Mitochondrial Psychobiology and Brain Energetics

Mitochondrial Psychobiology and Brain Energetics UCSF Dept. of Psychiatry and Behavioral Sciences 12.7K subscribers Subscribe Like Share Download Save 867 views Mar 12, 2024 Speaker: Martin Picard, PhD Associate Professor of Behavioral Medicine • Director, Mitochondrial PsychoBiology Laboratory • Departments of Psychiatry and Neurology • Columbia University __________________ Learning objectives Upon completion of this activity, participants will be able to: • Understand mitochondria as a processor and signal transduction organelle. • Define a sequence of hormonal and molecular events linking subjective experiences and mitochondria. • Establish the biological link between energetic tradeoffs and aging. __________________ UCSF Department of Psychiatry and Behavioral Sciences Grand Rounds presentations are for educational purposes and intended only for behavioral/mental health professionals and clinical providers. Transcript Follow along using the transcript. Show transcript Transcript Search in video 0:09 [Music] 0:19 welcome good morning everyone it's great to see such a good turnout for Grand rounds in person and on Zoom it is my 0:27 pleasure to welcome Dr Martin peard to our as a distinguished Grand round speaker today uh Martin is an associate 0:35 professor of Behavioral Medicine at Columbia University in the department of 0:40 Psychiatry he got his PhD in mitochondrial biology at Mcgill and he 0:46 did a postto at University of Pennsylvania with Doug Wallace studying 0:51 organel to organism communication his focus is linking this 0:57 to The Human Experience with molec and energetic processes inside the 1:03 mitochondria and it's actually mindblowing and remarkable about his 1:09 discoveries and how the mitochondria are social in nature how 1:15 they communicate within the cell and all the way to the brain and shape 1:22 Human Experience subjective experience and as we'll see mental 1:27 health he has a very vibrant lab a a large research group the 1:33 mitochondrial psychobiology group they combine clinical cellular and computational approaches to understand 1:40 how energetics and perturbations with mitochondria including people with mitochondrial disorders uh interact with 1:48 key brain body processes that both shape aging biology as well as human positive 1:55 Health he is a very integ creative and big thinker about a tackling questions 2:03 such as what is whole organism aging how is it related to cellular aging I have 2:10 to list some of his foundational discoveries he won't have time to mention them today um these were just 2:17 years ago but to him they're decades ago because he moved so fast so some of the foundational discoveries he's made 2:23 include uh study uh discovering that the mitochondrial Behavior inside the cell 2:29 follows social principles like the precursor of social behavior between cells of the body and the social factors 2:37 that operate between people he's discovered that mitochondria build 2:43 tubular structures and align their chiste provided the he provided the 2:49 first physical evidence of non-molecular communication transfer between mitochondria which is a foundation to 2:56 thinking of mitochondria as cellular antenna an information processing Network so he has created a paradigm 3:04 shift in how we View and understand how mitochondria function and work he's also 3:10 discovered that during stress mitochondria release their DNA into the 3:17 cell and so you can measure cellfree mitochondrial DNA as an indicator of 3:25 health and stress responses this has led to the idea that mitochondrial DNA acts as a hormone as a 3:33 communication signal to help promote both adaptation and resilience in terms 3:39 of his translational discoveries you might have read about him in the news a few years ago he published a paper 3:47 tracking people's life events over time and and examining their hair graying and 3:53 found that hair Grays in dose response fashion to stressful life events and 3:58 reverses so he was studying healthy people where the cells could actually still recreate 4:06 pigment okay so I will just end with that Martin is one of the most fun and 4:13 generous collaborators and mentors and many of us here um I'm looking at my 4:19 colleagues like Owen have had the opportunity to collaborate with him over the years and continue to do so he is a 4:26 a teacher of the public he has an amazing uh social media education program going on and masses of followers 4:34 the world is interested in mitochondria Your Time Has Come welcome 4:45 Martin well you've heard about what most of what I wanted to tell you about today thank you Alyssa it is so nice to 4:52 be here um beautiful building first time i' I'm in this building I was in in the 4:58 mission B campus 12 years years ago I think and this looked nothing like what it looks like today so the growth and 5:05 all of the exciting work that's happening here I'm really inspired by uh 5:10 and I was really excited to be asked to come and share some of her work on mitochondrial psychobiology with you uh 5:17 what I want to do today is I'll show you some data and I'll show you some of the things we've measured uh but mostly I want to convey some principles 5:24 bioenergetic principles if we think about the human organism if we think about the mind if we think about the 5:29 body from an energetic perspective how can this help us understand and develop a more holistic and accurate picture uh 5:38 of of what health is and what we can do to to support it so this is a little you know summary 5:46 of the the kind of things that we care about right the ability to to have cells proliferate maintaining your stem cell 5:51 pool respond to stress responses uh have neurons that fire and depolarize and 5:57 communicate with each other brain function cognition immune regulation wound healing healing physical wounds 6:04 psychological mental wounds uh and then development in aging Every Little Bit Of 6:09 Human Experience and human activity requires energy where does that energy come from 6:17 and uh as as you might suspect or as you as you probably know might a lot of the 6:22 energy that we consume come from mitochondria and specifically in 6:27 mitochondria what happens is that there's this very elaborate chain of of 6:32 processes uh and called the electron transport chain or the respiratory chain where carbon substrates or uh 6:41 disassembled and electrons are actually taken off of the carbon substrates flown into the electron transport chain and 6:46 this uh Quantum process of electron transfer actually leads to the production of a gradient an 6:52 electrochemical gradient so we have uh this little battery that gets charged 6:58 with uh this this transfer of charges and then the charge is used to make ATP at complex 5 as well as many other 7:06 things so mitochondria have dozens of functions many of us know mitochondria as an ATP producer but it's actually an 7:12 energy transformation platform that has dozens of of other functions but then you can ask well 7:18 where does that energy come from the energy that that actually fuels a mitochondria and as you know it comes 7:25 from the food we eat and the oxygen we breed so we ingest carbon substrates we 7:30 breathe in oxygen uh and then that those fun all into mitochondria and that the 7:35 energy to to make those products actually starts in Plants right so plants have this beautiful ability to 7:41 take CO2 