The 2020 Weston Lecture: David Sinclair, PhD
"Seeing the Future: Longevity Research and Glaucoma" was the topic of the 2020 Weston Family Lecture presented virtually on October 27, 2020.
The 2020 Weston Lecture presented by Glaucoma Research Foundation featured world-renowned genetics researcher and best-selling author David Sinclair, PhD, AO discussing longevity research and glaucoma. According to Dr. Sinclair, “Research on Aging is shedding light on new approaches to address vision loss,” and this is discussed in detail in the video recording.
The Weston Family Lectureship was established in 2007 with a grant from Gladys and George Weston, DDS, in memory of their son Daniel. Each year the lectureship showcases a clinician or scientist whose work is significantly advancing our knowledge of glaucoma, particularly in new therapies and progress toward a cure. The lecture is introduced and moderated by Thomas M. Brunner, President and CEO, Glaucoma Research Foundation in San Francisco.
Watch the video recording:
Video Transcript
Tom Brunner:
Good afternoon, my name is Tom Brunner, and I’m the President and CEO of Glaucoma Research Foundation. It is my honor to welcome you today to the Annual Weston Family Lecture. The Weston Family Lecture has been an in-person event for the past 12 years. Held in Palo Alto, California this annual lecture allowed us to meet with friends and supporters to highlight recent advances in glaucoma research. Today, as a virtual event, we’re delighted to welcome many more friends from across the country and around the world. Thank you all for joining us.
Glaucoma is the leading cause of irreversible blindness affecting some 4 million Americans, and more than 60 million people around the world. Glaucoma Research Foundation mission is to cure glaucoma, and restore vision through innovative research. Our newest research collaboration, the Catalyst for a Cure Vision Restoration Initiative, has been making great advances, and we are incredibly proud of the new team’s progress. Their goal is to come up with novel strategies to restore or replace retinal nerve cells, and reconnect them to the brain to restore vision loss from glaucoma. Their work is only possible thanks to our many generous donors, and dedicated volunteers who join us in this important mission. Thank you for your ongoing partnership.
Today we are honored to have Dr. David Sinclair as our featured speaker. David is a professor in the Department of Genetics and co-director of the Paul F. Glen Center for the Biology of Aging at Harvard Medical School. He obtained his PhD in Molecular Genetics at the University of New South Wales in Sydney, Australia. Dr. Sinclair is best known for his work on understanding why we age, and how to slow its effects. We are particularly inspired by his research that involves reprogramming or resetting specific genes to promote axon regeneration after optic nerve damage in glaucoma. David has co-founded many companies, and serves on the board of several others. His work is featured in five books, two documentary movies, 60 Minutes, Morgan Freeman’s Through The Wormhole, and other media. TIME Magazine named him as one of the 100 Most Influential People in the World in 2014, and one of the 50 Most Influential People in Healthcare in 2018. It is indeed a great pleasure to introduce Dr. David Sinclair.
Dr. David Sinclair:
Thank you, Tom, it’s great to be here, and thank you everybody for coming. I’m going to give a talk about some of the research that is going on in the field of longevity science, which is increasingly relevant to treating diseases of the eye, including glaucoma. Thank you to the Glaucoma Research Foundation for the honor of giving this lecture, I know that there are a lot of people to choose from to give this. I’m excited to be able to talk about it today because it’s not obvious when you talk about aging why it could be relevant to the eye. Part of the problem is that we tend to think that aging is a natural process, which it is, but then we make the mistake of thinking, “Well, something that’s natural and common is therefore acceptable,” and that logic in my view is wrong.
What we’re talking about with longevity research, and I’m here representing more than a 100 laboratories around the world who work on this topic, we’re talking about understanding the fundamental processes that make our tissues and our organs dysfunctional over time. We call this aging, but essentially this process, whatever it is, is causing not just glaucoma but it’s causing retinal degeneration in general. It’s causing diabetes, dementias, frailty, and even cancer — many cancers of course, not all. To give an example, if we were to look at how much smoking contributes to lung cancer, it’s about fivefold increase in your risk. Aging, on the other hand, from ages 20 to 70, increases your chances of lung cancer by many hundredfold. I know we take that for granted, but we shouldn’t, because if we can treat the causes of aging we could delay, of course diseases of aging, the ones I mentioned and many more, that plague the planet.
We could also prevent and [know how you] possibly treat diseases that are not typically thought of as just aging such as glaucoma. Really, the ultimate goal here, and I don’t want to be shy about it, is it’s not about making people live to a 150 and 200, that’s what newspapers talk about. What we’re doing in my lab, and the others around the world, is trying to compress the period of our lives that is morbid. That period where we need help, we need to be in a nursing home, where we cannot see, where we’re blind, we lose our other senses, we cannot walk, and if we can squeeze that period of our lives down into just a few months, spend the rest of the time productive and healthy, this is the world that I think we should strive for, and I think it’s doable, and it’s very personal.
