEMOTHERAPEUTIC DOSES Still being studied Reply @georgechristoforou991 @georgechristoforou991 7 months ago Dr Glorioso seemed to disagree and should have been more outspoken so that a proper debate could have been had. Reply @steve9189 @steve9189 1 year ago "Almost everybody sees hair growing faster". I certainly have not seen this at varying doses. Maybe a little bias is creeping in here. When you have a product that has made you millions of dollars even the most qualified scientist can start to believe things that aren't proven. Let's see the hard science on this claim. 9 Reply @CommanderRiker0 @CommanderRiker0 1 year ago Please have Dr. Brenner back without a guest so he doesn't have to educate them. 29 Reply 4 replies @ATKAUTO @ATKAUTO 1 year ago (edited) Which resveratrol are you talking about because there are two forms of it; CIS-resveratrol and Trans-resveratrol. CIS-RESVERATROL is completely useless to humans, so supposedly Trans-resveratrol what gives a positive affect. Trans-resveratrol can be a natural extract which is not water soluble and that is why it should be taken with something fatty according to Sinclair. Also it can be synthetic which is water soluble. Is synthetic Trans-resveratrol bad? Does anyone know? 1 Reply 1 reply @shuvashishroy6006 @shuvashishroy6006 1 year ago 1:03:00 resveratrol is not humanly available? Then how come it negates exercise benefits and how can it be a dirty molecule targeting so many things together coz it is not bio available? 1 Reply @masterjstory7887 @masterjstory7887 1 year ago This talk stinks of classic research envy.... To be clear, Sinclair focussed on gene specificity (DNA, RNA, m-RNA) when researching Resveratrol, and spent many years targeting gene control. 3 Reply @uelude @uelude 1 year ago 1:03:29 Resveratrol in 10 seconds. 3 Reply @vigothecarpathian823 @vigothecarpathian823 1 year ago That was hard to watch. It was like they pulled a random lady from the audience to debate a scientist. How do you come to a debate and have your only answer be: "Well its debatable." Yeah, that's why you're here... to debate. That was her answer even when the issue was 100% not debatable Reply @bororobo7036 @bororobo7036 7 months ago Sinclair is in a deep conflict of interest for long time, inclining toward marketing while using a science and artistic skills to fill-in missing gaps for hidden financial benefit. Reply @Simon-talks @Simon-talks 1 year ago In otherwords: Still nobody knows at all yet. So just eat less, get 8-9 hours of sleep, don't smoke, don't drink much, eat a natural, mostly plant-based diet, train hard and intense in the gym and go for regular walks and hikes people.... 1 Dr Brad Stanfield Reply @nomad_syndrome @nomad_syndrome 1 year ago I don't hv the energy for a long post, but just going on an emotional response, i sense a lot of animosity and uncritical thinking on Dr. Glorioso's part. Her attitude is unhelpful to me in appreciating science.. 3 Reply @blackmartini7684 @blackmartini7684 1 year ago In summary the body of evidence is not there yet to decide whether these drugs/supplements are overall beneficial or harmful and people should not be taking them yet. Reply @stevelampert2527 @stevelampert2527 1 year ago I find Brenner annoying. He seems to “mansplain” everything and there seemed to be a subplot by him that was very much against David Sinclair. This left me questioning his credibility. Unfortunately the woman seemed a little uncertain and perhaps wasn’t used to discussing out of the scientific arena. 2 Reply 1 reply @sandymoran5077 @sandymoran5077 1 month ago PubMed March 18, 2020 Resveretrol is said to be anti cancer Reply @clivelinsenbardt6826 @clivelinsenbardt6826 1 year ago Brenner wrong. Sinclair should be involved in this conversation. Problem with some resveratrol studies is that resveratrol is not water soluble or not bioavailability in that pathway... but it is very bioavailability with fats and quite effective. Reply 1 reply @endicotto @endicotto 1 year ago Not much time spent on NR. What about Liposomal NAD +? Not discussed bc no vested interest or no proof? Curious. Reply @mikesymth7243 @mikesymth7243 1 year ago All Dr Glorioso said was "we need more trials" and "I don't know" her options were worthless 7 Reply @nikhilreddy6476 @nikhilreddy6476 1 year ago I take resvetrol for my kidneys. Anybody who takes resevetrol for kidneys? Reply @patrino @patrino 1 year ago Try and get Dr Longo for an interview Brad 1 Dr Brad Stanfield Reply @factchecker9358 @factchecker9358 1 year ago I thought sirt2 would not be relevant if it was not activated. So why make sweeping statements about its dormant state or existence? Reply @francoistourigny3006 @francoistourigny3006 1 year ago Why did you invite this woman Brad? She didn’t clarify anything! Sinclair would have been much helpful! And you should emphasize on health issues with taking resveratrol! Like many person like me, that believes is value, not necessarily for sirtuin 1 or 2! Most importantly for cardio vascular issues, I just hear academic technical debate on sirtuin, the public don’t want to know that! Are we investing on product that is harmful?? is it possible to clear this part once and for all! thank you. 3 Reply @johnjallen @johnjallen 1 year ago I can’t finish this due to the repeated interruptions. Someone really needs to put this guy in his place. Let the woman finish. 