Gerald S. Shadel Talk title: The “Age” of Mitochondria

good afternoon if I could ask everybody to take their seats we're gonna get started and thank you so much for coming this is an incredible turnout for mitochondria so really a special welcome to all of our partners in research I see some of you here people who have included Salk and their estate plans we are incredibly appreciative for you and all of all of your generous gifts and for those of you who are just getting to know us welcome and we hope you enjoy learning about some of the incredible research that goes on in our labs here I am Cheryl Dean I am fen giving counsel here at Salk and I have had the privilege of working here for over 10 years and getting to know some of the fantastic science that goes on in our labs it's incredible I get to learn new stuff all the time because that's what they're doing the discoveries that come out are truly remarkable and as you'll see in just a few moments really will be impacting all of our lives for the better I'd simply like to remind you while you are all here promptly this is fantastic we were oversubscribed today and some people have been trying to RSVP as late as this afternoon please in the future so that we can best work our logistics if you could RSVP by the date the due date if at all possible we know things come up but that really helps our events team out so they asked me to remind you about that thank you so before I introduce our scientist speaker today I thought I'd show you a short video to just give you put this in a little bit of a broader context for some of the other research that we're doing in our optimal aging initiative so I will have Kent showed you our video one area that is emerging at the Salk Institute is our combined interest in aging and how we age as as organisms what's exciting about it for me is that we have between 10 and 15 existing faculty members whose programs are influenced or directed towards understanding how we aged individuals each one of these faculty members approaches the problem from a different perspective and this allows us to work cooperatively together on the different systems that we are working on in such a way that we can unravel the small components and then put them back together to get a better understanding of how we age why we age and how this affects our cognitive functioning I'm excited as part of the initiative to work across disciplines with my colleagues and cancer biology or immunology to really bring them into neuroscience so we can make big discoveries aging research at the Salk Institute has a long and successful tradition and it started with establishment of the Glenn Center for Research on Aging more than a decade ago and it has since continued through support by the Glenn foundation and also through support by the American Heart Association and Ellen initiative that are both interested in furthering aging research at the Salk Institute aging by far is the biggest risk factor for many common human diseases heart disease diabetes obesity cancer Alzheimer's and other neurodegenerative diseases but what we don't understand is how aging is the biggest risk factor for each of those individual diseases so I think a big push in aging research is to try to understand how different cells tissues and organs age in order to find the specific pathways in a person that has one or other of those particular diseases my lab is interested in understanding how individuals their organs and even individual cells within these organs age over the course of a lifetime the chronological age so the number that is on your birthday cake is actually not very informative and doesn't tell us much about how you aged there could be two 80 year olds one just qualifying for a Boston Marathon and the other one spending his or her days and assisted living facilities and what we'd like to do is to be able to compare now individuals or organs and cells that either have a younger biological age to the chronological age or have an older biological age and by comparing those two we hope to identify underlying mechanisms that allow some people to maintain health throughout life while others are not able to do that my lab works on telomeres and the DNA damage response and we are optimistic that through our approach by bringing different disciplines together and through in the incorporation of computational approaches that we will be in a unique situation to understand aging and to alleviate age associated disease telomeres represent an intrinsic shock in our cells that only allow them to double a certain number of times and thereby they prevent unlimited growth and immortality and of course cancer development my lab is particularly interested in the possibility that we'll be able to identify the factors that dictate how fast the ends of chromosomes erode and potentially identify how efficiently those factors act in different individuals in a human population and if so the big pie-in-the-sky goal is that maybe we could tweak the eroding process very early in life where we could influence in the first decade of life for example how fast an individual's telomeres are eroding so that late in their life they'll live well into their 90's without any of the pathophysiology of aging as the rest of us know it my research is actually directed at mitochondria which are organelles inside most of your cells that actually convert the air that we breathe and the food that we eat into chemical energy called ATP what my work has shown in that regard is that there's really quite a lot of data to support the idea that mitochondrial dysfunction is certainly involved in Alzheimer's disease so we really need new directions and new research to figure out the underlying reasons for Alzheimer's disease to find new therapeutic targets by studying the basic biology of aging and understanding why aging is the biggest risk factor for Alzheimer's disease such targets will be revealed so the work in my lab we're trying to understand the and how does that your brain changes with age it either in normal aging or in diseases like Alzheimer's so you're probably familiar with cells in the brain called neurons but what we work on other other cells called glia that actually surround the neurons and the reason we're excited about these cells is work we recently did showed that perhaps in normal aging