Sirtuins

THE MOST POTENT NATURAL SIRT6 Activator ~ 55-FOLD Increase ~ | Reverse Aging Revolution Reverse Aging Revolution 30,919 views Apr 2, 2022 #Quercetin #Berberine #DavidSinclair Sirtuins are enzymes regulating the expression of genes that control the function of cells through key cellular signalling pathways. Ageing causes changes in sirtuin function, and these changes contribute to the development of various diseases. There are many labs studies sirtuins, including Dr David Sinclair’s Lab, Dr Vera Gobunova’s lab and Dr. Haim Cohen’s lab. Sirtuin 6, or SIRT6 for short is a chromatin-bound deacetylase predominantly found in the nucleus. SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction. Flavonoids are a large family of naturally occurring polyphenolic compounds that provide health benefits to protect against age related diseases. A study on examining 18 natural polyphenols for modulating SIRT6 activities in cancer cells. The study shows that flavonoids can alter SIRT6 activity in a structure dependent manner. Increases the activation of SIRT6 enzyme which may reduce the growth of cancer cells and expression of cancer genes. Among all types of polyphenols, studies have suggested that anthocyanidins, may play important roles in helping to reduce the risk of many age-related diseases. Natural polyphenols as sirtuin 6 modulators https://www.nature.com/articles/s4159... Therapeutic potential of resveratrol: the in vivo evidence https://www.med.upenn.edu/baurlab/pdf... Please note that the links below are affiliate links, so we receive a small commission when you purchase a product through the links. 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The video content is purely for informational purposes. #SIRT6 #Sirtuins #Polyphenol #DavidSinclair #AgingClocks #Biomarker #Sirtuins #AMPK #mTOR #AgeFaster #Quercetin #Fisetin #senolytics #OliveOil #Sirtuin #HIIT #Resveratrol #aging #Lifespan #NMN #NR #Spermidine #Metformin #Berberine #ReverseAging #Epigenetic #OleicAcid #NMN #NAD #Sirtuins #Fasting #Longevity #RestoreYouth #Reprogramming #DavidSinclair #DrSinclairLab #Healthspan #Younger #antiaging #DrSinclair #NAD #longevity #Bioscience #Epigenome Music 1 songs Large Smile Mood Nico Staf Large Smile Mood Music Reverse Aging Revolution 66.5K subscribers Videos About 2:52 HOW MUCH To Turn On mTOR For MUSCLE BUILDING? | Dr David Sinclair Interview Clips by Reverse Aging Revolution 53 Comments rongmaw lin Add a comment... @ReverseAgingRevolution Pinned by Reverse Aging Revolution @ReverseAgingRevolution 4 months ago ~*~ Discount Coupon Code: REVERSE All-Natural Product DoNotAge SIRT6 ACTIVATOR 10% OFF https://donotage.org/product/sirt6-activator/ref/Reverse/ 🔬Renue By Science 10% OFF Pure NMN Powder 100 gram https://shorturl.at/fjxU2 Liposomal NMN caps https://bit.ly/3PZIfl4 Liposomal Trans-Resveratrol caps https://bit.ly/46OlFlr 🌏ProHealth Longevity 15% OFF NMN Pro 500 mg https://prohealth.pxf.io/NMN500 ProHealth Trans-Resveratrol 500mg Caps https://prohealth.pxf.io/TransResveratrol 🔶 Nuchido Time + 2nd Generation Boosting NAD Supplement : FIRST ORDER 20% OFF Discount Code : REVERSEAGING20 https://www.nuchido.com/REVERSEAGING Reply @jcyumei246 @jcyumei246 1 year ago Now I'm not feeling too guilty for having a raspberry cake!😂 5 Reply @valeriehopebennett @valeriehopebennett 1 year ago great thank you it was so educational success. 1 Reply @markvoelker6620 @markvoelker6620 1 year ago “Your mother was a hamster, and your father smelt of elderberries!!” 11 Reply 3 replies @susanc.2482 @susanc.2482 1 year ago Great news to me, I love all sorts of berries. They are lovely and tasty and extend my lifespan! 6 Reply @androidaccount7743 @androidaccount7743 1 year ago Should do a video sharing quercetin brands that actually contain what they claim. A lot of charlatans out there. 15 Reply @sparetoothbrush @sparetoothbrush 1 year ago would dried whole elderberries still contain cyanidine? Reply @charlessavoie2367 @charlessavoie2367 3 months ago I've become interested in Gotu Kola, Centella Asiatica, as the top telomerase activator. People are unduly worried about if telomerase gets activated it means cancer. No. Cancer worries are best addressed by taking lactoferrin daily. Cancer can't get started without iron. Reply @laurenflowers2023 @laurenflowers2023 1 year ago Here were were eating blackberries and raspberries because they taste good, are low on carbs and Costco always has them. 😀 15 Reply @juliahello6673 @juliahello6673 1 year ago Elderberries have the highest content by far. 5 Reply 2 replies @Elaba_ @Elaba_ 5 months ago This is old information. The person who gave the elderberry it's name knew this. 2 Reply @henryquenin6580 @henryquenin6580 2 months ago What is an optimal dose of cyanidin? The amounts found in berries are for each 100 grams which represents a whole lot of berries. Reply @markveen1373 @markveen1373 1 year ago I eat RAW elderberries. But be careful. Just a handful every now and then. Very potent stuff. 6 Reply 7 replies @stevesteve7175 @stevesteve7175 1 year ago This is extraordinary information. 