Cheryl Dean:
Good afternoon or good morning, depending on where you happen to be tuning in from. I am Cheryl Dean and I have the pleasure of being the moderator for today and I am also Salk’s planned giving council. We don’t really have a set schedule and I know that’s one of the questions I’ve received, but we do have our science series that we are doing virtually now, the Power of Science and today’s seminar will be given by our chief science officer, but we’ll get to him in just a moment because, while the current pandemic is not the topic of today’s presentation, we’ve received a lot of inquiries as to what Salk scientists are doing related to COVID-19.

So, here is a link to the web page that we have where we’ve got some information that can be found about Salk’s coronavirus research. We will be sending this to you as a follow-up of today’s presentation, but I did want to address this upfront, since that is certainly top of mind for many people.

And, as to today’s presentation, Zoom has a new feature that we are happy to let you know about. So, it’s now offering closed caption. In order to enable this, you can go to the very bottom of the screen where the little yellow arrow is pointing and then you can click that. Hopefully, you’ll be able to get a fairly accurate transcript of today’s discussion.

And, as for webinar participation, it’s not the same as being at Salk in our auditorium, where you can simply raise your hand, but we still have a way to have an interactive portion at the end of the presentation.

So, you can ask questions by the middle button at the very bottom of the screen, next to the yellow arrow. Then you can type your question there. Hopefully, we’ll be able to have time to get to most of today’s questions, but if not, we will do our best to get back to you before too long. And before the main part of today’s talk, here is Salk’s president, the esteemed Dr. Rusty Gage.

Rusty Gage:
Hello, everybody, and welcome to the Power of Science lecture series. I’m Rusty Gage, professor and president of the Salk Institute. I want to personally thank you for your interest in Salk research. In this interactive webinar, we will share exciting advances and cutting-edge discoveries.

We’re reminded during these sobering times of how critical basic science research is to our health, our community, and the globe. It was the basic scientific research of the institute’s founder Jonas Salk, that led to the first safe and effective polio vaccine, saving countless lives. At Salk, well-renowned experts in immunology, aging, cancer, plant biology, and other topics are similarly working to tackle some of the most pressing problems of our time.

In today’s lecture, we’ll learn more about Professor and Chief Science Officer Martin Hetzer’s important research on aging. Aging is the most significant risk factor for human diseases including cancer, Alzheimer’s, heart disease, and others. Much is still unknown about this complex process. However, we do know that human cells, tissues age at different rates depending upon the intrinsic properties, where they are in the body, and the environmental factors that impose of them.

Professor Hetzer will talk more about the science of aging as well as Salk research activities during COVID-19. Thank you all for your continued support and interest in the Salk Institute. We look forward to the day we can see you on campus again. Have a good evening.

So, our speaker today, as Dr. Gage had mentioned, is Dr. Martin Hetzer. He is absolutely unequaled here at the Salk Institute for biological studies. All of these titles refer to just one person. Vice president, chief science officer, Jesse and Caryl Philips Professor of Molecular and Cell Biology. He is an inimitable person, a force of nature. He received his PhD in biochemistry and genetics from the University of Vienna, Austria and completed his postdoctoral work at the European Molecular Biology Laboratory in Heidelberg, Germany.

He joined the Salk faculty back in 2004 and, as Dr. Gage mentioned, his research focuses on fundamental aspects of aging with a special focus on heart and central nervous system. Dr. Hetzer’s laboratory has also made important contributions in the area of cancer research and cell differentiation, so he is an incredibly busy person. He has won numerous awards over the years, just a few of them include the Senior Scholar Award for Aging from the Ellison Medical Foundation, a Royal Society Research Merit Award, and the Glenn Award for Research in Biological Mechanisms of Aging, and the National Institute of Health’s Director’s Transformative Research Award. And somehow, when he’s not in his lab doing all of this work, in pre-Covid times at least, he enjoys running, skiing, surfing, climbing, mountain biking, and he’s just an all-around really phenomenal person. Please welcome Dr. Martin Hetzer.

Martin Hetzer:
Thank you, Cheryl, for the nice introduction. Thank you all for attending this virtual event. I’m here in the Trustee’s Room at the Salk Institute and I wish you were here in person, but we have to do it in a virtual way to keep everyone safe. The events team, the tech team, but also you, at home, or from wherever you are watching this. I want to give a big thank you to Cheryl, her team, events team, and her tech team really to make events like this possible and stay connected with you. So, thank you very much and, again, thank you for attending this event today.

So, Cheryl asked me to say a start with a few words about how the coronavirus pandemic has affected Salk operations, and before I move to my science update, I would like to do that because, as you know, the risk of the respiratory virus SARS-CoV-2 poses to our community is far from over and if you’ve heard the numbers over the last weekend, it’s actually increasing not only in the US but also Europe. And the threat of SARS-CoV-2 has effected essentially every business, every family, and of course, also the Salk Institute.