and also neuro degeneration these are the cells that change and actually these changes in glial cells could be contributing to cognitive decline in the progression of all these different diseases so as part of these bigger initiatives that sort what we're really excited to do is to work with the other groups and ask what can we target these glial cells or the changes that happen in aging and see if we can slow down the progression of cognitive decline or even prevent it from happening we're right on the cusp of solving some really fundamental problems that I think are going to change the course of how we age [Music] so our optimal aging initiative as named is extremely ambitious but we have incredible scientists here so I have no doubt that you'll be reading and hearing more about our really fantastic discoveries coming out of our laboratories within this this initiative and today one of those researchers highlighted in our film you're going to hear from directly I am pleased to introduce dr. Gerry Shadle he's professor here at Salk and be Audrey Geisel chair in biomedical science he came to Salk via Yale School of Medicine where he was a professor in the department's of pathology and genetics and was director of the Yale Center for Research on Aging dr. Shadle earned his BS a few years ago in chemistry from the University of Nevada Las Vegas received his PhD in biochemistry from Texas AMM a and M before being a fellow in the Department of developmental biology at Stanford so his studies have taken him all over the United States he's received many many honors for his research including the Amgen outstanding investigator award breakthroughs in gerontology award Glenn award for research on biological mechanism and aging you don't want to hear me just keep on telling you about it his awards he's really smart he's done lots of great stuff and when he's not in the lab he enjoys spending time with his wife daughters enjoys outdoors and music and he's an all-around really nice guy help me welcome dr. Jerry Shadle well thank you sure that was a great introduction I really appreciate it and thank you all for coming wow this is a packed house I am really excited to talk in such and such an enthusiastic crowd so first of all think some thanks for all the support you're given to the salk and your interest in the science that's going on here I came here two years ago as Cheryl mentioned from Yale and you know one of the primary reasons I chose to move to sulk was I had a had been studying Aging but I really wanted to do more impactful aging research and really try to get into neurodegeneration research and you know there's a strong history and in neuroscience and neuro degeneration here at the Salk and I thought you know this was my opportunity to marry those things together and through this initiative we're doing that so it's almost as soon as I got here this started developing and turned my Wi-Fi off here a minute and we got a huge grant where though we talked to was talked about in that video where multiple labs are together interacting to try to solve the role of aging and in a major agenda everybody's Alzheimer's disease so I couldn't be more excited to have all of that just line up the way I planned it that's like one of the few things that ever you know nothing ever goes as I plan it so it actually surprised but really it's an amazing place and it's been the best move I've ever done this tis to be here so today what I was going to do is talk to you first a little bit about this Salk optimal aging initiative and unpack it a little bit from what you heard on the video and then I'll tell you two short stories from my own laboratory about mitochondria and sort of a different way to think about how mitochondria might be involved in Aging in sort of the traditional way and so I hope that'll be interesting for you so oops I guess I need to start the show we have great IT staff here too so as as I already said on the video age is in fact the biggest risk factor for most diseases almost all diseases and this graph really shows sort of the the risk of death as a function of age of different disease diseases that you can get and as you can see some of them like cancer and heart disease sort of just steadily the increased risk for that to steadily increases as you age but others like Alzheimer's disease and a kidney disease you know really take off after certain decades of life so that just shows you that there's different aging trajectories for different types of pathology and we really need to try to understand what it is about aging that is causing these types of increased risks at certain times in the life span of a person and really the the promise of aging research really is right now the way medicine is practices it's all siloed there's people who study there's cardiologists there's neurologists etc and each disease is treated individually more or less but if risk is rage is really the biggest risk factor for most disease if we could understand why and in attack those pathways we might be able to start preventing multiple diseases at once and what that will do will lead us to have healthier live healthier longer or increase what we call a health span so the idea is not really to make everybody live to be a 200 years old it's to live healthier longer while we're alive and the way we think we can do that is by understanding the pathways of Aging and how those are intersecting with pathways of disease so why is this such an important problem with it's a huge problem in the United States and in the rest of the world but in the United States the baby boomers turned 65 in 2011 that's a lot of people and so in the number of people are going to be 65 and older in 2050 is going to double and the people that are going to be 85 and older is going to triple so in other words our demographic of our society is shifting towards a more aged pop and I just told you that agency's biggest risk factor for those chronic diseases that means chronic diseases are going to increase with over the next two decades and that's a big problem because it puts a huge burden economical burden on the country there it caused soaring health costs it puts burden on younger folks who have to take care of elderly folks it limits the workforce availability in other words it's this is a huge socio-economic problem and something we need to really