1 Reply @linuxphone9063 @linuxphone9063 1 year ago I'm suspicious of someone who's trying to win a debate rather than share knowledge. 1 Reply @willyouwright @willyouwright 1 year ago Omg. I've been duped. They lied and they have only ever been about pr and funding. 😡 Reply @korniszon68 @korniszon68 4 months ago (edited) So to summarize - you are angry with one guy that gets popularity on the part of the science that you generally don't agree on... I get your point but the other side has their arguments as well... Reply @mshkt1620 @mshkt1620 1 year ago Lol… ‘He’s an aging scientist in LA….’ Careful who you call an aging scientist! ;) Reply @nandoluislopes @nandoluislopes 1 year ago (edited) if olive oil can activate sirtuins. And is consumed for centuries. Why keep discussing resveratrol? doesn´t Olive oil deliver the results? Reply @GM4ThePeople 1 year ago Sam Hyde knows a guy who will put up USD 1M in BTC for Charles Brenner to fight David Sinclair. 1 Reply @RJay121 1 year ago Why isChristin on this program? Next time if you're asking 1.5 hrs of our attention please better vet your guests please. Charles was brilliantly cast 6 Reply @temp7350 1 year ago (edited) I see you've read and deleted my comment criticizing this interview despite I wrote in a respectable manner. I do not appreciate it. Regardless it's still good you're raising awareness to the aging research, but hope you do it not by gaslighting or propagating controversies/debunking, and do it in an impartial empirical way. It's hypocritical that you called out Dr. Sinclair for blocking you when you do the same for deleting comments. I won't comment nor watch your content anymore. Best wishes. 1 Reply Dr Brad Stanfield · 1 reply @treewx @treewx 1 year ago Sirtris = Theranos? :) 2 Reply @Rafi2002M 1 year ago Unfortunately this interview demonstrated the inverse relationship between bluster and knowledge... Reply @jeremiahhandcock1795 1 year ago David Sinclair v.s. Dr Brenner please 2 Dr Brad Stanfield Reply Dr Brad Stanfield · 4 replies @mrrosenthal85 1 year ago what's the conclusion TLDR Reply @ticketforlife2103 @ticketforlife2103 1 year ago can someone tell her to talk closer to the microphone ? Reply @dext2624 1 year ago Dr Glorioso seems confused about everything. 5 Reply 1 reply @stuartbowenjr8393 1 year ago Dr G is Dr (I don’t) No. Too easy to shrug off everything as incomplete. 2 Reply @Ninun721 1 year ago This is and interesting subject, addressed in such a boring way! Sorry, buy I couldn't follow. Try listening and learning from Peter Atia's discussions, and his conversations with Marty Makary and Monica Gandhi. They make any subject so interesting and available to the non medical community. 1 Reply @michaelsalzle1529 1 year ago 1:13:28 "Well even metformin is a little unclear. Even statins are a little unclear". Please never bring her back. 7 Reply 1 reply @Pixel-junkiesOrg 1 year ago This would have been better if one certain male individual didnt spend the entire podcast passive aggressively bashing other scientists very little actual science was discussed. The drama is real here. Reply @cryptocents 1 year ago Dr.Christin Glorioso had nothing to say. Just wasted everyone's time. Reply @ticketforlife2103 @ticketforlife2103 1 year ago Brad please don't bring this lady in any of the future discussions, absolutely annoying 1 Reply @riddlescom 1 year ago Sinclair blocked you . Lol. 2 Reply @BakamonNO 1 year ago lol. what an awkward debate. 8 Reply 5 replies @happyjourney8675 1 year ago Blah blah blah. She needs to go get a job running cover for sinclair Reply @luxaeternae 1 year ago This guy Charles is annoying. "its been written thousands of times" 3 Reply 3 replies @levondarratt787 @levondarratt787 1 year ago as discussed RV is (rightfully so) - wherever you read feedback from people who use it (Youtube, Amazone, etc), there are so many people saying that they feel and look younger, and not by a small margin. Hundreds and hundreds of people saying this based on their own findings. How much it works. Not a proof, but still interesting to note. 1 Why TMG (Betaine) Supplements Are So Popular Dr Brad Stanfield 207K subscribers 132,240 views Mar 19, 2023 #Muscle #Longevity #Betaine Trimethylglycine supplements (also known as Betaine) have good human studies not only for improved muscle performance but it may also help to reduce dementia rates. Let’s have a deep dive into the research. 