And Salk’s scientists and staff had to adapt and adopt a completely new way of doing research and business. And, in March, when the coronavirus hit first, we moved to what we refer to as the maintenance mode.

But this was really significantly reducing research operations down to the central part, really the bare bones, just to make sure that the institute infrastructure is well maintained, that the health of our animals can be ensured. And so we really reduced it down to probably around 20% attendance.

And during that time we formed, what we called the COVID-19 task force that I, in the role as chief science officer, chaired. It’s a task force that is composed of the crisis management team, which is really composed of people leading different departments at the institute but also included faculty. And we developed what we referred to as a guidebook for the phased reopening and ramp-up of research activities at the institute. And over the last two months, we moved from this maintenance mode to phase one and phase two. And very early on, as you can see here, one, it was clear that safety is obviously our key focus and really the key components and you’ve heard this now many times and it’s no different at Salk, to keep us safe at Salk, to really minimize the spread of the respiratory virus is to maintain physical distancing so everyone on campus has to maintain six-foot distance. They have to wear a mask to prevent the spread of the virus through aerosols, and we also implemented and enhanced many procedures.

And we also ask every individual who comes on campus to fill out the daily symptom screening that they cannot access the institute without having filled out that form. They also have to go through a county-mandated temperature check. And so, this took some time to get everyone used to wearing masks and being socially distant and I have to really give a big shout-out to our community because people have been following our guidelines very well and the compliance has been extremely high.

But as we were ramping up the research activities, we needed other tools. And so now we’re in phase two, which means that we are back to the 75% of research activity and we have implemented additional measure. One important one is a contact tracing tool that we have, so this is an electronic, it’s almost like an app that you can download and that helps us trace, if there is a positive case at the Salk and we had two positive cases, it was the only two positive cases over the last seven months. This contact tracing tool is extremely helpful for us to identify what we would refer to as close contact, so those are individuals that had a potential contact with the person who tested positive.

We continue to do obviously symptom screening. We restrict access campus to visitors so one of the reasons why you cannot be here today. And the way is very important and that took really significant effort by all labs. We require each lab to provide a weekly lab plan. And that means that labs have to tell us where each individual is located on the lab plan, the floor plan, and they all have to be at least six foot distance. It also, for many labs, it means that they have to organize shift work so we have three shifts, people coming in the morning shift, the afternoon or evening shift or night shift and if people use shared equipment or shared rooms, they actually have to schedule because we don’t allow group gatherings of more than three people. So, there are no seminars but also if you share a room, you have to schedule. So, it’s really to control and minimize the occupancy at any given time.

And so, as you can imagine, we asked a lot of research community to follow those new guidelines. And, on top of it, we develop risk mitigation plans and those were important and they became important a month ago, when we realized, while we still have to perform training of new employees, of students, of postdocs who come to the lab in order to make sure that knowledge that has been developed in the lab is actually transferred to the next generation of scientists and many of those training events require shoulder-to-shoulder training so you cannot stay six-foot distance for any less than 15 minutes.

And so in that case, we developed and asked people to develop risk mitigation plans submitted to the CSO office and with EH&S and with safety people, we review those and only if we have an approved protocol, which might include wearing an N95 mask, additional physical barriers, then you can engage in a training session. And so, with all these measures, we were able to get back to 75% roughly at research.

The next phase, when it will come, the numbers are still unfortunately going up, so we’ll be in phase two for a while, but we’re already planning obviously for the next phase, which will be bringing more people back and also have [inaudible 00:13:59], but the final part I want to cover is testing and screening.

And very early on, we’ve focused on complying with the safety measures, so again, physical distancing, wearing masks, enhanced screening procedures, but we also had available testing and this is really led by big part by Mark Bouchard from EH&S health and safety department, that people who suspect they might have had close contact with someone who tested positive, can drive up to a site that is provided by UCSD. It’s a RT-PCR-based diagnostic test and I’ve done it. It works really well and you get the results back in less than 24 hours.

In addition, we have testing for individuals who actually work with the virus because we also have research ongoing in that area and so people actually have to work with the virus and in most cases, in all cases, it’s inactivated virus, so the risk is not high, but we still want to make sure that people are safe, so they require two tests and they go through UCSD.

And also, we’re preparing now and finalizing an agreement with UCSD for people who are planning to travel over the holidays because Thanksgiving’s coming up and a holiday season in December and we want to use testing provided as an option for people not having to self-quarantine for two weeks after the travel.

And the final part is what we refer to as asymptomatic screening. So, this is a program that we kicked off a few weeks ago and doesn’t use this RT-PCR test that you’ve heard about. This is a different test, a very rapid test. It’s a colorimetric test. It’s basically a test where you take a tiny bit of saliva of an individual, put it in a tube and then if the tube changes its color from a sort of purple to a yellow and this is an indication of the presence of a virus. And we are rolling this out so we have a screening of every individual once a week moving forward.

