48:04
10/09/2024
Episode 11

Epigenetic Aging in Mood Disorders: Exploring the Role of Lithium and Future Therapies

In this week’s episode of the Everything Epigenetics podcast, Dr. Gabriel Fries and I discuss the fascinating intersections of epigenetics, aging, and psychiatric disorders. Dr. Fries, an Assistant Professor in Psychiatry and Behavioral Sciences at UTHealth, shares his groundbreaking research on the molecular underpinnings of mood disorders such as bipolar disorder and suicide risk. We dive into how psychiatric disorders are linked to accelerated aging, how drugs like lithium show promise in reversing these epigenetic changes, and the future of personalized medicine through pharmacoepigenetics.

In this podcast you’ll learn about:

– The importance of epigenetics in psychiatric disorders
– How psychiatric disorders accelerate the aging process
– The anti-aging effects of lithium in bipolar parents
– How epigenetic markers can help predict treatment responses
– The future of interventional trials aimed at reversing epigenetic aging
– The challenges facing the field and the need for replication studies

About this Guest

Gabriel Fries

Gabriel R. Fries, PhD, is assistant professor in the Faillace Department of Psychiatry and Behavioral Sciences and a translational researcher in the field of biological psychiatry. His research focuses on the epigenetic basis of mood disorders, with a particular interest in bipolar disorder, suicide, and molecular mechanisms of stress.

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UTHealth Houston Profile

welcome to the everything epigenetics podcast where we discuss DNA regulation in the insights it can tell you about

your health I’m Hannah wet and I’m the founder of everything

epigenetics today I have an awesome guest for you his name is Dr Gabriel

Freeze first we hop right into it you all will get a nice introduction in hear from him about his personal journey into

his psychiatric research focusing on molecular biology and

epigenetics we then hop right into epigenetics and Psychiatry so what are the epigenetic mechanisms mediating the

interaction between genes environments and playing a key role in psychiatric disorders like bipolar disorder and

suicide risk specifically we also talk about aging in Psych psychiatric disorders so how

psychiatric disorders are really linked to accelerated aging and higher rates of age related diseases his research really

highlights that bipolar disordered patients especially those with suicide history have older epigenetic ages we

also get into lithium in aging so lithium may have H shown some anti-aging

effects such as tmar length elongation and bipolar patients and then we dive

into ongoing research um Dr freze is specifically looking at um markers um

and and investigating drugs that could Poss possibly prevent or reverse epigenetic aging we finish up talking

about future directions and where he’s taking um his his Interventional studies

um in the future with some invitro drug trials uh focusing on reversing those epigenetic biological age clocks we then

end by speaking about his challenges and future work he’s excited to continue on

so very briefly about my guest today Dr freeze is an assistant professor in the

a department of psychiatric and Behavioral Sciences and a translational researcher in the field of biological

Psychiatry again he focuses on the epigenetic bases of mood disorders

particularly bipolar disorder suicide and mechanisms of stress all right um he

also collaborates with basic and clinical investigators to search for the genetic and epigenetic underpinning of

severe mental ill illnesses now he’s received several grants he’s a principal

investigator and he’s currently funded by the National Institute of Mental Health um and um is running the UT

Health Department of Psychiatry and Behavioral Sciences and now for my guest

Dr Gabriel freze welcome to the everything epigenetics podcast Dr freeze I’m

excited to have you today thank you I’m excited as well thanks for the invite yeah and we’ll

start off with just some general know knowled about your background you know I’m always so curious to hear how people

end up in their particular field whether they took a very traditional path or maybe not so traditional so your history

How Epigenetics Mediates Gene-Environment Interactions in Mental Health

in particular is extremely interesting to me um because of the subject we’re

we’re going to be talking about today so can you just give us a little bit of background on your journey and and how

you ended up you know doing what you’re you’re currently studying and looking at

sure well it’s supposed to be a simple question but sometimes it is I know how

to answer that but I I’ve always known that I wanted to do scientific research and medical um research in general um

and when I started my undergrad um my college experience I started to try out

a couple of topics you know I immediately entered into a research lab but then you know fell in love with uh

biological Psychiatry as we call like this idea that we can contribute to the

psychiatric research um by providing some biological insight and some molecular underpinings to these