💊 My full supplement stack: https://drstanfield.com/pages/my-supp... 💊 MicroVitamin (multivitamin & mineral): https://drstanfield.com/products/micr... 💊 Supplements I use from Amazon: https://amzn.to/44oEGZz ✨15% Discount Code: BRAD ✨ • ProHealth: https://www.prohealth.com/collections... ✨10% Discount Code: BRAD ✨ • DoNotAge.org: https://donotage.org/products/ • Renue By Science: https://renuebyscience.com/?rfsn=5206... ✔️ Roadmap - Look Young & Feel Strong: https://drstanfield.com/pages/roadmap ✔️ Twitter: / bradstanfieldmd ✔️ Patreon: / bradstanfieldmd Here are the links to the research papers referenced in the video: https://ods.od.nih.gov/factsheets/Exe... https://pubmed.ncbi.nlm.nih.gov/28426... https://jissn.biomedcentral.com/artic... https://pubmed.ncbi.nlm.nih.gov/21744... https://www.ncbi.nlm.nih.gov/pmc/arti... https://www.ncbi.nlm.nih.gov/pmc/arti... https://www.ncbi.nlm.nih.gov/pmc/arti... https://alz-journals.onlinelibrary.wi... If you like this video please smash the thumbs up button, it really helps with the Youtube algorithm :-) #Betaine #Muscle #Longevity The links above are affiliate links, so I receive a small commission every time you use them to purchase a product. The content contained in this video, and its accompanying description, is not intended to replace viewers’ relationships with their own medical practitioner. Always speak with your doctor regarding the content of this channel, and especially before using any products, services, or devices discussed on this channel. Transcript Follow along using the transcript. Show transcript Dr Brad Stanfield 207K subscribers Videos About Shop the Dr Brad Stanfield store MicroVitamin: A Low-Dose MultiVitamin & Mineral $49.00 Achieve your recommended daily intakes of vitamins & minerals without mega-dosing. Blended with Hyaluronic Acid for glowing skin, and TMG for exercise performance. With over 75% of Americans taking dietary supplements, multivitamins have become a staple in our daily routines. But have you ever stopped to question whether your multivitamin is truly giving your body what it needs? Introducing MicroVitamin: A Thoughtfully Crafted Low-Dose Multivitamin. Most multivitamins on the market today contain excessively high doses of vitamins and minerals, which may lead to potential side effects and wasted resources. MicroVitamin is different. We’ve carefully crafted our formula based on scientific research to help you reach the optimal recommended daily intakes of essential nutrients (both vitamins and minerals) while promoting a balanced diet and healthy lifestyle. A Balanced Diet Comes First: MicroVitamin is designed to complement a healthy diet, not replace it. We believe that obtaining nutrients from a variety of whole foods is crucial for optimal health. MicroVitamin aims to fill the gaps and support your nutritional needs when your diet falls short, ensuring you maintain a well-rounded and balanced approach to your health. The MicroVitamin Difference: ️ Embrace Moderation: MicroVitamin is meticulously designed to deliver the perfect balance of vitamins, minerals, Trimethylglycine (TMG), and hyaluronic acid. This careful formulation avoids overloading your body and eliminates the risks associated with excessive supplementation. ️ Achieve Glowing Skin: Our unique blend includes hyaluronic acid 200mg, a powerful ingredient known to promote skin health and hydration, giving you a radiant complexion from the inside out. ️ Enhanced Performance: MicroVitamin doesn't just provide improved cognition through balanced nutrition, it also includes 750mg of Trimethylglycine (TMG). This compound has been shown to boost strength, power, and endurance when coupled with exercise. Additionally, TMG serves as a methyl-donor and helps lower homocysteine levels, providing an added health advantage. ️ Trust in Quality: Our commitment to excellence means that MicroVitamin is made with only the highest quality ingredients, rigorously tested for purity and potency, so you can have complete confidence in the product you’re using, which means peace of mind for you and your loved ones. Quality Assurance We’ve partnered with a USA supplement manufacturer called ‘Makers Nutrition’ to produce MicroVitamin. Their facilities are GMP audited and FDA registered, so you can be assured that MicroVitamin is meticulously produced and thoroughly tested for quality. SHOP Dr Brad Stanfield 383 Comments rongmaw lin Add a comment... @DrBradStanfield Pinned by Dr Brad Stanfield @DrBradStanfield 7 months ago 💪 Join Patreon for early access to my videos, the '5-Years Younger' online course, & Discord chat: https://www.patreon.com/bradstanfieldmd 💊 My full supplement stack: https://drstanfield.com/my-supplements 📜 www.donotage.org/products | Use code BRAD for 10% off 🔍 The largest database of nutrition and supplement research: https://examine.com/refer/drstanfield 15 Reply 3 replies @MikeVarnco @MikeVarnco 7 months ago Excellent presentation Dr. Brad. I regularly take TMG along with NR and this video has cleared up some questions I had. 27 Dr Brad Stanfield Reply Dr Brad Stanfield · 5 replies @samuelbrainsample @samuelbrainsample 4 months ago I'd like to see a comprehensive video on which supplements to take to boost exercise performance (NR, NMN, any adaptogens, etc) and which ones to avoid that might prevent/blunt hormesis (antioxidants, metformin, berberine, etc). I'm really more interested in the latter. 6 Reply @SkepticalCaveman @SkepticalCaveman 7 months ago Just a tip for those who don't know, lifting heavy 1-3 reps over 90% of your Maximum does give maximum strength gains with minimal muscle growth, if you don't care about optimizing for strength, but instead want big muscles then you can choae any rep range from 6, all the way up to 35 reps to get very similar muscle growth as long as it is done close to failure. So if you start with a weight you can do 6 reps with then you don't have to increase the weight until you can do over 30 reps until failure, if you prefer that. This is great for those who likes to lift light weights (must be at least 40% of max) instead of heavy. Just don't lift too light weights,.if you can make above 40 reps in a set then it becomes more of endurance training instead. 56 Reply 26 replies @mimimoon6082 @mimimoon6082 7 months ago Another terrific video Dr. Brad! I was taking TMG with NMN from DNA but ran out. Time to repurchase! 😊 14 Dr Brad Stanfield Reply @ClassicalLiberalWarrior @ClassicalLiberalWarrior 7 months ago Another good, smart, brief, no-nonsense video on longevity science! But I still think our current best radical treatment to enhance human longevity is thymus organelles (improving immunity function). I wish like hell someone would do a quick study on this to see if rat longevity expands by 30-50%, as I speculate it probably will. Reply @TheAnzack @TheAnzack 7 months ago (edited) I have early dementia symptoms and I’ve taken tmg today, made me feel a bit shaky, wired and nauseous, especially when I have my coffee, but I’m feeling a bit clearer and more energetic. I’ll report back. It’s not as good as bena gene, I wish you’d do a video on that, that’s by far the most effective supplement I take. Edit : tmg is much better than bena gene, I feel happy, calmer, more energetic my dementia symptoms have reduced significantly. But I am taking tumeric, collagen, vitamin k 2 . Hylaronic acid (sometimes) magnesium threonate,, l theanine and rhodiola. I feel Amazing 25 Reply 9 replies @TheBiffsterLife @TheBiffsterLife 7 months ago Great info as usual Dr Brad! Are you concerned about the potential to raise TMAO, which is associated with coronary artery disease? 8 Reply 5 replies @justingoldberg7115 @justingoldberg7115 3 months ago Wouldn't betaine anhydrous be better suited for endurance athletes compared to people who resistance train given its hydrating benefits? Getting a pump is fun but I feel like it's more useful for endurance athletes to help prevent dehydration. Reply @andrewnorris5415 @andrewnorris5415 7 months ago (edited) Thanks for this! I always noted I bulked up more and performed better speed wise on my cycle while eating wheat. But have a slight allergy and found I felt better overall off it. I have ordered some TMG powder. Does not seem expensive at your recommend dose. If I remember will report back how it works as a reply to this comment. 1 Reply 1 reply @philliponfitness @philliponfitness 7 months ago when you didnt know dr brad was a BEAST 💪 270 Dr Brad Stanfield Reply 8 replies @scottmiller2591 @scottmiller2591 7 months ago Interesting. I was not aware of the osmolytic effect of TMG, but this may explain why taking TMG makes my dry eye better and vision clearer for a few days after I take it - better hydration of the cells in the surface of the eye. Also, the omega-3, which is good for dry eye by itself by affecting the secretions of the meibomian glands, sounds like it has some synergism with the TMG as well. It took me a while to figure out that TMG was the component that was helping, since it kicks in a few hours after I take it, but lasts for several days, making it hard to figure out what's going on in a Latin squares experimental design that changes every day. This means the TMG isn't clearing by the time the next supplement combo is used, and confounds the results = longer intervals are needed for testing. This gives me a mechanism to explain my observation. Hopefully this doesn't mean some opportunistic doctor will attempt to patent TMG as a drug and get it pulled from over-the-counter, especially since the observation is posted publicly here, not that such a thing has has ever happened before 😃. 