So, that’s our goal. We have a pilot program for you and having tested several departments who are in a high-risk situation, so we’re very, I think, happy with the progress that we have a multipronged approach towards the testing that’s available.

And so, as you can see, we are not back to hundred percent, but with all those measures, we’ve been able to accomplish a remarkable amount of research and I’m sure if you follow our newsletters, our weekly and monthly media outlets, our website, you see that science is still going on at full speed at Salk and many, many discoveries are being made.

With that segue, I would like to move to the research that is done in my lab that relates to aging. And I would like to start by saying that, and I think many of you have heard me say this before, and it is still one of the big mysteries of why it is that when you get older, that your risk of developing a disease is, in some cases, increasing exponentially.

And so, acknowledging that getting older is and remains a major risk factor for many human diseases, we would like to understand why this is the case, the underlying principles. We also would like to understand what aging really and how aging affects different organ systems. We’ll tell you that aging doesn’t affect every organ the same way and obviously we would also like to find treatment options for interventions that might include pharmacological interventions but also lifestyle choices, but actually reduce or even prevent some of those age-related diseases, but I’m really in my lab mainly focused, and you can see with this title page of the runners’ magazine, very much on healthy aging.

So, we want to understand, for instance, why it is that, as you get older from your 30s, 40s, 50s, through the 60s and so on, your performance declines. We don’t know the underlying principles of that. I would like to mention also that, while we see this decline for a population, we still should keep in mind that there are 80 year olds who can outperform 60 year olds or in 50 year olds or younger, so there’s a huge heterogeneity between individuals of the same age. And that’s why it’s important to move away from just looking at us and using chronological age, so again, the time has elapsed from the day you were born to actually something that we do refer to as biological age, which is a much more accurate reflection of your health stance.

And the three points I want to cover in my presentation are, the first is that you might not be as old as you think you are, and I’ll talk about our attempts to measure biological age and some of the exciting findings, the discoveries that we made doing that. The second part I want to talk is some of your organs are definitely older than you think they are, speaking to heterogeneity within organisms and we have to understand both this heterogeneity and I’ll explain that a bit.

And then, something that is very exciting to us, that actually factors in the blood, in our circulatory system that can make us younger. At least when it comes to vascular, which is really important for healthy aging and it’s also unfortunately the factors that we identified that can make the vasculature older, and so I’ll talk about that in a bit.

So, physicians have known for a long time that the chronological age, that the number that is on your birthday cake is not a very valuable and useful tool clinically, because you can have, as I mentioned, an 80 year old who is in a nursing home, not doing very well and you can have an 80 year old who just qualified for the Boston Marathon. And so, it is really this biological age of an individual that we would like to understand. And right now, there’s really no quantitative measure, so really something that we can quantify what’s the biological age of an individual.

And there are many attempts, people have done this, so you can go to a website such as this one and measure your biological age in two minutes. You can see by my level of completion, zero out of 25, that I don’t think this is a very useful approach.

Now, people have made interesting progress. This is a Chinese paper where they were able to predict the age of a person by 3D reconstruction of their faces and the features of their faces and that’s pretty remarkable so that apparently we are aging in somewhat of an unpredictable way and certain facial features are changing, but that doesn’t work for everyone, as you know. So again, as promising as they are, they’re really not molecular mechanisms to understand biological age.

So, the process and the approach we took is summarized in this slide. So, we took cells from the skin, those are called dermal skin fibroblasts, from people at different ages and those are very benign skin biopsies that they didn’t leave any scars. It’s a fairly low evasive method to collect some cells.

What we do with those cells, we culture them in the lab in the dish. And then what we do is we analyze those cells through methods such as, what we refer to as RNA seek, and what this method does, it allows us to quantify how many molecules are present in a given cell for each of the 20,000 genes that are expressed in this cell.

And so, the idea was and the hope was and the question really was, by measuring the relative levels of each of those 20,000 plus products of genes, can we predict the age of a person, basically do we find a molecular signature that would tell us, "Oh, this person is in their mid 40s or this person is in mid 60s." And we used machine learning algorithms that we specifically developed for the purpose and I don’t have time to go into that. And what we found is very remarkable.

You see, all these blue dots here that fall right on the line that represents the chronological age. So, this already tells us that for many and actually most people, the fine molecular signatures that precisely allow us to identify the chronological age, which is pretty remarkable. But what’s even more interesting, I think, is that you see individuals that actually predict younger than they should be according to the chronological age, but also predict older than they should be.

And so, this now opens up an avenue for us to understand what’s up with those individuals up here who should be in their mid 20s or in their 30s but they already have a biological age that appears that is much older. And equally interesting is, people in their 70s or 80s have a biological age that is more in their 40s. And, as you know, there are some people who age very successfully, some even push way beyond a hundred, those are called centenarians, while others have a much lower lifespan.

