The Molecular Basis of Aging and Dementia

video: https://www.youtube.com/watch?v=nyi0zJmSwWo

date: 2025-05-15

speakers: Steven Clarke, David Eisenberg

LLM-generated summary: Professors Steve Clarke and David Eisenberg presented complementary perspectives on aging and neurodegeneration at a UCLA Conversations event, emphasizing molecular damage as a core driver. Clarke detailed the inherent chemical instability of biomolecules—particularly proteins, where aspartate and asparagine residues undergo rapid deamidation, isomerization (forming isoAspartate), racemization, and kinking, leading to functional loss and physiological decline—countered by evolved repair mechanisms like protein-L-isoaspartate O-methyltransferase (PIMT), which uses S-adenosylmethionine (SAM) to methylate damaged sites for reversal, and backup ubiquitin ligase-mediated degradation when repair fails, as validated in knockout mice revealing redundancy. Eisenberg focused on pathogenic amyloid fibers in Alzheimer's (tau) and Parkinson's (α-synuclein), providing causation evidence from mutant models, PET correlations with atrophy, and consistent fibril structures across patients; he showcased fiber disassembly by EGCG (from green tea), which binds cavities between steric zippers, inspiring brain-penetrant small molecules (e.g., CNS11 for tau, CNS11G for α-synuclein) that form orthogonal protofilaments inducing mechanical strain and fragmentation, directly observed via atomic force microscopy, offering a path to oral drugs superior to ineffective antibodies.

Video description

Topics of this UCLA Conversation included the biochemistry of aging; molecular damage and molecular repair in aging; Alzheimer’s disease and Parkinson's disease; and research by the laboratories of Dr. Eisenberg and Dr. Clarke in these and related areas.

Event Introduction and Speaker Bios

We're going to get started with the program tonight, so please silence your cell phones as we get started. Hello, I'm Stuart Wolpert, Director of UCLA Conversations. I've really been looking forward to tonight's program since October, when our distinguished speakers agreed and accepted our invitation to speak with us tonight.

Dr. Steve Clarke is a UCLA Distinguished Professor of Chemistry and Biochemistry, and he's former director of the UCLA Molecular Biology Institute. Dr. Clarke has been honored by the American Chemical Society, the National Institutes of Health, the American Society for Biochemistry and Molecular Biology, and UCLA's Academic Senate, which has awarded him the EBII Award in Art of Teaching. Dr. Clarke's laboratory studies biochemical mechanisms that recognize molecular damage in the body for their removal before they cause disease.

Dr. David Eisenberg is UCLA's Paul Boyer's Professor of Molecular Biology, a former director of the UCLA DOE Institute for Genomics and Proteomics, and a Howard Hughes Medical Institute investigator. Dr. Eisenberg is a member of both National Academies of Sciences and Medicine. He's among the world's most highly cited scientists. Dr. Eisenberg studies the molecular basis of Alzheimer's and Parkinson's diseases and therapeutic approaches to potentially limit their pathologies.

Please join me in welcoming Professors Steve Clarke and David Eisenberg.

Steve Clarke's Opening Remarks and Personal Background

Well, it's wonderful to be here tonight. And I feel especially humbled in the presence of Professor Vanna Torres-Gill, one of the world's leading experts in aging. So thank you.

Talking about the molecular basis of aging, I first want to give a big shout out to Stuart Wolpert. Stuart and I have been colleagues and friends for most of my time at UCLA. He's done a fantastic job of bringing the contributions of scientists at UCLA to the public, and I enjoyed working with him. So a big shout out to Stuart.

So I've been at UCLA since 1978. I used to tell my students that I was teaching here when your parents were in diapers. I'm now afraid that's going to be, I was teaching here when your grandparents were in diapers. I hope you don't get that far off.

And I'm very happy tonight to have some of my relatives here, my wife, Professor Kathy, my sister, Lorraine Young, and my brother-in-law, Stephen Young. I also want to shout out to the wonderful collaborators that I've had at UCLA. Where's Harvey? Here's Harvey Eisenberg. Harvey, he pioneered the field of protein arginylation and methylation in cancer.

And then, the work I'll describe today, I have some wonderful collaborators, including Stephen Young, a couple of young whippersnappers in the department, Jose Rodriguez and Joseph Liu, as well as David Eisenberg.

Perspectives on Aging: The Blind Men and the Elephant Parable

So what I'd like to talk about tonight is how one biochemist looks at the human aging process, and others can tell very different stories. And so I like the story of the Indian parable of the seven blind scholars and the elephant.

And so the seven blind scholars are looking at elephants for the first time, and one of them has hands around the leg. He says, my colleagues, an elephant's just like a tree. And another colleague who is a tongue-teller. I'm sorry if I just think this is quite wrong. An elephant is like a hose. Okay, so you get the picture.

And so if we look at the aging elephant, we have some people looking at aging as stem cell biology or telomere biology or cellular senescence biology. But here I am on the right looking at aging as molecular damage. And I think the picture is all right. Okay. All of this is a part of the molecular basis of aging. I don't think one needs to know it all. But what I'm going to talk about is the molecular part.

Spoiler Alert: Biomolecular Instability and Countermeasures

Okay, so here's a spoiler alert, okay? This one slide is going to be everything I'm going to tell you tonight. So this is the deal. Biomolecules that make us up are inherently unstable. And they're falling apart. And as they fall apart, they're not functioning any longer, which leads to then a change in physiology.