5 Reply @charlessavoie2367 @charlessavoie2367 4 months ago I'm reading that Japanese fucoidan is the top SIRT-6 booster. Reply 2 replies @arnoldpillay9834 @arnoldpillay9834 1 year ago Excellent information 1 Reply @paulkiesow7588 @paulkiesow7588 1 year ago I take 330mg pure cyanidin each day. Hard to find, and would be a hard sell since it's one of the most staining substances. Handle with care or you'll need new flooring. 2 Reply 2 replies @miracoli16 @miracoli16 1 year ago (edited) Why didn't aronia berries get mentioned? As far as i know they are even far more potent then black elderberries 2 Reply 3 replies @phsal5182 @phsal5182 1 year ago thank you 1 Reply @brianmelton7946 @brianmelton7946 1 year ago Does elderberry wine activate SIRT 6? A glass a day perhaps? 4 Reply 1 reply @pavelmirov5328 @pavelmirov5328 1 year ago Cyanidin or Fucoidan ? 1 Reply @MrGiooshow @MrGiooshow 1 year ago But is it safe to eat 100g of black elderberries? 2 Reply @Kurio71 @Kurio71 8 days ago Can you take dried berries? Reply @davidross7028 @davidross7028 1 year ago Aronia berries? One plant for abundant source. Attractive in landscape. Freezes or dehydrates well. 3 Reply 1 reply @edwhite2255 @edwhite2255 1 year ago Can you obtain a therapeutic dose from these berries; enough to measurably amp up SIRT6? 2 Reply 3 replies @benv.5170 @benv.5170 1 year ago What study did they find it activated SIRT 6 55x more Reply 1 reply @ReverseAgingRevolution @ReverseAgingRevolution 1 year ago (edited) ☑ DoNotAge Supplements 10% OFF Discount Code : REVERSE https://donotage.org/ref/Reverse/ All-Natural Product SIRT6 ACTIVATOR 400mg Caps https://donotage.org/product/sirt6-activator/ 🌎 ProHealth Longevity 15% OFF Discount Code : REVERSE https://www.prohealth.com/discount/REVERSE 🔶Restore Our Cells Ability To Make NAD - Nuchido Time+ Supplement ~*~ FIRST ORDER 20% Discount Code: REVERSEAGING20 https://www.nuchido.com/REVERSEAGING 3 Reply @ssg.derrellbrock6425 @ssg.derrellbrock6425 5 months ago Ok I (HATE!!) having to read my videos. So are you to cheap to add voice to this video?. I do so love the subject but this just can’t happen again do with that I’m giving this video a full on…(THUMBS DOWN!!) until you repost this video with voice. Skip navigation Search 9+ Avatar image 1:01 / 27:45 Dr. David Sinclair on Sirtuins (an In-Depth Explanation) Health Tips 4.72K subscribers Subscribe 51 Share Download Clip Save 1,389 views Oct 11, 2021 Please check out the original interview here: • #27 – David Sinclair, Ph.D.: Slowing ... Support the amazing author Peter Attia at peterattiamd.com and the guest at twitter.com/davidasinclair. I do not own the video, I'm just reposting it is so that this beautiful message gets more noticed. For more of these, click here to subscribe: / @healthtips8041 Key moments View all Transcript Follow along using the transcript. Show transcript Health Tips 4.72K subscribers Videos About 2 Comments rongmaw lin Add a comment... @yassermohamed8782 @yassermohamed8782 7 months ago great Reply @donotmissDutch @donotmissDutch 1 year ago Too difficult for me. Sorry. Health Tips Reply Transcript Search in video 0:00 talk me through this whole sirtuin thing 0:04 that's a pretty broad question 0:06 let me narrow it down a little bit talk 0:07 me through what you were just about to 0:09 allude to that what was lenny onto when 0:11 you showed up well genetics is is a 0:13 fabulous tool because you don't have to 0:15 go in with any hypothesis that biology 0:17 will tell you the answer 0:18 and the gene that had just been cloned 0:20 by brian turned out to be what's called 0:22 surf iv 0:23 now 0:24 so four didn't turn out to be a 0:26 mammalian 0:27 conserved gene so so far is 0:29 not been as exciting but there was this 0:31 partner of the surfboard gene 0:33 i was called so two 0:34 and so two and so three and so four form 0:37 this complex of proteins stick together 0:39 in control of all things gene silencing 0:42 that's what sur stands for silent 0:44 information regulator in this case 0:46 number two 0:47 and that was very unexpected in those 0:49 days 0:50 if you think back the cause of aging was 0:52 thought to be dna damage mutations free 0:54 radicals so we were all expecting to 0:56 find genes that controlled dna repair or 1:00 antioxidants at that time because i go 1:02 back and i think god at that time i was 1:04 still in college studying math and 1:05 engineering i didn't know i hadn't taken 1:06 a biology course so i can't think about 1:08 it through the context of my own 1:10 education how well was it understood 1:12 that there were introns and extrons and 1:14 that much of the genome wasn't even 1:16 coding and stuff like was that all was 1:18 that well understood at that point in 1:19 time it was in yeast actually they were 1:21 ahead of anybody else in eukaryotes we 1:24 knew that there were introns and not 1:25 many introns in yeast anyway 1:27 but we hadn't seen the full genome it 1:29 was still bits and pieces maybe 5 10 was 1:32 known 1:33 my phd was sequencing three genes that's 1:35 all it took 1:37 so 1:38 things were changing rapidly this new 1:40 thing with pcr you could move tubes into 1:42 hot tubs and amplify genes it was all 1:44 very exciting 1:45 but what we didn't 1:47 have any clue was that why a silencing 1:49 gene that controlled 1:51 