The Peter Attia Drive - #303 - A breakthrough in Alzheimer's disease： the promising potential of klotho for brain health, cognitive decline, and as a therapeutic tool for Alzheimer's disease

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.200 of a subscription. If you want to learn more about the benefits of our premium membership,

00:00:57.980 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Dina

00:01:06.120 Dubal. Dina is a physician, scientist, professor of neurology at the University of California,

00:01:11.780 San Francisco, and holds the David Coulter Endowed Chair in Aging and Neurodegenerative Disease.

00:01:17.140 She is also an investigator with the Simmons Foundation and the Bacar Aging Research Institute.

00:01:23.200 Her work is recognized for its significant potential towards therapies to help people

00:01:28.400 live longer and better. She directs a laboratory focused on mechanisms of longevity and brain

00:01:34.180 resilience that integrate genetic and molecular approaches to investigate aging, Alzheimer's

00:01:39.380 disease, and Parkinson's disease. In my conversation with Dina, we focus around something called

00:01:45.440 clotho. Now, if you've heard me talk on this podcast and other podcasts, you've probably heard

00:01:50.920 me bring up clotho, either the protein or the gene that codes for the protein. My interest in clotho

00:01:57.280 really started a couple of years ago when I became aware of some of the genetic data in humans about

00:02:03.680 the relationship between clotho and Alzheimer's disease prevention, particularly in people who

00:02:08.280 are carriers of the A4 gene. This, of course, has led me deeper and deeper down the clotho rabbit hole

00:02:14.560 and really all roads lead to Dina if you want to have this discussion. So we begin our discussion

00:02:20.180 with an overview of clotho. What is it? How is it formed? How does it get around our body and what

00:02:26.140 does it do? We talk about the mechanisms regulating clotho in the body and in particular in the brain.

00:02:33.140 We also talk about things that impact clotho levels such as stress and exercise and to what extent

00:02:38.220 they do. From there, we look at the research that's being done in how clotho relates to various

00:02:43.420 cognitive functions as well as its role in brain health across different species and across

00:02:48.360 different ages, as well as understanding how clotho treatment may be helpful in treating

00:02:52.920 neurodegenerative disease, particularly Alzheimer's disease. We wrap up this discussion speaking about

00:02:59.080 the broader impacts of clotho on organ health in addition to what its potential may hold for the

00:03:05.920 treatment of Alzheimer's disease in the future. Before getting to this podcast, I'd like to mention

00:03:10.980 a conflict of interest, which is that I am an investor in a company called Jocasta. Jocasta is a company

00:03:19.100 that is trying to bring clotho, the protein, into human clinical trials for treatment of Alzheimer's

00:03:26.580 disease. So without further delay, please enjoy my conversation with Dina DuBall.

00:03:31.820 Dina, thanks so much for joining me today. This is a topic I've been very interested in for the

00:03:43.820 better part of about a year and a half to two years. And obviously, there's no better person to

00:03:48.220 discuss this with than you. I also suspect that this is a topic not enough people know about,

00:03:54.740 given its potential implications and significance vis-a-vis Alzheimer's disease, which we'll get to.

00:04:00.560 But maybe before we get into this, let's give people a bit of a sense of your background. Tell

00:04:05.900 me a little bit about your clinical work, your research work, what you did during your PhD and

00:04:11.260 how that carried forward during your tenure. Sure. Well, thanks again for the invitation.

00:04:16.580 I'm delighted to join you today. By way of introduction, I'm a neurologist and I'm a neuroscientist,

00:04:23.160 and I direct a group that is deeply involved in the discovery around clotho. And I was thinking back

00:04:31.000 to when my interest in aging actually began, what was this journey? And I thought back to

00:04:37.840 my undergraduate days at UC Berkeley, when I was a 19-year-old that was oddly interested in aging,

00:04:46.160 kind of obsessed with aging. I worked with a medical anthropologist at Berkeley, Lawrence Cohen,

00:04:51.680 on what it meant to experience dementia in different cultures. What was it like in India versus the

00:04:59.200 United States? And then simultaneously, I took a class on the physiology of aging. I remember it so

00:05:06.060 clearly in Dwinnell Hall, and I was at the edge of my seat learning about cellular senescence.

00:05:12.380 And I remember thinking, this is amazing. This is happening to us day by day aging, yet we don't

00:05:20.380 know so much about it. And we don't know much about brain aging per se. And I was committed as an

00:05:28.360 undergraduate to really learn more about brain aging and possibly to do something about it.