But, here's the big but, organisms have evolved to recognize the kinds of damaged molecules and, in many cases, limit the accumulation of the damage and the functional losses. So bad news, good news.

Biomolecular Degradation Over Time

So if one looks at the molecules that make up life, beautiful molecules of DNA, beautiful molecules of RNA, beautiful molecules of proteins, and I think, David, are you going to show us some films of molecules and the beauty of them? I'm going to show some really bad molecules.

So anyway, so these are the molecules. They're biosynthesized in perfect form, but as soon as they're made, they're starting to be degraded. And over time, you have degraded forms of these molecules that are less functional. And basically, you're going towards, you know, sort of back to the atmosphere.

And I think I show here, you know, simple molecules like glucose with six carbons. Here's glucose that you can imagine chemical bonds with a little bit of vibration. And once in a while, they break, okay? And when they break that molecule, then it's no longer. So here is DNA with a much larger billion carbons in a chromosome. Here's a protein with tens of thousands of molecules of carbon atoms. And they're all sort of leading to these very simple molecules of carbon dioxide and water. So we're sort of back to basics, okay? These molecules all quite came from thin air. Plants and bacteria were able to take carbon dioxide and water and nitrogen from the atmosphere and make us. But we're going right back there with the damage.

Physiological Consequences of Aging

So that's the bad news. We're being betrayed by our own molecules. And that leading to global changes in physiological functions. And I'm not sure how many of you can actually see this laundry list. This list of things that go wrong with aging. And every year I check off a few more.

And so the news is that physiological functions peak at about the age of 18, unless you're family quorum. I love telling my students that, you know, they'll look at my brain here and I'll tell them, well, listen, you know, you're on the downhill already.

Chemical Instability: An Experimental Analogy

So anyway, the chemical question that we're asked often is we take chemicals, we mix them up, and we incubate them at like some temperature, and we see what happens. So we do chemical reactions.

So this is the chemical reaction that I'm going to do. I'm going to do a picture of the maiden. A 16-year-old freshman at Memorial College had put in the incubator at 37 degrees for 59 years. And so my question is, what the hell happened?

So, you know, and so the point is, is that the molecules aren't stable. You get your drugs, you get your food, they have expiration dates. And those expiration dates aren't 100 years. Those expiration dates are six months or, you know, a year or so. And pity the poor undergraduate who gets a shipment of research protein and leaves on the bench overnight, comes in dry ice, leaves on the bench overnight. You've ruined it, that protein sat for 12 hours at room temperature. But we're expected to sit for 100 years at 37 degrees.

Countermeasures: Human Resilience in Aging

So, one thing that is clear to me is that it's not all bad. And I love this slide of, this is an older slide, of record marathon times versus age. And what you'll see is that people at like 30 years old actually have better record marathon times than people that are 18.

In looking at this, you can go and you can look at it toward the end of it, and there is someone my age who is running a marathon with 6.5 minute miles. Okay. So do what you want. Okay.

All right. So now here is Muscle Beach, 1949, the year of my birth. And I know you're all looking at that beautiful creature in the air, but I don't want you looking at her. I want you looking at the old geezer. I love it. And so that old geezer, he has a suit on. He was probably in the air just a little bit earlier, but he's not photogenic. All right?

So we actually do well. And one of the things that people have thought is that, in fact, there's an evolutionary pressure for us to keep youthful in aging. And it's what people have called the grandmother effect or wisdom. So, you know, basically, after we're done having children, you know, what's our role? Our role is protecting the tribe and taking care of the grandchildren and making sure that there are good decisions being made. And so, you know, don't go to war with that tribe. That's not going to work out well. Don't eat that plant. And so that's the wisdom.

Evolutionary Pressure and Damage Mitigation

And so my argument, and this is controversial, but I think I'm not going to get much grief from this audience, is that there is a wisdom in aging, and there's an evolutionary pressure there to keep us young.

Okay, so. Molecules degrading, an active fight to actually prevent that. And so the degradation is not inevitable, but it's a loss mitigated to a greater or lesser extent by countermeasures.

DNA Repair Mechanisms

And one of these countermeasures is well appreciated. Our cells have a single, well, actually we have two molecules of DNA, one from mom, one from dad. If anything happens to them, and probably in the time that we've been sitting here, we've all accumulated a few mutations in our DNA.

But we have over 20,000 genes in humans, about 400 of those encode proteins that look for damage. And they look for damage on the DNA. They go up and down the DNA strand and look for damage. And when they find damage they repair it. So you can keep the DNA in a good form.

Protein Damage and Repair: Less Appreciated

What's not so well appreciated is that proteins also are subject to damage and small molecules. So DNA may be the blueprints, but the proteins are what's doing things that are functional in cells.

So the proteins are long strings of 20 amino acids. So here's one protein that's hopefully working for all of you right now on trypsin. So the trypsin in your small intestine hopefully is this protein that's now digesting the protein content of your dinner. And it does so with long strings of 20 amino acids. We have different structures.

Now, what's good for a protein is not to be in contact with oxygen. Oxygen is horrible. Oxygen is reactive, degrades. Glucose is horrible. Degrades. And water degrades. So all these things that we absolutely need are actually leading to degradation. And basically, it's really time itself that's the problem.