water and then with uh a few reactions actually make the carbon stuff 7:48 that we eat the oils the fats the proteins the carbohydrates and then make to oxygen the reaction inside the 7:54 mitochondria generates very interestingly carbon dioxide and and water so EX what plants need so 8:00 mitochondria closed this life cycle between the the Plant World and and the animal world then you might ask well 8:07 where does that energy come from because energy is never created nor destroyed so 8:12 that energy comes from this nuclear reactor that sits out there in in outer space so there's Quantum electrodynamic 8:19 processes that happen in the sun you have nuclear fusion creates this energy wave right this immaterial form of 8:25 energy beam down as light as photons to to onto chlorophyll and pl and plants 8:33 and then this whole Cascade starts so some would say the the light of Consciousness comes from outer space is 8:39 materialized into chemistry and mitochondria have the ability to unpack this chemistry back into an imerial form 8:45 of energy is electricity and then this Powers the human body it Powers a human 8:51 mind and and Consciousness so if we put this into context right what we're looking at here 8:57 is a MIT entric View of the world uh so you have mitochondria there and other 9:03 organel that are here in the middle this is the the energy transformation Hub of cells right and we know mitochondria 9:10 talked at a nucleus where that's the the passive repository of about 20,000 genes 9:15 that are brought to life right by by the energy flow from mitochondria U and the 9:21 communication between the mitochondria I won't talk about too much but is critical for the health of the mitochondria for the health of the cell 9:27 um and it is a communic ation between the mitochondria actually allows cells to then communicate with each other and 9:34 then we we know that communication between neurons is the basis for cognition or memory most likely and for 9:40 immune responses and so on and then the ability of cells to talk to each other is actually the basis for functional 9:46 organs right so what makes a functional brain and functional brain networks is the communication between its different 9:52 components and then we know that communication between organs is actually what makes a functional organism so we 9:59 need the brain and the heart to talk with the liver with the kidneys and and it's the the whole social ecosystem of 10:04 organs within the organism that makes health and and life possible and then once you have a 10:11 functional organism then you can have people talk to each other and exchange information so it's and then like we're 10:17 doing this morning we're exchanging information and we're creating uh better and and and greater things together in 10:23 communities so there's flow of information from mitochondria right this little energy Transformer and inside the 10:30 cell uh out to cells to organs to organisms and then to to communities but 10:35 very importantly there's flow of information the other way around as well right and the forces the social forces 10:40 that we experience at the interpersonal level also Ripple down to influence our brain to influence our heart and to 10:46 influence our cells and to influence our mitochondria this is what mitochondrial psychobiology is is about uh and one way 10:54 to think about this we need to break this down into hypothesis into testable questions how do we do this so this is 11:01 one model very simple model where you have psychosocial factors that we experience on a minute by minute basis 11:08 on a day-to-day basis they shape aging biology they shape aging physiology and 11:13 and how the the the human organism functions here many of you will 11:18 recognize this as a castet as a mediation model right so we're asking could it be the mitochondria and the 11:24 accumulation of mitochondrial disregulation we call mitochondrial allostatic load uh building on the systemic allostatic 11:31 clo concept from Bruce mccuan could it be that mitochondrial disregulation mitochondrial allostatic clo actually 11:37 mediates this relationship right that psychosocial factors and chronic stress 11:43 let's say has effects on Aging biology because it affects MIT quria so there's 11:49 a few pieces each Arrow here is can be turned into a hypothesis that's is 11:54 testable and we've been for the last few years at you know trying to test different facets of this of this model 12:02 and the idea behind mitochondrial psychobiology is that uh it examines the interactions between the subjective 12:10 Human Experience psychological States and the molecular and energetic processes that happen in 12:15 mitochondria um and there there many open questions more open questions than than answers at 12:22 this point but what I'll do today is is tell you about some of the uh questions that we've been asking using this model 12:30 and I'll start with hair gray that Alysa mentioned uh hair gray is a Hallmark of 12:35 aging and who knows about the the beautiful wheel Hallmarks of aging from 12:41 Lopez Orton and and others okay so a few people um so this is a physiological 12:48 Hallmark of Aging right everyone who ages gets gray hair at some point and there's a large variation of people 12:53 start in their 20 some people uh start much later but there's this is something that happens in in uh in humans uh and 13:02 one question that's been around for a long time is whether life stress is linked to hair grain who thinks that 13:10 life stress can cause gray hair okay we have a 13:16 majority not it's not unanimous but we have a majority so there's actually not a lot of good research on this and uh up 13:23 until a few years ago there was no objective quantitative evidence that life stress was actually l to to hair 13:30 graying but when you think about hair graying there's another thing that's really striking is on the same person 13:36 you look at a person that has a given genome right and that has a a given experience and a given set of exposures 13:42 and U on the same person you have hairs that are dark and seemingly you know 13:48 youthful and then you have hairs that are gray so there's this heterogeneity right and and every every hair has the 13:54 same genome right and all of these other exposures so what makes one hair go Gray when you're 30 and one hair remain dark 14:02 until you're 60 if we could understand this we thought this could 14:07 actually uh open some interesting um ideas about What might explain the inter 14:14 individual variation in how we age and why some people age faster and or slower 14:20 than than others uh so can we learn something from the heterogen and hair grain so these 14:26 were the two motivating question that initially brought us into thinking about about hair grain and uh so Shannon and 14:35 and IET two uh young students in the lab started to go with this and then what 14:40 the the remarkable finding at some point is that we were thinking what if it what if you could find a hair that's dark 14:46 right the tip is dark but then the root is white so and then you you could actually pinpoint in time if you know 14:52 how quickly the hair grows you could say ah like two months ago something happened and the hair that was youthful 14:59 and and dark actually turned old and white right it lost pigment so we could situate in Time Life events that would 15:06 correlate with with hair graay and uh my partner Mary