negatively controlled genes other genes 1:53 why that would have anything to do with 1:55 aging it was totally bizarre it led to a 1:58 string of cell papers 2:00 and one after another every few months 2:02 we were actually publishing something 2:03 new and we had a science paper and 2:06 that was the the gold rush of this 2:07 discovery because it really turned on 2:09 the lights in this cave of a whole new 2:12 area of biology 2:13 and we're still trying to understand 2:14 actually why those silencing proteins 2:17 are relevant to aging but what we do 2:19 know 2:19 for sure is that these same genes these 2:21 sort of in all life forms whether 2:24 they're from plants all the way to us 2:26 do play a protective role in responding 2:28 to energy 2:29 and nutrients just like the empty kinase 2:31 in the import pathway do so 2:32 you alluded to cert ii 2:35 was that first found in yeast yes it was 2:38 it was known already actually 2:40 lenny and we didn't discover so too it 2:43 was already known as a silencing protein 2:44 that controlled the mating type in other 2:47 words the sex of a yeast cell 2:49 and if you don't have the silencing what 2:51 happens is that the yi cells get 2:53 confused because they're now turning on 2:55 genes for a and alpha which means male 2:57 and female and a yeast cell that doesn't 2:59 know if it's male or female will not 3:00 mate and it's become sterile 3:03 and turns out that's a hallmark of yeast 3:04 aging is sterility so if you you know 3:07 you the way you can tell whether a yeast 3:09 cell is truly old 3:11 is is it sterile or is it just sick and 3:14 that's how we used to tell but now we 3:16 actually understand the cause of that 3:18 sterility it's the actual the the 3:20 movement of so two protein away from 3:23 those genes that it should be at to go 3:25 deal with other problems in the cell i 3:26 see so it's not that sir two becomes 3:29 deactivated it just 3:31 for lack of a better description shifts 3:33 its attention elsewhere right it becomes 3:35 distracted by other things going on in 3:36 the cell and and we we had a cell paper 3:38 in 1999 with kevin mills and lenny 3:41 where we discovered and a couple of 3:43 other groups should also get credit for 3:44 co-discovering this is that the sirtuins 3:46 are also involved in dna repair when you 3:48 get a broken chromosome it's the cer2 3:51 complex that goes along helps unwrap the 3:53 dna we think and put it back together 3:55 and repair that and while the sort ii 3:57 complex is doing that 3:59 it cannot be also silencing there's not 4:00 enough of it to go around 4:02 and you might ask well why would the 4:03 cell do that why don't you just make 4:04 more so too what we think is that this 4:06 is a very ancient system that 4:08 coordinates 4:10 controlling mating 4:12 and dna repair you don't want to be 4:14 mating and dividing 4:16 if you've got a broken chromosome so 4:17 this is a way of coordinating those two 4:18 events 4:20 and it's very ancient it's a very active 4:22 system you need dna checkpoint signaling 4:24 so it's not just random 4:26 but what we also have come to realize is 4:28 that this 4:29 let's call it this distraction of the 4:31 sertuans 4:33 it's conserved we find this happens in 4:35 our own aging process as well so there's 4:37 really two roles 4:39 there's gene silencing 4:41 and dna repair 4:43 now sirtuins are 4:46 hdacs is that correct are they all age 4:48 tags so hdac histone d acetylases this 4:51 is the old name for 4:52 protein deocetylases now because what 4:54 we've all come to realize is histones 4:56 are just one of the things that sertons 4:58 and these other hdac's do they can 5:00 target what are called non-histone 5:02 proteins and they remove not just acetyl 5:05 groups but also other types of what are 5:07 called generally acell groups and so 5:10 that's a whole new world that means that 5:12 sirtuins the family there are seven of 5:14 them in mammals five of them in yeast 5:16 target 5:17 other proteins proteins that are in 5:19 cytoplasm in the nucleus even in the 5:21 mitochondria and that's their role it's 5:23 not so much only about controlling the 5:26 chromatin and histones 5:27 but also about controlling signaling and 5:30 metabolism as well and they can do that 5:32 by targeting any protein theoretically 5:35 in the cell so 5:36 what are the 5:37 you know again thinking back to daf 2 5:39 daf16 as the parallels with foxo and igf 5:43 were there elegant experiments in the 5:45 yeast that could show you extreme 5:47 conditions of 5:49 lots of cert no cert and what that 5:51 phenotype is oh yeah these were the 5:53 first experiments so i'll try to take 5:55 you through them correctly in sequence 5:57 so the what we showed with brian first 5:59 of all in the 1996 cell paper was that 6:02 we were looking for this movement there 6:05 was this so-called aged locus we didn't 6:06 know what it was we didn't know where 6:08 they were going we just know that they 6:09 knew that they left the silent mating 6:11 type locus 6:12 so what we did was we stained it so 6:13 brian had moved on actually to his 6:15 postdoc and 6:16 kevin mills and i student at the time 6:19 our job was to find