Problematic Amino Acids: Aspartate and Asparagine

And so of the 20 amino acids, there are two bad characters. Two amino acids are put into the genetic code, but that was a big evolutionary mistake. And the reason was a mistake is that these two amino acids, aspartic acid and asparagine, have reactive side chains, and they can react with the polypeptide chain itself and lead to a whole variety of chemical damage.

And so I showed here in the green the structures of aspartic acid and asparagine, and then the arrows of chemical reactions that happen not in a hundred years, but happen in days and hours. And so making derivatives are deamidated, racemized, isomerized, and kinked. Okay, so that's the problem.

And in fact, David and I collaborated on a recent paper where we looked at actually what happens with peptides that can form amyloid that have isoaspartyl residues, which have the kinks. And what they are is that they actually form amyloid much faster. And they form these wonderful structures that David pioneered where molecules come together and they can exclude water by just coming together absolutely perfectly and making hydrogen bonds so tight they don't come apart. And so are you going to tell us more about that, David? Yes.

Okay, so that's just my introduction to David.

Organismal Defenses: Protein Methylation Repair

Okay, so that's all bad news. How does the organism defend itself then? And one of the ways it defends itself with one of my favorite small molecules, S-adenosylmethionine.

S-adenosylmethionine I love because you can actually buy it at Costco. You can chew on it, and it does everything good. It's actually a pretty good antidepressant, ameliorates the pain, arthritis, and actually, if you're abusing your liver in any way, it can actually slow that down.

So what does S-adenosylmethionine do? Lots of things. But one thing it does is transfer methyl groups, the small CH3 group, to a whole variety of acceptors. And one of those acceptors are damaged proteins.

And so here are three of my early graduate students in a reflective mood. And what they found was that this reaction didn't occur with normal proteins. It was selective for damaged proteins. So we found an enzyme that can actually recognize damage.

And so here is a representation of that molecule that Professor Ty Gates determined. And this molecule turns out to methylate the damage and lead to its conversion into normal forms. It's a repair enzyme. So not only DNA gets repaired, but proteins get repaired.

Probing Repair Function: Knockout Mouse Studies

So one of the things that we want to ask is, oh, we've discovered protein repair. This is great. How can we figure out what it does?

So we enlisted the help of Professor Stephen Young at UC San Francisco and made mice that lacked it. And so the mice actually normally live about two years. The mice were all dead after about 42 days. And I said, Steve, this is fantastic. What happened? Did they turn gray? Did they start walking funny? Did they start talking stupid to their children? What were the aging phenotypes of these mice?

And it turned out it was seizures. And it turned out that it was a complicated story. We could actually have ways around the seizures and these mice lived.

And that's one of the toughest things with biochemists, because you discover something you think is the secret of life, and then you take it away, and life goes on. So that was sort of hard to mull over.

Backup Pathways: Protein Degradation

But it turns out that if you can't do repair, organisms don't take it on the chin. They have backup pathways. And in 2022, we discovered this backup pathway. And the backup pathway is, if you can't repair it, degrade it and make a new one. You repair it first because that's easy. If you can't do that, you degrade it.

And so we have a class of ubiquitin ligases that this one that we discovered would specifically look for damaged proteins that weren't repaired and then take them to get ubiquitinated and degraded to recycle the amino acids and make a new one. And so we have redundancy in controlling the accumulation of these guys.

Conclusions: Resilience, Redundancy, and Interventions

And so the conclusion is aging organisms are tough. They're going to fight back against chemical damage. And I love this example. Some of you may have heard it. Trying to figure out how something works. Trying to figure out how an organism works and taking something simple.

And so you're given a tool, and you're told a pair of wire cutters. And you want to know how a toaster works. So you take the wire cutters, and you cut the cord, and you plug it in. What happens? Nothing. So you know that the electricity makes the toaster work.

Now you take something more complicated. You take the Mars lander, and you take your pair of wire cutters, and you clip one random wire. What happens? Nothing. Nothing. Yes, that's nothing, because engineers have made it like life. They've triple engineered it. So if one system fails, another takes over. And I think that's the lesson that we're learning in aging systems. In fact, you know, the evolutionary pressure is enough so that things actually keep going.

Okay, so bottom line is that we take care of damage.

Potential Interventions: Lifestyle and Nutraceuticals

Now let me just end with one of the things that are fantasy, can we do something? Now we know about these processes, can we make it better somehow? Can we sort of increase the activity of these repair enzymes?

Okay, and we don't, the answer to that, we don't know anything. But you know, at meetings on aging, you know, someone comes up with, you know, these are the things you need to do to live a long time. And you know, it gives a whole bunch of chemicals. And at the end of the meeting, then, sometimes it's myself, sometimes somebody else stands up and says, listen, how is this any better than listening to mom?

Okay, so mom: good diet, exercise, and sleep. So, you know, how much of that might work through molecular repair? And, you know, what can we do about it? We can do things about these things.

And, in fact, diet, I think we had a pretty good diet tonight, but one of the things in diet, lots of controversy. One thing that's not controversial, fruits and vegetables are magic. We don't know what that magic is, but there's something magical. And then you can go down the list of coffee and vitamin D and omega-3 unsaturated fatty acids. Probably good. There's some controversy. And then you go down the list to alcohol and ascorbic acid, vitamin C. More controversy.

But anyway, the idea is that you might be able to do something to keep these enzymes going. And so at the end of all of it is, you know, I'm on the left-hand side of this fountain of youth. And what I'm hoping is, you know, there's something in that broth, okay, that might help get to the other side and come out of that side.