hit head-on and so that's the other reason I think this is a critical right now to be studying aging research to try to combat this this rise in chronic disease that's going to be coming up so what about aging so aging is complicated that's one of the reasons we haven't solved it yet and this is a really nice diagram showing that there are multiple different biological systems and mechanisms that we know are involved in aging that go haywire with aging and as was pointed out by dr. gage in the very first part of that video many of us study these individual cogs in this wheel but as this demonstrates all of these are intersecting with each other one system can impact another and so what we really need to do is sort of come out of our shells and start working with each other so that we can understand what these intersections are between these different aging pathways and how we can come back combat them furthermore there's obviously environmental influences on Aging as well exercise diet toxins pathogens other fun stuff so we need to understand all of these types of interactions if we're really going to try to solve this problem and so just to point this out and why Salk is a perfect place to do this is if you look at the existing aging research itself as was alluded to in that video we have experts in most of those cogs in the wheel there and so they're already here and so what we need to do is it work together to try to understand these intersections and to get a broader understanding of age and how we might intervene as John Carlos later pointed out in the video there is already a Glenn Center for the biology of Aging funded by Paul Glenn Foundation that's been here for 10 years or so and as I already pointed out there's a great strength in neuroscience so I think there's a real opportunity here and this is the thing we took advantage of first is to really focus in on age-related neuro degeneration as our first target and year or so ago we received a really nice grant from the Alan AJ Institute which funded collaboration between ten labs here at socks so you heard from five of them on the video there's five more that were funded by this and we're all working together to really try to attack the problem in the way I've already stated that is we want to look at the different hallmarks of aging understand them in the context of an aging brain and then understand how they're intersecting with each other in order to understand aging more comprehensively and really the breakthrough event that allowed us to really come together and culminate around this idea was from dr. gages lab where he was able to show that you can take skin cells from different aged people and directly convert them into different types of cells in the brain for example you can take fibroblasts and convert them directly to neurons for example and you know we'd known how to do some of this stuff for a long time actually and the way we used to do it you go through what's called an induced pluripotent stem cell stage and when you do that you sort of erase all the aging features of the cells and so that's not that's not good if you wanna study aging right so what he was able to show that if you do this new direct conversion technique you maintain a lot of the aging features of those cells and now you can make an aged neuron in an aged aster stud in an aged vasculature etc and if we can do that and we're working on that we can study the five systems and each individual cell type we can mix those cell types together and what's called an organ eye and ask how the different cell times that are interact with each other and this generates a massive amount of data and so we need computational methods and machine learning methods to try to understand the network of what's going on and we have great biologists and computational biologists here that are going to tell us what it all means at some point so that's sort of a broad goal this is an 8 year grant it's very ambitious there's other aspects to it that I don't have time to get into but this is really what we felt was a cornerstone or a nucleating event for a bigger initiative on Aging which we're calling the optimal aging initiative and so really what we want to do is expand this project if that wasn't big enough right we're gonna even expand it further we want to understand the role of aging and other neurodegenerative diseases and other types of age-related brain pathology so we want to make it a bigger than it even is we don't do anything small here itself we just we just sort of go for it right and then the whole other aspect which to be honest we're still developing exactly how to go about this but you know clearly it's fine to understand agent but you really want to intervene and do something about it as I stated right so we really want to have another arm of this initiative where we're trying to find interventions that can actually counteract some of these aging pathways and prevent disease pathology so that's the goal the bold idea and in terms of those interventions this is where we can sort of bring together many other people at the Institute who are working in other areas that are important for aging for example we have experts that are working on diet and circadian rhythm I think Asajj and panda talked was the last speaker at this event talking about fasting and how that can be beneficial if you do it right we have people who are experts in metabolism and microbiome the bacteria that live inside your body and how that impacts your physiology we have great immunologists who are working on inflammation and other immune related factors so we think these are points them that we can intersect and intervene in aging and we want to build out the initiative to target those pathways and that takes a banner of existing centers here Sulc are ready so we're looking this is a broad initiative and I think in the end you know it could probably involve I don't want to say all but it could probably involve 75% of the investigators here at the song all right so then just to close this part out and then get to mitochondria I know that's why you came right this is we sort of view it as a top-down approach and that is you know we're gonna focus on the brain aging and the neuro degeneration as I already stated first and we think that's a can be a template for and that's a huge problem this