disorders which normally are not seen or not necessarily seen as um medical

diseases in that sense right it’s easy for someone to understand cardiovascular disease or something that is related to

molecules and all that so when it comes to psychiatric disorders there sometimes are some um you know limitations and

some restrictions as to okay that makes not be the case but in fact I truly believe that it is and we’ve been doing

this work for many years now so I I did my masters and my PhD specifically in

Biochemistry so I really wanted to get into the the molecular uh level of

everything with a focus on psychiatric disorders came to the US so I’m

originally from Brazil so I came to the US to do a post do uh eight years ago um

here in Houston and you know the the topics come out of each other right so we

started working with epigenetics in general that has led us to study epigenetic aging and aging in general

when one thing keeps leading into one another but I still am very passionate about the field and excited with what it

can lead to and the contributions that we can make in the future yeah for sure

and I think it’s safe to say you’re an expert in the epigenetic basis of of

mood disorders and Psychiatry you perfectly out what we’re going to be talking about

today you know so so that kind of leads me ex directly into my next point which is is great I want to really dig into

this though because you have all of these really great papers um I think it’s better if we start big picture like

you mentioned and just talk about epigenetics as a subject so why is it

important to study this more in particular the psychiatry in relationship to

epigenetics yeah so epigenetics is a really interesting um route to study Psychiatry

for a couple of reasons so just um for the sake of introduction right so we’re we’re talking about mechanisms that can

Epigenetic Aging in Psychiatric Disorders

affect gene expression in response not only to our genotype or to our genetic

background but also to the environment and that fits perfectly with what we believe um is implicated in mental

health or psychiatric diseases right so they are all known to be multifactorial diseases meaning that one needs a risk

genotype to interact with environmental triggers or you know things that happen throughout life um and and so it just it

makes sense to think that epigenetic mechanisms such as DNA methylation noncing rnas or histon modifications are

mediating this interaction between genes and environment um so we’ve known for many years that psychiatric disorders

are heritable meaning that um they are clustered in families um

offspring of individuals with diagnosis tend to have a high risk of developing

this disord so there’s this genetic component that right now cannot be fully

explained by just looking at the DNA sequence and and that’s where where you know epigenetics and our work comes into

play is to try to to complete that whole picture right to paint the whole picture

um in addition to ongoing genetics studies first say that are actually looking at varians and mutations and

things like that MH sure yeah I just think it’s so interesting I think if I were to go back through school I I

definitely took a very traditional route of the general biology degree path um I

would go back and do more of like the bioinformatics or definitely psychology I remember I took like Psychology 101

and it was just fascinating I’ve always been been interested in that so again that’s why I was so excited to to have

you so now we’ll we’ll go a little deeper but talk um I guess more more

General in terms of epigenetics and then Aging in Psychiatry right so we get to this idea of epigenetics people usually

tie it into aging so you know how can we look at these factors and maybe mitigate or reverse some of them as well so you

know when you’re looking at psychiatric disorders and epigenetic aging from a broad perspective what are you really

finding and and you know we we can go through some of your papers later as well um but you can even go a little bit

into this spefic specifics too yeah so the the big picture here or

the the basis of all of these aging epigenetics and Psychiatry um studies

that we do are based on the fact that most of these disorders are associated with a premature

mortality and or a higher incidence of um age related diseases and you know

cardiovascular disease diabetes dementia um or a faster clinical uh

cognitive decline you know over time so there were these clinical suggestions now that an

acceleration of the aging process may be taking place uh in some patients with

psychiatric disorders and in a sort of independent line of research there have

Exploring the Accelerated Aging in Bipolar Disorder and Suicide Risk

been many studies proposing that the process of Aging includes epigenetic

mechanisms as you know and I’m sure you’ve talking about this over and over with different guests here so this is

when these things came into play right we thought a couple of years ago and uh we were certainly not the first uh to do

this we thought well maybe epigenetic mechanisms may be underlying these um

you know as the these findings that people were having that there’s an accelerated

of the Aging processing these diseases one sort of lwh hanging through to study

this is using DNA mation levels to estimate these so-called epigenetic clocks or you know markers of pace of

aging and these things that um you guys are very well familiar with and so by we

started doing that with a lot of the sampol that we have in in our lab we’re particularly interested in bipolar