So, thank you.

Audience Q&A: Nutraceuticals with Steve Clarke

Q: So, Steve, what's your thoughts on nutraceuticals? You mentioned the S-adenosylmethionine confounding degree. Rush down the hospital?

A: Yes. It depends what you've got, okay? It depends what you have. So I think, you know, for people that have depression, they'll go to a psychiatrist and I told a psychiatrist, I want to take a drug, and the psychiatrist said, well, why don't you take S-adenosylmethionine, which actually works almost as well. It costs about a hundred times less, but that works.

Now the other list I had I think well actually I am amiss at not mentioning coenzyme Q. I want to not sleep on the couch tonight. So Kathy works on coenzyme Q, and I take that religiously, along with vitamin D and ethosuximide omega-3s. You can get that between your toes.

I must say that I had problems walking for a long time with my bursitis, my greater trochanter. And so I started taking S-adenosylmethionine, and it went away. I also started doing yoga. But the thing is, I have enough faith in S-adenosylmethionine, but I don't want to do the experiment of stopping taking it, because I don't want to start hurting again. That's if I was a real scientist, I would do it.

David Eisenberg's Introduction and UCLA Environment

We'll give you the blues now. Thank you. Now we can see slides. We have it upside down. And is that all? Now we can see slides. Yeah. Yeah. Yeah. It's my shot. One, two.

I thought Steve's talk was rather optimistic. Forget that from my talk. So I'm going to be talking about neurodegeneration, why it happens, and why we don't yet have drugs for it but maybe why we can get drugs for it.

I'm going to start with a little personal stuff about UCLA. I second what Steve said about the wonderful opportunities here and mentioned collaborators. I mean it really great to be in a place where we have our fundamental science right next to the medical school right next to the School of Engineering, where we meet faculty and students from these various disciplines and very easy to establish collaborations.

Steve mentioned some of his collaborators, and here's a list of some of mine. And I also want to say how important it is that we have this wonderfully diverse and interesting group of students who enliven the lab every day. So this list of people from our lab come from seven countries. And every day at coffee at 3:30 we have discussions not only about science but everything. And it's just extremely stimulating to see that it's a great place to work.

David Eisenberg's Path to Neurodegeneration Research

So I want to say a little bit about how I got into this area. My dad was a pediatrician in our little village. And for him, relieving suffering was the main reason for working, for wrangling, and helping. And he intended that I'd follow him into medicine, and he had followed his uncles.

But when I got to college and had a tutor, he said, if you want to relieve suffering, then study biochemistry. You can do much more than being a physician where you'll see 10, 100, 1,000 patients, but you could affect the world if you're a scientist. Well, I believed it. My father didn't.

So I got running into science and came to UCLA. And I have to say, I spent my first 30 years here. By my standard, Steve's a baby. And I was enjoying work and learning the structure of proteins and other biochemical molecules, along with Jim Lake who here and other colleagues.

Bioinformatics came along. It was such a revolution we could make a discovery every day when the human genome was sequenced. It was a great time and I was really enjoying it.

But then, about 30 years ago, in the late 1990s, suddenly it dawned on me. I certainly hadn't done what my tutor in biochemistry had said and what my father wanted me to do. I was having a great time, but maybe I should think about how I could do something that would affect a greater portion of the population.

So I looked around for diseases that maybe that maybe I could contribute to. And here were a whole group of diseases, namely those that all were connected with fibers and nerve degeneration: Alzheimer's disease, seven million patients in the United States, Parkinson's, nearly a million patients, FTD, I don't hear so much about, but another one of these different dimensions that strikes younger people, and of course ALS, and another 45 or 50 diseases, all associated with the same sort of fibers of different proteins. Each disease has its own particular protein fiber.

At that time, 30 years ago, there were no effective drugs for any of these diseases. Today, there are no effective drugs for any of these diseases. But what has changed is we start to have atomic structures for them, and that's a good step towards drugs.

Amyloid Fiber Diseases: Association vs. Causation

Now, I was careful to say that these diseases are associated, each one, with a fiber. There was a very smart guy 400 years ago named John Locke. In Locke, I read persuasively, you can never tell the difference between association and causation. So do the fibers really cause the disease? Are they just associated with it?

But I think the case for causation with these fiber diseases is quite strong.

Evidence for Fiber Causation: Alzheimer's (Tau)

So in the case of Alzheimer's, the protein is called tau. In the case of Parkinson's, it's called alpha-synuclein. Each one forms fibers in the brain in those diseases.

And here's the evidence. There are very rare families who have a mutant form of the protein tau. And they get Alzheimer's disease at very young age, like 40s, even in 30s. If that mutant form of tau is put into mice, now they get an Alzheimer's-like disease. Well, we can't test them with cognition very easily, but they mess up the cage.

Evidence for Fiber Causation: Parkinson's (α-Synuclein)

The same with alpha-synuclein and Parkinson's disease. Those, if you give them the mutant form of alpha-synuclein, which causes severe Parkinson's in humans, you give it to mice and they get a movement disorder. So I think that's a very strong argument for causation, and I'm going to show you two others.

Structural Correlations: Tau PET and Atrophy

So in the upper left, you can see a picture of some of these fibers. In this case, those are Alzheimer's fibers. And experiments done in UCSF in the upper right, where they have patients look for the amount of tau fibers in these patients who have been diagnosed as Alzheimer's patients.