is cognitive decline it's nerdy generation this is a huge issue currently in the United States and but we want to use that information that we gain from it from that to ask how other parts of the body age as well and I think we'll learn a lot from what we're from focusing on the brain first but then I think it'll be applicable to other tissues and organs in the body and then again the the really the idea is to if we can understand that we can stop fighting disease as one at a time and target these aging pathways as a way to more globally affect the body and have a huge benefit at for people as we age and so we can live healthier longer so that's the goal so we're passing the hat around now if you want to back that okay so I'm gonna switch gears now and talk a little science if that's all right and tell you about a couple of stories from my lab and they'll have both of them have cute names which is I think will be entertaining for you by the way this was a good opportunity for me to show off the artwork of my daughter my 13 year old daughter Jayden who made this I actually asked her two days ago I said I'm commissioning you to make me a really cool piece of art that I can put in my talk and she said how much you're gonna pay me and I said I'm gonna feed you so get the word okay all right so it goes back to this idea of this energy these these hallmarks of Aging and of course one of them is what I work on mitochondria and I think you could argue it's the most important one rusty fiber wouldn't have agree with that you might though actually he's coming around he's actually kind of a mitochondrial guy now that's it so what our mitochondria I'm sure most of you have at least heard of mitochondria you might remember from high school you know what it well does he what is it what's this moniker that's a good one but not a storehouse that's like I've been or something the powerhouse of the cell right come on that's it so what is it so if you think about a cell a cell's made up of many different functional units called organelles and these are different membrane bound or other large structures that are inside all of your cells that each have specific functions to help the cell work in fact there we you can think of it as if it takes a village right so this you know you can think of it as a village of organelles that are that are working together to make the cell work so what do you need in a village well first of all you need manufacturing you need to make stuff so there are organelles that make proteins or organelles that make nucleic acids and things that you need for a cell to work you need infrastructure you so there are railroad tracks and roads that run throughout the cell to give the cell shape to give it infrastructure that give it allow things to move around inside you need distribution and global trade so there are organelles that sort out components and move them to where they need to go even send an outside you have to have international trade too so there's lots of things going on here you need a trashcan so there are organelles that get rid of the trash you need an IT unit and so the nucleus that's where the DNA is right where you get half from each of your parents and that's sort of the blueprint for everything but you got to keep the lights on right so you got to have something that's allowing the energy that you need to do all of this stuff and that's what mitochondria are and that's what we're going to talk about today so what does it mean to be the powerhouse of the cell what it actually means mitochondria are they have two membranes and on this inner really cool folded up inner membrane here there are large enzyme complexes in there there's about he's about 80 different protein subunits in these huge complexes and what they do essentially not essentially what they do is when you're eating your food that gets broken down into smaller constituents like amino acids glucose sugars fatty acids etc those get fed into the mitochondria and the high-energy electrons from that food get transduced down this system and extract the energy from those molecules and what they do is a pump protons from one side of that membrane to the other and protons are charged particles a positively charged so if you separate charged across a membrane you make a battery right and so you can utilize that battery and we do this enzyme here it's called the ATP synthase it zips those protons back through extracts the energy from that and makes this really high-energy bond into what's called ATP or adenosine triphosphate ATP is the energy currency of your cell it's used for everything you need to do for to think to move your muscles to fight infections everything and so you're eating and you're churning out ATP in order to do everything your cells need to do your tissues need to do and you need to do and the key point key additional point is to oxidize your food you need oxygen and this is actually the reason you breathe this is the reason you've eaten breathe is you need the oxygen that's the last place the electron goes in this chain so you're breathin to fuel and fire up into mitochondria to oxidize your food to make energy powerhouse of the cell one issue with the oxygen dependency on this is the following so normally what happens it's a beautiful system the electrons get put onto oxygen and they make water no big deal right but unfortunately sometimes the electrons hop off the bus a little bit early and get onto oxygen and they can form a molecule called superoxide and that can be converted to another molecule called hydrogen peroxide or hydroxyl radical these are things that are called reactive oxygen species or ro s these are damaging molecules they can damage your genetic information that can damage your membranes that can damage your protein damage anything essentially and this leads to oxidative damage and oxidative stress and this is a known way that when mitochondria start misbehaving contribute to diseases and aging so sort of a damaged mediated concept and so in fact there is a long-held mitochondrial theory of Aging and the theory goes as follows and so you have your normal mitochondrial metabolism that I just described to you but you sometimes make our OS and that our OS can cause damage and if that gets out of control you start to mess with the formation of the skin zaimes that are actually producing