Often when I have discussions, and one could call them arguments, but discussions with people who say, “We should just live a normal God-given lifespan and not worry about it,” I say, “What would you give for an extra few weeks with your mother, or your father, or your grandparent?” Then things change, right? If you talk about your own family it’s very different, or your own family’s eyesight, it’s very different.
What we believe in my lab, and I’ve recently written a book about this called Lifespan, is that we should no longer think of aging and diseases related to aging as separate entities. In fact, the only difference between these two groups is that the group on the right occurs to less than half the population, and the group on the left happens to the majority of people. That’s the only difference. We look at it instead like this, that if we can understand why we age we can have a great chance of delaying, and possibly reversing diseases. I’m going to, as quickly and coherently as I can, explain what we think aging is, how do we measure it accurately, can we slow it down, and can we even reverse it. And if we can reverse it does that mean that diseases that occur the older we get will also be reversed.?
Now, this is probably the most complicated slide I’m going to show. What it shows really is that in the top two examples we can … we’ve known for many years, since the 1970s, that you can rejuvenate life, you can take the DNA from an adult, put it into an egg, in this case it was a tadpole egg, frog egg, and grow a new organism, we call it cloning. In the cellular reprogramming, second line, this is a more recent discovery that won the Nobel Prize in 2012, Dr. Yamanaka showed that there are four genes that are normally turned on during development and embryo genesis that you can put into adult cells and make those adult cells into stem cells.
These days those stem cells are used throughout the research community, and even there are some medicines that are based on replacement of stem cells with your own artificially generated pluripotent stem cells as they’re called. But also, naturally other organisms such as this hydra axolotls of salamanders, and even human livers are able to, we believe use the same processes to regenerate their body. We, as mammals lose this ability very early in life. But as I’ll show you, I think we can restore these amazing rejuvenation effects even when we’re old.
So, what is aging? My belief put forth, it’s a hypothesis I should say, it’s called the Information Theory of Aging, and the idea is that we have DNA which is digital, A, C, T, G, four bases, and they are relatively intact in an old body. Sure, we have mutations, but I don’t believe they’re the main driver of the process. What I think is more important is the other type of information in the body, we call this the epigenetic information, and this is the way the cell turns genes on and off in response to development in the embryo, puberty, and even the environment. If we don’t eat a meal the epigenome will change and it may influence how these genes are turned on and off. The equivalent would be if our DNA is the digital information, the epigenome is the reader of that information, and what we think in my lab is that aging is similar to scratching a compact disc so that it cannot read the information as well.
Similarly, if I draw now what a nucleus would like in a cell, when our DNA is very young our cells function perfectly, essentially perfectly because the genes that should be on in a particular cell type, let’s say the RGCs at the back of the eye in the optic nerve, they know that they’re nerves because the gene for being a nerve is switched on, but unfortunately what we see is that over time these genes get switched off, and vice versa. So that nerves at the back of the eye, and probably every cell type we looked at, perhaps with the exception of eggs and sperms, and certain stem cells, they lose their identity, they don’t have what we call a youthful gene expression pattern anymore. I’m going to quickly tell you what we think is a driver of this process, in other words what drives aging, and why cells become dysfunctional leading to diseases such as glaucoma. Then the second part, towards the end I’ll tell you how we think we can reset this system, essentially polishing the scratches off the CD.
If we zoom up into the nucleus and look at DNA, it’s not actually just flailing around like a long chemical, even though there is six foot of DNA in every cell, it needs to be packaged tightly, much more tightly for genes that are switched off, for instance a liver gene in the back of the eye is not likely be turned on, with a specific gene that is. The way the cell does it, is it wraps the DNA, as I’ve shown here by the metaphor of this strand of nylon, and there are histone packing proteins that the DNA is wrapped around. This bundle can stay for 80, 90, 100 years in the body, making sure that cells don’t lose their identity, and lose their function, but as I mentioned, it does slowly happen.
Why does it happen? Well, what I need to tell you is that there are chemicals that get added to the DNA molecule that are known as methyls, it’s basically a carbon and three hydrogens, and the process of adding that chemical to our DNA is called methylation. There are enzymes that add them and take them away during embryogenesis to make us this functional organism with 26 billion different cells in the body, each one slightly different. Of course most of them have the same DNA. We need to basically tune the piano, and methylation is what does that in part. Now, there are other chemical modifications on proteins that we won’t talk about today, because this methylation of DNA seems to be extremely important for this packing process, and for aging itself.