where are the sur 6:21 proteins going so we stained them and we 6:23 could look at them on the microscope and 6:24 what we saw was they were going to this 6:27 little place in the nucleus which we 6:29 eventually figured out was the nucleus 6:31 which is 6:33 what makes the rrna which makes the 6:35 ribosomes 6:37 it's a really important part and the dna 6:39 that's within the nucleus is called the 6:41 ribosomal dna or the rdna 6:43 and that's where they were going 6:45 not just during normal aging but also 6:47 during 6:48 an accelerated form of aging so there's 6:50 a whole story that was lost in history 6:52 actually that maybe i'll just quickly 6:54 touch on one of the first things i did 6:56 when i got to lenny's lab was to work on 6:58 werner syndrome which is premature aging 7:00 disease and these are kids that die in 7:02 their teens or twenties aren't they no 7:04 that that's a different hutchinson 7:05 girlfriend syndrome this one weren't as 7:07 they lived together 40s yeah yeah 7:10 but the gene was just cloned by george 7:11 martin and his team out there 7:13 and the homologue in yeast is called 7:15 sgs-1 and i i picked up the paper it was 7:18 in science i recall went into lenny's 7:20 office and i said i've just been scooped 7:23 but there's a yeast homolog i'm going to 7:25 work on that is that okay and he said 7:27 yeah go for it 7:28 and so we worked on sgs1 for a little 7:31 bit and what we found was that they were 7:32 going through accelerated aging as well 7:34 so we had a science fair on that 7:36 and what was exciting about that was 7:37 that they were also becoming sterile and 7:39 the so too complex was moving as well 7:42 just like the normal aging so we had 7:45 this model rapid aging model and you 7:47 might say well so what's the big deal 7:48 you've got a rapid aging model 7:50 but ada told us that there was some 7:52 universal process that 7:54 results in premature aging in humans 7:56 probably in yeast the same thing and we 7:58 could also study this much more easily 8:00 than an old y cell 8:02 consider that to find a single old yeast 8:04 cell 8:05 it's really hard especially if you're 8:07 just studying replicative aging which is 8:10 the number of times they divide each 8:12 mother cell 8:13 produces 8:14 on average 10 to the power of 25 8:16 offspring wow okay so that's by my 8:19 calculations about 30 million 8:22 offspring and you have to pull out that 8:23 one cell and study it biochemically wait 8:25 you said 10 to the 25. yeah that's not 8:28 sorry 2 to the 25. oh okay okay 8:30 yeah but in any case that's that's way 8:33 more uh so what we used to do is to sort 8:36 out the old cells we'd label them with a 8:37 chemical and pull them out with magnetic 8:39 beads 8:40 but it was a real we couldn't get many 8:42 of them you'd just get a handful but 8:43 with these sgs werner's proteins you 8:45 could get a bunch of them the mutants we 8:47 could get a lot more and so we made a 8:48 lot of progress using that but every 8:50 time we made a discovery with the sgs 8:52 protein 8:53 mutants we went back to the normal yi 8:55 cells and verified 8:57 but we were actually able to figure out 8:59 with that mutant what the distracting 9:01 problem was for the circumplex 9:03 and that was actually 9:05 dna breaks and dna recombination that 9:07 was occurring at the most repetitive 9:09 regions the most unstable region of the 9:10 genome which is the rdna which is in the 9:13 nucleolus and that was what was 9:14 distracting those proteins interesting 9:17 when you knock out cer2 is it easy to 9:19 knock it out yeah so that was the next 9:21 experiment okay so then we wanted to 9:23 know the prediction is if you knock out 9:25 sort two you should get a lot more of 9:26 this instability at the rna yes and the 9:28 question is does it translate to 9:30 accelerated aging or not necessarily 9:32 solid aging but more cancer or some 9:34 other phenotype right well in yeast it 9:35 led to accelerated aging through the 9:37 process i was telling you about genomic 9:39 instability dna repair went went down 9:42 and also that happens in animals 9:44 although it's a little more complex 9:46 because it's embryonic lethal in a lot 9:48 of in a lot of mice so you can't easily 9:50 do that experiment 9:52 but you can do is the opposite you can 9:54 turn on or over express the so2 gene in 9:56 a yeast cell and if we're right you 9:58 should get a few things that are going 9:59 to happen you'll have 10:01 more genomic stability at this 10:03 particularly this rdna locus in the 10:05 nucleolus and the yeast cells should 10:07 live longer and that experiment was done 10:09 by an incoming graduate student matt 10:11 cabellon and one what a fantastic 10:13 project to get when you walk in 10:15 he did it and the day that he got 10:17 lifeband extension with extra sur2 was a 10:20 very good one for him and the lab so 10:22 what's the next step from there the most 10:24 obvious thing is how do you develop a 10:26 compound that would do this without the 10:28 genetic mutation that empowered it yeah 10:31 that was the issue because you can't 10:32 easily genetically manipulate humans so 10:34 the question was how do you