00:05:35.620 That led me to an MD-PhD at the University of Kentucky. I trained with Phyllis Wise, a neuroendocrinologist

00:05:43.760 who studied brain aging, who was an amazing PhD, learned so much, fell in love with the discovery

00:05:51.560 process of science. And fast forward, I then trained as a neurologist at UCSF, where I am now. And that was

00:06:01.220 over 20 years ago, 2003, and I'm on the wards. It's a regular day of patient rounding. And the former chair of

00:06:09.780 UCSF neurology, Steven Hauser, turned to me and he said, Dina, when you go back to the lab, do things that are

00:06:18.620 big and important, and not incremental or mediocre, because they'll take you the same amount of time. And that

00:06:25.500 really clicked with me. It became my mantra. And after an Alzheimer's fellowship, both clinical and

00:06:32.480 basic science, I had the chance to build a group and to really start my own scientific discovery.

00:06:39.040 And we focused on clotho, the subject of what we'll talk about today, the Greek fate who spins the thread

00:06:45.040 of life. And the idea of studying clotho was to understand whether factors that help us to live longer

00:06:53.000 could help us to live better. Whether this longevity factor could actually help the brain,

00:06:59.680 could help it stave off Alzheimer's disease. And that's where we began.

00:07:04.720 So let's go back to the first time clotho crossed your radar.

00:07:10.140 Yes. Well, I was just beginning my junior faculty days and was thinking, what were we going to focus on?

00:07:17.600 What was going to be our chance to do something big and important? I was very intrigued by a few

00:07:24.200 decades of work that was emerging that aging itself was malleable. And the first work with this was

00:07:30.680 Cynthia Kenyon and worms, where she demonstrated that tweaking genetics, aging in worms could dramatically

00:07:38.780 increase lifespan. And I really wanted to know whether that could have effects in the brain.

00:07:44.100 Clotho had emerged as a longevity factor. And it was a chance to understand, could clotho

00:07:51.600 do something in the brain? Nothing was known about clotho. Very little was known about clotho

00:07:56.660 when we started. A colleague had observed that the levels decreased in the white matter of monkey brains,

00:08:04.220 that a variant of clotho that we can talk about in a bit was associated with decreased stroke risk.

00:08:11.380 And the person who discovered clotho had noted that mice without clotho moved slowly and they were

00:08:18.940 cognitively a little slow. But, you know, I was the right person at the right time and had the chance

00:08:25.860 to really dig in. It was risky to start with something that not much was known about in the brain,

00:08:31.500 but it was a chance to do something maybe big and important.

00:08:34.680 So, let's talk a little bit about the discovery of clotho. So, was it discovered through the mice

00:08:41.820 that were deficient? Was it deliberately knocked out? What was the process of discovery? I mean,

00:08:46.640 just contrasting it with Cynthia's work, obviously, she knocked out a gene that is, I think,

00:08:52.380 sort of the analog of one of the IGF genes, if I'm not mistaken. Correct?

00:08:56.960 Yeah, the DAF-16. So, how was clotho discovered? It was in 1997. Makoto Kuroo, a Japanese scientist,

00:09:07.500 accidentally discovered it. And it's such a story of serendipity. He was studying hypertension,

00:09:14.080 and he engineered a mouse to insert a gene, which I believe was a sodium proton channel. So,

00:09:22.240 he engineered mice, he inserted this gene, and then he noticed that in a few lines of these mice,

00:09:29.960 maybe it was just one line of these mice, there was this premature aging phenotype. So,

00:09:35.860 the mice lived to about three months instead of about 30 months, and they developed normally,

00:09:43.120 but around two weeks of age, they became proderoid. They looked like they were rapidly aging

00:09:49.260 with osteoporosis, atherosclerosis, emphysema. They looked, and they moved slow. They looked really

00:09:57.940 old. And so, he went back to that mouse, and he mapped out what had happened. And he had accidentally

00:10:05.640 caused a mutation by inserting his sodium proton pump. So, he went back, he mapped what had been

00:10:14.160 disrupted. And that was Klotho. That was the first time Klotho was found, and he named it after the

00:10:20.300 Greek fate who spins the thread of life, daughter of Zeus. Klotho, the Greek fate, is C-L-O-T-H-O.

00:10:28.720 He named it K-L-O-T-H-O in homage to his discovery. His name is Kuroo, K-U-R-O-O. And a longevity

00:10:38.280 factor isn't something that just causes premature aging if disrupted. So, it was very important for

00:10:45.380 him to then go back and see what would happen if he overexpressed it. Then he engineered mice to

00:10:51.300 overexpress Klotho, and those mice lived 30% longer. So, that was a longevity factor. That

00:10:58.860 disruption caused premature aging and overexpression extended lifespan.

00:11:04.180 And it's such a beautiful story. It's a great story for people, especially maybe who don't do

00:11:09.720 or haven't done science, because it illustrates the role of curiosity and serendipity. And look,

00:11:16.000 there are some people who maybe wouldn't have even gone back and done the experiments that he did

00:11:21.800 to understand what turned out to be the most relevant thing. I'm sure that whatever he was doing

00:11:25.840 with a sodium proton pump exchanger seemed interesting at the time, and that what he observed was

00:11:32.720 actually kind of a disappointment in that it ruined one of his lines of mice, but obviously it led to

00:11:37.980 the far more relevant finding over the long arc of time. He opened the field. He followed the science.