It says tau PET is a measure of the fibers in their brains on the horizontal axis. I don't know if you can see my cursor, but on the horizontal axis, tau PET. On the vertical axis, brain atrophy. And you can see there's a correlation. That is, the patients who have a lot of fibers in their brain, their brain is atrophied and they are demented. Even in individual patients you see that.

So that says to me if we could stop the formation of fibers maybe we could halt maybe we reverse Alzheimer disease.

Consistent Fibril Structures in Disease

And one other thing that says the same thing to me is that we are now able to get magnified pictures of these fibers. So the fibers in the upper left, those are magnified about 10,000 times in the electron microscope. In the lower right, it's more like several hundred thousand times magnified. We're looking at the cross-section of the top protein. We're looking down the fiber. We're looking at one slice through the fiber.

And every Alzheimer's brain that we've studied, and now it's dozens, if we extract the fibers from the autopsy brain that some family has donated to the brain bank, we see the same fiber always. If you have Alzheimer's disease, you have this fiber with this structure in your brain. So again, that says to me, if we can stop this fiber from forming, we can maybe halt the disease. So that's what we're up to.

Therapeutic Strategy: Fiber Disassembly with EGCG

So how do we do that? Well, here is more pictures of Alzheimer's fibers. And what we found is that there is a small molecule. This is called EGCG. It's in green tea. And that molecule has been known for a long time, found by others. It will break up these fibers.

And if we look at this column here, these fibers from the brain at the top, after three hours, most are gone. And the ones that are left don't look in such good shape. After 24 hours, we only found one fiber of the brain in the hundreds. So EGCG really breaks up the fibers, but it's been tested many times as a drug. It's failed every time it's been through human trials.

And the reason it fails is it's very water-like. You can see OH around it. Water is H2O. So it water-likes. It can get into the brain? Our brains are fatty. They're covered with lipid. And EGCG doesn't get in the brain. And so it's not useless. It's useless as a drug.

Mechanism of EGCG: Binding Sites and Pharmacophore

But Paul Sievert, postdoc, he had a good idea. He said, let's trap the EGCG working on the fibers after just three hours. So we'll see how it works. We'll find out how it works, and now maybe we can then get other molecules which are more drug-like if we see how EGCG works.

And what he found is that EGCG binds to these tau fibers, forms a column in this crevice between the two different columns of fibers. So here we're looking down a fiber with 10 or 15 layers, but in our brains the fibers will have thousands, tens of thousands of layers. And that's where the EGCG binds.

So what good is that? Well now we know what the binding site is. And we call it a pharmacophore. It's a place where drugs might bind.

Drug Discovery: Brain-Penetrant Molecules

So now we ask, are there other molecules that might bind there that are more brain-friendly? So Kevin Murray, who was an MD-PhD student in our lab, he's now a neurologist at Brown University.

He took 61,700 molecules, which were thought to be brain friendly, at the end of the blood-brain barrier, and he puts each one in this pharmacophore space, and he sees how well it binds. These are the molecules that, at least theoretically by the computer, bind well here. EGCG is what we call a positive control. It binds well, and so do others.

He orders the ones that bind well, the catalog, he found some 47 of them, and we test them. And sure enough, some of them, like CNS11, so-called, yet when we put it on the Alzheimer's fibers, it breaks up. So now we've got something that's brain friendly and seems to break up the fibers. Does break up the fibers.

Another one that came out is CNS11G similar but different and it breaks up alpha-synuclein fibers, the Parkinson's fibers. Here are the Parkinson's fibers taken from the brain of the Parkinson's autopsied patient, and CNS11G breaks those up.

In Vivo Validation: Worm Models

And here's a worm. You can get worms that get a Parkinson's-like disease, and when they do, they get these fluorescent dots in them. We feed the worm CNS-11, and most of those fluorescent dots disappear, meaning the fibers are gone. And CNS-11G, all but one of the fluorescent dots goes.

So now we have small molecules, and these molecules we consider small, molecular weights as such, that they can be formulated as pills. In principle, we can make a pill.

Critique of Current Pharma Approaches

What is pharma doing about Alzheimer's disease? They make antibodies. Why do they make antibodies? Well, that's what they can make. So they have a hammer, and they use that hammer no matter what the nail is. They say we're going to cure Alzheimer's with antibodies. It doesn't work. Antibodies get into the brain very sparingly. They don't get into cells. And you have to give them some infusions, patients, to take the living drug. You have to go to the hospital once every two months. How are we going to treat 7 million people, sending to the hospital every 2 months? No, impossible. We need a small molecule that can be formulated as a pill.

Detailed Mechanism: Competing Fibers

So, I'm almost done here. I'll just tell you that we've learned about the mechanism. That's the work of a graduate student, Xiaowei Wu. And here's the Parkinson's protein. Again, we're looking down the fiber of many thousands of layers. This is the Parkinson's protein alpha-synuclein.

And here it is bound to the CNS11G, a molecule that breaks it up. And that CNS11G, it forms a fiber that runs right along the fiber of the Parkinson's protein. And that fiber, the two fibers together, they're fighting one another. And when the small molecule fiber gets long enough, that's when it snaps the Parkinson's fiber.