the AR OS and they make more our OS alright and if that keeps happening now you got a cycle of that's going to lead to even more ro s more damage you can imagine how this could fuel it forward and can be really a deleterious situation and in fact in the end that can lead to an energy crisis in your cells lots of damage and even death of cells and tissues and that's thought to be a driver of age-related pathology you can also envision how environmental toxins mitochondria are kind of a sponge for environmental toxins infections and in fact mitochondria in different way inflammation other disease states can actually impact in anywhere along this chain here and exacerbate the situation so that's sort of the standard mitochondrial free radical theory of Aging and of course antioxidants are why are what you would do to get rid of this because antioxidant rid of those ro s and could be beneficial right this should be right well unfortunately it's a little more complicated than that and this is where my laboratory has contributed that you know life's never as simple as it seems at the very beginning and there's actually a lot of controversy you know there's a lot of evidence for this and there's a lot of evidence that doesn't support this and I'm going to show you some something we discovered a few years ago that sort of contradicts this idea and what we did is we were actually working doing very fundamental research on yeast yeast is a single cell eukaryotic organism it has all those organelles I talked about but you can actually use it not only to make bread and beer and champagne etc but to actually understand fundamental aspects of cellular aging and what we actually showed was that if you give a yeast cell a little bit of mitochondrial stress and make a little bit of those reactive oxygen species it actually extends their lifespan doesn't make it shorter that's completely opposite of what you'd expect based on the mitochondrial theory of aging right so that's cool what's going on I'm gonna talk to you about something called hormesis so let's say you art if you are being exposed to any toxic substance any poison whatever usually what happens is the more you take the worse it is for you right it just there's a correlation between how much exposure you have and how how much damage it's doing but some compounds actually at lower concentrations have a beneficial effect before they have a toxic effect this is called hormesis and actually you know Nietzsche actually knew about this because what doesn't kill you actually makes you stronger but I think I don't read German but I'm pretty sure there's a chapter in there of what is hormesis my toe hormesis and so so that discovery in yeast actually and others had shown in other model organisms that similar things were happening and so there's concept now of NIDA hormesis that a little bit of mitochondrial stress can lead to adaptive cellular and systemic changes are actually beneficial for you and in yeast and other organisms can actually extend lifespan ie are anti-aging right so we assure a couple years ago that we wanted to know how yeast is fine I mean you know nobody's gonna ride home tonight and say wow they made a yeast Olivia longer that's great maybe the wine industry or somebody would like that but that's not what you're interested in so we actually did an experiment in mice a few years ago to try to test out this theory is this happening in mammals and if it's happening in in lower mammals like mice maybe it's happening in people and this is something we can do and so what we actually did is we spent like forty thousand dollars and made a mouse that I could actually allow you to do this and what we did is we were able to give mitochondrial stress by knocking out an antioxidant enzyme inside mitochondria inside of pregnant mouse so we could cause a little bit of stress to the embryos inside the mom without her getting any stress so we're only giving stress to the babies the embryos they weren't even babies understand embryos and some of them got stress and some of them didn't and then we let the let him be born and they were no longer experiencing stress and asked were there any changes in their tissues or did they was there any difference between these mice and so the first thing we looked at was liver and what we found was really super interesting is that in the liver of the ones that saw the stress there might occur day had more mitochondria they had remodeled their mitochondria in a way that they're making fewer of those toxic reactive oxygen species and they've up regulated cellular pathways that would normally get rid of reactive oxygen species so that would be my toe hormetic or protective effect and we actually show we took cells from those mice and I we showed that the ones that saw the stress actually were resistant to a second exposure to oxidative stress so they were protected compared to ones that did not see the stress what doesn't kill you makes you stronger so we believe that these might automatic pathways are operating in mammals now we want to understand the tissue specificity of it and we also want to start aging these mice and see if they live healthier longer and if they do I think we'll try to figure out what the actual signal transduction pathways that are leading to that and those are things we can target hopefully as a health span mediating therapeutic all right that's Story number one the second one yeah like I told y'all have cute names this one's my Toph LeMay shin now okay so my toe hormesis is might inflammation you could say that I have a kind of a one-track mind when it comes to mitochondria all right so what do I mean by this this is actually a really really cool equally cool story and to start it off I wanted to emphasize that there's something everyone knows and that is with aging there is low-grade chronic inflammation in your body all right and that inflammation is a contributor to many of the age-related diseases that we know our age is the biggest risk factor so there's but nobody knows actually excuse me what the cause of this information is and so I'm going to give you one hypothesis I have not proven this but this is what we're working on so I have to tell you another fun fact about mitochondria first and that as mitochondria actually came from bacteria so 2.5 billion years ago which was right after