disorder and suicide those have been the main focus even though we’ve worked you

know in collaboration with other groups that um have included samples from other diseases and in general we do see a

pattern that’s similar to what we would expect in a way we see higher or older

epigenetic ages or age estimates in patients with these diagnosis or

individuals with these diagnosis compared to non psychiatric controls and um well a couple things we that’s not

seen in every single patient so that’s an important thing to to establish now

it’s not a deterministic Association and we seen we see some clinical

associations that may be of interest so for example in the context of bipolar disorder in general you see that the

diagnosis is associated with the higher acceleration of the epigenetic aging process but within individuals those

that have a um history of a previous suicide attempt may have an even higher

um acceleration of the epigenetic agation process so we see these nuances

and and differences even Within the large diagnostic clusters that we talk about gotcha yeah and why do you think

that is that’s is that what your you know your main questions are now is trying to dive dive into that a little bit further because I I have here as

we’re we’re kind of going through you know our agenda you look at all of these different um disorders right you

mentioned mostly the the bipolar and and suicidal but I have you know schizophrenia different anxiety

disorders you know substance use disorder as well so it’s it’s you’re really really trying to find those

different subgroups and all of these factors which may be affecting those clocks and what that means yeah I mean

that’s the that’s the the question now now is to try to find the drivers of

these uh findings now that we’re just seeing I think that to some extent we’re just finding the you know final outcome

if you will but we’re not getting a sense of the process and what’s necessarily leading up to those alterations that we see most of our

studies so far have been in cross-sectional studies so these things need to be seen with a grain of salt

we’re looking at that one time point in the life of the patient um even though we we discuss it as an

acceleration process really when it comes down to it since we’re not following up these patients um with

these markers we can’t really argue that there’s an acceleration what we see is that something that happened up until

that point has led them to have older epigenetic ages and we of course

extrapolate and generalize those findings but I always like to think that you know we need to be a little bit cautious of that um so in even in the

limited context of a cross-sectional study um you can make inferences or at

least look for correlations and associations with clinical factors and other things that can maybe generate

hypothesis for future studies um and so we see for example that within

individuals with bipolar disorder those that have a older epigenetic age

compared to their chronological age they tend to have um worse cognitive

dysfunction if you will now so we see this logical but yet for the first time

actually empirically shown association between the aging process and its acceleration with higher degree of

cognitive dysfunction or C being paramid however you you like to call that um

like I said we see association with history of suicide attempt which is an

interesting finding as well to think that this one possibly very traumatizing

event in the life of a person can have an impact in you know your biological

clock um in in fact there’s a lot of evidence suggesting that um survivors of

a previous suicide attempt also die earlier in a way and that cannot be fully explained by Suicide itself so you

know that it makes sense that maybe that aging process accelerates after that um

I think that also overlaps a lot with the PTSD um literature that I’m not you

know a part of but I follow in the sense that these um these individuals also

seem to have accelerated epigenetic aging so there’s a lot of discussion about the importance of these traumatic

stressful events um no leading up to those so yeah this is you know there’s a

lot to explore there in terms of the causes but since we’re seeing these associations with potential consequences

now which serves as a basis for most of these studies I think that’s interesting I think that’s worth pursuing the

mechanisms that are leading up to those alterations um so that we can start to Target them in fact right so of course

it’s only hypothesis at this point but what if we can somehow prove that it’s

through these accelerated epigenetic aging processes that you know a lot of

these age related consequences end up taking place in patients what if we then

can use some of the findings that we have to propose ways to Target the Aging

prevent those consequences and ultimately increase lifespan and promote healthy Aging in patients I mean this is

the the significance at least that we try to focus on when doing these types of

studies exactly seems like everyone I’m interviewing and all of my guests who

are phenomenal they all have that same goal eventually right they may be studying different subjects or different

um this diseases or disorders but yeah it all comes back to hey if we can identify this take more of a preventable

approach preventative approach then we can get a better outcome so I just think that’s that’s really the beauty in in

looking at these markers and I know you mentioned you’re basically getting the

the data from one time point are you able to follow up with a lot of those um people from the study are you able to

get any longitudinal analysis is that of of any interest it is definitely of interest um our group here in Houston we

have some patients that come it really depends on the study that they’re involed uh for um but we haven’t been