5 Dr Brad Stanfield Reply 6 replies @raidchaser443 @raidchaser443 1 month ago 2000 mg of betaine (2g) looks like a good idea. Creatine(5 g) is also helpful with a pre workout(6 g citrulline malate,3.2 g beta alanine,2g taurine) needing 1 g of l tyrosine to delay muscle soreness. I'll have to buy betaine & 1 g l tyrosine.(garter snake veins are on the way. Farmer carries also build grip strength...) Reply @arykgrosz @arykgrosz 6 months ago Does timing matter at all? Do you get any benefit on your work out days to take it before the workout vs after or is it like creatine which sort of accumulates over days in the body? 3 Reply @maksymzavershynskyi2663 @maksymzavershynskyi2663 7 months ago TMG converts homocysteine to methionine which reverts back to homocysteine, which makes it an inefficient mechanism. Plus even when TMG decreases homocysteine, it increases methionine which is not good for longevity. So to decrease homocysteine it is better to take Serine+B6 which not only does not produce methionine but it also contributes to glutathione production, which is a powerful antioxidant. 37 Reply 4 replies @michaelmonski1466 @michaelmonski1466 2 months ago I really like you being critical in your general approach. Great job! 1 Reply @manmoth4 @manmoth4 7 months ago Nice gains. I take collagen + AKG + creatine + TMG, those are the main supplements that have been known to aid muscle growth. After a year and a half I can overhead press 80kg for 5 reps, people think I'm on steroids, only lift 3 days a week, it's great. Not sure if due to the supplements, but I have a pretty positive impression of them so far 36 Dr Brad Stanfield Reply 10 replies @wayneshepherd5933 @wayneshepherd5933 7 months ago Thanks doc, keep up the good work, straight to the point. 👍 💙 Dr Brad Stanfield Reply @GHJK-rq4tv @GHJK-rq4tv 7 months ago Doctor what are your thoughts on emerging popular adaptogens such as Fadogia Agrestis and Tongkat Ali?Are you optimistic about their potential possible benefits? 10 Reply @andrewandreas5795 @andrewandreas5795 7 months ago Thanks Dr Brad, this was a great video. i wonder if you could make a video about supplements that can enhance or create a healty hormonal environment for males. Thanks Reply @unreactive @unreactive 7 months ago There's a study that suggests Betaine at doses over 4g a day can increase LDL cholesterol, so your dosage of 1g a day seems to be a good recommendation! Is there any evidence, that supplementing MTG alongside Creatine gives additive effects? I'm afraid that the mechanism for muscle performance behind MTG is too similar to that of Creatine's. Nevertheless, all the other benefits of Betaine look promising! 5 Reply 1 reply @danielberkowitz1304 @danielberkowitz1304 7 months ago (edited) Thanks for the video. I want to take the TMG, but I'm worried about a side effect that I heard of that it can cause body odor. Is there any data that supports that claimed side effect? Or it is a negligible risk? Reply 1 reply @9xqspx6 @9xqspx6 4 months ago I read this somewhere: "The breakdown of TMG in the body can make trimethylamine. TMG supplementation can cause a person’s urine and sweat to smell fishy" Any comments on this from people already taking TMG? Thank you. Reply @H.C.Q. @H.C.Q. 7 months ago I take a product with Betaine HCl. It’s called Doctor’s Best Betaine HCl with Pepsin and Gentian Bitters. It is formulated as a digestive aid to help with acid indigestion by making the stomach more acidic. It does work well for that. It contains 650 mg of Betaine per capsule. 1 Reply 1 reply @andrewnorris5415 @andrewnorris5415 7 months ago Could heart enlargement be an issue? Just a random thought. With new (not well studies) things we cannot be sure of the gains vs issues long term? Why I would stick to your safe dose. It does occur naturally in healthy foods in small amounts. Reply @KingRockets @KingRockets 7 months ago What's the difference between TMG (Betaine) and Betaine HCl? Would you still get some of the benefits of TMG by supplementing with the latter? 1 Reply 1 reply @Homo_Pestis_GMO_exHuman @Homo_Pestis_GMO_exHuman 7 months ago I take TMG for homocysteine and because its a good methl doner which I think is beneficial for certain longevity supplements. For muscles I take creatine and HMB. Mostly because I'm afraid my work, which is basically 12 hours of cardio, is burning muscle instead of building it. 6 Reply 3 replies @michaelzumpano7318 @michaelzumpano7318 5 months ago Love your videos. But there is another video from “conquer aging or die trying” that claims B6 and Serine may be a better choice than TMG for longevity. 