00:11:44.300 He opened the field. He looked into the mistake, the oops of science, and here we are, maybe on the

00:11:50.680 cusp of a new therapy. Yeah, exactly. So, let's talk a little bit about what this gene does. How big is

00:11:56.300 this gene? How preserved is this gene over other species? And tell us a little bit about the protein

00:12:02.420 that it codes for. What regulates it? So, clotho itself is a pretty big protein. It's about a thousand

00:12:09.860 amino acids by weight, maybe 130 kilodaltons, if you look at it on a Western blot. And it codes for

00:12:17.740 the aficionados, a type 1 transmembrane protein, which means that its end terminus will sit in the

00:12:25.800 extracellular space. It has one pass through the membrane, and it sees the terminus as inside the

00:12:31.820 cell. Now, the part that sits outside the cell has two repeat domains, KL1 and KL2. And those

00:12:41.980 domains have high homology to proteins that are found throughout mammalian, worm, and fly biology.

00:12:50.620 So, they're homologues of clotho throughout species and pretty conserved in mammals. So,

00:12:57.100 clotho is a big protein. It's a transmembrane protein. And then what happens is there are a few

00:13:02.800 forms of clotho. It's made primarily in the kidney, also in the choroid plexus of the brain,

00:13:09.660 but it's made in the cells of the kidney, and then it gets transported into the membrane.

00:13:15.340 And then enzymes come across base, atom 10, atom 17, and they clip that extracellular portion of

00:13:23.900 clotho and release it into the blood, or in the case of the brain, release it into the CSF.

00:13:30.420 And that form of clotho is known as a soluble form of clotho or the secreted form of clotho.

00:13:35.820 I call it a hormonal form of clotho, the clotho hormone, because it's released at one site and

00:13:43.100 then can act at different sites at multiple organs. So, that's how it's made. Those are the major forms.

00:13:50.640 So, how big is that N-terminus piece that gets clipped that now goes and acts like a hormone,

00:13:55.360 basically?

00:13:55.700 It's the majority of the protein itself. The part that's inside the cell and crosses the

00:14:02.860 membrane is very small. So, it's really the majority of the protein is the hormone itself.

00:14:08.260 If we were to take a blood test and measure a person's clotho levels, what could we observe about

00:14:15.860 it across people of the same age, people of different ages? What factors do we think might

00:14:22.740 influence the expression? And does the expression and production of the protein become the sole

00:14:28.560 determinant of the soluble factor? In other words, is there also variability at the cleavage

00:14:34.080 efficacy, or are there other factors that lead to consumption of the protein or degradation of

00:14:40.060 the protein in the periphery?

00:14:41.180 So, starting with levels of clotho across the lifespan. Well, first, clotho circulates in us,

00:14:48.720 it circulates in mice. And when we started our studies in mice, I really wanted to make sure

00:14:54.520 that this was going to be relevant to the human condition. And it is very relevant to the human

00:14:59.380 condition. So, we have circulating levels of clotho. We're born with about six times the levels that we

00:15:07.280 have now in our cord blood. And then throughout our lifespan, clotho levels decline. In our, from,

00:15:15.140 say, 40 onwards, they can decrease by half during aging. So, we're born with very high levels and

00:15:23.000 they decrease across our lifespan. They also have a circadian rhythm or a diurnal rhythm in that when

00:15:30.440 we wake up, we have high levels of clotho. And by 4 p.m., 3 p.m., when people are looking to grab a cup

00:15:37.580 of coffee, the clotho levels are really starting to decline. And then they nadir by around midnight.

00:15:43.500 It can be a 40% or so decrease. So, there's a circadian rhythm to clotho. It changes across

00:15:50.140 the lifespan. Sorry, Dina, just to make sure I understand that. What explains the daily variation?