I graduated from UNLV people still argue about how this actually happen because we don't really know but the idea it was there was an ancient cell and there was if there's probably two different weird bacteria in fact that started commingling together and eventually decided that it was more beneficial to stick together than be apart probably for metabolic reasons or because of the environment in the earth and etc but eventually one of those bacteria became what we now have in US which is mitochondria so they actually came from bacteria well bacteria are free living single-cell organisms too they don't have a nucleus but they have DNA and turns out that your mitochondria have DNA too so normally when you think of DNA I'm sure you think oh well half came from mom right I mean half came from dad but actually a little bit more comes from mom so your mitochondria actually have this circular mitochondrial genome that only comes from the mother it's maternally inherited in mammals and I encourage you to do this tonight there is a really cool video called a biologist Mother's Day song where this guy does this beautiful song about all the things you get from your mom and including mitochondria and other stuff from the egg right the eggs huge just sperms really small okay so you get lots of stuff from your mom but this DNA is the most important thing because it's actually encode genetic information and can cause problems so what is that mitochondrial DNA do well not surprisingly that mitochondrial DNA has genes in it it actually has 13 genes that are subunits of those complexes that make the ATP alright so a subset of come from the mitochondrial DNA see here the rest come from the nucleus and get imported into the mitochondria to assemble with those so the mitochondrial DNA is part of this energy you transducing system well DNA is DNA I mean TNA gets mutated or if you get that can be pathogenic and mitochondrial DNA is no exception in fact there are now over 200 known pathogenic mutations in mitochondrial DNA that cause maternally inherited human diseases all right so this is a big area I'm not going to go through they're super complicated I'm not but I don't need to go through that but the other key point is that mitochondrial DNA damage and mutations also accumulate with age in you as you get older so the not only the mutations that you inherited them you're also gaining more mutations in the mitochondrial genome as you age that's part and parcel of that mitochondrial theory of aging idea and if you actually look at the pathology that's caused by those maternally inherited and other forms of mitochondrial diseases if you look at the pathology they caused in aggregate it actually overlaps quite remarkably with age-related pathology so I think it fits this paradigm or at least it's consistent with the idea that dysfunctional mitochondria it could be involved in aging but again I'm going to tell you a completely different way I think mitochondrial DNA is maybe impacting aging and that's as follows we discovered a few years ago now that normally the mitochondrial DNA is all the way inside the mitochondria member I told you there's two membranes there's the purple there's two one outer membrane and then there's this inner weirdo membrane and the mitochondrial DNA is all the way inside but we found a couple of circumstances where that DNA escaped it gets outside of the mitochondria and remember this mitochondria came from bacteria right when that happens the sensors that are in your cytoplasm that normally would detect a bacterial infection or a viral infection which have also have DNA get activated and go whoa we're infected with something right but they're not they're infected with mitochondrial DNA all right and what we showed is that when that happens you activate these inflammatory genes in the nucleus so there's a signal that goes from the mitochondria through the DNA all the way into the nucleus to activate inflammatory genes and so now the organelles are talking to each other we've got an interaction between the nucleus and matica and that's a huge new area of biology of how all these organelles actually physically and functionally interact with each other but the key point here for aging is you're causing inflammation from an endogenous source and so that's what we think may be going on I'll show you one movie of a in red here is this is a cell with the the mitochondria is stained red and green is the mitochondrial DNA stained and if you look right here you can see the most you'll see a DNA molecule escaped the mitochondria it's almost Dallas so now it's out it's just kind of like cruising around outside of mitochondria so that actually is what activates this these inflammatory pathways in these cells so the idea I want to leave you with in this with this last story is that you know my Nicandro DNA we showed can activate these pro-inflammatory pathways and so I might add on or alternative to the sort of classic mitochondrial theory of aging is that the mitochondrial DNA it's not from damaged and energetic deficits although I'm sure that it's not mutually exclusive but I think mitochondrial DNA could be getting out and causing inflammation and that could be part of the chronic low-grade inflammation that's happening with aging if that's true we need to figure out how to prevent that DNA from getting out or getting rid of it when it gets out or inhibiting the pathways that are being activated when it gets out and those what again I think could be potential targets for age-related pathology and if you just sort of broaden this out it's now been shown that the RNA from the mitochondria gets out and activates different sensors and you know again they came from bacteria there are other molecules in mitochondria that look like bacteria when your cell seems bacteria it thinks I'm infected and does an inflammatory response so I think there's a whole biology here that we're in covering that where mitochondria can contribute to inflammation in different ways and of course aging pathogens themselves affect mitochondria and environmental stimuli I think is a way where these other factors could happen so that's what I had to tell you today other than now we've uncovered this pathway I have several really fruitful collaborations with other P is here at Sauk studying the role of this might of flamenco with