turn on 10:36 these genes now we 10:37 we spent about three four years working 10:40 on caloric restriction in yeast and then 10:42 in mammals and 10:43 my lab and some others were 10:45 leading the charge and showing that 10:47 sirtuins both in yeast and mammals were 10:50 not only necessary but were sufficient 10:53 when you overexpress them to mimic 10:54 calorie restriction 10:56 put another way if you knock out so too 10:58 you don't get the benefits of connecting 11:00 with the benefits of cr 11:01 right and that's also now being shown by 11:03 others to be true in mice as well 11:05 so that that led to the idea that is 11:07 that the truth in all mice i couldn't 11:09 say you know there's even in yeast you 11:11 can get around the need for certains if 11:13 you stress the yeast really intensely 11:15 with very little amount of calories 11:18 but there are you know there are aspects 11:20 of of calorie restriction benefits such 11:22 as a lifespan extension that are 11:25 ameliorated lessened by a certain 11:28 knockout but it's still 11:29 complexified by the fact that it's 11:31 lethal in embryos and you have to knock 11:33 it out in the adult to do a really it's 11:35 the same sort of issue that cynthia had 11:36 with the dafts which was if you do too 11:38 early you see elegance doesn't make it 11:40 into an intermediate stage you know what 11:43 somebody hasn't even done the proper 11:44 experiment which is to take a 11:47 a mouse that you can knock out cert one 11:49 in an adult whole body and then calorie 11:52 restrict 11:53 something that we probably should have 11:54 done years ago 11:55 we didn't 11:56 but the technology is there to do that 11:58 but what what we did learn actually was 12:00 both in east and in mammals was that 12:03 it's not just one of these genes that's 12:04 important it's the whole family 12:06 and that if you knock out take yeast for 12:08 example if you knock out so two and 12:09 yeast 12:10 you lose the ability to respond to some 12:12 mild calorie restriction but if you 12:14 really calorie restrict them they'll 12:16 still live longer and there was a big 12:17 debate actually between brian matt 12:19 myself 12:20 about that and where we settled on 12:23 was that these other 12:25 sir two related genes uh we're also 12:27 helping and they work as a family and if 12:29 you knock one out the others can 12:31 compensate you used to only have one you 12:32 used to have five you said five and 12:34 humans have a whole family like eight or 12:36 something seven oh okay so only two more 12:39 that's interesting little known fact 12:40 most people ignore the other yeasts or 12:42 two ones but they're just as interesting 12:44 and what we've found is they also 12:46 can extend lifespan as well so when you 12:49 actually it's funny i was gonna go back 12:51 to something else you said a second ago 12:52 a bit what's the teleologic explanation 12:54 for why 12:56 caloric restriction and sirtuins would 12:58 move hand in hand like for many of you 13:00 you talked earlier about your 13:01 appreciation for sort of 13:03 evolutionary biology so 13:05 an organism is 13:07 you know in a nutrient-deprived 13:09 environment it still has to be able to 13:11 do a bunch of things if it's going to be 13:12 fit do we believe that that's an 13:14 environment where we need to see more 13:17 stabilization of the genome or repair or 13:19 silencing or what do we think is the 13:21 biggest insult during that period of 13:22 time yeah so the biggest insult to any 13:24 life form is a broken chromosome that's 13:26 lethal if you don't fix it and do we see 13:28 that more likely happening during 13:30 nutrient deprivation i'm gonna see that 13:32 is i would have assumed to be honest i 13:33 would assume that was independent of 13:34 nutrient exposure or at least if 13:37 anything inversely 13:39 if you don't have enough nucleotides to 13:41 complete replication you're going to 13:42 break a lot right so they do go hand in 13:44 hand 13:45 but the bigger picture is that the 13:47 sirtuins evolved we believe what are we 13:49 talking about three and a half billion 13:50 years ago in the first life forms early 13:53 life forms 13:54 maybe just after the first one of the 13:56 first proteins to actually evolve we 13:58 think would be a certain and its job is 14:00 to sense stress biological stress in the 14:03 environment 14:04 whether it's 14:05 dna damage or it's you know a burst of 14:08 cosmic rays 14:09 change in temperature or a lack of 14:11 nutrients and their job is to allow that 14:15 organism to hunker down and survive stop 14:17 mating stop breeding we can do that in 14:19 another day if we don't survive this our 14:22 offspring aren't gonna die anyway 14:24 so they control we think we they control 14:26 which genes to turn on and off in 14:28 response to adversity and they allow 14:31 those organisms to survive but they're 14:34 also talking to other pathways so 14:35 they're going to talk to empty are 14:36 they're going to talk to cynthia's daf 14:38 pathway and collectively these are the 14:42 the genes that we've settled on as the 14:44 longevity pathways but they didn't 14:45 evolve for longevity they