actually found two hairs as 15:11 we were talking about this in the living room she said well I've had hairs like this that are two colors went to the bathroom came back with two hairs that 15:17 were plucked that a segment was dark a segment was white like who okay we have to study this so how do you study this 15:25 so the idea is is this that you have in the hair uh follicle which is this 15:31 little mini organ that lives under the skin every hair has a little follicle this is from which the hair grows um 15:38 this is you know now and then the tip of the hair is older right and then as the hair grows the same segment gets further 15:45 and further away from the body so if you don't cut your hair you actually walk around with a bit of biological history 15:51 attached to your scalp and people have used this to study cortisol and you can if you take like three centimeters of 15:57 hair that represents roughly three months of like cumulative exposure to cortisol so they and also people youve 16:04 use this to look at chemical exposure and and toxicity and things like that so we thought what if you can pluck a hair 16:10 and then you can digitize it you put it on a high resolution scanner the same way you scan a a picture in the old days 16:17 uh and then you could actually make a profile right you you would track along a hair the hair is dark dark dark dark 16:22 and and boom it goes white um and so this we call the Hair pigmentation uh profile or hair pigmentation pattern so 16:29 you would say the hair is dark and then it Grays and then you can ask what happened here but this was the idea and this is 16:36 one of the most remarkable hair so we started to sample people and we asked people to send this hair in Ziploc bags 16:42 through the mail uh and then this was one of the most remarkable hair what we're looking at here is the air from an 16:47 Asian 30-year-old woman U and this was beautiful because the part away from the 16:53 scalp the older region was dark and then there was a white segment right that hair 16:59 got got old it lost pigment and then it regained pigmentation so you see on the right here the hair pigmentation pattern 17:08 the hair was dark a grade and then it went back to being dark again fully Rec full 17:13 recovery um so then we ask well what happened in this person's life right so 17:19 we developed a little survey uh to uh to quantify this and uh the survey 17:25 basically asked people take your calendar take your phone whatever you know modality you use and then now is 17:32 May and then go back a year right the past 12 months and then Mark on on this 17:38 little chart with these grids the most stressful time of the past year and then 17:44 for her was very easy most stressful time least stressful time okay least stressful time and then Mark notable 17:50 events in the past year six to eight notable events and then you do this then you connect the dots right then you get 17:55 this profile retrospective profile of stress not great but better than nothing 18:01 in this case it was it was um fairly convincing she said well I was doing my 18:07 PhD and it was pretty stressful uh and then the most stressful two days of my 18:12 two months of my life personal relationship issue broke up with her boyfriend do I move to the 18:18 east coast do I not she Liv in California uh and then there a lot of you know life um dilemas like I think 18:27 many of us have have experienced most stressful two months of her life then she moved to New York City finds this new job reunites with her boyfriend 18:34 stress drops this is a stress profile aligned with the hair if you do a statistical test it's 18:41 highly significant right something happened in her subjective experience that translated into hair biology and in 18:49 this case hair grain which was remarkable so this was the first quantitative evidence of a link between 18:56 life stress and and hair graying again retrospective the best way to do this would be to do this prospectively 19:03 but then we were about to ask well what changed biologically right how does this happen and then behind the back of her 19:09 mind could this have to do some something to do with mitochondria so we did proteomics and then we contacted 19:15 some proteomic scores like proteomic on hair forget it especially in a single hair but what we did was to take the 19:22 single hair chop it into pieces and then to do proteo mix on single pieces of single hairs so this was a proteomic 19:29 toward the force I was told it was really challenging for sure but what we learned was that there's a bunch of 19:35 proteins in the hair that were upregulated when the hair loses color and then some proteins that were down 19:41 regulated as expected maybe you lose color you lose other things but look at the proportion there are many more 19:46 proteins that were upregulated in the white hair that were down regulated and then you can visualize this as a volcano 19:53 plot some of you might have seen these these kind of plots on the right if something's on the right it means it was 19:59 increased or it was upregulated in the white here and then on the left was uh 20:04 decreased what do we notice here many more upregulated protein right 20:10 so the hair loses color yet it upregulates all these things and then you can do functional annotation of 20:16 those proteins what what are these proteins turns out we did this across two different proteomic core on on a few 20:22 different uh sets of samples five proteins replicated across to 20:28 experiments all of those MIT all of those proteins were mitochondrial proteins so in the white hair as the 20:34 stress happens to the to the hair there's an upregulation of mitochondrial proteins and this 20:41 uh we found this at the same time as this other paper was published in in nature in mice showing that if you 20:47 activate the sympathetic nervous system you expose mice to stress norepinephrine actually causes hyper metabolism it 20:53 activates metabolism in the the hair bulb and this causes grain so this started to to make us think could it be 20:59 that there's something among energy metabolism and and mitochondria that's it actually plays a causal role in hair 21:06 grain and and uh and in human aging some kind of energy deficit uh so Natalia and the lab who 21:13 partnered with julin and Alysa and uh started 21:19 a an analysis in vitro in a very simple model of cellular stress and uh this was 21:26 building on data from Gabriel who was here in the audience who uh was courageous enough to do a whole cellular 21:32 lifespan study a longitudal study of cellular aging uh and this is how Gabriel did 21:39 this he took cells from a few healthy people put them in a dish right each dish now becomes the the surate for this 21:46 for this person uh and then every five days passage those cells for a whole 21:52 gestation period nine months nine months uh without missing a week your real 21:58 Passage cells for up to 42 time points uh and then because this is launch tunal 22:03 every five days that you pay put yourselves from one dish to the next you can actually take a little sample right 22:09 so it's like doing a blood draw uh if you were to do a launch study in a person then you can measure how many 22:15 cells are there how quickly they're dividing or how slowly they're dividing uh how big they are you can measure the 22:21 metabolic rate by putting them in this instrument uh you can sample DNA right and then if 22:28 