The first clue that DNA methylation was relevant to aging came from a study by Steve Horvath, who showed that if you look at where those chemicals are added on our genome it actually is quite predictable for age, and I could take some of your DNA, take it back to my lab and predict when you’re going to die based on which genes have these methyl addition or subtraction. Some people at a certain age, say age 70, would have aged more quickly, typically if you have bad genes, you smoke, you don’t exercise, you become obese at an early age, that’s what will happen to you, and vice versa. If you do all the right things you can actually live another 14 years just by doing the five top things that doctors tell us to do, and nutritionists. But we can also modify this slope, and as I’ll show you, we think we can reverse it as well. So take someone up here, or at least the eye of an animal that’s up here, and bring it back down here within just a matter of weeks.
What drives this process? First of all, we wanted to push it in the forwards direction, and we think one of the things that scratches up this CD and causes aging are breaks in chromosomes. You probably don’t realize if you don’t think about it often like I do, that our DNA’s breaking all the time, 26 billion times every day, and this process of having to repair the DNA ends up misfolding this packaging process. We could do that, we could take a mouse that was young, cut its DNA and let it heal for a few weeks, and if we’re right this process should unravel the DNA, and accelerate the aging process. Now, this mouse was treated 10 months before, and still looks very healthy, it’s currently 16 months old, and not showing many signs of aging, except maybe some blindness because the eye is one of the first tissues, or organs, to age in a mouse, and also in a human.
Here is what its sibling looks like. This mouse, again, was the one that had the scratches, the DNA was unraveled in its packaging, and we get a facsimile of aging. In fact, if we look at the age of this mouse on the right versus the one on the left, it is literally 50% older when we look at that clock, those DNA methyl changes, but the question really is, now can you reverse that? Now that we know that that packaging seems to be important for aging, can we get a cell to turn on the genes and play the music of youthfulness, polish the scratches, or in other words, play the symphony perfectly again?
But that’s a tall ask, right? Because we’re asking a cell to take messed up DNA packaging in a cell, in fact, thousands of cells if not millions eventually, and put it back to this state. How would it even be theoretically possible? Where would the information be to tell a cell, “Take that mess and wrap it up again this way?” I have to admit, we don’t yet understand in much detail how this occurs, where that information is held in the cell, but I can tell you that it does exist.
Now the way we did this was to rest on the shoulders of Shinya Yamanaka, who I spoke about earlier, and he had shown that these four genes create stem cells from skin cells and other types of adult cells, but if you put these genes into an adult, animal or a human, what you’ll get is either death or cancer, because you do not want to have stem cells in your body that are just growing wildly. So, what we did was we left off this gene here, which is called c-Myc, it’s an oncogene that causes cancer, and my graduate student, Yuancheng Lu was very brave and said, “Okay, let’s just work with these three.” He found that he could turn back the clock in human skin cells, but only partially so they didn’t become stem cells, but they became younger and more functional in the dish. Then we turned to … we thought, “How do we do this in a living animal?”
So we packaged up those three reprogramming genes that are normally only turned on in young animals or embryos, and we packaged in viruses. These are adeno-associated viruses that are FDA approved, and used in gene therapies around the world. Spark Therapeutic, for example cures retinal diseases, genetic mutations, rare diseases, and so we said, “Let’s try to do this with a drug, or at least a system of a drug that’s approved.” So we packaged up those three genes, we put them under the control of an antibiotic, doxycyline, and now we could put them into the eye, or anywhere really, and then turn the genes on when we wanted to, to ask the following: if we damage the retina or the optic nerve, and then turn on our reprogramming and make the eye young, well, first of all, does it become young? And if it does, does it heal like a young animal or even an embryo would? There are even animals such as fish, that constantly can rejuvenate their eye, so it’s doable in other life forms.
We could also ask, “Well, that’s just damage, but what about other chronic diseases, glaucoma, and even just simply old age?” So that’s what I want to tell you about now. We chose the optic nerve because it’s part of the central nervous system, it doesn’t look like the brain, but it’s actually projections from the brain. When you’re embryonic you actually … you can take those nerve cells and they grow back if they’re damaged, but I think, as you all know, if you damage your brain or your optic nerve, or your spine, it’s not going to grow back. We tested this, “What happens if we make these cells very young again?”
This was the key experiment that was done. Now, a couple of years ago, and we hope … We’re probably going to publish this in the next couple of months in the journal, make sure it’s in press. So just to orient you, this is the eye on the right. This is where the optic nerve was pinched, and then three weeks later this is what you see, the dye for the optic nerve, which is staining orange, a lot of those nerve cells have died off here. This should be bright orange, and the brain is back here, left of the screen, and what you can see is a lot of nerve damage has occurred. We’ve had degeneration of the axons, and of course this mouse is never going to see again. I want to mention that this was done in collaboration with Zhigang He’s Lab at children’s hospital, who maybe you’re familiar with.