And so now, with this method, we have a way to tease apart different age groups and study what distinguishes the healthy ages from the people who don’t age as successfully. And for physicians, that’s an interesting tool that they can potentially use to determine, okay, this patient here predicts to be older in the biological age than actually is expected from the chronological age so really we have to come up with treatment options, to identify treatment options and maybe whole lifestyle changes to really make them younger in their biological age. So, this is both, we hope, relevant for clinical diagnostic but also really dig deep into the mechanism of why it is that some people age more successfully than others.

This brings me to my second part. Some of your organs are definitely younger than you are. And I’m going to start with this cartoon from The Boston Globe about one of our studies that we published a few years back and I like this very simple cartoon because it highlights two main organs, the brain, you’re on a skateboard, really happy, and here’s the liver, who’s using a cane and not doing so well. And what this tries to capture is the interesting phenomenon that organs in our body don’t age at the same rate. So we have to deal with what we call heterogeneity within an organism. And only when we understand this heterogeneity, we actually can understand the aging trajectory for each individual because it might be that, for me, for instance, my vulnerable organ would be the heart, but for someone like you would be the liver or the brain. And without knowing that, if we just look at the entire organism, we’ll not get very far.

And I just want to show you one example why we think this is really important and this comes from a new method that we developed and applied which we actually borrowed from the geoscience.

So, here’s an instrument, it’s called, it’s a long name, it’s multi-isotope imaging mass spectrometry. It is an instrument that we use. One is at Caltech in the Earth Science Department and what those people use it for is they study the age of meteorite by the presence of certain isotopes and you should know carbon dating is a really effective method to determine the age of fossils and other geological formations. And they use it for meteorites, for instance.

Now, we have developed a method where we can use this and borrow this amazing technology, but look at isotopes that we trace in an organism in different organs. And I show you, here is the pancreas is one example. These are performed in animals like in mice. And what you see when you see a purple color here. These are individual cells but you even see subset of the structures that are purple. And what the purple color means is that there is an enrichment of a specific isotope that we feed those animals. If this isotope persists in a location, we know that this is a very, very old structure and in some cases, we identify structures that actually are never replaced throughout the entire adulthood of an organism. So, we identify structures that are never replaced.

And the pancreas is particularly interesting because, as you know, its main function is to control glucose levels and the cells that you see here, those little dots here are called beta cells. Those are those insulin-producing cells. They are activated when you have a meal, if you eat an ice cone, they are activated. They use insulin to lower the glucose levels. And what we found in this particular organ is that the majority of those beta cells are never replaced throughout adult. And this goes against some of the thoughts in the field and we’re now in the process of understanding if people have very unhealthy diet, such as high fat diet, or have a very healthy diet such as we restrict calorie intake and [inaudible 00:29:52] other extended health benefits but also, you don’t develop any disease. It’s actually the healthier you are, the fewer cell divisions, cell turnover you have.

So, there’s a new principle that we discovered that actually cells want to stay and want to stay getting old without dividing, without being replenished through stem cell population in order to stay functionally intact. And by studies like this, we are now able to distinguish in each of the organs we look into, what are the cells that are old and what are the mechanisms that allow them to function for decades in humans and what are the cells that are replaced by stem cells and what are they aging at.

And with this now, with these tools and many others that I don’t have time to talk to, we can really drill down on understanding this heterogeneity that I was talking about at the beginning, really down to the cellular, even subcellular level and with this, we hope will make major progress in understanding aging.

As a final part of my presentation is related to the vasculature and you probably know me. I tell you now that cardiovascular health and complications with the cardiovascular system are associated with most deaths in the world globally. So, cardiovascular health is critical for healthy aging, but also problems with cardiovascular function are linked to a whole array of diseases such as Alzheimer’s disease, dementia, and many more.

And, in fact, on part of my lab is part of a consortium at Salk now. It’s funded by the American Heart Association and the Allen Foundation to study cardiovascular health in the context of Alzheimer’s disease.

And I want to share one approach that we use to study actually the factors in the blood that are circulating every second in our body and what’s the impact on the vascular system. And we use a 3D model, sort of a tissue on a disk in which where we have one chamber, shown here in red, that is separated by another chamber through endothelial cells and the endothelial cells are the cells that form our blood vessels. And we have a measure to detect the integrity of the barrier that is built between the blood and the tissue. As many of you know, there shouldn’t be anything that shouldn’t go out of the blood into the tissue because then you typically get inflammation in this tissue and it’s currently thought that this is a major driver of aging, of multiple age-related diseases.

The in vitro system now here where we can co-culture, again, cells that we get from patients of different ages. So, we take healthy endothelial cells and incubate them with fibroblasts from other cell types that we get from young adults or from older adults. And what you see here that the barrier that is supposed to work really effectively is actually stopping to work properly and starts to fail. You can see here now there’s much more of this reporter dextran not able to go from one compartment to the other, which is an indication that the barrier’s not functioning properly anymore which is quantified here. So, something in those cells that we get from older individuals is able to damage the barrier function that is maintained in healthy individuals.