you you measure DNA ventilation tele length mitochondrial DNA copy number uh you can measure the the Integrity of the 22:35 The genome mitochondrial DNA deletions can do RNA sequencing so you can ask what are these cells trying to do right 22:41 which genetic programs are activated which genetic programs are are being repressed and then you can look outside 22:47 of cells as secreted factors which would be the equivalent of looking in the blood and you can query your favorite 22:52 cyto age related cyto uh inter luuc insx for example or gdf15 this interesting 22:59 marker of metabolic stress or cell-free mitochondrial leing which mitochondria can can release um and cells can release 23:06 and under certain context but this is a cellular lifespan data set um Gabriel 23:12 published this as this multi Oma L little aging data set uh this data set is available if anyone's interested 23:19 Gabriel created this beautiful shiny app you go there you pick the cell lines the donors you want you pick which Gene you 23:25 want to look at and boom it draws you the beautiful TR cies over time you can download all the data visualize 23:31 correlations do PCA all sorts of beautiful things so what Natalia did is she used a 23:37 the data from cells that aged normally under normal conditions without stress 23:42 and then cells that Gabriel exposed a chronic dexamethasone a chronic glucocorticoid receptor agonis so now 23:49 you're asking what's the experience of the human cell chronically being 23:55 activated with the glucocorticoid receptor what Natalia find found is that these 24:02 cells even though dexasone or glucocorticoid stimulation is not damaging by itself but these cells mount 24:08 an an Adaptive or an anticipatory response to to this Challenge and this 24:13 uh is what we call a cellular allostatic load and it involves a number of things 24:19 cells shrink in size they divide more slowly they started to upregulate a number of Gene programs involved in 24:25 making more mitochondria called mitochondrial biogenesis they accumulate mitochondrial DNA damage uh they 24:32 increase respiration so they actually their mitochondria working harder and they suppress glycolysis this other path 24:37 for energy production so there's this metabolic rewiring um and they start to secrete a 24:44 bunch of things cyto and sell free mitochondrial DNA which cost energy so 24:50 what Nala found is that glucocorticoid signaling alone increases energy expenditure by on average 24:57 60% so the cells are there in the dish doing not much in normal if anything they're doing less because they're 25:03 dividing more slowly and they're becoming ccent or quiescent and they're burning more 25:09 energy longterm what does this do if a cell starts to burn energy faster what are the consequences of this and uh what 25:17 Natalia found is that these cells actually age faster and on average 10 to 40% faster telome erosion rate which J 25:26 analyzed DNA metalation cost clocks or the epigenic clocks were accelerated as well about 30% uh and a number of other 25:33 features including cell death uh more the cellular equivalent of mortality was accelerated right so the chronic stress 25:41 leads to an excess energy consumption or transformation which leads to an 25:46 accelerated cell aging so using the cell uh Lipan system 25:54 uh we've been able to ask a number of other questions and um one of those questions is what happens just with 26:00 normal human aging so this is a a cyto array we're looking at secreted proteins 26:07 some of you might know of the syence associated secretary phenotype or the sasp so these are different cyto kindes 26:14 that are part of the SAS these are things that older cells start to make more of and it starts to spit out uh 26:21 what we're looking at here in this heat mapper these are the young cells from donor one this one person and then the 26:26 first time point and then the second time Point third time point and so on for up to 258 days Kudos Gabriel for 26:33 your courage to do [Laughter] that and then the color marks the level 26:39 of the Cy how much there is so notice here this is that the scale if you go from minus five to plus five this is a 26:46 10 unit on a log two scale that's a thousandfold so there are proteins 26:51 virtually that young cells don't make that's young cells have a very nicely contained epig genome and the chromatin 26:58 some genes are very solidly repressed and they're not you know expressed uselessly and then as cell's age there's 27:03 epigenetic drift and transcriptional drift and then some proteins randomly start to be made and and can be 27:09 upregulated up to a thousandfold uh so what we see here is this progression from low levels of protein to very high 27:16 levels of protein across lifespan then Gabrielle repeated this in two other donors where you see the same kind of 27:21 pattern of of age related upregulation so some proteins upregulate by more than 27:27 30 fold across the lifespan this is here the the validation of the specific protein 27:33 gdf15 um I'm curious to know who he is heard about gdf5 27:39 before few people it is at the moment I think the most studied protein in the 27:44 biomedical scientist there's if you if you set yourself a pbet alert for gdf15 27:50 every day you get an email um H so it's it's it's the best uh 27:56 marker of human Aging in terms of prot single protein it's very highly ulated in the blood it's a predictor of 28:02 mortality it's a predictor of uh cardiovascular events it's It's 28:07 associated with a number of different diseases in cultured human cells cells in a dish where you isolate one thing 28:13 the passage of time you see this exponential increase in gdf15 uh that uh 28:18 Peaks around 90 fold on average across people cells also start to secrete cell-free mitochondrial DNA which we 28:25 suspect now are actually cell-free mitochondria so cells are actually spitting out their mitochondria and spitting out mitochondrial DNA 28:32 potentially for signaling purposes this increas is tfold we're not talking 50% 28:38 or onefold twofold increase tfold the cost of building mitochondria the energetic cost of building mitochondria 28:44 replicating DNA and then spitting it out uh is is is high and as well as making 28:50 proteins so what this ends up doing uh when Gabriel Quantified here the the 28:55 amount of energy that cells are burning per per unit of of cell this is the 29:01 equivalent of Basil metabolic rate how much energy is the human body burning per kilogram of per pound of of body 29:07 weight this is equivalent at the cellular level and you see also this exponential increase um that is on 29:14 average fivefold uh from from Young days early days to to end of life but during 29:21 this process cells are actually not dividing right and some of you may know this from hylick the the the hylick 29:27 limit experiments from many years ago where leard hli took human cells and 29:33 passaged them in the dish and then at some point they they sto dividing and then they go ccent or quient right so 29:39 cells are not dividing yet they're burning way more energy what are they doing seems like they're spending all of this energy producing uh proteins so 29:47 syence and quiessence come at a cost there's a lot of energy that goes into 29:53 this building this uh and maintaining this inessence program so I think most of us has sence and quence in mind 30:01 meaning like you go dormant like a bear hibernating or