So if we reprogram the optic nerve, remember we injected the virus through the front of the eye with one treatment, if we turn that on after the crush, in fact, we can do this three days after the damage, we can preserve a lot of the neurons, and you start to see after three weeks that the nerves start to grow back towards the brain. If we leave this, this is a mouse of course, but if we leave the mouse for 16 weeks we get nerves reaching the chiasm, the part where the optic nerve reaches the brain. Some of the interesting things about this is that if we look at the genes that are switched on here, these genes are actually involved in neurogenesis, they’re involved in embryogenesis, they impart these particular functions in the nerves. But interestingly, we also see that what’s going on in these cells is that aging is happening rapidly, and we think that’s why they’re dying, and that our reprogramming has delayed the aging process caused by the damage.
Now perhaps most importantly for this talk is this experiment, which was done in collaboration with Bruce Ksander and Meredith Ksander at Gregory’s Lab, and what we took … what we did, you maybe familiar, is you can increase intraocular pressure, IOP, for a month in a mouse by putting these microbeads in this region of the iris, next to the iris. There’s no draining going on so you get pressure in this orange zone, then we could add our viruses, turn on our reprogramming genes, and then test if the nerves are functioning, if the eye looks more normal, and if those mice can see. This shows you the pre-treatment and the post-treatment, we’re getting electrical signals back again, these nerve cells were actually younger, and then, now we could do a vision test.
These are moving lines on a LCD screen that changed their width, you might be familiar with it, and if the mouse moves its head in the right direction you score this, and it’s called the optomotor response. This is the baseline before treatment, and you can see that when we turn on the reprogramming many of the mice regained either all, or at least some of their vision, which is a first, because as Tom mentioned, glaucoma is not considered a reversible disorder currently.
We also did something that was, I think, brave of my student, Yuancheng Lu, so in collaboration with Bruce’s lab we just took old mice, these are one-year old mice that as I mentioned they’re blind, they cannot see these lines, and you can tell because it’s not moving its head to right. But if we turned on in the eye of an old mouse the reprogramming genes, now we could get vision back, we could reverse the age of the optic nerve, and now they functioned again, and that beautiful youthful pattern of gene expression and packaging was restored.
I’m sure you’ve got a lot of questions for me, I want to end by saying this study is quite revolutionary. We’re excited about telling the world about it in a couple of months. There was also another study that was shown when you put all four of these factors, and just turn it on for a couple of days, you could rejuvenate a short-lived mouse, and that credit … and perhaps a prize one day will be awarded to one Carlos Belmonte, at the Salk Institute. Now, the drawback of this particular study was, as I mentioned, if you mentioned c-Myc in there it either hurts, kills the mice, or causes tumor, so we’ve come a little bit further than that now, and we actually could show that the clock literally does turn back.
This was a group of people from a nursing home that we treated the other week, and you can see that they’re doing very well. Of course I jest, this is actually the group that did the work. This is Yuancheng Lu, and there’s also Xiao Tian, who helped (he’s the second author) as well, they did a remarkable job. I’m just really luck to work with such young enthusiastic people on really important work that I think will change lives. If you’re intrigued about what it was like to make these discoveries, and what the future holds, I wrote a book about it (Lifespan), and it’s available if you’d like.
Lots of people went into the study and made it possible, I mentioned the Ksanders, Zhigang He. The people who did the clockwork and showed we could reverse aging are listed here, Steve, Vadim, Morgan, Margarita, George Church is a leader in gene reprogramming and delivery, and really I just am blessed to work with such great people at Harvard, and around the world. Thank you to the people who funded the work, because without the funding I cannot do any research. Then I’m happy to pause here, remind everybody that this research is not about living so long, but more about the quality of life, and rejuvenating the body in ways that we only dreamed of a few years ago. Thanks again for the honor of giving this lecture.
Tom Brunner:
Thank you, David, what a fascinating talk about your amazing research. I think we do have a few questions from our attendees, and I also have a couple of questions for you. To begin with, a little bit off the topic of aging, but I’m just curious about how you got interested in science and biology in the first place?
Dr. David Sinclair:
Oh, gosh. Well, I’m not that good at anything else, to be honest. I’m terrible at languages, music, I don’t like crunching numbers, I’m more of a dreamer, and artist, somebody who likes working with teams. I would say I went in to biology because I wanted to help people. I learned that people are the most important and interesting things on this planet, possibly the universe. I also was taught by my grandmother, and my parents to try and leave the world a better place than I found it, and I’ve dedicated my life, besides my family, every waking hour to leaving the world a better place than I found it. I do come from a family of scientists, my parents were biochemists, and at the dinner table they talked about science all the time so I think that was a big influence too.
Tom Brunner:
Well, certainly I think if each of us could just leave the world a little better than we found it, that would be a wonderful thing. What about, moving into research on aging, how did you start in that direction?
