0:00 this video is sponsored by longevity technology so hello and welcome to the cheeky science show where in this video we're going to talk all about certain six and why it's called the longevity saturn so first we'll introduce the basics or setones where you can find them in a cell and what their cellular activities are and then we'll look at a series of studies that have shown a link between seton sex activity and lifespan in different muscle organisms and then that will nicely lead us on to looking at sir two and six activators and why there's currently a lot of interest around finding molecules that can activate so two insects and so we'll discuss that at the end of the video but firstly what are sartunes well
0:47 said twins are considered a family because in mammals including us we have seven different setuans which are conveniently called seton 1 to ce2 and 7. and the reason that they are a family is because these proteins all share an enzymatic domain but they have different tears at either end of their protein sequence that recruits them to different parts of a cell and influences what other proteins and molecules they interact with and so the different setuans are structurally related but they can perform different functions within a cell although for some of them that activities do overlap slightly so what are their activities well saturants are nad plus dependent enzymes so what that means is that their
1:32 enzymatic activity depends on the availability of nad plus standing for nicotinamide adenine dinucleotide and nad plaster is a really important cofactor that's found within cells so with the availability of nad plus so two wins can carry out protein deathelation which is the removal of acell groups from different proteins and they also possess mono adp ribosomal transferase activities and so you don't really have to understand what either of that means but basically they have the ability to modify what marks are present on different proteins and by modifying these marks it can affect the stability localization and activity of a variety of different proteins and so this is why the different setuans vary because due to
2:18 their different structural differences they interact with different proteins and this is also influenced by their cellular localization as they'll only be able to interact with proteins that are localized in the same area and so out of the seven saturants so two in one six and seven are primarily found within the nucleus of the cell so where the dna is found whilst so two and three four and five are found in the mitochondria and so two and two is mainly in the cytoplasm and so even though sed2n1 and 6 are both found in the nucleus they're not tripping over each other's toes because they have different binding affinities to different proteins and the reason i pick on said two in one answer two and six is because this helps to segue into
3:04 looking at longevity research in connection with certains because if we go back to 1999 when a study came out that showed that yeast lifespan was extended by 30 when it had an extra copy of a gene known as cer2 and this was thought to be achieved by stabilizing the yeast genome hinting at its activity being localized in the nucleus and so if you didn't guess by the name the yeast sir2 is a homologue of the mammalian saturns and so that raised the question of well what would happen if you had additional copies of mammalian saturants well studies have been done to investigate this and one thing that's worth mentioning is that it's a two and one and so two and six protein levels have been shown to increase upon dietary restriction
3:51 and fasting in various mouse tissues and human cell lines with dietary restriction still being one of the most consistently seen interventions that can extend lifespan in a variety of different muscle organisms but more interestingly mouse models have been made whereby they can actually overexpress different settlements and so when there was whole body certain one over expression of mice they found that it improved several parameters reflecting health span but it didn't seem to extend lifespan however other studies have shown that over-expression of cert one just in the brain of mice did show a lifespan increase and there's still interest surrounding so 2n1 activators such as resveratrol pterostilbene and other tattooing
4:36 activating compounds known as stacks that do share benefits to enhancing certain one activity but i said in this video we're going to talk about said two and six so what happens if you have additional setup and six well that's been done in mice as well and a nature paper that came out in 2012 showed that over expression of said two and six in mice and so this is whole body over-expression it was found to extend the male lifespan but not the female lifespan and in this early study they also found that the male mice that had over-expression or cert-1 had reduced levels of igf-1 and so igf-1 is a major growth factor responsible for stimulating growth in different cell types anyway differences weren't seen in the
5:22 females and whilst to some extent it's thought that females have lower levels of igf-1 compared to males they also found a lot of differences in liver gene expression between male and female mice anyway despite the sex-dependent differences observed in this study a paper that came out earlier this year has shown that cert six over-expression in a different mouse strain did extend lifespan in both males and females and you can see that in this figure here whereby it led to an extension in median lifespan of 27 in the males and 15 in the females and you can also see in a study that they also had over expression of cert 1 which in cooperation with the earlier study was shown here to not extend the lifespan of the mice
6:07 and further support from that comes from the fact that when you over express both said two and six and so two in one there isn't any enhanced benefits and that it overlaps with said two and six over expression alone but the curious thing is why in this paper they did see a lifespan extension in the females whilst the previous study didn't well one explanation that the authors give is that this time they did see a reduction in the igf-1 levels in the females at old age when they were over expressing certain sex which in the previous study they didn't see any change however two and six over expression had a milder effect in the females in a variety of other parameters that were looked at in this more recent paper for example the treadmill endurance benefits