something like this though those terms are misnomers uh if 30:07 you look under the hood or if you if you peel the plasma membrane of the cell you look inside the cell actually there's a 30:13 lot more going on even though on the outside the cells just look like they're staying there doing nothing just like if 30:20 you're in front of your of your computer you get this threatening email that your Grant was rejected or something like 30:26 this and and you say they comp pose inside your heart is beating and your hormones are are going this this hyper 30:32 metabolic State um so why do aging cells become 30:39 hyper metabolic and start to burn energy so much faster uh there's a number of things that happen uh and I won't go 30:45 into the details here but cells accumulate damage and most aging scientists uh agree to say that damage 30:52 accumulation is a major driving force for cellular aging right so you have mutations that accumulate in the D 30:58 there are chunks of DNA that start to jump called the retrotransposons chunks of the mitochondrial DNA can be 31:05 translocated and then integrated like a piece of viral DNA into the the nuclear genome so there're all of these things 31:11 that destabilize aging cells over time these are stochastic you know entropic 31:16 processes this triggers stress responses so cells are not blind or insensitive to 31:23 this they actually Mount stress responses as they accumulate damage those stress responses trigger 31:28 energetically demanding stress responses like protein secretion that I was just mentioning the sasp is a very 31:34 energetically expensive process release of self through mitochondrial DNA transcriptional noise and expressing 31:40 genes that used to be repressed will cost energy for making more mitochondria will also increase the energetic cost of 31:46 the cell and then reshaping Metabolism from using your mitochondria to using glycolosis their inefficiency is there 31:54 all of this converges towards hyper metabolism so it is the stress responses 31:59 in the Aging cells that we think is a driver of the cumulative energetic cost of cellular 32:06 aging and sense and quence might actually be compensation as opposed to 32:11 being the driver of these phenotype stopping cell division might just be because cells are running out of energy 32:17 and they can't afford to divide so aging cells become hyper metabolic that's that's quite clear but 32:24 the whole body does not right so if you think about an aging organism 32:30 there cells here and there that are scattered pretty uh you know sparsely 32:35 that are becoming hyper metabolic yet if you look at an older individual uh the whole body does not become hyper 32:41 metabolic this is the best data we have uh of human energy expenditure across a 32:47 human lifespan from zero to 100 you see this beautiful blip here as the developing Childs are growing and 32:54 developing and building personalities and wiring their brain and learning about the world uh there's this 32:59 beautiful the highest level of energy expenditure is in childhood which might be the basis for vulnerability and 33:06 during this this these critical periods of of development but uh something else 33:11 to notice here those people that are above here right they're burning energy faster this is basil energy expenditure 33:18 how much energy you're burning based on uh relative to what's predicted for your 33:23 your gender sex and your um uh body weight 33:28 uh if you burn energy faster than you should there's a lot of good data showing as in cells cells that become 33:33 hyper metabolic die earlier people that are hyper metabolic also die earlier for reasons that aren't quite 33:41 understood but the whole body does not become hyper metabolic it actually declines at the end of life right so you 33:48 have accumulating cells that are hyper metabolic here and there in your organs yet the whole body becomes hypom metabolic this creates a kind of a a 33:57 question and this is just more data showing that uh with advancing aesis 34:02 from blsa the Baltimore laal study of Aging by Luigi fuchi and if anything 34:08 uh basil metabolic rate de declines in females and in males and this is just 34:13 more recent data showing the the same thing in over a thousand people so sales 34:19 become hyper metabolic the whole body doesn't what's happening this seems like an energetic Paradox right how can this 34:26 happen and we think that this Paradox can be resolved by putting the brain in the picture right if we if we stop to think 34:33 about what we're actually looking at is not a bunch of cells that are just glued together right this is a cell Collective 34:41 that obeys I think what looks like social principles uh and that are regulated by an integrative an 34:47 integrating principle that the brain is kind of in charge to to to mediate um so 34:53 one way to resolve this is to think about the effect of these cellular Hallmarks of aging and the cellular 34:59 hyper metabolism the molecular imperfections the the molecular damage that I mentioned cells in essence this 35:05 trigger signals right the inessence associated secretary phenotype inflammaging maybe some of you have 35:11 heard about this metabolites other factors the brain has evolved to know about what happening in the body just 35:17 like when you're mounting an immune response the immune system makes cyto kindes the brain knows feels those cyto 35:23 kindes and then triggers what's called sickness Behavior right you feel sluggish you want to be in bed conserve 35:28 energy for your immune system so here's similar idea aging ccent cells are producing those signals reaching the 35:34 brain and then the brain says Whoa there's I'm going to run into an energy deficit if I keep going like this 35:41 there's something in in the body that's burning so much energy let me conserve energy this is the conservation energy 35:47 conservation responses and the brain is able we know this very well to produce affective States right to make you feel 35:54 uninterested in life and in others uh to drive sedentary behavior and an activity 35:59 to suppress a production of costly hormone growth hormones thyroid hormones 36:05 uh testosterone and and to turn down physiology so that you it limits the 36:10 energ energetic expenses and also to blunt your sensory uh uh capacities and 36:17 and to produce other deficits so the manifestations of Aging as we know it and what at the extreme we call Frailty 36:25 could be brain driven processes you know just say a bit more about this so this 36:30 is a bit more of a detailed view of how we think this is happening so you have aging cells that are accumulating damage 36:37 they're activating stress responses like I mentioned earlier like the integrated stress response the ISR producing cyto 36:44 and metocin which can trigger immune activation which can further increase this cells as I mentioned will release 36:50 mitochondrial DNA which uh might activate some DNA sensing Pathways and 36:56 there's uh some complexity there that might create a negative positive feedback loop this leads to the release 37:03 of cyto Kines and metabol kindes and chemokines and the circulation in the blood which we know increase with human 37:10 aging those are sent by the brain the brain has this beautiful elaborate uh these elaborate structures 37:17 that are covered by receptors for cyto so that it can the brain can know what's happening in the periphery and and then 