Dr. David Sinclair:
I’m glad you asked, Tom, because there’s a misconception which I try to dispel in my book, that I care about my own longevity. Anyone who’s seen me drive my Tesla knows that that’s not the case, I’m more interested in extending health. I watched my grandmother go through 10 years of sickness at the end of life, my mother who didn’t take care of herself had lung cancer, and her lung removed at age 50, younger than I am now, and 20 years of not very high-quality life.
But I really got into aging because I felt this was an area of biology that was not being addressed in a rigorous fashion, and that the future as I saw it, in the 80s and early 90s, was in genetic engineering as we used to call it, now we just call in genetics, but I thought that that would be an area of big impact. I was fortunate, I don’t know why my younger self realized this, it’s kind of interesting that I thought that the increase in the number of aged people, and therefore the increase in age-related diseases would give an opportunity for me to help, and I’ll be honest, attract funding for research.
Tom Brunner:
Well, certainly as we all, I like to say ‘as we all get less young’ there definitely is this increase in age-related diseases, as you point out, and being able to solve that could be a huge contribution. You did talk a little bit about your mouse experiments, and Glaucoma Research Foundation has been funding vision research for many, many years, and one of the questions that I’d like to ask you is: there’s evidence, a fair amount of evidence that successful experiments in mice don’t really translate well to humans. I’m just wondering what about non-human primate research, are you … is that in your plans for the future? It seems like that would be an important aspect of really showing that this has a high probability of working for humans.
Dr. David Sinclair:
Yeah, absolutely. Well, it depends on the disease of course. Cancer has been cured in mice a thousand times over, but diabetes for example is, Type II diabetes is quite predictive, but in terms of nerve crush we’ve tested this reprogramming effect on human neurons, in the dish at least, and it works effectively to protect those cells, and let them regrow, and make them more youthful. At least we know it can work in a human neuron, but the proof of it is actually ‘in the pudding’ as they say, and we will, first, go into primate models, in macacques, with Bruce Ksander’s help, he’s working very closely with myself. And we have a program to, if all goes well, treat our first patient within the next 24 months.
Tom Brunner:
Wow, so within two years, that would be amazing. So that was going to be my next question: when do you think it could really be ready for humans.? You also mentioned earlier the fact that gene therapy is already in use for treating a type of rare childhood blindness, so it does seem like a lot of the technology that you need is available, and as you said, FDA approved, viral vectors to package the genes that you want to put into the eye, or other organs. I guess one of the things that is fascinating to me is that the eye, and I guess I would be interested in your thoughts on it, because of the fact that it’s so accessible, and because with this gene therapy for this childhood disease you just use a needle to go and inject that viral vector right under the retina. It’s a very delicate procedure, but they’re able to do it, and in your case you were injecting these three Yamanaka factors just into the globe basically.
Dr. David Sinclair:
Exactly, intravitreally. Now, the mouse size is structurally different than a human, and we’re talking to our experts about whether we need to come in from the back of the eye, but that’s also quite doable as well. We will figure that part out, and that’s where we’re at, we’re looking at safety of course because that’s the main thing, but also route of delivery, but other than that this isn’t rocket science as you said, these vectors are ready to go.
Tom Brunner:
I guess we’re starting to get used to it. It still seems like rocket science to me.
Dr. David Sinclair:
One of the problems right now is gene therapy is so hot in biotech, it’s hard to get your vectors made because companies that make these, they get three requests for every deal they can do. Gene therapy is coming, no question, and what you see on the market already is just a tip of the iceberg of what’s to come.
Tom Brunner:
So when you talk about reversing aging, for example the cure of glaucoma, are you talking about reversing aging for the whole body, or you’re thinking of specific organs? Because you talked about also treating the eye specifically with your ‘gene cocktail’, these three Yamanaka factors, can you expand on that a little bit?
Dr. David Sinclair:
Right. So we chose the eye for a number of reasons, business-wise, science-wise, for the reasons you mentioned already, there are drugs on the market that it’s immune privileged, it’s got a relatively … it’s a well-known safety profile, it’s certainly safer than delivering it through intravenous methods right now. But the good news is we have tested this treatment intravenously as well, and there’s no sign of any toxicity, no sign of tumors at all after a year in mice, just blasting these genes but instead of three weeks which we do in the eye, blasting it for a year. But I’m not keen on trying to find a universal cure for aging at this point, theoretically we could all go to my lab, and inject ourselves with this stuff and see what happens, but that would be kind of risky.