1 Reply @RogueCylon @RogueCylon 6 months ago Love my TMG. I get a huge muscle pump overnight on whatever muscle I have worked out. Reply @wallexx-rl9nj @wallexx-rl9nj 6 months ago Hey Brad, I am not sure why don’t promote folic acid for homocysteine lowering. I don’t know a study that shows a significant effect with only 1g of TMG. +higher doses can possibly increase LDL/ApoB. So the meta analysis you stated concludes: „Folic acid has no adverse effects on blood lipids; and therefore, folic acid supplementation should remain the preferred homocysteine-lowering treatment in healthy humans.“ 2 Reply 1 reply @bigguy130 @bigguy130 6 months ago I wonder, how does TMG compare to DMG? Do they have similar results or is one better than the other? 1 Reply @danpictish5457 @danpictish5457 7 months ago Thanks again Doctor Brad for the important info. 2 Dr Brad Stanfield Reply @ricklanders @ricklanders 7 months ago TMG also enhances the antidepressant effects of ketamine, while mitigating the psychotomimetic effects. 1 Reply @Battery-kf4vu @Battery-kf4vu 7 months ago Low vitamin B6 is strongly associated with Alzheimer. Those who have a high level of B6 have 4 times less chances of getting it. So I wonder if using B6 to protect the brain from degeneration and as a methyl donor to lower homocysteine wouldn't be even better, all the more than for TMG to work it would take a really high dosage. Reply @SpencerMack @SpencerMack 3 months ago If I take TMG consistently for a week or more I end up super lethargic, nauseous and vomiting. Happened 3 separate times before I could peg it to a specific substance I was taking. Any idea why this would be? I know as tmg breaks down it can smell fishy, wich is apparently the smell of TMAO Perhaps my body can’t handle so many excess methyl groups? Reply @ScottSummerill @ScottSummerill 7 months ago (edited) Not that interested in the exercise effect as I’m no longer an athlete. But the homocysteine thing scares the crap out of me. Also a link to cardiovascular diseases. Another channel recently mentioned homocysteine and he started taking B6 and L-Serine to bring his levels down. I believe he mentioned a study that, or at least his theory was, B12 had no effect on homocysteine levels. Unfortunately B12 is usually prescribed. 1 Reply @yesbabyji68 @yesbabyji68 2 months ago Good morning Dr Stanfield. Is TMG the same as Glycine? I am having 600 mg of NAC and 1000 of Glycine daily and planning to start NMN + Resveratrol. Do I need to take TMG along with NMN or the Glycine I am having along with NAC is suffice? This is such a new field. Would appreciate your suggestion and guidance. Thanks. Reply @blueshoes8481 @blueshoes8481 7 months ago Speaking of methylation, please do a video on MTHFR mutation and how, or if, to treat it. There is tremendous disagreement between the functional and the 'conventional' medical professionals. Everything from "change you diet completely and carefully titrate these specific supplements" (methyl-folate, methyl-B12, etc), to "it's no big deal at all, requiring no intervention". Which is it? Reply @backcast4220 @backcast4220 7 months ago Do you know if betaine hydrochloride will be as effective as straight betaine? Have been taking betaine HCL for a long time to control gastric reflux with excellent results, if there are other benefits then that’s a fortuitous bonus. 6 Reply 7 replies @pardogg @pardogg 7 months ago What are the differences between TMG and glycine supplementation? 9 Reply @ronaldkoch2766 @ronaldkoch2766 7 months ago I would mainly take TMG to prevent a methyl deficiency when taking an NAD+ precursor. 2 Reply Dr Brad Stanfield · 3 replies @charlespoole2320 @charlespoole2320 7 months ago I was taking TMG, 500 mg, 2X/d, but stopped, forget why. Next week running up a hill pulled a calf muscle. Major ouch for over a week. Back on TMG then and forever since. 2 Reply @HeartFeltGesture @HeartFeltGesture 6 months ago 50% of humans have methylation issues because of the MTHFR gene mutation. TMG can help with this, taken together with a methylated B-complex. Reply @georgig26 @georgig26 7 months ago (edited) I was taking TMG but started having very frequents events of arrhythmia , my heart rate becomes very high . Are there some evidence for TMG and arrhythmia ? Also i have MTHFR mutation and my Homocysteine is a bit higher 1 Reply 1 reply @samvandervelden8243 @samvandervelden8243 7 months ago How can you know that the benefits of TMG aren't from the increased creatine concentration? A lot of people supplement creatine so I think this is an important question to answer 4 Reply 5 replies @auslanderbuchsbaum5623 @auslanderbuchsbaum5623 5 months ago What about the concerns about increased LDL with betaine supplementation ? 1 Reply @mwroutledge @mwroutledge 7 months ago I under methylate and also have histamine intolerance, so I take it with NAC as an alternative to SAME. Been using it for years. If not for this is be on antihistamines daily. 