37:23 there's this elaborate neural circuitry that's involved in integrating those those signals 37:28 in turn then the brain produces outputs neural outputs endocrine outputs that can uh affect systemic metabolism and 37:36 shape behavior and then in turn those chronically changes in metabolism changes and behaviors will lead to 37:42 anatomical changes right the brain can shrink your muscles by decreasing physical activity 37:48 and reducing activation of the neuromuscular units the brain won shrink muscles which is a very good thing to do if you're running into an energetic 37:54 deficit sh shrink your brain right people can live with much smaller brains 38:00 and than they actually eat to so that's another way of of saving costs and there's a number of things you can the 38:05 brain can also do simplifying the immune system suppressing immunity for example so all sorts of things that we associate 38:11 with bad aging consequences might be driven by the brain and the product of this is decrease whole body energy 38:19 expenditure so we have the situation here we have cellular hyper metabolism leading the whole body 38:26 hypometabolism um I'll just skip this which is a was a 38:33 a summary of the uh the brain body energy conservation signature the key 38:39 Point here is that it's an organal to energetic to organism biionic principles 38:44 that coordinate this this uh communication from aging sessing cells to the brain uh and with an 38:53 understanding like this I think we're better positioned to make good decisions about what kind of interventions are likely to be useful in the short term as 38:59 well as in the long term so the brain is an important piece in this in this 39:04 puzzle here um turns out the brain is packed mitochondria and it's one of the most 39:11 energetically expensive organ in the body and one question that has not been resolved to this date is how are 39:17 mitochondria distributed and how do they specialize across the 39:23 brain uh the brain has enormous uh an enormous energy budget and it's constant 39:29 so on the left here you have the size right the relative mass of different organs in the body you see here the 39:36 skeletal muscles very big chunk of of the human body um fat for most people is 39:41 is a fair chunk as well other tissues this is the brain the little blue sliver here about 2% of body weight so 39:48 relatively speaking the brain is pretty tiny and in the whole body this is the fraction of the energy that the brain 39:55 Burns per minute per hour the brain burn uh 20 to 25% of the whole body energy 40:02 budget despite it's very small size uh and interestingly there things like 40:08 skeletal muscle if you're sleeping or if you're sitting passively listening to a talk your muscles aren't burning too 40:14 much energy but if you start to run or you're trying to um you know Run for the bus avoiding the rain in the morning uh 40:21 then the muscle energy expenditure can actually increase 10 to 20 fold um the 40:27 brain and not brain changes in energy cons consumption actually is in a few percent 40:33 it's rarely about 5% so there's something in the brain that's costing a lot of energy um and I think the the 40:40 debate is is still out as to what is it about this and about sustaining Consciousness or or other other 40:47 processes that's costing so much energy so that energy is coming from mitochondria and we know this very well 40:53 if you stop breathing or if you olude blood flow to your brain five seconds later you're out right the the flow of 41:00 energy through mitochondria is directly linked to your to your Consciousness um 41:05 um so there's something critical there so how do we figure out how mitochondria 41:11 are distributed in the human brain this is a really challenging problem for a few reasons one the brain at the scale 41:17 of mitochondrial biology operates at the scale of cells and uh the micro scale 41:22 the brain is a macroscopic organ and it's it's beautiful this is this is a 41:28 picture here of a human brain this is a a single section of of the the human 41:34 brain and what we wanted to do is to create a map of mitochondria across the brain so we call this a mitb brain map 41:40 version 1.0 uh the goal was to create this multifunctional mitochondrial atlas 41:45 of a single human coronal section at fmri resolution right so we can actually 41:52 bring this to to Bear uh this was a huge team effort this was three years of work 41:57 uh led by IET student I mentioned earlier and and 42:02 Eugene who's a scientist whose office is right next to mine who's he thinks about life like an engineer but he's a chemist 42:08 by training and he works in a neuroscience lab so you bring these things together and then with a bit of mitochondrial infusion uh and then this 42:16 this can happen so uh the goal was to close the gap between organel bioenergetic profiling and the whole 42:23 brain neuroimaging modality right these are two completely different worlds people who do cognitive Neuroscience never think about what happens inside 42:30 the cell and people who look at things inside the cell never think about what happens in a whole 42:35 organs um so what Eugene did was to take this beautiful look at how beautiful this is this is some of you might know 42:43 but this the white stuff is the white matter these are axonal tracks that can be you know multiple centimeters you 42:49 know inches long uh this is here the paman here's the Corpus colossum that connects it two hemispheres right the 42:56 the brown stuff here is a gray matter that is a cortex this is the hippocampus 43:01 the Beloved hippocampus that is involved in memory and Alzheimer's and so on so all of these beautiful areas in the same 43:07 organ how the hell do you partition this in a way that you can do mitochondrial science on this so Eugene thought well 43:14 let's let's order a a CNC cutter a computerized cutter like do if you want 43:20 to engrave a heart on a piece of wood for your mom for for her birthday right you use these kind of machines so Eugene 43:26 programmed a TNC cutter to engrave a grid right he's doing horizontal lines 43:32 now he's doing vertical lines uh and then if we do this and we engrave three 43:38 millimeters deep then we could actually turn the brain into 3x3 by3 millimeter 43:45 cubes and if we do this this is the the standard resolution for neuroimaging so 43:52 then you can and and neuroimaging people speak in terms of boxal right so the MRI 43:57 turns the whole brain into little voxal that are two 3x2 X3 or 2x2 x two so this 44:02 is physical human brain voxal and this is what they look like from up close 44:08 it's that little Cube there and IET and sneal went at this for hours and then 44:13 one voxel by one you know pluck it out record it register it um and then uh 44:19 once you have these little cubes with little samples you can actually run biology on them um so as expected each 44:25 boxold 3x3 by Tre should be 27 milligram so you get this beautiful distribution peaking at at 27 milligrams uh the edges 44:33 of the brain are a little smaller you look at protein abundance gray matter white matter seem to be roughly have the 44:40 same protein abundance with kind of quality control so we've turned the brain in the slice section of brain into 44:47 73 pieces of brain now can we do mitochondrial biology this so we've 44:53 miniaturized some mitochondrial assays in the lab that we've called mitochondrial health index that