able to run these analysis yet um so in fact this is one of the things that I’m

doing right now is I’m trying to um you know reactivate this discussion our department to start

recruiting those people again um because of course they all volunteers it’s it’s

The Power of Second-Generation Epigenetic Clocks (PhenoAge, GrimAge)

it’s a hard process right any longitudinal study is tricky um or even

find collaborations maybe a listener uh of the podcast who has similar samples

that you know would be interested in in letting us hype with the process of measuring some of these markers that

would be wonderful because I think that’s a a very logical next step in our research and something that we want to

pursue I mean like I said we are extrapolating a lot of things from these cross-sectional findings and that’s

great Al be limited but the next step is exactly to see what comes first right so

we have some unpublished very preliminary evidence that maybe some of these uh accelerated epigenetic aging

markers um they are associated for example with metabolic dysfunction or inflammation so you know not going to

talk much about it but we just see these things and now the question is what comes first right is it um is is it the

case that these diseases these disorders are leading to some of these somatic

medical changes that ultimately lead to the accelerated aging process also

mediated by the environment and all that which makes a lot of sense but is it the

opposite right is it maybe an epigenetic aging process that’s

already accelerated that may be to some extent is already being dictated by the genetic profile of these individuals

then then contributes to a lot of these metabolic inflammatory and you know many

other alterations that will end up activating and and leading up to the higher risk for age related diseases

dementia etc etc I think that this is an interesting discussion that will probably only be explained when we

really look at large groups of people over time right

longitudinally yeah it’s an interesting interesting way to look at it but as more of the data and research comes out

we’ll be able to answer some of those questions which will be great yeah um keep digging a little bit deeper here

and um you know this comes up I would say quite frequently but I really want your take on this as well you know there

are a lot of epigenetic age clocks out there and and they’re all great I think there there’s ways you can use each of

them and they each have their own application um in your most recent work however you note that one of the

strongest associations with mental illnesses have actually been in those newer second generation based clocks um

and those are going to be the biological age ones you know we we’ve defined that in previous shows before rather than those chronological ones um so these

second generation ones you know the pheno Age based on clinical measures of phenotypic age and then we have the Grim

What is DunedinPACE? The Pace of Aging and Psychiatric Disorders

Age based on DNA methylation surate plasma proteins linked to different outcomes so can you just speculate on

that why do you why do you think that is yeah I think it has to do with their the

way by which they were developed which Echo what you just said right um the first generation clars as we call them

Horvath theum they they had the sole purpose of predicting chronological age

or you know the time since you were born um and again how great it it is to have

a marker like that for many different reasons for for insects even um a lot of different application

but we know that chronological age is a very poor predictor of age related

conditions um so just by having something that predicts your chronological age when you look at the

clinical significance of that is probably just as limited as the chronological ages a variable itself

right I think I mean again we can extrapolate we can compare that to the chronological age and see if it’s older or younger and make estimations out of

that but that was not the point of those original know clocks um now like you

said pheno age Grim age these second generation clocks they were the idea was

exactly the next step was to not focus on time since birth rather on actual

biological markers of Aging or things that were related to the process of Aging one of them being the time until

death right time to death um which makes a lot of sense for me Ian this is the ultimate um consequence of the process

of Aging which is the grimage itself so it’s it’s really not a surprise for me

when we you know we published a lot with the first generation clocks when we started uh calculating the second

generation clocks that’s when most of the very interesting findings started to

to come to light um because of that I think that we’re finally capturing

meaningful biological aging um processes um and of course um we nowadays have

even more sophisticated ways to estimate that which is you know these third generation quarks

that you wereare well aware of yeah I think we’ll start to see the research

shift that way I at least hope right it’s it’s nice if you get first gen second gen you can you know maybe all of

them in there so you you may be able to see correlations and Trends but I I really hope to start to see that shift more of those second generation clocks

because sometimes I I really don’t think that people are aware of those different Generations right they hear biological

age and get so excited so I just always like to to point that out and and note that that difference but yeah you’re

exactly right what about the denin pace you I I heard you throw it in there uh

at the beginning so have have you looked at the implications of psychiatric disorders and and all of your work with

the pace of Aging metric yeah so I’m I’m going to disappoint with my answer here because we we started looking into that

so we used a lot of the data sets that we we’ve worked um to up to now and

generated need Cas from them I mean thankfully the codes and algorithm are open for researchers so cud us to you