And so, using this type of approach and this is all in human cells, those are all cells derived from individuals, from patients, you can build your own sort of, if you wish, cardiovascular system in a dish and study what factors are in your blood or in your cells that damage your blood vessels, and by doing this, you not only find that old fibroblasts, for instance, are able to damage the barrier as indicated here.

What’s even more striking is if we take blood in the serum of plasma from older individuals, it can also damage the blood vessel in this in vitro system. And we identify factors such as this protein here, angiopoietin L4, don’t have time to go into details. This is a protein that decreases during aging. And if we introduce it again into the plasma, we can actually make, at least in this in vitro system, the blood vessels healthy again, younger again. We can restore their function. And my last slide really is to show you that this is not only I think relevant in understanding the healthy aging part of the vascular system, but we can also tease apart what the pathological consequences and effect in the context for Alzheimer’s disease.

So, we compare, for instance, blood from healthy individuals or Alzheimer’s patients and measure, again, the intactness of the barrier. And do you see that in Alzheimer patients, they lose this barrier function and we identify through multiple measures components in the blood that are circulating in Alzheimer’s patients that damage those blood vessels and when we use a drug, JMS-053 in this case, to specifically block one of those damaging components, we can actually restore vascular function in vitro.

So, with this, we can see that with this straightforward in vitro system, we can learn not only a lot about the health of the vascular system in the context of cellular integrity like endothelial cells and other cells that are surrounding blood vessels but we can also look at the blood, its circulatory factors, and identify factors that damage to make the vasculature older or even reverse some of this age-relating defects by blocking toxic components in the blood and making those blood vessels healthier.

And so, this, I hope I gave you an overview that we really tried to understand in an evidence and a rigorously quantitative manner, what is the biological age of each individual. We’re planning to do this longitudinally to follow individuals now over many years and see how their biological age is changing depending on changes in lifestyle or if they are going through a chemotherapy, whatever it is that they are experiencing, or stress level.

Secondly, we have made major progress in understanding the heterogeneity of aging, so again, that organ systems age differently in each of us and we have to identify their weak spots for each of us. And then the final part is this very hopeful message that there are factors in the blood that we can block from damaging the vasculature but also identify factors in young blood that will hopefully help older people who already have some vascular issues in rejuvenating the vasculature and since the vasculature is one system that connects all organ systems and a failure in proper vasculature can cause inflammation in multiple organs, we think this really is central feature of our fight against pathological aging.

So, with that, I hand it over to Cheryl. I want to thank all of you for your attention and, again, for joining this event and I’m looking forward to new questions and happy to answer anyone if there any questions that you might have. Thank you very much. Bye.

Cheryl Dean:
Thank you, Martin. Very happy to have you take the time to share some of your insights from your research with us. Thanks so much. And I wanted to let you know what our first question is today. This is something that many of us, I’m sure, are wondering. Besides exercising, not smoking, eating well but not too much, essentially everything that our grandmothers taught us, what can we do to be one of those healthy centenarians?

Martin Hetzer:
Yeah, Cheryl. So, I’ve magically moved from the Trustee’s Room to my office. So, here I am to answer the questions. Yeah. This is obviously a question and the key motivator of our research to provide strong evidence for this specific lifestyle, for a specific diet, and, more importantly, how our age as we move from our thirties to fifties and seventies, how those requirements really change.

And the points that you already made now are derived from basic research and understanding some of the hallmarks of aging, so we know that exercise is very beneficial for the cardiovascular system, for oxygenation of various organs, so that has been proven in multiple systems to be very beneficial. In addition, you have mentioned diet and I’m sure most people have thought about diet and changing your diet one point or another in their lives. And whatever your personal diet regimen is, unhealthy diet, there are clear culprits of an unhealthy lifespan. It’s fairly easy to identify some of the components such as I try to cut out sugar. Sugar is really bad. Like a high fat diet as you get older is really bad, but really in the area of the diet and to understand how it affects aging, you still have to learn a lot and the final part that we also agree on is very important are social interactions, so people who have a rich social network tend to age better and especially in the context of cognitive health.

So, while those are all derived from basic research and there are sort of really good recommendations to maintain a healthy lifestyle. What the key question is, what is right for you individuals, so kind of a personalized recommendation for each of us and what’s right for you when you’re 30 or in your 50s and that might be actually different. And there we still have to do a lot of work. Some of the answers will be lifestyle changes but there will be, for sure also, other forms of interventions such as pharmacological interventions that I mentioned in my presentation where we identify factors in the blood for instance that we can block by using tools that we have developed in the clinic to actually prevent those from damaging. And so, with this type of approach, we can hope to mitigate or at least, if not rejuvenate, but at least slow the aging process itself.