Visualization: Atomic Force Microscopy of Disassembly

So I'm going to show you, this is my last slide. This is now using another form of microscopy called atomic force microscopy. And on the right side you see an atomic force microscope, a schematic of it. We have a cantilever and it has a very fine tip. By these tips they're made of silicon nitride and they get down. It's such a fine tip that it's as small as molecules.

And now that cantilever, it hangs up and down, ring ring ring ring ring ring ring ring ring. And it runs across whatever your sample is. The sample actually moves underneath the tip. And then there's a laser that reflects off the mirror on top of the cantilever, and you can see how high the object is on the cantilever. And the higher it is, the brighter it is.

And here we've got a Parkinson's fiber, and we're starting to measure it after we've added our small molecule, and we follow it for about 12 minutes as it's coming apart. And that's going to be a movie that you're going to see in the central part.

Ooh, I hope you're going to see it. Yeah, there it is. So we're watching it over 12 minutes compressed. You can see that this small molecule takes apart the fiber into pieces, and now those pieces are taken into smaller pieces, and then the smaller pieces and the still smaller pieces and so forth, and that fiber is completely degraded.

Summary of Therapeutic Advances and Next Steps

So what I've tried to show you is that through these structural methods, we've identified small molecules and the molecular weights below about 400 and short peptides—I didn't go into that—both of which take apart fibers and detoxify them from both Alzheimer and Parkinson proteins.

The mechanism I didn't go into except to say that both of these form a small molecule and peptides, they form fibers which then attack the pathogenic fibers.

In the background of all these slides, you can see some of these Alzheimer's fibers. I didn't mention that they are exceedingly stable. They're stable in boiling detergent. So it's pretty amazing that these small molecules and small peptides can take them apart, but they can. They can because they form fibers.

So, what's the step from these molecules to the drug? Unfortunately, there's still a lot of steps. So, in our case, we're collaborating with UCLA chemist Patrick Herzig. He's made variants of the molecules that we have. We're testing them to get ones that are more brain-penetrant and have good efficacy and are also safe.

And we've had tests in mice, which are encouraging. Working with mice for us is very expensive because you need a lot of mice to get a good answer. So we've frequently run out of money. And we're hoping that it'll work with human cells instead of mice.

And then if we get to that stage, we're trying to take about three years, we might be in a position then to apply to the FDA to do a phase one test would be a test on humans to see if whatever molecule we got at that time is safe. So there's still lots of steps.

Of course, right now, as we've heard, future funding is very uncertain, so we may not be able to do it.

Lab Acknowledgments and Funding Challenges

I just wanted to show you again the list of people who are in the lab and hear some of your faces. Paul Sievert who now is a professor at Erlinger University USC. David Boyer is an expert in electron microscopy. Jauret Lu discovered these fibers of small molecules. Well I guess we're over here. Kevin Murray is now a neurologist. He says he can do a phase one for us, but don't forget there.

Michael Sawaya is an expert in computational work. And Lisa Luter did the atomic force microscopy where you can visualize breaking up of the fibers.

We've had funding from NIH has been very strong. Now suddenly it's completely uncertain. We put in a huge request to do the work that I'm talking about. We were told that that grant won't even be reviewed. They won't even look at it. That's the situation.

We have other funding from Spark NS. We've had wonderful support from our department of pathology, which applies to the brain tissues. And of course, they depend, we depend on donor families. We're grateful for that.

So I've probably told you a little bit more about this than you wanted to hear. I hope it's interesting.

Moderator Close and Q&A Start

Well, thank you very much, Professor Steve Clarke, Professor David Eisenberg. So let's take some of your questions now. Who'd like to start? Okay, let's start over here.

Q (Edward Keenan, linguist): Hello. Thank you. My name is Edward Keenan. I'm a linguist here. I have a totally naive question. I understand, perhaps wrongly, that some animals live much longer than others, like lobsters. Would it be true that they have more stable biomolecules or fewer tau fibers?

A (David Eisenberg): Actually I know in the case of whales they do have systems for getting rid of these fibers. And some of us I think live like 200 years. So at least some species have been able to evolve systems that are helpful.

Steve Clarke: And Ed is a friend of his neighbor, expert in linguistics.

Q: How long are the peptides that interact in this?

A (David Eisenberg): Seven residues. Right. So various lengths. Why? Wasn't it a young woman in your lab? Because they, because that particular sequence of seven residues forms fibers that then bind to tau fibers. The monomers bind and then form fibers against the tau fibers in a metastable way creating a strain which then breaks the tau fibers.

Q (Professor Bartosz of Biostatistics): Excuse me. Is it possible that maybe some drug company can help you with a clinical trial that you have in mind?

A (David Eisenberg): That's certainly a hope. I'm trying to get support from drug companies. You may know that both Amgen and Pfizer eliminated their neurology divisions completely. In the case of Amgen, I was able to talk with not the CEO, but the person right below him. And the CEO said, I don't want to rate tangents for the bone. And it takes too long to develop neurological drugs.

Q: I have two questions. First one is how much is research being shared around the United States and around the world on aging and Alzheimer's, et cetera? The second question is what is your opinion of David Sinclair's recommendation about taking NAD?

A (Steve Clarke): Okay, so David Sinclair is an amazing young man because I think he's probably 50 now. He looks like he's 15. So that's a great advertisement for what he's saying. The nicotinamide chemistry is interesting. I'm not convinced that that is a solution.

And, you know, if you look at all of these treatments, whether it's, you know, vitamin D and omega-3 and saturated fatty acids, what you find is it's really hard to find out in human populations what something does. I like to get the example of, you know, testing a compound.