2 Reply @theyoungknight.3119 @theyoungknight.3119 7 months ago I first heard of betaine for its possible benefits for liver health is there any strong evidence to support its positive effects on the liver? Reply 1 reply @cyclist5000 @cyclist5000 7 months ago For increased exercise performance, does it matter when it is taken? 4 Reply @sncnutrition7118 @sncnutrition7118 5 months ago Whats a good starting dosage for methylfolate if your positive for it? 1 Reply @lolhai6430 @lolhai6430 7 months ago (edited) Betaine is a great supplement. I take the pre work out and post work out from advanced molecular labs. It is a wonderful supplement. I am not sponsored by this company - edit Reply @mtbgo7860 @mtbgo7860 7 months ago Love the channel. What do you think about probiotics? Having trouble finding reliable information. Reply @williamtomkiel8215 @williamtomkiel8215 7 months ago Dr. Rhonda also covered this very well about 3 years ago so your update is appreciated. 1 Reply @lazarus8453 @lazarus8453 7 months ago I always like your videos they are very easy to digest . 1 Dr Brad Stanfield Reply @PedroGuzmannimbus @PedroGuzmannimbus 7 months ago We can see that no one have the imagination to give basic info like the best time of day to have it, and with what is better the assimilation, maybe plain water, and also if there are synergetic supplements to take with TMG? So important. Reply @lairheron9489 @lairheron9489 7 months ago What are your thoughts on technological advancements in the next 10-15 years as far as health and longevity? Like nanobots in and lab-grown organs from patients genes themselves. Reply @grugnotice7746 @grugnotice7746 7 months ago Wonder if regular glycine will have a similar effect? I take a half a teaspoon every evening along with NAC and magnesium to help me sleep. I could probably benefit from getting back on an exercise routine. Reply 1 reply @MichaelBWhiteMusic @MichaelBWhiteMusic 7 months ago (edited) Could TMG serve the same benefits as GlyNAC, if TMG is combined with NAC? 2 Reply @donotageteam451 @donotageteam451 7 months ago It is in our top 3 best sellers Brad! 6 Reply @JacquesTreehorn @JacquesTreehorn 7 months ago What is the difference between Glycine and TMG? If I am taking NAC should I be taking glycine or TMG with the NAC? I bought just regular glycine and have been using that with NAC. Is this right or should it be TMG? I am not doing a workout if this helps. I am confused. I noticed NMN is available on Amazon again. 4 Reply 3 replies @evgenyv.4436 @evgenyv.4436 1 month ago And I have seen materials that say that betaine serves as a precursor to TMAO in the intestine and is associated with atherosclerosis. Reply @mattiassmedsgaard494 @mattiassmedsgaard494 6 months ago However there are studies showing that TMG supplementation is increasing LDL cholesterol levels, so it's a no for me. 1 Reply @tilmanbiallas2488 @tilmanbiallas2488 7 months ago Very good work you are doing!!! Reply @cubalkan @cubalkan 7 months ago Choline is merabolized in betaine. Is there any advantage of taking TMG vs choline? 1 Reply 1 reply @lernenderzukunft @lernenderzukunft 3 months ago Do these positive effects also include betaine HCl? 1 Reply @snake1625b @snake1625b 7 months ago Do you have to take it right before your workout or does the timing not matter? 2 Reply @CJWass09 @CJWass09 7 months ago It raises methionine though and that's usually implicated with reduction in lifespan. Reply @littlehuey5679 @littlehuey5679 3 months ago Dose it effect the kidney or the blood test for kidney function? Reply @Dr_b_ @Dr_b_ 7 months ago my heart sank when i heard that taking tmg and sitting on the sofa wasnt effective 😢 25 Reply 3 replies @ancesthntr @ancesthntr 7 months ago Does TMG confer the same benefit as glycine itself WRT combining with NAC to give the body precursors to glutathione? 4 Reply @MisterFeatherss @MisterFeatherss 7 months ago Does TMG need to be taken as a pre workout? I always take it upon waking with niacin, workouts are usually 4-6 hours after taking TMG. 1 Reply 1 reply @michaelacton6246 @michaelacton6246 7 months ago I take 1.5 grams 3 times a day. But I live an active lifestyle and lift weights 6 days a week. But I also take all the regular life extension supplements. Glynac etc. 2 Reply @juanhartwig8620 @juanhartwig8620 7 months ago Great video a as always Brad, will love to hear your opinion on MOTS-c ! Reply @MrBeckala @MrBeckala 7 months ago I take 500 mg TMG every other day and eat beets several times per week...limit red meat to keep TMAO lower...likewise limiting animal protein lowers the amount of methionine (feed back) might inhibit homocysteine to methionine conversion...(your thoughts?) 