Lithium’s Anti-Aging Effects in Bipolar Disorder

know the group of ser offord and all that for for making this available um and we’re starting some analysis on that

I can see that they’re very exciting um but there’s we haven’t published

anything it’s really what’s what we’re doing right now is trying to follow up with these new markers which I’m very

excited about I mean I think that being able to capture pace of

Aging uh for one thing is is a huge advantage in in the case of our research

questions over the existing clocks that are out there um not to say that the

clocks are limited in a way but they’re limited for what we’re currently using them for in our research right so we

make a lot of extrapolations about the acceleration of the aging and we make a

lot of assumptions that really are about pace of Aging if you think about that um

and so that’s why like I’m excited to actually have a marker that nowadays can directly assess that um yeah so it it’s

it’s ongoing um I hope to have some some really cool things coming out soon well

good I I’m I like how you laid the groundwork you said all right you all will be disappointed but here it is well

no you’re you’re currently looking at it right and that’s kind of where my mind went when you said you know we’re

looking at people who had uh a suicide attempt and they’re aging afterwards right like my mind went to oh wow that’s

that’s super interesting I wonder how their Denon Pace would play out after that right so even furthermore the

longitudinal data of the Denon Pace to right before and after so it’s just it’s all super interesting and I think we’ll

unlock some some different levels you you start to dig dig more into that yeah yeah and and the suicide is a you know

obviously super sad event but it’s a fascinating topic of research in that sense because you have different

phenotypes as well so all of this I just shared with you that’s published that’s related to suicide attempt but we’re

doing a couple of you know studies nowadays to see what happens during the suicide radiation for example um and and

that’s the type of of markers in Jen P that would be really interesting to

check because for example we’re looking at Patients during an acute sociation event and after recovery from that

episode and so how cool would it be to see whether the pace of Aging changes as you recover from these um very toxic

brain events yeah yeah no that would be be great and I can just tell how passionate

you are about everything you you talk about so I have to ask what’s your favorite um you know subgroup to study

or or where does your passion really lie do you have a favorite um well I probably should say bipolar

disorder um just because of the you know the track record of it I mean I’ve I’ve

been studying it since my Master’s Degree back in the day uh when I was in Brazil and this has led me to come here

to continue working with bipolar disorder it remains um the main topic of

our studies even though we try to expand a little bit and see you know other events and other phenotypes in the

context of bipolar so that’s when we talk about suicide attempt and ideation within patients with bipolar disorder

and things like that um yeah it’s just a topic that’s of really great interest to

me um I think that there’s a lot of opportunities to help patients um yeah

and I hope to be able to continue in the fut yeah no that’s great I I had to ask

because it it’s just radiating radiating through you so we we’re appreciate we appreciate all this this great great

work you’re doing um we’re going to keep keep digging into this further so one

one other important point you mentioned um in your work is that the feature of features of this accelerated aging are

not found in in all patients but there’s um with substantial heterogeneity so

even within the same clinical diagnosis and you can explain what that all means um but I think this is profound and I’d

like to understand this a little bit more so can you discuss why you see this and maybe what it means just a little

bit a review for our listeners yeah well I think well it’s not surprising that

you know whenever we measure any sort of biomic or biological ceration in in these

individuals um you never see the same pattern in all of them

let’s say compared to people that do not have the disorder I mean the same way that you if you compare to people in

front of you that have uh diagnosis of bipolar disorder let’s say they’re going to be very from one another clinically

speaking right they probably don’t have the same combination of symptoms and

that that comes you know it comes with that discussion of how heterog heterogeneous the diagnosis is it when

you go to theology um so even if as a group the

diagnosis is associated with a higher you know process of Aging uh like we’re

saying if you look at the individual data you have patients that of course have very high but you do have patients

that have very similar uh epigenetic ages compared to controls it’s really an effect of the

you know the group and when you apply a statistical method there you see the difference and that’s when I that’s what