6:52 and changes in the liver transcriptional profile showed milder changes in the females than the males as if we put the information from both studies together it does suggest that the female benefit is less than in the males but why that is the case still does seem a little bit unclear but it emphasizes as well how important it is to repeat studies in different mouse models because evidently things can vary and this is one of the reasons why translating data from mice to humans is also such a challenge now the other interesting thing to mention about this paper is that they showed that so two and six over expression helped to restore energy homeostasis and to some extent that isn't surprising because sotoman activity is dependent on nat plus and nad plus is often referred to as a
7:39 metabolic sensor the abundance of nad plus varies depending on the energy status of a cell i say what they show in this paper is that in the mice that had over expression of cert two and six they found that there was increased mitochondrial biogenesis and a liver and this was correlated with higher expression of the gene pgc1 alpha which regulates the expression of genes involved in mitochondrial biogenesis i realize this isn't the clearest of figures but the green bars show mice overexpressing ce2 and 6 and the blue shade the control mice with the first two bars being young mice and the last two bars being old mice and so you can see that there's an increase between the old saturn overexpressing and and the old control mice and so this
8:24 work fits in nicely with the previous studies showing that certain 6 levels increase under fasting but saturn 6 doesn't just seem to be involved in metabolism it also plays a critical role in the response to dna damage and interestingly a very nice study came out that found a positive correlation between certain six ability to repair dna and lifespan in different rodents whereby rodents that live longer seem to have more efficient settling six enzymes that can repair dna damage and so these different rodent species have slight variations in their so two and six protein sequence and that causes differences in saturation activity and what they seem to suggest that that is that that could be contributing to the differences seen in
9:10 their maximal lifespan now one of the things that i thought was quite interesting about this paper is that when they compared the activity of the the mouse certain insects and the beavers are two and six so the mouse being weaker than the beaver which corresponds with the beavers having a longer lifespan than the mice was that there was a much stronger increase in the beavers set two and six activity of mono ribosylation as opposed to the protein theotolation suggesting that this monoadp rhoboscillation activity is more strongly involved in the dna repair function of certain six and the reason i thought it'd be interesting to mention that is because this brings us on to the last point which is other ways of actually being able to
9:56 activate so 2 and 6 without having to over express the gene now activators tend to be less common than inhibitors of enzyme activity and that's partly because for an inhibitor the rationale is that you just have to block the binding site of the substrate which and without getting too biochemical is easier to do based on structural models than to find activators besides the point there has actually been some studies that have found so called allosteric activators or so two and six and so allosteric refers to the fact that these compounds are binding to settle insects in a different location to where the substrate would bind and so by binding elsewhere it can alter the conformation of the protein and hopefully activate the protein and so in this study they identified the
10:41 compound mdl 800 that could activate saturn vi dtelation by increasing the binding affinity of soto insects to acetate substrates now the interesting thing with this study is that we actually have some in vivo data in mice whereby injection of mdl 800 to the mice reduced tumor growth in a cenographed model whereas all other proposed set 2 and 6 activators so far have only been examined in vitro and more on from that no saturn 6 activator so far has been shown to have any connection with lifespan extension or health spine extension but going back to what i was saying about the diacetylation activity versus the mono adp ribosylation activity is that this mdl800 seems to only
11:28 activate the acetylation activity not the adp ribosylation activity and so based on the work from the other study showing that the adp robustlation activity might be more important for dna repair it would therefore be interesting to find compounds that might preferentially outer fade this adp-ribosylation activity but um besides me getting a two biochemical again what can we conclude from this video well saturn 6 is evidently involved in a variety of different cellular processes and that's partly due to the fact that it can influence the activity of many different proteins the involvement of seton 6 and the repair of dna damage seems like one of the more important functions especially tied with its longevity connection but it can't be avoided that psyton sets
12:14 can also influence metabolism within a cell it will be interesting to see if saturn 6 activators can be identified and more on from that shown to have benefits in health span and lifespan but this would require in-five models probably than in mice to really evaluate the efficacy it would also be interesting to see how the certain six activators might work in combination with mechanisms of increasing nad plus levels since saturn 6 evidently needs nad plus and so it is likely that they would synergize together but i think it's clear from the work so far that tattoo and 6 can be considered the longevity settlement given the lifespan extension seen in these mouse models when they overexpress a two and six albeit the sex dependent differences are
13:01 definitely very interesting and the identification of safe and tolerable compounds that can activate saturn sex would definitely be exciting in terms of its potential to delay the onset of different age-related diseases or even aging itself so with that i'd like to thank the sponsor for this week's video longevity technology for which i'm very grateful longevity technology delivers high quality daily news and insights on research investments and technologies that extend health span and lifespan find the link to their website in the description so i hope you've learned something in this video and learned a lot more about certain sex without me getting too biochemical but um i can't help it so thank you to my patreon supporters and thank you for listening