So let's take hydrogen cyanide. You take hydrogen cyanide, you give it to five people, they drop dead instantly, you know it's a toxin. For these other ones, you know, the effects are very mild, and you have to have, you know, thousands of people and, you know, tens of years to figure it out.

And if you look at something like coffee, you know, coffee's good this month, it's not good next month. I think coffee, I think, in the long run, looks like it might be good. But also, humans are different. We're each different at one base out of 1,000 in our genomes, and those differences probably are important in how we respond.

And so if you really want to do it, you need huge groups to find out who's responding and who's not responding. And so it makes it really, really difficult to actually find out if something is worthwhile or not. And that's the reason for the huge cost of phase 2 and phase 3 clinical trials. You need so many movements?

If something worked immediately, we'd find out. So that's the easy part. But most of these effects are relatively small. And the question then is, if it's a 5% effect, if you look at the distribution of who's helped, they're often overlapping. So there's no guarantee. Even if there an overall 5% improvement in the population you're going to be helped you not. So that's the frustrating part.

The other part is that I teach a course in research integrity and you know the mantra of that course is, don't trust anyone. I was telling somebody, you know, if your mother says she loves you, check it out. And there are so many examples where things just are wrong. Someone published a paper in 2005, and the title was, Why Most Research Findings are False. So it's tough. It's very tough.

But things that work well, you know, those things work well. So, you know, when people found out that stomach ulcers were connected with the bacterium, you know, you took the antibiotic and your ulcer went away. Boom. But I don't think we've been that lucky so far.

And the sad thing with Alzheimer's are these treatments that were based on a fiber that David didn't talk about, beta-amyloid. These are the fibers that make extracellular deposits. And I think David can correct me, but my reading of literature is that those extracellular deposits have nothing to do with disease. And there are drugs that can remove them, monoclonal antibodies that can remove those, effectively no change in cognition.

So as David emphasized, the bad actor is tau. And so, or obviously Parkinson's. And so that's what you have to go after, which means that we're, I don't know, hundreds of millions or billions of dollars of NIH money and company money that's basically gone down the drain following the beta-amyloid plan.

I guess I got away from your question, but...

A (David Eisenberg, on sharing): I think the first question, which had to do with international cooperation. I think it's very strong. Scientists tend to be generous in helping others, sharing materials, reviewing papers, which is a lot of work, peer review, and cooperating in large projects. So it's all a big plus.

And there's a new development that I think is significant, which is biology's bioRxiv, where in the old days you send your paper to a journal where it might sit for weeks or months or longer and be reviewed. At this point now you can send in your paper to bioRxiv and it's published online immediately for everyone to see. Hopefully it gets published somewhere in peer review, but I think it's a mark of how collaborative scientists are willing to share their results at very early stages.

Q (Dr. Rose, School of Medicine): Okay, we have a question here. Yes, hi. Thank you for those good lectures. This is Dr. Rose from the School of Medicine. You had a slide about mother. Diet, exercise, and sleep. I know for a fact that exercise helps, and that certainly not getting fat doesn't help. But what about diet specifically? More vegetables and fruits. That's what our mother told us. But is there anything more specific? Like, is meat bad? Is fish bad? Is it better to be meat or vegetarian?

A (Steve Clarke): The answer is it's complicated. One person I love is a glycobiologist at UC San Diego who gave a talk on sialic acids, sialic acid, like carbohydrates attached to proteins. It turns out the sialic acid in humans and chickens is the same. The sialic acid in beef, pork, and lamb is different. And so, in fact, those are the red meats. And so it's very clear that the reaction, that red meat is actually, which I just had, is not good for us. It's inflammatory because of those molecular differences.

So we are learning some of what the specifics are for different compounds. But I think the other advice is, you know, you have your dinner plate, half of that should be vegetables. Because, you know, if you do studies on coffee, for example, it's like 495 say it's good, 401 say it's bad. If you look at fruits and vegetables, it's more like 95 to 1. And so there is, I think, saying that fruits and vegetables are magic, I think, is not an overestimation.

Q: Yeah, what is your view on pathologic process that actually makes these fibers implicated in causing disease?

A (David Eisenberg): That a key question which has not been answered. So the major risk factor in all these diseases is age. So at age 65, about one person in 11 experiences dementia. And age 95, it's like 8 out of 10. So age is the major risk factor.

But there are other genetic risk factors, like one protein. ApoE. One type of ApoE is a major risk factor. There are probably environmental risk factors, too. Some scientists believe that viral infection can be a factor. In the case of Parkinson's, it's clear that there are environmental factors such as pesticides. You probably recall that Central Valley farm workers have experienced a lot more Parkinson's. But your genetics are a major, major factor, so I look to your ancestors.

Q: Are there any other questions? Yes. Hi. I'm just a lay person, but I've been reading a lot about the regenerative aspects of the brain. It's more flexible than previously thought. If the fibers are successfully removed or broken up, can the brain then regenerate, say, a person younger who has Alzheimer's? Or what is the worst state was still possible?

A (David Eisenberg): We're gonna have to see, but I think once neurons are dead, they're dead. I don't see, and they don't divide. There are regions in the brain you have neurogenesis going on in the hippocampus and in the ventricles. And so there we have some possibility of neuroregeneration but in general it doesn't happen.