we've used before in a study with Alyssa um so 45:00 now we could do the mitochondrial Health index the enzyme assays on these brain samples and we partnered with colleagues 45:06 at UCLA uh to do a different kind of mitochondrial profiling method on the same samples bring those two together 45:13 for additional robustness and then you get mitochondrial profiling in all of these voxal and now put this into the 45:19 context of the brain so what you're looking at here is three years of work uh to profile the 45:26 mitochondrial activity the heat map yellow and orange is higher activity black is lower activity so 45:32 roughly you see that the cortex right the outside of the brain where there's a lot of cell bodies lots of synapses tend 45:38 to have more mitochondria but not only more mitochondria more mitochondria that are specialized for energy 45:45 transformation and what we're looking at here is oxos specialization oxidative phosphorilation you can have a 45:51 mitochondria that specialize for making hormones like in Dum glands for example or you have mitoch that are specialized 45:57 for transforming energy with the electron transport chain these are this is a map of the specialization of 46:03 mitochondria across the human brain and you can quantify different 46:08 brain areas I won't go into the details here but compar to the white matter right those white matter tracks these 46:14 axons they have very few mitochondria that and that they're not specialized 46:20 for for energy transformation compared to this most cortical areas and some cortical areas more than others or 46:27 particularly specialized for energy transformation uh you can project all of this data into lower dimensionality 46:34 reduction space like umap which people use for single cell analysis um and what you see is that there's a distribution 46:42 um non-random distribution of of mitochondrial properties then we wanted to bring this at the scale of the whole 46:48 brain right so we profiled it took three years to profile a single section of the human brain how do we bring bad at the 46:53 scale of the whole brain and we did the math it would cost a lot it would take a lot of time to do the whole human brain 47:00 uh so one approach that we decided to take instead is to use neuroimaging uh data and we registered our human brain 47:08 section into standard m& space the Montreal Neurological Institute space that people in neuroimaging world use so 47:15 now you have this brain morphed into a standard neuroanatomical space there are 47:20 thousands tens of thousands of of people and data set for neuroimaging that we 47:26 were able to bring together so now we can ask using standard neuroimaging modalities like fmri bold which looks at 47:34 blood oxygenation T1 T2 just structural uh brain scans or diffusion Imaging to 47:40 to do tractography and to look at white matter can we use that information uh 47:45 average information across hundreds of people map this onto the mitochondrial brain map and then build a predictive 47:52 model so we used 80% of the 73 Bo train the model and then try to predict on new 47:59 voxal unseen voxel from the model this is the the prediction accuracy you see 48:04 observed here that's what we measured this is predicted R square of 36 I'm 48:10 told by my neuroimaging colleagues this is really good if you're comparing one brain from an average from hundreds of 48:16 brains uh it's hard to expect better than this and then if you look at different brain areas this is collapsing 48:23 multiple voxel that belong to the hippocampus for example or to the frontal gyrus or medial temporal gyus 48:28 you see that this the the the prediction is is quite strong and then we had from the same brain uh the occipital a 48:36 different area that we didn't initially use in the model and there's also kind of internal validation of of the model 48:44 there um so what uh this allowed us to do is to create a whole brain 48:51 probabilistic map right using real measured mitochondrial biology in one section You can predict the whole human 48:58 brain and this is the the the predicted map of mitochondrial respiratory capacity the the second generation of 49:05 the mitochondrial Health index um across the the cortical surface here so many 49:11 questions now that we have this this resource many questions we can ask about large scale brain networks a default mod 49:18 Network the sence network and all sorts of of cool things that Neuroscience um neuroimaging people are are interested 49:25 in so I'll finish by uh talking about one analysis that Caroline Trump pooc 49:33 who was a pooc in her lab and now was a faculty and and leading an exciting research program building mitochondrial 49:39 psychoi biology to the world epidemiology and what Caroline wanted to ask is whether brain mitochondrial 49:45 phenotypes are linked with psychosocial exposures and experiences in people how 49:52 do you do this in in in people so what cholin did is she uh leveraged a Ross 49:57 map cohort uh which is based out of Chicago and it enrolls participants age 50:03 65 and over and then every year follows them up so every year you get a measure 50:09 of psychological well-being of depressive symptoms of anxiety of social network size and other contextual 50:16 psychosocial factors um positive and negative uh and then at the end uh when 50:23 people die half of the hemisphere goes for analyzing Alzheimer's disease 50:29 pathology and the other half is Frozen for molecular analysis uh on the molecular analysis uh what was done by 50:36 the the Ross map team is to measure um is measure a number of things 50:42 including proteomics and bulk rnac can now they've done single nucleus rnac so there's deep molecular multiomic 50:48 profiling of these brains and then this is the The Design This is death here 50:54 postmortem you get the brain you can do all of these interesting measures and then ortm or premortem then you get 51:01 positive and negative psychosocial experiences so then that allowed Caroline to ask okay can I correlate is 51:07 there any association between what people reported experiencing before they died and then their brain mitochondrial 51:14 biology after they 51:19 died this is what Carn found uh looking at the association between psychosocial 51:26 positive negative psychosocial experiences you could think people who report more positive 51:33 experiences probably report more less negative experiences there's some colinearity between those but not 51:40 completely uh and then if you look at the correlation between that the composite score and mitochondrial 51:45 complex one abundance complex one is the first protein that brings electron into the electon transport chain to build the 51:51 life uh sustaining gradient in mitochondria there's a significant correlation the proportion of shared 51:58 variance here is 18% R square 18% so 18% of the variance in the the 52:06 the abundance of complex one mitochondrial complex one across people's brain based on this analysis 52:12 could be explained by um psychosocial exposures or uh if you have more complex 52:19 one protein in your brain maybe you perceive the world in a more positive way right so we can't uh know what the 52:25 what direction this is um coming from but this Association is is um um 52:33 intriguing uh there's also single nucleus RNA or single cell analysis in 52:38 those brains and Caroline did an analysis that I won't uh describe now but she looked at this