I mean when I when I say that it it it’s not a process that takes place in every

single patient and I think that’s important because it it shows you that um first of all anti-aging

um uh interventions for example may not be useful for all patients right we may

be focusing on one very particular subgroup uh within the

diagnosis um and on the contrary there may be potentially more severe

presentations where you would already see accelerated aging patterns in let’s say very young people um so it it’s

interesting to see this heterogen because you also it opens up for a lot of other sort of clinical implications

um if you think about treatment for example it’s very common that even gold

standard mood stabilizers an psychotics anti-press anti-depressants they do not

all patients respond to those drugs the same way in fact I mean it’s it’s a very well-known fact that there’s you know

for example lithium only onethird of patients will respond you know accident

in an excellent way to to the drug so you have this variability that may be explained and may be captured by some of

these epigenetic markers that we’re studying for example aging now like lithium has antiaging properties we’ve

seen this in vitro um but it may not be beneficial for patients that do not have

an accelerated inun process in that sense and maybe that overlaps with lithium response if you I mean I’m just

really coming up with hypothesis here that we have not tested but uh it’s one of the opportunities that finding these

subgroups of patients may offer sure sure and we um no that makes makes a lot

of sense so I’m I’m it’ll be interesting to see the reasoning be behind that as well um I’m going to run with the

lithium that you just brought up and and we’ll we’ll switch to that subject so this is going to sound so silly I’m

going to say it anyways as I was looking through your research you know putting the agenda together and everything I was

like oh this is just going to be such a great conversation and I spend most of my time speaking with

healthc care providers about aging and different interventions and you know the the studies of what’s been published and

I’m like I need to go back to that lithium study I always talk about with my providers and um see what Dr freeze

may think about it and then I was like this is his work I I just didn’t put two

and two together and I should have known um so it’s a little bit of an embarrassing backstory but here we are

and um we’re going to chat about it so yes you have that mini review um

and it’s called the anti-aging effects of lithium and bipolar disorder so um you know I think we like you said we’ve

always known in vitro that it’ll have a effect or or you know something with aging so can you um describe what you

found in this study I think most people who at least my healthcare providers who are listening are going to be interested

in this part yeah there so there’s a vast literature on lithium showing how

neuroprotective it can be or you know how about the effects of like lithium on

Future Directions: Personalized Medicine Through Pharmacoepigenetics

inducing um anti-inflammatory processes or protecting increasing self resilience

against you know stressors and things like that oxidative stress you name it it’s it’s a well-known

neuroprotective drug at least you know preclinically speaking that’s very uh clear

um what people have found and we later replicate in our lab is that lithium

also interferes maybe through all of those Pathways in terms of um oxidative stress and inflammation it interferes

with the Tome length which is as you know very classic uh marker of Aging um

and there’s in fact you know there are a lot of studies even going deeper into the mechanisms by which it can take

place I mean through gsk3 beta inhibition you can um activate a bunch

of Pathways that ultimately interfere with the tase enzyme that can lead to the extension of that portion of the

chromosome um we found a couple of years ago and we published this here in Houston that if you treat cells from in

that case it was lymphoblastoid cell line so it’s one cell line that was reprogrammed from lymphocytes from

individuals with bipolar and controls we found that in the cells from the

patients lithium was indeed able to expand and elongate the til length

showing you know that it providing some evidence of its anti-aging properties

however we did not see a similar effect in the cells from the healthy

controls um so in a way it shows that yes lithum can have an

anti-aging effect but it may not have the same protective effect across all

cell types right so it’s still not a good idea to put lithium in our test

water or something like that if you will um it’s still something that can come

with a lot of adverse side effects it may be protecting in you know in patients and in in certain situations um

but it does seem very convincing again this was a replication of findings from many other groups showing that lithium

can have that effect in addition to its uh neuroprotective effects yeah you that’s that’s great to

hear I wanted to to grab on to to that that that snippet that you mentioned so so thank you for that um what about the

future development of of your work you know what is all this this great research that you’re doing tell us about

novel treatment strategies for these these diseases so maybe you know they could be more specific based on the sub

group or where do you think that will lead to yeah yeah that’s what we’re tating into right now in ourwork is you

first of all really understand what’s driving these aging processes

and by doing that identify ways to prevent that or even reverse if you will

if that’s at All Pro possible and finding um trying to find the you know

what can we do what we can do to prevent that so we’re we have a study now right

now testing or screening a bunch of drugs that for a couple of reasons we

believe may have anti- epigenetic aging effects um so we’re working off of the

hypothesis that as you know one of the main um one of one of the strongest

findings in the anti- literature is Cal restriction right so it’s the thing that we don’t want to do but if you stop