Q: Would that be I'm sorry would that be the uh executive functions or would that be just the limbic system type of basic hippocampus?

A: Well, the hippocampus is the home of sort of short-term memory, and I'm not familiar with that literature. I'm really correlating if you can actually make differences in it. I think one of the things in all of us is that our hippocampus is shrinking, in spite of the fact that they could make new neurons and it's correlated then with neurodegenerative disease.

Moderator: Have there any other questions? If not, uh... I have a question. Who has a question? One. One question. Oh. You can.

Q (from department of speakers): Sorry. And you and I serve from the department of our speakers today. So it is established that sugar is metabolically important and yet the recent publications about the damaging effect connected to Alzheimer of increased sugar intake. How individually those things are different different individually and how will the boundaries establish.

A (Steve Clarke): So talking about the toxicity of sugars, you know, glucose for example, as an aldehyde, is chemically reactive, and that's reactive of our proteins all the time. There are actually repair systems that have been found that will help take away the sugar aggregates from proteins. And, you know, sugars also can degrade into compounds that can cause cross-linking of molecules.

So we're absolutely dependent on glucose, right? It's the heart of our metabolism, and yet it has a dark side. And that dark side is, in fact, these reactions that are dependent on the electrophilic nature of glucose. So, you know, it's like oxygen we can't do without, very toxic. Glucose we can't do without, pretty toxic. Water we can't do without, makes things fall apart.

Moderator: Any concluding comments for us, or have you said what you wanted to?

Speakers: We're looking forward to joining the association.

Thank you very much.

Insights

• Molecular Damage as Central to Aging: Intuition that biomolecules (DNA, RNA, proteins) are thermodynamically unstable, spontaneously degrading via bond breakage, oxidation, glycation, etc., leading to loss-of-function and physiological decline; countered by evolved quality control (repair first, then degrade), with redundancy (e.g., PIMT repair → ubiquitin ligase backup) ensuring resilience, akin to engineered fault-tolerance in complex systems like spacecraft.
• Specific Protein Damage Mechanisms: Aspartate/Asn side chains undergo non-enzymatic deamidation → isoAspartate (kinked backbone), racemization, isomerization on timescales of hours/days; isoAsp accelerates amyloidogenesis by stabilizing steric zippers (dry, H-bonded interfaces pioneered by Eisenberg).
• Repair Enzymology: PIMT selectively methylates isoAsp carboxyls using SAM (ubiquitous, nutraceutical-accessible), enabling succinimide intermediate reversal; knockout lethality (seizures) rescued by alternatives highlights pathway crosstalk.
• Amyloid Causation in Neurodegeneration: Fibers (tau, α-synuclein) causal via mutants inducing disease in humans/mice, PET-atrophy correlation, identical ex vivo structures; stable even in SDS-boil.
• Fiber Disassembly Trick: Pharmacophore from EGCG binding inter-column crevices in multi-layered fibrils; screen ~60k BBB+ molecules computationally → CNS11 (tau), CNS11G (α-syn); mechanism: orthogonal protofilament fibers induce steric/mechanical strain, fragmenting host fibril (visualized by AFM time-lapse).
• Drug Design Pivot: Avoid hydrophilic polyphenol failures; prioritize MW<400, lipophilic small molecules/peptides (7-mers) forming metastable competitors over antibodies (poor BBB penetration, infusion logistics).
• Broader Insights: Aging mitigation via lifestyle (fruits/veggies >> controversial nutraceuticals) likely boosts repair; pharma "hammer" bias wastes billions on amyloid-β decoys; bioRxiv accelerates collaboration.

Transcription errors?

• Names: "Stephen Clark" consistently → Steve Clarke (standard spelling for UCLA prof). "Vananna Torres-Gill" → likely "Vanna Torres Gil" (audience aging expert; ambiguous). "Stuart Wolpert/Stewart" → Stuart Wolpert (UCLA comms director). "Harvey Anderson" → likely "Harvey Eisenberg" or collaborator Howard Abrams? Context: protein arginylation pioneer → best guess Harvey F. Lodish? Uncertain. "Ty Gates" → structure determiner of PIMT → likely "Tim Richmond" or mishear; PIMT PDB by others (e.g., Tycko?). "Paul Seider/Sievert/Cycler" → Paul Sievert (postdoc). "Jauret Lu" → likely "Jauhar Lu" or "Joseph Liu" (mentioned earlier). "Lisa Luter" → likely "Lisa Wiltzius". "Patrick Heron" → Patrick Herzig (UCLA chemist). "Xiaowei Wu" → clear.
• Terms: "Protein arson" → protein arginylation (posttranslational mod.). "Spartic acid and aspirin" → aspartic acid and asparagine. "S-andesylmethionine" → S-adenosylmethionine (SAM). "EBI Award" → likely "Emil B. Mrak Award" or "Dickson Art of Teaching Award" (UCLA senate). "Vector basis" → molecular basis. "Family quorum" → unclear, poss. joke "Tom Brady" (peak athlete). "Maiden" → human? "Ethosolmogamia" → omega-3s. "Rate tangents for the bone" → waste tangents on the bone? (Amgen exec mishear). "Spark NS" → SPARK (UCLA funding?).
• Technical/Other: "Kinked" → isoAsp. "Pharmacopore" → pharmacophore. "Office of Newfoundland" → alpha-synuclein. "Bloody archive" → bioRxiv.

See also

• Steven Clarke 2009 talk
• longevity