my wife Susan Keck we're studying this in the context of melanoma we're studying with Diana hard grades we have a new grant on colon cancer I already told you about the Alan h.a initiative where we're looking at aging and Alzheimer's disease and to really try to figure out how this DNA is getting out and it's going on we're collaborating with a super-talented investigator here early manner who runs the biophotonic score here at saw so with that I'll stop I was told I had to stop at 15 after so I got one more minute to tell another joke but I actually I want to end with the most important slide you know none of the work any of us do could be accomplished without really dedicated students postdocs staff scientists technicians et cetera and that's certainly true in my lab as well and so I have an amazing group of people that I work with day-to-day who are super dedicated to science and super intelligent and it's a pleasure to work with them and then I've already talked about many my collaborator collaborators etc so with that I'd be happy to take any questions and thank you for your attention [Applause] hi I just want I know that there's a lot of people who are interested in talking to Jerry Shadle if you could wait until the mic comes to you so that everybody can hear I'd appreciate it do you see improvements coming from the development of pharmaceuticals changes in the environment or changes in behavior I have I think you hit all three of the most important nodes that we need to focus on I think there are a unique opportunities and all three of those spaces that could have huge effects on increasing health spans in humans I think you know one of the big you know let's just talk about diet and which is a behavior and an environmental influence on your genetics it's been known for many many years that caloric restriction extends lifespan and many many different organisms that have spent acid in so reducing the amount of food that you eat to a certain degree to where you're not starving that will kill you can actually lead to a might account for Matic type of effect that can actually lead to beneficial adaptive changes that can be beneficial for healthspan I think Clarice Jackson isn't that fun and that's where Sachi ins work here at the Salk is really interesting because he's really trying to investigate intermittent fasting regimens to where you eat only during certain times of the day and certainly and that can really have an amazing impact on your metabolism and he's shown that there's effects on mitochondria to this so I think best is one example that's not pharmaceutical that's changing your behavior and when you eat can have a huge difference you know exercise exercise you know there it's clear that there's a there's a benefit to staying active and exercising but I don't think we really fully understand what the pathways downstream of that are and we have investigators that saw Ron Eben's etc who are really trying to figure out you know what are the pathways that are activated by exercise and why are they beneficial if you understand the pathways then you have the chance for pharmaceutical intervention to try to tickle them maybe without starving yourself or maybe doing not running a marathon but doing just a little bit of good exercise so I think you're you're right on the money it's a I think all three environment what would be a good environmental example don't smoke yeah cleaner air yeah two questions please going once law a few slides back nadh is that in the nicotinic acid salt which one it was about halfway through the presentation oh sorry NADH yes NADH is a nucleotide and I nuclear tired of nicotine and nicotine Mike thank you and then your comments regarding alcohol in general in terms of inflammation and stress as it might be related overall health and the type of alcohol that you would prefer if you were a drinker well I'm what answer do you want I am a strong believer that alcohol is hormetic so a little bit will eventually make you live longer and I'm just joking so interestingly there were and this ties into nad and maybe this is the genesis of your question but David Sinclair many many years ago showed that there's an element in red wine called resveratrol which actually activates an nad dependent enzyme and can have health spam promoting effects and so I wouldn't say go home and drink a ton of red wine because there's so many other things that are deleterious about that and the physiology on your liver etc but for sure that you know alcohol can chronic alcohol consumption is not good for you it leads to liver fibrosis at least a fatty liver it can even lead to liver cancer so alcohol is not the route in which you want to try to extend your class yeah but I think there are you know the David Sinclair thing I think pointed to an important idea and that is that you may be able to take certain metabolic activators that can have a very beneficial effect but I don't think I'd do that through alcohol itself and it does cause inflammation so recently I've seen the opening of clinics that are offering nad therapy and I'm curious what your opinion is of and where the clinical research is in terms of nad and its potential benefits yeah I mean it's clear that nad declines with age and that in in studies in mice through the mechanism I just talked about by activating these enzymes that are called sirtuins actually has beneficial effects on age-related pathology at least in model organisms I think you know there's a whole I think it's illicium pharmaceuticals that's marketing nad to take for this reason I think the jury's still out on the beneficial effects in humans and there hasn't been any really systematic clinical trial to assess the efficacy of nad per se but I think it's you know it came out of basic biology of aging research it has effects I think it's still a viable area that we should be studying and it's a potential way to to have anti or healthspan promoting effects I think so yeah I believe is it rusty yeah so the NAD interesting in terms of what's going on mitochondria the NAD is actually made inside mitochondria when you're you turn nad into NADH and those are the high-energy electrons that feed that chain to make ATP so there are probably direct effects on mitochondria from nad supplementation but there are many other enzymes that require nad and the other interest the