So instead, our focus at the company, there’s a company that I co-founded in … I don’t know if I should disclose that verbally, not just in the first line, it’s called Iduna, it’s the name of the Greek goddess of … not Greek, Nordic goddess of longevity, at Iduna, we are committed to treating glaucoma as the first disease, and all of our experts, or almost all of our experts are expert in that. We are doing other studies in collaboration with the Mass. Eye and Ear scientist that I mentioned, in diseases such as macular degeneration as well, and we have some early promising results there. But yeah, we’ve been working on this now for 18 months, and glaucoma, we’re way ahead in our research there.
Tom Brunner:
You did mention Zhigang He, as you’re aware, and I think some of the participants in the lecture today may also be aware that he is one of the five scientists who are advisers to our Vision Restoration Catalyst for a Cure Initiative. We have four laboratories working collaboratively on that same mission, to try to figure out how to restore vision either by the type of thing you’re doing where you’re restoring the cells that are already there, and enabling them to regrow their connection to the brain, or even in the idea of being able to put stem cells into the eye that could form new retinal ganglion cells, and again reconnect to the brain. But changing topics a little bit, and thinking just of longevity, can you share with us a little bit what you personally do to make sure that you live to be a 150 without any, as you call it, comorbidities?
Dr. David Sinclair:
Well-
Tom Brunner:
You mentioned five factors that our doctors tell us.
Dr. David Sinclair:
Well, those are the easy ones. I don’t know if I can remember all of them, but it’s don’t smoke, exercise, don’t overeat, get good sleep, and I think it might be have a good social network, something like that, but I try to do all of those but not very well. I’m not making it to a 150 unless there’s a real breakthrough. I have terrible genes, but I try to do what I can. I skip meals, I typically don’t eat breakfast or have a very late lunch, because fasting is one of the best ways we know, in adults not in teens or younger of course, we’re not talking about malnutrition or starvation here, so that’s one thing you can do. Try to lose your breath a few times a week, either running a treadmill or something else, and if not that at least move, and that’s where I fell down. I’m writing another book, I’m sitting and doing Zoom meetings like probably a lot of us now, that’s not healthy.
I do try to keep my muscle toned, males in particular, but females as well, lose muscle mass as they get older, and that’s dangerous as well. If you fall, and break your bone that’s one of the quickest ways to reducing your lifespan. I take a few supplements that are based on my research, one is called Resveratrol, which you might remember we showed was helpful in animals, and others have shown maybe helpful in humans, that’s this red wine molecule from 2006. I continue to take that. There’s one that boosts the levels of NAD. NAD is a molecule that declines as we get older, and we think prevents the body from fighting aging, and actually can increase neuronal susceptibility to damage. It’s capital N, capital A, capital D, but Tom, instead of going through a laundry list of things that I try to do, and in most cases do, it is on page 304 of my book.
If you want to cheat, and just jump to that place, you’re welcome to, but I do encourage everybody to read more than that, because what I do may not be perfect for everyone else, I’m a different age, demographic, my lifestyle’s different than everyone else’s. My ability to skip meals at certain times of day is different than others, and by reading my book you’ll have a better idea of, I think, why these things work, and you can tailor it to yourself. There’s also information about how to measure yourself, whether it’s standing up without helping yourself, or taking a blood test and getting information that way. But yeah, the goal, as I mentioned is to give people the best lives that their genes will allow.
Tom Brunner:
Now what about the age of starting to, shall we say live right, if someone is 60 or 70, or even 80, is it too late, or can you do that anytime?
Dr. David Sinclair:
Well, it’s not too late. People have studied older people in 80s, and just moving, and walking, and lifting weights makes a big difference. I’d like to use the example of my father, of course not a clinical trial, but he in his 50s started living the kind of life that I was talking about. He did take a few of the supplements that I had mentioned, so we don’t know if those are helping, but he is now 81, he’s stronger and fitter than I am, and I’m 51. I know that I’m not exaggerating, we have actually tested ourselves. He has no aches, pains, he barely needs glasses, so at 81 he’s doing great. He actually went back to work in his 70s because he got bored, and this is … maybe it’s just luck of the genes, we don’t know, but he certainly seems to be beating the odds.
What he’s finding though is that as long as he stays healthy, and has a social life, which he definitely does, he’s in no rush to die. And so that’s really my point, is if we can all stay healthy and productive, and have a nice social network then isn’t that what we would want for our family and for ourselves, and for our children? So that’s what we’re trying to do. The other point, given that this is the Weston Lecture, is that the discovery of the ability to enhance the body’s repair systems, and to rejuvenate the body has come out of aging research, but this could be applied to most diseases that I can even think of. We’re going to target the eye, glaucoma first, but that will pave the way for other rejuvenation processes, whether it’s rebuilding a new liver, skin, spleen — the sky is the limit at this point. We’re only held back by our imagination, and hopefully some luck along the way.