So, I think those are all the things that you mention. We should still keep doing, not smoking, should avoid anything that damages ourselves, our genomes, but there’s still, truth be told, a lot to be learned and really what we hope to achieve here at Salk in this effort to identify what’s right for you as an individual at your age, at your specific age. Because, then again, it’s different when you’re 30 or when you’re 70.

Cheryl Dean:
Thank you. Someone else asks, "What can one do to prevent damage to blood vessels?" So, you mentioned that in your talk that you’ve got a compound that you were using but is there anything that we currently can do out here who are not in your lab?

Martin Hetzer:
Yeah. Vascular health is, and I learned a lot about this and, again, based on our research and I think there are very interesting opportunities down the road to understand vascular health. I think one thing that I would like everyone to understand is that the vascular is, you can look at the vascular as a pipe system that runs through our body. Just the sheer length of our vasculature in a typical adult is about a hundred thousand miles. Imagine the number of cells that you need to form such a complicated system. What make the vasculature really challenging is that previously thought, it’s the same type of cells that make all the vasculature in our body but that’s actually not true. It turns out that the blood vessels in your brain are actually quite different from the blood vessels in your liver or in other organs.

So, to answer that question again, you can already identify some factors that are really clearly bad for your vasculature system. So, smoking, having diabetes, having a high blood pressure, having too much cholesterol, having poor diet too much … So, those are all factors that have been shown clinically to have, are associated with the poor cardiovascular health. But where we still need to do a lot of research is not to understand if you change your diet or if you pick up a habit, in an individual, what are the critical and the more vulnerable parts of the vasculature because that might be different. For some people, it’s the vasculature in the brain. For other people, it might be the vasculature in the pancreas.

So, what we trying to do here is to understand the complexity and, again, the heterogeneity of the cells that form the vessels and then identify what damages the vessels within the different organ systems and it might be different between all of us and then intervene, either through all those good lifestyle measures that we mentioned but also again, I think we come in, we need more tools to maintain vascular health through pharmacological interventions and then also quantitative measures to determine whether if you change your diet to more antioxidants, does it actually help you? Or do you need a different type of intervention? And there’s still a lot to be learned. That’s why we do research, there’s a lot that we don’t know yet and so I hope, with our research, we’ll make contributions to better understanding of vascular health.

Cheryl Dean:
Thank you and there are a lot of people out there who are not only wishing you well with your research but they, I’ve got quite a few questions up right now, people who are volunteering to participate to help with your research and folks who are asking if there’s any way that they can take a test at Salk to see what their internal, biological age is and what you might have already done in living humans with your research.

Martin Hetzer:
Yeah. So, the beauty of this system is that you can take cells that are fairly easy to get access to, so we take skin biopsies of people and these are not the skin biopsies that you typically get with an oncologist, so actually there’s really sort of micro biopsies that really don’t leave any scars. I mean it’s minimally invasive. And then we use those cells and divide from the skin or from the blood and study them.

And the reason we have to do this is obviously that we don’t have easy access to very interesting cells. So, we cannot have very easy access to blood vessels in the brain or the heart. Those are really difficult to obtain from a healthy individual or from an living individual, for the fact. We have a lot of postmortem analysis when someone has passed away, then we can study it, but as people go through their aging process, it’s very hard to do that. And so we take those skins cells and remarkably, if we convert them to, for instance blood vessels, with a specific protocol or into nerve cells or into cardiomyocytes, different types of cells. If you do this in a particular way, these cells actually tell us about the aging pattern of this given individual.

So, this is a way now to start to monitor the biological health of this individual, but what we would like and what we are doing now and we’re looking for people who want to volunteer is actually to decide from molecular signatures from those skin cells that also would tell us something about the health of other organs, because so far, we basically were able to identify the biological age of an individual, but as I said in my second part of my talk, it’s probably that the organs have different biological ages in different people, so we need to and we go, again, using the blood and different types of cells that are circulating in the blood to learn about the health status of organs that we don’t have easy access to and we can study them at the molecular level.

And so if you want to participate, we have an agreement with UCC. There is a center called the Center of Translational Research Institute, where volunteers can come in and give their biopsies. And then we will take those biopsies, bring them to the lab, grow out the cells and then study them for each individual. And so far, we have, I know, hundreds of individuals and that’s good, but what we really like to get into the thousands and what’s very important is to have longitudinal studies. We don’t just take a snapshot of an individual at a certain age. We want to see how actually the biological age of individuals is changing as they get older and ideally we capture individuals who are going through a transition in their life. For instance, if someone changes from a not too healthy to a healthy diet, we would like to measure. Well, this is actually now really reduce the biological age. Does it really make people healthier and once we have those clear measurements in place, I think we can really provide tools for physicians and the clinic to assist in identifying proper adjustments in lifestyle choices but also, as again, in pharmacological treatment options.