evolved for 14:47 survival of during adversity how 14:49 conserved are these across 14:52 let's you know use the big four models 14:54 of eukaryotes from yeast worms flies you 14:57 know larger mammals like mice and 14:59 rodents is this relatively well 15:01 conserved the way the tor pathway is 15:03 conserved or does it have more 15:05 bends in the road well they're 15:06 surprisingly concerned that 15:08 you can just manipulate one gene in each 15:11 of these organisms and get lifespan 15:13 extension or one drug works in all of 15:14 these organisms i would challenge anyone 15:17 to use a chemotherapy to help a yeast 15:19 cell 15:20 so this is a quite a magical discovery 15:22 that the same pathways 15:24 are that well conserved and that ancient 15:26 and that's actually one of the 15:27 advantages we have aging is 15:30 actually not that difficult to be able 15:32 to control and that's because our models 15:34 are very good 15:35 if we can i truly believe that if we can 15:37 extend the lifespan 15:39 of a yeast a worm and a mouse humans are 15:42 so close right if you can do it across a 15:45 billion years you should be able to make 15:47 that leap to a few other 100 million 15:49 exactly it's really just the regulatory 15:51 agencies and making sure that we don't 15:52 do any harm and it's safe but the 15:54 biology is all still there going way 15:57 back three and a half billion years ago 15:58 so 15:59 it was 2006 2007 when did resveratrol 16:03 emerge as an early sirtuin activator 16:06 2003 okay and uh yeah the story behind 16:10 that was that we were looking 16:12 for an activator we're hoping for an 16:13 activator were you in your own lab at 16:14 this point you finished your post talk 16:16 i'm guessing yeah i i 16:18 managed to 16:20 move to harvard in 1999. 16:22 so 16:23 that was the year when a lot of things 16:25 happened while i while i was moving 16:28 we published this dna repair but just 16:30 going back to a silly sort of social 16:32 question did you at some point think i 16:33 want to go back to australia and set up 16:35 a lab here like was it a difficult 16:36 decision for you to stay in boston as 16:38 opposed to because you came from sydney 16:39 if i recall right well the goal was to 16:41 because like those are pretty different 16:42 climates 16:44 i've been to sydney once i spent two 16:46 weeks there i could stay there yeah i 16:48 miss that but i also like adversity i 16:51 thrive on adversity and so i've come to 16:53 like living here 16:55 the intention was to come here for two 16:56 years i had a job to go back to and but 16:59 the first week of being here in boston 17:02 was like a city i could only dream about 17:04 this is the 17:05 athens of ancient greece the rome of 17:07 ancient rome for biology this is it and 17:09 so i was in heaven i'd never experienced 17:12 a city where you're on the train and 17:14 people around you are reading science 17:16 magazine and nature that that's that's 17:18 my dream so it was 17:20 a very easy decision not to go back to 17:23 australia for reasons that if you really 17:25 want to change the world 17:26 you got to do it from here so now you're 17:28 in you're in the process of kickstarting 17:30 your own lab which comes with its own 17:31 stresses right you've got to secure 17:33 funding and all those other things and 17:36 then what's happening in the on the 17:37 front of 17:39 this stuff yeah so 1999 17:41 a few major things happened one was this 17:43 dna repair connection the second one was 17:46 lenny's lab uh published that nad was a 17:49 requirement for swatun activity and 17:51 chinema who's at washington 17:53 was the postdoc who made that 17:55 somewhat serendipitous but brilliant 17:57 discovery 17:58 and then the third thing was the 18:00 connection to calorie restriction was 18:01 happening around that time too going 18:02 back to the second thing 18:04 we talk about it now today like it's in 18:06 textbooks it's so obvious right that 18:07 sirtuins are nad dependent deacetylase 18:11 okay 18:12 nad is so ubiquitous in cells 18:14 that 18:16 if the 18:17 quantity you could have in a cell varies 18:19 on a scale from one to ten 18:21 what is sufficient to produce this 18:24 deacetylase activity is it anywhere from 18:26 two to ten or does it have to be you 18:28 know quite a high concentration it can 18:30 be two to ten you can actually get very 18:31 low levels in some disease conditions 18:33 and the 18:34 animal is still alive so it's basically 18:36 only saying that 18:38 nad is 18:39 necessary for sirtuins to work right 18:42 well without nad we'd be dead in 30 18:44 seconds but by other reasons as well i 18:47 mean wouldn't we be dead just from not 18:48 being able to do electron transports we 18:50 would and there's more than 500 18:52 reactions that you really need to just 18:54 to survive but what we didn't know in 18:57 the 2000s and it was actually quite a 18:59 crazy thing to think that nad was 19:01 regulating anything 19:03 and that was actually what we first 19:04 worked on in my lab was the control of 19:06 saturn's with nad levels 19:08 the reason it's crazy is you read 19:09 textbooks and nad is the the most 19:11 