I want to mention one thing that nobody except the insiders would know, is that I was at a conference a couple weeks ago with all 15 of us talking about this reprogramming work, and a lot of it is not published yet. I’ve seen things that make my head spin, the ability to turn back aging in a whole animal, and there were three Nobel Prize winners there as well, and by the first day there were four Nobel Prize winners, because Jennifer Doudna won her Nobel Prize for building CRISPR.
Tom Brunner:
Right.
Dr. David Sinclair:
So this is a big deal, the field thinks it’s a big deal, and I’m fortunate I was able to tell you a couple of months before our paper comes out.
Tom Brunner:
Now, another question that has come in is related to duration of injury. We all know that glaucoma is a slow, progressive disease, and the animal models with the nerve crushes, kind of a traumatic injury which is probably different than glaucoma. The Microbead model that you mentioned has long been used to try to simulate glaucoma because it causes a slower nerve degeneration, but what’s your thought for people that have already sustained vision loss, people that may even be blind, do you think there’s a chance of actually restoring someone who has very minimal vision, and has had glaucoma most of their life? Is that something that might be in the cards? Is there hope there? What do you think?
Dr. David Sinclair:
Well, consider the old mice, they’ve had vision loss for many months, and later in life, that’s a-
Tom Brunner:
That was naturally occurring vision loss? (David nods ‘yes’) … Oh, okay.
Dr. David Sinclair:
That was reversible very easily, just in a few weeks, a couple weeks even, so I don’t yet think there’s a limit, we’ll see of course, but given that result I am optimistic that we’re not just talking about helping fresh wounds or wounds that are … not wounds, but diseases that have just begun. I think as long as the neurons are still intact, and haven’t died, then we have every chance of reprogramming them to get back their youthful function, and it’s been very successful. If we look histologically at the back of the eye when we treat it, those nerve cells that get the gene therapy, almost always have the benefit. It’s not that, “Oh, only 5% work.” Literally every time a cell gets this treatment it gets rejuvenated, and so I’m really optimistic if we can infect a large amount of the retina in humans, 30%, 40%, maybe 50% then we should have a great chance of restoring vision.
As to how long it lasts, we’ve gone out a few weeks, but we don’t know if it’s going to lasts for years, but one reason for optimism is that those chemical additions that I talked about, the DNA methylation, what we’re doing is we’re stripping those away, and typically those changes lasts for decades. In fact, that’s why the cell uses those methyl chemicals so that a cell in your brain that’s programmed to be a nerve cell, will stay a nerve cell for most of your lifespan. That’s why I think that we’re going to need one reset of the retina, or optic nerve, and then I presume that disease will come back, maybe it will be five, 10 years, and then it could be that your doctor prescribes you another round of the antibiotic that turns the genes on for three weeks, and then you get reset again. We don’t yet know how many times you can reset the age of a complex tissue like the eye, but I don’t see any theoretical reason why we couldn’t do it many, many times.
Tom Brunner:
I do know one of the other scientist advisers for our Catalyst for a Cure group, Jeff Goldberg at Stanford, who’s a neuroscientist, has been doing work with neurotrophic factors as a way to help neurons regain their vitality. I don’t know if you’re familiar with his work or not, but what do you think about that idea? I guess that wouldn’t be called reprogramming, I don’t know what you would call that, supplying nutrients I guess, but any thoughts on that?
Dr. David Sinclair:
Right. So we’ve been trying that approach as well in my lab for over a decade, and it does have great effects actually. I’ve mentioned this NAD molecule, it can rejuvenate nerves, and in fact many parts of the body as well, and it’s a great approach. The difference though in this new approach that I talked about, is the chance for it to be a one-time treatment, and to have a dramatic effect, whereas the other treatments which I’ve been involved in, so guilty as charged, these are drugs that rejuvenate but not a one-shot treatment. But perhaps what we’re talking about in the future, are complimentary approaches that you get reset and then you continue to take the rejuvenation cocktail, whether it’s NAD or some other nutrients that helps the disease or staves off the disease for longer. I think that more approaches that are complimentary the better. There isn’t going to be just one solution to something as complex as glaucoma, but that’s one that you can appreciate, is quite a noble approach, so I think that it maybe very helpful in combination with others.
Tom Brunner:
As you’ve mentioned, glaucoma is a very complex disease, which I think is why we’re still searching for ways to cure it or to, as you say, to reset the cells, and that does raise another question in terms of other … some of the different sub types of glaucoma. Do you think some of your ideas could be applicable to pseudoexfoliative glaucoma or congenital glaucoma, other types of glaucoma? Have you looked at that idea?
Dr. David Sinclair:
Well, only by discussing it, we haven’t actually done any science on that. I would say that our results suggest that defects that are caused by malfunctioning components of the eye, we’ve shown it most strongly for RGCs, but we’re starting to show it for other cell types such as the RPE layer in the eye. Epithelial cells need to be working as well for reprogramming. If those diseases have intact neurons, and components of the eye, and the structure is largely intact, then I would be optimistic that we could make those cells function well again.