Cheryl Dean:
So, that sounds like an incredible amount of data that you’re collecting and obviously that’s going to grow not only with the number of people enrolling to help you with your research but also, over time. You mention these longitudinal studies that you’re hoping to do or planning on doing. Do you have any prediction as to how long it might take with your following certain factors to be able to come up with practical recommendations for the public?

Martin Hetzer:
Yeah. I think we do. So, for instance, I mentioned this one in my talk, of one compound, it’s a small chemical compound that at least in this tissue on a ChIP assay rejuvenated the vasculature. Once you have a discovery like this, then the next step is you try to recapitulate and test whether this compound has a similar effect in an animal model, and then if that is a positive, then you move into clinical studies. And those take several years. So, that’s a typical procedure.

The good news is that we have right now, in the blood identified about 12 factors that are either toxic, so we want to find strategies to block them or eliminate them from the blood, but we also found components that seem to be very beneficial and rejuvenate the vasculature.

And once we have confirmed those in, we call those in vivos, but those are in animal models, we will move forward swiftly to explore the clinical potential of those compounds. And I think that this is obviously time that can be measured in years. It’s not that we will have those ready in months, but what’s really important I think is that this is foundational work that will allow us to quantitatively determine and this is really important.

It goes beyond the anecdotal evidence that you all have heard and that we have heard. "Oh, eating blueberries is good," or, "Doing this and that is good." Which, nothing against blueberries, but what you really need to do is to measure and have an evidence-based recommendation for each individual and with both the measuring of the biological age, understanding the heterogeneity of organ systems and identifying factors in the blood which are relatively easy to access and either enhancing the factors that rejuvenate the vasculature and blocking the toxic ones, I think we’ll be able to provide really useful recommendations to the public in years and not decades. So, that’s sort of the goal but it won’t be weeks, also, either. So, I want to make sure people understand.

Cheryl Dean:
Well, I think given and how everybody’s been following the development of the COVID vaccine and how that’s been extremely accelerated, I think we all be happy with years and not decades. So, that’d be great.

Slightly different tact question about research subjects. Someone, well, first says, "Thank you for the fascinating presentation," and then asks, "Whether you’re looking for individuals from different countries for the chronological versus biological study." And they say one example is people from certain countries can tend to look, appear older at a younger age and also have a lower life expectancy. Is that anything that you are looking at?

Martin Hetzer:
Yeah. So, this is a really fascinating question and really an important one. It’s both, obviously, geographical location, which that is important to know. It’s often associated with this specific form of diet. We all know the Mediterranean diet. We know about the blue zones where people have disproportional representation of centenarians, those are people who live healthy way beyond their hundredth birthday and there are many, many studies on the way they study their genome, like what makes those individuals special?

So, having both the capacity to study at that scale, we need to and that’s a very practical and real limitation, those studies that I described are expensive because they drill down as they grab to the cellular and molecular level. So, we are in the process of reducing the complexity and associated cost with some of those studies because what we have to do in order to accomplish what this question really encapsulates is we have to be able to screen in ideally tens of thousands of individuals from all kinds of, across different ages, across different socioeconomic backgrounds and geographic locations.

And I think, if we do that, then I think we will be able to, in collaboration with other people like Satchin Panda at Salk, who’s actually looking at the dietary habits of individuals across the globe and with other programs that are available, we will be able to provide a completely new way of understanding the interplay between an individual’s genomic and genetic aspect of aging and the influence that comes in through diet, through the lifestyle, the quality of sleep that people have, people who travel, who go under enormous stress. There are people in areas of conflict or poverty are likely to have maybe different aging patterns so really to understand on this longitudinal base, what individuals go through under different conditions but have, again, a way to measure the health and the aging of someone who is healthy. That will be important so we’re trying to reduce the cost, really scale up those studies and we are actively pursuing those.

Cheryl Dean:
Sounds like you’re going to be busy for a little while. One other question that we have touches on something that you alluded to just briefly. And this person says, "As we age, a major issue is isolation, but we must be isolated during COVID-19 and, in addition, this person is deaf and in her 80s, so it’s really difficult because she can’t lipread when people wear masks, further enhancing the isolation and the feeling of solitude." So, do you have any thoughts on that?

Martin Hetzer:
Yeah. Social isolation, it’s a very good and important question that’s being raised and it just happens that it’s not my research but research of five of my colleagues at the Salk Institute came together and they started to work on the impact of social isolation on cognitive health.

So, that’s a start. It’s very poorly understood. It’s known that people who have social interactions, a rich social network tend to live longer, tend to stay healthier longer. We know that but why that is and what really the triggers are, that when you have a rich social network, what that does to cognitive health and then even more so on organismal health. That remains poorly understood, but we have a group of five faculty members who came together to just address this question and it’s a fascinating question and so important, especially now in a time of a pandemic where we are all much more isolated and we all know how much we miss social interactions and humans are social animals. They thrive on social interactions and we need them to stay healthy.