eating uh reduce significantly with without inducing malnourishment you I

mean seem to um delay the process of Aging so in fact there are some drugs

nowadays that can mimic the molecular mechanisms of that calie restriction without actually forcing you to make

that caliber restriction so we’re testing them in the lab and you know both in cells from healthy controls in

from individuals with bipolar disorder to see whether they can in fact prevent or modify that epigenetic aging process

we comparing that to for example lithium which is like I just said a drug with um

Interventional Drug Trials and Preventing Epigenetic Aging

alleged um anti-aging properties and more than that we’re trying to see whether we can expand these results into

the ran um the clinical like real world um setting right so maybe patients that

respond to lithium are more likely to benefit from anti-aging drugs or maybe

uh individuals that have a high accelerated aging process at based lar

are the ones that are more likely to benefit from a specific type of drug um so on and so forth so this is where it

comes into play and I think that that um relates a lot to this idea of phac

weapon genetics in a way that um maybe based on these Baseline epigenetic

markers be it epigenetic aging marker or

specific genes that are mated or groups of genes that are mulated demolation we

can predict whether someone can respond well to a particular treatment or

not yeah and oh that’s just that’s fascinating um and and is that um are

those studies ongoing right now the ones that you mentioned where you’re looking at different that mimic caloric restriction yeah exactly we’ve gotten

funding from The milkin Institute to do some of those experiments and I think that the ultimate goal is to find drugs

that can be either fully you know newly developed or even repurposed like drugs

that we already know are safe for humans I think those would be the ideal ones and that’s those are ones that we’re uh

testing right now um and you know based on our results in the laboratory setting

potentially propose some clinical trials you know with maybe starting with um healthy volunteers uh I mean non-

psychiatric volunteers and then maybe even patients see if that can have a positive effect as an add-on or even as

a standard long medication and Dr fze I I want to touch in on that point there

so I I know there’s this need in these studies to have more true Interventional

Challenges in the Field and the Need for Longitudinal Studies

studies so you know with everything we were just talking about are those going to be purely ventional trials what are

some things you’re starting to look for in your lab yeah so far um they are

Interventional and the since that we’re testing their direct effect on these aging markers in an invital setting um

so we’re not testing them in patients um but that’s ultimately the goal right so

what we’re doing right now is we’re screening several different drugs that have this calorie restriction mechanism

um link to them and then we hope to find those that have the the most promising

results in the epigenetic Aging realm and then maybe propose them as clinical

trial later on for both individuals with a particular diagnosis or even for the

general population yeah I I think that’s great of course we we know the the need for that in in in this epigenetic world

I should say most people are excited about that but they don’t realize there’s a lot of work that goes into it beforehand too

to actually get to that point so with those Interventional trials or even

maybe some things that you’ve done previously in your work what are some of the challenges in in your field that you

think should should be addressed or you know as as a researcher what do you run into that’s that may be a little bit

frustrating that’s a good question I think that we we La replication of a lot

of the findings that we end up having um so for example my own group we’ve published quite a few

papers trying to convince people of why epigenetic aging is important in the context of bipolar disorder suicide and

all that but I want to say that most of the studies have all been performed with the same data set pretty much right or

the same group of people here in the Houston area so I really want more groups to start testing them in their

own cohorts and I think we need that for the field in general we need replication

we need large groups of people being tested for the same thing so we can see what are the findings that survived this

not this this replication uh trial um I think that in the realm of

epigenetic Aging Psychiatry we definitely need more longitudinal samples to be run um we are making a lot

of inferences and assumption about acceleration but at the same time we’re studying crosssectional data so it’s

really not the ideal data set um to test this so definitely longitudinal samples

um by doing that I hope that we can start exploring in more details this

heterogenity of patients like we talked before it doesn’t look like every single

patient has an accelerated epigenetic aging process and I think that one of

the perspectives of the field is trying to understand why that is what makes one individual more likely or at higher risk

for premature aging and While others you know don’t show the

same pattern maybe those that do have accelerated aging processes will benefit

more from certain types of treatments like the ones that we were talking about or any type of intervention that can