other important thing about nad is it's a couple it's a it's a couple with another molecule at NADH and the ratio of that is important too because it's an indicator the amount of basically oxidative stress or oxidant load that you have in your cells and so it's tricky business to just add in one and hope the ratio stays the same so I think there's still plenty of research be done to figure out if that's going to work out or not but it's on the table for sure I have a question about the mtDNA release yeah where are you that does does that go across all ethnicities so whether you're from Africa Asia India Alaska is it true for all humans you I don't know the answer to that in fact the what I will speak to that I think is an under studied area with regard to might the role of might economy and disease in general is that each of us have a specific type of mitochondrial genome that we inherit from our mom we're not all identical and different ethnic groups have different subgroups of what are called snips different mutations in the mitochondrial genome that are slightly different in function and it's a really an area we don't understand well at all is that what is the role of those in human disease or and I don't know about to DNA released yet this is brand-new stuff but this is left I mean we the scientific community tries to figure out what the genetic basis is for many different kinds of diseases and they do what are called genome-wide Association studies where you look at different mutations and then put together guess what they throw away first though Ida Condor algae no they don't even look at it and try to ask what is are there associations between mutations or snips in mitochondrial genome at compared to the nuclear genome it's completely ignored in the in the community and I think that's a big problem given the fact that mutations cause human disease right I don't know separately there's a point mutation in my county net causes diabetes right and so in a Geo set for diabetes I've never seen an association with mitochondrial genotype ever and I've asked people into in of them why you don't oh it's complicated there's too many copies I don't want to deal with it but maybe I should do that yeah I have my eye I was wondering if there's any interaction between the mitochondrial system to my contract DNA and the immune system can somehow the system that tech mutations in mitochondrial DNA that have caused that to go bad and create antibodies to kill it off and would the cells create new good mitochondria after the bad ones have been removed and do you notice this in people who age well in a people aged poorly is there a difference in their mitochondrial well that's a really terrific question so what I showed you already was activation of the immune system by mitochondrial DNA so if it gets out it's binding to that's an innate immune pathway that's being activated so that you know you're being infected by bacteria or viruses etc so we showed that there's activation of the immune pathway by mitochondrial DNA but your questions a little bit different you want to know if the mitochondrial DNA can produce something that's antigenic and can stimulate the adaptive immune system and yes the answer is yes but there are pathways to prevent that from happening or you'd be autoimmune all the time but there have been a couple of studies by heidi McBride and in Canada who have shown that there is a mitochondrial antigen presentation system and that this can contribute but nobody has looked at it yet in terms of doesn't contribute to aging or any disease state yet but that's a really fantastic question yeah got one behind you first and what promote what promotes might effigy promotes what promotes might Alpha Chi might offer G well so the standard answer to that question you know the the main investigator who first identified my top G the way they did it was to sort of poison the mitochondria - you know I told just like a battery of develops that potential with the protons if you poison that and collapse the battery that's a signal for the mitochondria to go into the autopsy pathway and there's thought to be specific receptors that recognize dysfunctional mitochondria and that's the Mai Tawhiti pathway to get rid of defective mitochondria interestingly two of the mute genes that get mutated in Parkinson important inherited Parkinson's disease are members of this my top og pathway they're called Parkin and pink one and these are actually proteins one of that are on mitochondria they are part of that maitake pathway and so there's data that in fact the MTD and they release that I showed you that when you have defective my tofu Jie you get more of that empty DNA release and activation of the inflammatory pathway so it's a whole new way of thinking about maybe mitochondrial mediated inflammations involved in Parkinson's disease but I think they're I think those are not the only signals for my topic there's multiple different proteins that recognize different aspects of mitochondria that can drive it into the maitake pathway but it's dysfunctional or damaged mitochondria are recognized to be gotten rid of so you can replace them with new ones is the idea have you studied where they're not anti-inflammatories medications have an effect on that breaking through of the DNA that triggers the inflammation we haven't yet that's certainly something wanted it we don't know if there's a feedback where inflammation causes more release and and what's going on there that's part of the what we're trying to understand right now is how we can prevent it either after it's released or prevent the release altogether and actually we're still trying figure out how it's getting out but even but yes that's a real that's a viable Avenue that we're looking into for sure well those were all really intriguing questions after a really fascinating talk doctor Shadle has agreed to stay with us during our reception because trying to keep everybody on schedule I know that some of you don't like to drive during rush hour so we respect that who does exactly but you're all welcome to join us for a reception [Music]

Channel: Salk Institute

Views: 4,344

Rating: 4.8805971 out of 5

Keywords: Salk Institute, Biology, Science, Jonas Salk, www.salk.edu, mitochondria

Id: j6thcFfzcWY

Length: 57min 41sec (3461 seconds)

Published: Tue Feb 18 2020