question right is 52:44 there a cell type specific association between psychosocial exposures and certain brain cells so this signal where 52:51 we're seeing 18% of shared variants is this because the neurons respond more to psychosocial exposures are strongly more 52:57 strongly related to psychosocial experiences or is it the alad dendrites or is it the asites or the Beloved 53:03 microa right which cell is it and it turns out the gleo cells is where the action is at so this is a project that's 53:12 um still in in development but there there's cell type specific associations 53:17 between psychosocial factors and mitochondrial oxas not every cell seems to be related in the same way to what 53:24 people are experiencing 53:29 so this is overall as I said earlier the the model that we've used to to guide or inquiry into these questions right we've 53:37 asked questions about the effect of Psychosocial factors on mitochondria in immune cells I didn't talk about this in 53:42 the human brain I just showed you an example of a psycho biological question 53:47 in uh mitochondria we know if you perturb the mitochondria you perturb cellular aging uh we know this from 53:53 Gabriel's cellular lifespan study if we perturb if we apply stress factors we accelerate cellular aging so we're 54:00 starting to test a few of those arrows and to understand some of the energetic principles that might be guiding 54:07 cellular resilience or cellular vulnerability to to stressors I want to come back to this 54:13 picture this is I think the most um accurate the least precise but the most 54:19 accurate picture of how the whole system is wired uh and intrinsically it's wired 54:26 uh to respond to energetic signals right cells naturally will respond and choose 54:32 to divide or not divide or die based on the energetic signals they receive uh function of the brain is regulated by 54:38 energetic factors and uh up to social behaviors and there's beautiful evidence 54:44 and in animal models showing that if you perturb the mitochondria you actually change things like so sociability or 54:50 social dominance and these kind of complex behaviors uh we we know now we 54:55 subject to to energy so energy doesn't just play uh a life sustaining role it 55:00 actually plays an instructive role in in those processes and very importantly again there's flow of information 55:06 downwards and the stuff that we experience on a daily basis the environments we create for ourselves the relationships we are embedded in and 55:15 that we experience end up trickling down probably all the way to mitochondria and more work is needed to understand how 55:21 this happens so thank you so much for U 55:33 I just want to say this is our team who's uh doing the work now that that I presented and and some of that I didn't 55:40 here's Caroline who's uh co-leading our team and and supervising some of our lab 55:45 members uh and here's Eugene who did the Mito brain map um um brain voxelization 55:52 we have several precious collaborators that uh make work possible and I'm so grateful for in particular I want to 55:59 thank the bazooki group uh that's has been supporting us in in expanding uh 56:05 towards exciting projects that our NIH grants uh can support so thank you so much again for your attention thank you 56:11 so much we have five minutes for questions any questions from the audience um the 56:18 bazooki group just awarded Martin a $1.5 million prize for his amazing research 56:25 and I guess also forgot to mention um he has eight ro1s I don't know 56:32 anyone um so he's a very busy person and I um uh so anyway we have a question from 56:39 the zoom room um so first we'll have Rob and then we'll have our 56:44 question Martin a real tour to force thank you um two things that have come 56:49 out recently regarding mitochondria energetics and cell aging 56:56 cell death are the fact that mitochondria seem to split and when they 57:01 split they don't have nearly the oxidative phosphorilation capacity and 57:07 the other is Bob nav's work about extracellular ATP actually leading to 57:12 cell damage and being a marker for cell damage it seemed to me that mitochondrial DNA promoting hyper 57:20 metabolism versus extracellular ATP looking at cell damage might be an 57:27 appropriate marker for what's actually going on have you looked at either of 57:32 these two phenomena and whether or not this then 57:37 explains what's going on and gives you you know uh cause to go backwards as to 57:43 what the you know what what the source of that is yes thank you good question so the question um was twofold one about 57:50 mitochondrial Dynamics and mitochondrial vision and fragmentation and then about ATP not just as an energy currency but 57:58 also as a signaling Factor um uh we've done some work looking at the 58:03 mitochondrial morphology and how this relates to Cellular this energetic State and and and stressors I didn't show any 58:11 data here others have done a lot of work showing that the shape changes actually precede and are required for functional 58:17 changes in mitochondria uh so the the the function of mitochondria is related to their morphology and their morphology 58:23 is one aspect of their behavior of their social behavior uh that is regulated in the minute time frame so you can look at 58:30 a cell under microscope and you see the mitochondria move and change shape and and respond to all sorts of beautiful 58:36 signals um and the fact that ATP is a signal right that inter cellular cells 58:43 talk to each other by secreting ATP and sensing ATP I think says a lot about uh 58:48 the need for the organism to be tuned to uh to energetic signals so ATP is is 58:54 both an energetic signal and you know probably plays a lot of other roles 59:00 between cells in systemically in the blood we haven't looked at this specifically but certainly something 59:05 that that we should look 59:11 at one last quick question from the zoom audience is can mitochondrial biology 59:17 help explain the positive effects of fasting yes so there there are two 59:24 things we know really well that um helps promote lifespan and health span 59:29 is um one moving being physically active and two not eating too much uh and 59:35 there's a lot of interest for understanding how um fasting intermittent fasting and maybe some 59:41 version of calorie restriction has positive health benefits what seems to happen in cultured cells if you do 59:47 fasting on cells is the mitochondria right away become more social or they it promotes Fusion so mitochondria that 59:54 that are you know challenged or difficulty can actually fuse with a good healthy robust mitochondria and now they 59:59 can support each other uh so it seems to um you know I think our interpretation 1:00:05 is that it puts this the organism in a state that forces collaboration and and Partnerships and you see this at the 1:00:12 level of mitochondria fusing with each other uh and there's good evidence that there's also signals between cells that 1:00:18 are being triggered by byting yeah amazing answer um thank you so much 1:00:24 Martin Martin has a few minutes if you have a question you can come and visit him thank you thank [Applause] 1:00:31 [Music] 1:00:49 [Music] you 1:00:56 [Music] UCSF Dept. of Psychiatry and Behavioral Sciences 12.7K subscribers Videos About Twitter Facebook Instagram 176 Psychiatry and Behavioral Sciences Grand Rounds by UCSF Dept. of Psychiatry and Behavioral Sciences