Tom Brunner:
Certainly if you were able to repair the retinal pigment epithelium that could be a major factor for macular degeneration, and again, assuming other parts of the eye are still functioning well, and you have that particular cell type that’s not doing as well, and that you were able to rejuvenate that, that could be an amazing result.
Dr. David Sinclair:
One of the things that’s notable about this new approach, which I’m told by experts in the field is that it’s different than trying to put stem cells into the eye or the body to try and replace what’s missing. I know it’s an area of very active research, and that it holds a lot of promise. What makes this different is that we’re not hoping for the cells that we put in to find their place and grow, we’re taking what’s already there when we were born and working with that. Those are nice complimentary approaches as well, and may have different benefits depending on the particular form of glaucoma.
Tom Brunner:
Well, thank you very much, David. This has been really fascinating, and thank you for making the time available, and for answering so many of our questions. We all hope that that extraordinary research on reversing aging will really help to restore vision loss to glaucoma. I will be checking back with you to see how those primate studies are going, and we’ll be hoping maybe two years from now we’ll … or three, we’ll give you another year, that we might have some actual clinical trials in human patients, that would be amazing. Now it’s my pleasure to introduce our Glaucoma Research Foundation Board Chair, and the Executive Director of the Glaucoma Center of San Francisco, Dr. Andrew Iwach.
Dr. Andrew Iwach:
Thank you, Tom, and thank you, David, what an impressive and inspiring presentation. Today’s event was made possible through the remarkable support of the Weston Family. Through their generosity we have hosted this lecture for many years. Although this year we are unable to gather in person, this virtual platform is a wonderful opportunity to highlight important advances in glaucoma research, and recognize the Weston Family for their enduring friendship. Gladys and George Weston established this lecture in memory of their beloved son Danny, who passed away of a brain tumor in 1998 at the age of 47.
This annual gathering showcases a nationally recognized clinician or scientist whose work significantly advances our knowledge of glaucoma. In February of this year, Dr. George Weston passed away, and his wife Gladys, and daughter Jane Weston, wished to continue this lecture as a tribute to Danny, and also honor Dr. Weston’s passion for the work of the Glaucoma Research Foundation. We miss George dearly, and are so grateful for his sincere commitment to our mission to find a cure. It is now my honor to introduce George and Gladys’ daughter, Dr. Jane Weston, to say a few words.
Dr. Jane Weston:
Thank you, Dr. Iwach. As you know, you were the inspiration for my dad’s involvement with the Glaucoma Research Foundation, your skill as his doctor kept my dad’s vision intact throughout his life, and your passion for glaucoma research served as a great source of inspiration for him. When my brother died in 1998, my parents were searching for a way to memorialize him, inspired by Dr. Iwach, they created the Annual Daniel S. Weston Lectureship, which now, since my dad’s recent passing has been renamed the Weston Family Lectureship. This annual event has been one that my mom and dad, and now my husband and I, look forward to every year. The lectureship brings state-of-the-art knowledge and understanding to an audience of interested adults, many of whose lives are touched by glaucoma in one way or another. Over the years the lectureship has taken place in different venues, but most recently has been a well-attended event at the senior living facility of Moldaw Residences in Palo Alto, where many of my parent’s friends and neighbors were able to easily attend the lecture.
Now, with the recent changes brought about due to the coronavirus pandemic, I’m excited to welcome an even larger audience of interested listeners to this lectureship, unconstrained by geographic boundaries. In reality, this is as it should be, since the research and advances that the Glaucoma Research Foundation supports are advances that deserve a worldwide platform. On that note I’m excited you have chosen to join us for this year’s lectureship. I hope you have enjoyed it as much as my family and I enjoy supporting this most worthy cause. Thank you so much for joining us today.
Tom Brunner:
Thank you, Jane, and all of you for joining us today. We will be forever grateful to you, and your family for their outstanding support. Please visit our website at www.stg-glaucomaresearchfoundation-stg.kinsta.cloud for more information about glaucoma, and our research programs on vision restoration. Use the Search Box in the upper right corner to find articles on any topic or question. You can also download our newest edition of Understanding and Living with Glaucoma, which has the newest treatment information, and tips on working with your doctor. At Glaucoma Research Foundation we believe no one should go blind from glaucoma. All our activities focus on our important mission to cure glaucoma, and restore vision through innovative research. We are incredibly indebted to our donors, and corporate partners for their ongoing investment in our work. Every gift makes a difference, and we would be honored to have your support. Thank you for joining us, and have a good evening.
First posted November 4, 2020; Last reviewed October 21, 2022