ubiquitous important molecule in the 19:13 cell 19:15 how could it possibly be varied 19:17 during aging let alone during the day 19:20 when you eat something or your circadian 19:21 rhythm now it's obvious we know nad goes 19:24 up and down it changes with age but in 19:26 those days people thought if you changed 19:28 nad levels you'd probably die 19:30 and that's not true was it known at the 19:32 time that 19:33 doesn't complex one of the mitochondria 19:35 basically convert nadh to nad 19:39 so 19:40 that you would at least know that in the 19:41 mitochondria the concentration of nad 19:43 must go up and down or else you couldn't 19:46 actually respire well locally it goes up 19:48 and down but the steady state level is 19:50 pretty constant and and when you say 19:52 going up and down are you talking 19:54 cytoplasmic nuclear plasma what are we 19:57 talking about yeah we had a paper i 19:59 think was 2007 where we had a quite a 20:02 surprising result which told us that 20:04 it's not just the cytoplasm that it goes 20:06 up and down 20:07 it was the also the mitochondria going 20:09 up and down 20:10 and we didn't know that we actually we 20:13 stumbled upon it we found that if we 20:16 kept cells with high amounts of nad they 20:18 would survive better dna damage others 20:20 insults 20:22 and we could deplete nad in the 20:23 cytoplasm but they still the cells still 20:25 lived and we didn't understand that how 20:27 did you do that by the way how do you 20:28 deplete nad actually come to think of it 20:30 we could either over express nad 20:32 depleting enzymes but actually the way 20:34 we found it was this when you damage 20:36 cells with a dna damaging agent say 20:38 chemotherapy 20:39 drug the cells themselves deplete nad 20:42 naturally with this enzyme called parp 20:44 one which is an nad 20:46 consuming enzyme and actually that's 20:49 very well known that if you hit a cell 20:51 with a dna damaging agent the reason 20:52 that it dies is n80 depletion so we were 20:55 measuring the nad depletion 20:57 in the context and that's because the 20:59 cell is trying to utilize that nad to 21:01 repair the damage you've just caused 21:03 right right so you didn't know that at 21:04 the time no that was well known so part 21:06 one is a known dna repair protein and 21:08 that's if you block pop you also protect 21:11 cells but what was interesting was that 21:13 we could over express 21:15 give more copies of a gene that made nad 21:18 and 21:19 this is called an mpt which is the 21:21 equivalent of the 21:22 pnc-1 gene in yeast which we found was 21:25 important for lifespan in those 21:26 organisms 21:27 so we were over expressing this amputee 21:29 cells had more nad 21:31 we hit them with the toxin they'd 21:33 survive better than the regular cells 21:35 but the nad was still being almost 21:37 completely depleted from the cytoplasm 21:39 sorry just because this is this is sort 21:40 of at the crux of it did they survive 21:43 because they were unable to deplete 21:45 their nad no we we saw that nad just 21:48 disappeared from the cell but they 21:49 survived but they still survived but 21:51 there was a place we weren't looking at 21:52 the time and we tracked it down to the 21:54 mitochondria 21:55 so this begs the term the mitochondrial 21:58 oasis hypothesis so myself and anthony 22:00 solvay from cornell coined this term 22:02 because what we found was that as long 22:04 as the mitochondria stayed active with 22:05 their nad 22:07 it didn't matter the cell could survive 22:08 and recover from that stress 22:10 and actually turns out that the levels 22:12 in mitochondria 22:13 nad levels are even more important than 22:15 cytoplasmic nad levels for survival that 22:18 makes sense and of course that's a hard 22:20 thing to measure isn't it it was 22:21 extremely hard that's where anthony came 22:23 in anthony is a chemist in biochemist at 22:26 heart 22:26 and it was extremely hard to isolate 22:28 these mitochondria or preserve the nad 22:30 in them 22:31 we had to use new technologies to be 22:33 able to do that well how was that done 22:34 we were using mass spectrometry for the 22:36 first time to measure nad and what 22:37 anthony did brilliantly was to make 22:40 labeled versions of nad and its 22:42 precursors and he could spike those in 22:45 and use those as references to measure 22:46 energy levels in these compartments and 22:49 nad if i recall from just biochemistry 22:52 you don't get to move that in and out of 22:54 plasma into cells 22:56 it's made de novo in the cell you have 22:58 what you have you can make more you can 22:59 bring in precursors but you don't get to 23:01 shuttle nad between cells correct uh as 23:03 far as we know right okay 23:06 yeah it gets sort of like an atp problem 23:08 like it's really hard to quantify atp in 23:10 a cell 23:11 by the way does nadp do any of this as 23:14 well well it's important no doubt it's 23:17 part of this whole 23:19 problem that we're working on 23:21 but if you add nadp or even nadh which 23:23 is only different by one hydrogen yes 23:25 they don't those don't work to activate 23:28 serotonins only nad plus will do that 23:30 and i mean not to