have an anti- ugene effect um another maybe bottleneck here that

we’re trying to explore is trying to understand what drives these processes

right what what are the underlying molecular mechanisms that actually lead

Final Thoughts: What’s Next for Dr. Fries and His Research

to accelerated aging uh processes in these patients and maybe by knowing

those we can Target them and ultimately prevent and or reverse epigenetic aging

in in individuals with bipolar disorder with previous history of suicide attempt and so on and so forth and ultimately

use that to to proposed novel treatments and again tying it back to what we just

discussed about this new potential anti-aging drugs that can benefit patients in in a lot of ways and

I think that’s the ultimate goal of our research is to help patients help their families help clinicians and hopefully

reduce morbidity premature mortality the incidence of AGM related

diseases so on and so forth of course I think those are all very valid points

and as I have more people on the podcast I’m getting more of a consensus of those

points as well so um it’ll be interesting to see how how we we attack

that um but again with time I think all of those will come right we’re going to get larger training uh data sets we’re

going to get larger validation data sets we’re going to get more information as to causation rather than correlation

right and then you know again setting up these uh you know I I don’t I don’t know

the right word I’m looking for but these fundamental I should say choric restriction trials things like that and

being able to use that as a proof of concept study and then follow up with that cohort you know 10 years later down

the line 20 years later it really sets the framework and the groundwork for um

more things like that so um all heading in in the right direction but I think it’s very important that people are

aware that um it’s it’s not easy right there there are there are some Road bumps and and things that we have to

overcome um so we’re we’re getting really close here one of the last questions Dr freeze what’s next for you

uh what are you excited about I know you have a lot going on some of those Interventional trials but is there like one thing that really sticks

out um I think I kind of mentioned some of those when I was talking about the

perspectives of the field I basically was listing the things that I expect to do in in our group um so again we’re

following up on those um molecules in an inv V sort of setting but we work with a

lot of clinicians here in the department that you know can help us with the next step which is to actually do small

clinical trials with with individuals with bipolar disorder um I’m very

excited with new collaborations with these larger samples that we can then test the same sort of questions that we

we have answers for in our own Houston sample and see how how those things behave in other cohorts looking for

longitudinal samp exles um and yeah just collaborating with the fud and and

contributing to this very exciting possibility which is to maybe Target

aging and by doing so improve the lives of patients so I guess that’s that’s

what’s hopefully next for our group and for the feud as a whole good good well I’m I’m I’m glad to hear that and

excited to to follow you along in this journey um and and look at all of the the work you and your your team are are

doing and continue to do so uh one of the the very last questions this is more

of a curveball I always say it’s very random and it wasn’t on the agenda but

uh Dr freeze if you could be any animal in the world what would you be and

why wow okay uh unexpected

question um I think it would be a dog maybe a lazy a lazy an

but I’m a I’m a big dog person and I I cannot think of a better life than to be

a dog in a family in fact my family just got a puppy so we’re all about that

right now um very cute what kind of dog or what’s its name it’s so her name is

Abby she’s an Old English sheep dog um she’s adorable and she she lives the

best life that one could have right so she sleeps she eats she gets treats she plays why would I

not want that life so I agree I’m a big dog person too um I I have a dog she’s a

Bernice mountain dog and her name’s Eevee and I do look at her sometimes and

just say like I just wish I could be her today like eat get like you know belly rubs

and everything can we switch lives for a day and you stay here I’ll stay here and you

go write the grants for me at work yes there you go well you know we’ve come to

the end of this amazing podcast interview and for anyone listening who wants to connect uh with you Dr freeze

where can they find you yeah um so I’m on Twitter at freeze

Gabriel um and you can also find me in the UT Health University of Texas Health

Science Center in Houston Department of Psych website there you can find links to our to our projects and to to our

publication and you can always send me an email with questions or requesting papers I’m always happy to to talk to

people um not just researchers but you know patients family members it would be

a pleasure to share some of our work with you definitely and I I’ll put everything in the show notes that way

people can can get in contact if they’re they’re wanting to so thank you so much everyone for listening and joining us at

the everything epigenetics podcast remember you have control over your epigenetics so tune in next time to

learn more thanks a lot Dr freeze I appreciate your time thank you