1 Reply @vistdaan @vistdaan 6 months ago Hi love you chanel just a quick question can TMG increase cholesterol levels??? Reply @johannesx7958 @johannesx7958 7 months ago in these studies wouldnt their 1RM and other tests not go up just from training alone?especially in the youth players? was this adjusted for? Reply Dr Brad Stanfield · 2 replies @sunmoon-84 @sunmoon-84 7 months ago What happens if a person takes these supplements then suddenly stops taking them? Is there any rebound effect? Reply @NumberSixAtTheVillage @NumberSixAtTheVillage 3 months ago So can you take TMG without exercising for preventing Alzheimer's? Reply @darealrulezbreaker9493 @darealrulezbreaker9493 7 months ago i wonder if its important to take the betaine with food for absorption or if it doesnt matter since its water soluble. Reply @michaelransom5841 @michaelransom5841 7 months ago (edited) Brad got Jacked! But.. I have to ask the question again... why TMG as opposed to just taking Choline??? TMG is a metabolite of Choline, so why wouldn't you start with choline to get the cognitive benefits from the boost to acetylcholine levels as well...... I used to think it was to avoid boosting TMAO levels, but that also occurs with Betaine, albeit to a somewhat lesser degree. I've never found an answer to this.... 5 Reply @unholyquail4560 @unholyquail4560 7 months ago Lower homocysteine can be achieved by just eating a plant based diet in general. That is not where the TMG is required. Reply @cularu1 @cularu1 7 months ago (edited) Does choline have the same effect as TMG? Choline is transformed in TMG biochemically. 1 Reply @arijitbanerjee6572 @arijitbanerjee6572 7 months ago (edited) Dr. Brad kindly make a video on Science based Ways for fat loss. 2 Reply 1 reply @rikishi555 @rikishi555 5 months ago should i take TMG with NAC or Glycine with NAC? Reply @LukasEvents-kd9jl @LukasEvents-kd9jl 7 months ago Dr.Brad what is Your opinion about TMAO which is genereted from TMG,choline and l-carnitine? New reaserch is showing that TMAO is bad for cardiovascular system. I am confused couse in one hand lowering homocysteine is good and other hand we make more TMAO which is bad... Reply @WhereNerdyisCool @WhereNerdyisCool 7 months ago I thought TMG was suggested if you were taking NR or NMN? I asked Niagen about that and they said it wasn't needed TMG sounds interesting but I will await more data Reply Dr Brad Stanfield · 2 replies @enricopuno8276 @enricopuno8276 7 months ago Should I take it before or after workout? Reply @rezabidar1042 @rezabidar1042 7 months ago (edited) Two different brands of TMG, supposedly high quality, gave me headaches, I would rather to get betaine from Spinach , beets and wheat germ and stay away from supplements that I am not sure about purity and identity. 1 Reply @amielynn2657 @amielynn2657 7 months ago How to figure out which supplements to take? NMN, NR, NAD+, NAC, Reversatrol, TMG, etc... I'm 48 female 135lb 5' tall wanting to get fit. I'm on hormone replacement therapy estradiol patch, progesterone, testosterone gel. Plus I take levothyroxine a low dose for hypothyroidism. I want to turn back time as much as poosible but I honestly don't know where to start with all these supplements. Out of those supplements which one has the lowest amount of niacin? Reply @indridcold4210 @indridcold4210 7 months ago Might TMG improve heart function in people with heart failure? Since the heart is a muscle? 1 Reply 2 replies @gz625 @gz625 7 months ago Hi! I added physical exercises (not very intense) but I'm having elevated heart rate the whole day after exercises (like my normal resting but not sleeping HR is about 75-85bpm) about 95-110bpm. What could be the cause? 6 Reply 16 replies @ytsux9259 @ytsux9259 3 months ago I take ALL the supplements available on the market so I'm covered. Each hour of the day I take 10 supplements. I'm going to be Superman soon. 💪 Reply @owambocontrol4218 @owambocontrol4218 1 month ago 4 mins video, you don't see that very often. I like it a lot!! Reply @ohheyhowyoudoin9635 @ohheyhowyoudoin9635 7 months ago Is Betaine or TMG give the same benefits as Betaine HCL? Thank you. 2 Reply @dancrunk1063 @dancrunk1063 7 months ago I have a metabolic disorder where protiens don't get turned into muscle energy. I'm becoming so weak it's honestly extremely frightening living this shit. 2 Reply 11 replies @haidersyed6554 @haidersyed6554 7 months ago I heard TMG can harm heart health as it may produce excessive methionine and offset the homocystein vs methionine balance? 3 Reply @Erictraiven @Erictraiven 3 months ago Isnt the tmg already produced in our body? Reply @sunmoon-84 @sunmoon-84 7 months ago Are vegan Omega 3 supplements as effective as fish based supplements? Reply @Sofia99988 @Sofia99988 7 months ago I always like your videos.Thanks you. 1 Dr Brad Stanfield Reply @krystianbernacki7553 @krystianbernacki7553 7 months ago What’s your opinion about BPC157 in capsules? Reply