So, it is really important again, basic research has to be done and to identify the molecular and cellular underpinnings of social isolation and the negative effects on it because you’re right. We’ll always have situations where we will be in some form of isolation or another where we maybe have a choice. So, to have then tools at our hand that would mitigate some of the negative impacts will be critical, but again, it’s an active area of research at the Salk Institute.

Cheryl Dean:
Thank you. Just a couple more questions. Are fibroblast cells from different areas of the same person the same age?

Martin Hetzer:
So, that’s also fascinating, very good question. So, fibroblasts are cells that are really important in wound healing so that’s where they’re really kind of well understood and it turns out that fibroblasts are very different, just as your fibroblasts around in your skin, you have them in pancreas and different organs and not only are their lifespans very different so some of them keep proliferating throughout life while others don’t divide at all so they’re almost as old as nerve cells, which are, we have known for a long time are sort of the oldest cells in an organism and they also have very different genetic, gene expression programs.

So, whoever asked that question has addressed something very important that the fibroblasts we get from the skin are a subtype of the available fibroblasts. Again, we work with them because it’s very easy for us to isolate both, but we do study fibroblasts and many other cell types in organs and study how they age and, in part, a lot of research that I didn’t have time to talk to, we have other methods that allow us to study the gene expression of each individual cell, of individual cells and we do this in really the key organs that most of the organs that we are interested in are the brain, the pancreas, which is important for glucose homeostasis and diabetes and the heart and increasingly the liver.

And so, we were deriving aging signature and the rate of aging across different cell types and different organs, but the answer is yes, fibroblasts age differently depending on which organ you’re in. Good question.

Cheryl Dean:
Thanks. And the final question for today, sorry we couldn’t get to everybody, but I think this is going to sum it up for a few people as far as practicalities. You already mentioned that you are limiting your sugar intake, but someone is asking, "How have you altered your lifestyle based on what you’ve learned from this excellent and novel research?"

Martin Hetzer:
Yeah. I have to say this is the first time in my scientific career that actually I act on the research we do in the lab, so it is really personal and I started off with the image of the runners’ magazine because I like to run, as Cheryl mentioned, and I just wanted to understand how my training regimen, what do I have to do in order to be able to run into my 80s if I’m fortunate to live that long.

And so why did I really, why I’m trying to cut down on sugar so much? Well, it came out of a study that we did last year. It’s not published yet, but where we were able to show that the insulin response in beta cells at least in male humans is dramatically reduced after the age of 50, so there is really a shift in the ability of those beta cells, those insulin-producing cells to respond to sugar after a certain age. And as we produce more and more, or create new insights, it’s not only my lab obviously but other works, and again, I mentioned, for instance, Satchin Panda at the Salk Institute studying sleep patterns of aging. And so, sleep is an important aspect of healthy aging.

And so what I do know is I try to take care of my sleep quality and pay attention to it. And so that’s how I do … And as, I think, many of you probably know, as you get older, your quality of sleep is not as great as it used to be. So, we drink much less alcohol or in many cases no alcohol because the sleep is better and then, do it again, a lot of exercise that you actually are tired so your quality of sleep’s important. And so there are many, many things that come out of research, not only from my lab, but from other labs at the Salk Institute and we take it.

And another big is caloric intake, like fasting. Again, fascinating work from Salk scientists that show that you can take the same caloric intake but if you space it out and fast for 14 hours, you have many health benefits. So, there are clearly important lifestyle choices that you can pick up and they will have beneficial impact but, again, still a lot to be done, but I’m certainly a big exercise fan and I think exercise is really important for a healthy lifestyle.

Cheryl Dean:
Well, and I’m sure that that helps reduces some of your stress, which you must have, as everyone does, during the pandemic and-

Martin Hetzer:
Everyone has, yeah.

Cheryl Dean:
… your important role as a chief science officer at a biomedical research institute during this time. So again, to everyone whose questions we didn’t get to, I will see if I can get a little bit more of Martin’s time over the next week or so and then get back to you individually to answer your questions. And thank you all for spending some of your valuable time with us. We really appreciate your interest and support here at the Salk Institute.

As one of our attendees mentioned, we’re all feeling the isolation since this started at the beginning of a year, so even though this isn’t quite the same as being in our auditorium or at least the same community together supporting each other and we truly appreciate your attention and your encouragement because our scientists are working really hard right now just as Jonas Salk did all those years ago to try to improve human health.

So, a sincere thanks for all of us. There will be another Power of Science talk actually very soon. Later this month, you will get invitations to that and you’ll get a follow-up link to this presentation in case you didn’t happen to capture all of it on the first go-around.

So, thank you. We encourage your feedback. If you have anything, any suggestions as to what we could do better in the future, I encourage you to let us know and thank you.