get too nerdy on this 23:32 or but is it 23:34 it's obviously more than just the charge 23:35 but the charge must play a role if nadh 23:38 can't work right yeah so it's probably a 23:39 combination of the charge and some other 23:41 size size yeah 23:44 okay so 23:45 now you've made this these three 23:47 discoveries the second of which we just 23:49 went into in a little bit more detail 23:51 how does the story unfold now you've got 23:54 your spanking new lab well we worked for 23:56 a little while on the sts-1 bonus 23:58 protein yes and telomeres put out a 24:00 paper on that and we didn't work on 24:02 solutoons for about a year because lenny 24:04 said i don't want you working on 24:05 certains when i left the lab which was a 24:07 bit of a shock why 24:09 he doesn't want didn't want the 24:10 competition i suppose but i thought a 24:12 year was enough to give him a head start 24:14 but we quickly started working back on 24:16 is that a common request of people when 24:18 post-docs leave their labs no of course 24:20 not but 24:21 what am i going to do i mean they got 24:22 the guy trained me yeah i go in my 24:24 career but in those days it was very 24:26 competitive and so you know the lenny of 24:28 today is not the lenny of previous years 24:30 and he's a wonderful friend and mentor 24:32 to me but that's how it was in those 24:34 days it was very cutthroat i see but if 24:36 it were to up to you you would have 24:37 continued to work on sirtuins right so 24:39 then now we're basically back to 2001 24:42 2002 you're the moratorium is up you're 24:44 now back to working on it and nobody at 24:46 this point in time has yet figured out a 24:47 way 24:48 to 24:49 exogenously manipulate sirtuins more 24:52 than the stuff that we've already talked 24:54 about which is nutrients stress and 24:56 things like that yeah we were trying to 24:58 feed yeast nad and we gave them 25:00 nicotinamide which is a precursor to nad 25:02 vitamin b3 and actually kevin bitterman 25:05 who's now a very successful venture 25:06 capitalist my first student 25:08 he put nicotinamide on yeast and we 25:10 could measure the so2 activity by the 25:12 color and if so two was more active they 25:14 turn red 25:15 and he walked into my office one of his 25:17 first experiments when we worked on 25:18 sirtuins and he said david something's 25:21 weird we didn't get 25:22 activation we got inhibition so the 25:25 yeast had gone red and i said kevin it 25:27 doesn't matter what happens if it's 25:28 unexpected that's even better so that 25:30 led to a paper that said that vitamin b3 25:32 high doses is inhibitory of certain so 25:35 now the labs around the world use 25:38 nicotinamide as an inhibitor for saturn 25:40 then i wouldn't recommend taking really 25:42 high doses of nicotinamide why is that 25:44 there's a few answers by chemical answer 25:46 is that there's a an evolved pocket in 25:48 the sertuan structure 25:50 that measures nicotinamide levels and 25:52 it's a feedback loop so nicotinamide is 25:55 to get nerdy is the product of the 25:57 reaction it takes nad 25:59 cleaves it oh i got it so it's just a 26:01 negative feedback 26:02 it's seeing too much b3 and it's saying 26:04 i have too much of my output 26:07 starting to turn it down exactly so we 26:09 struggled with that we couldn't get nad 26:10 to go into cells it's too big even with 26:12 mammalian cells is difficult 26:14 as we were looking at ways to make more 26:16 nad in the cell that was our original 26:18 thesis before resveratrol was on the 26:19 radar 26:20 and we were 26:22 turning on and discovering the genes 26:23 that made nad and yeast 26:25 and we cloned some of the genes in that 26:27 pathway and there was one particular one 26:29 that was called pn is called pnc1 and 26:32 it had been studied in the context of 26:34 tuberculosis 26:35 and what we found was that when we 26:38 calorically restricted yeast cells this 26:40 was one of the most highly upregulated 26:42 genes in the whole yeast 26:44 cell 26:45 which was very unusual people had 26:46 discovered this before in their own lab 26:49 but they were wondering what the heck is 26:50 this nad 26:52 synthesis pathway got to do with calorie 26:54 restriction got to do with stress 26:56 but we knew exactly what was happening 26:58 this is a stress response that was 26:59 turning on nad 27:01 production and activating certains so we 27:04 had a our first nature paper actually on 27:06 that 27:07 2002 i think 2003 27:10 and we found that pnc-1 27:11 could mimic color restriction and raise 27:13 nad availability and then if we knocked 27:16 out the pnc-1 gene 27:17 yi cells didn't live longer when we 27:19 calorie restricted them and what's 27:21 really interesting about that i think is 27:23 that pnc-1 doesn't just get turned on by 27:25 clock restriction it's turned on by heat 27:28 low amino acids 27:30 salt high salt and so this is a gene 27:33 that senses the environment and turns on 27:36 this returns exactly what i was 27:38 explaining earlier about those early 27:39 life forms on the planet sense their 27:41 environment and through nad and other 27:43 ways they can turn on these pathways for 27:45 defense Reply