00:15:56.180 Is it some sort of quote-unquote consumption or is it being turned over that quickly and the supply

00:16:02.840 of clotho is decreasing by the time of day? The answer to that is not known. What regulates

00:16:09.480 the daily levels? Is it, how is it being degraded? Is the expression being increased? The half-life is

00:16:16.040 short in mice. In mice, it's maybe seven to 10 minutes. But in humans, well, I would say in

00:16:22.300 monkeys, it's much longer. It's at least a day or so. So, it's unlikely that the production is really

00:16:31.040 actually increasing and decreasing because when it's made, its half-life will be longer in non-human

00:16:36.900 primates like us. So, I would speculate, though I don't know, Peter, that it may be sequestered in

00:16:44.300 organs or degraded or not sure. I've seen a couple of reports of this diurnal variation and it's really

00:16:51.920 not clear why it's increasing and decreasing. But it is known in aging, for example, this longer-term

00:16:59.740 decline and slow decline that we see, it's been observed, and this was work by Fabrizia Ambrosio's

00:17:07.680 lab, that there is a hypermethylation around the clotho promoter that occurs with aging that stops

00:17:16.120 its transcription and essentially transcription and translation. So, that's an interesting thing to

00:17:22.940 think about if we wanted to preserve our clotho levels. How can we interfere with that methylation

00:17:29.800 that happens with aging? That's interesting. So, more methylation there leads to inhibition of the

00:17:36.740 promoter. A lot of times you'll see the opposite. It's the loss of methylation that shuts off the

00:17:42.560 promoter, correct? I don't know about that. In general, or clotho at least, the methylation really

00:17:48.820 turns things off. Off. Okay. I could be wrong about that, but I think that that's definitely the case

00:17:55.160 with clotho. And is that believed to be the main mechanism driving the reduced production of clotho

00:18:02.960 is the increase in the methylation of the promoter? That's what's known so far. There are other

00:18:09.640 possibilities, like maybe organs make it less. Maybe the kidney is less efficient at making it with

00:18:15.940 aging. That's possible. I think that Ambrosio's lab is really onto something. They showed it in

00:18:21.520 chondrocytes and aging chondrocytes, but it was really the first molecular demonstration about why

00:18:27.300 clotho may be decreasing. Now, there are other things, Peter, that decrease clotho. One big one is

00:18:35.160 chronic stress. We did a study with Alyssa Eppel and Eric Prather here at UCSF and mothers with

00:18:43.480 neurodevelopmentally typical or atypical children. And the mothers with high levels of stress with

00:18:51.800 children with autism spectrum disorder had much lower levels of clotho, as well as shorter telomeres.

00:18:59.720 Their level of stress, increasing stress, there was a decrease in the clotho level.

00:19:05.840 Did you demonstrate in those folks a higher degree of methylation of the promoter relative to their age?

00:19:12.440 Did it basically look like they were older at the level of the promoter?

00:19:17.580 I think that would be so neat to look at. We haven't done that, but it would be really neat to

00:19:22.280 look at. So in other words, we don't yet know the mechanism by which chronic stress could be

00:19:27.360 mediating the reduction. Ryan Brown here at UCSF and Eric Prather and also Alyssa Eppel and myself

00:19:33.600 looked at whether there might be a relationship between clotho levels and telomere length in these same

00:19:40.200 women. And there is a very direct relationship with a very tight correlation between shorter telomeres and

00:19:48.300 lower clotho levels. So there may be some convergence around these different hallmarks of aging, maybe some

00:19:55.260 relationship of them regulating each other, or maybe they're changing in parallel. It's hard to say,

00:20:00.880 but here's some really good news that in thinking about what changes clotho levels, we do know that

00:20:08.960 stress associates with lower clotho levels. But one of the most robust interventions that increases

00:20:15.980 clotho levels is exercise. It's been shown in study after study and in meta-analysis. It's been done in

00:20:23.040 about 12 studies, but the data are that after 12 weeks of what people call chronic exercise, that

00:20:31.280 clotho levels increase by about 30% and maybe even increase in a study with preliminary data. In mice,

00:20:40.600 they can even double acutely after a 45-minute treadmill run. And how it's increased, it's unknown,

00:20:48.240 but it's beginning to be thought of as an exerkind, something that is produced and released in the

00:20:54.120 body following exercise. How would this stack up in your mind compared to something else that we would

00:21:01.020 think of along these lines, BDNF, where I've talked about this at length on the podcast, of course,

00:21:06.780 if you really look objectively at all of the modifiable behaviors around dementia, routinely exercise

00:21:13.520 is at the absolute top of the list, more potent even in its magnitude than lipid management,

00:21:20.660 glucose management, and hypertension, all of which themselves are enormously powerful. But something

00:21:26.320 about exercise seems even greater. It could be that it indirectly mediates at least two of those three.

00:21:33.620 But of course, people point to something else that's going on and BDNF is often discussed. Do you

00:21:39.740 think that maybe part of that effect is clotho, and do you think that the effect of clotho may be even

00:21:44.120 more potent? I was recently asked the same question at an Alzheimer's conference at the

00:21:49.780 Salk Institute, and I don't know the answer, but I think it's a really important question. Is there a

00:21:56.120 relationship between clotho and BDNF? Does clotho increase BDNF levels in the brain? I don't know.

00:22:03.400 BDNF has a very striking effect in the brain. Maybe, Dina, just tell folks a bit about BDNF.

00:22:09.320 Sometimes I forget that maybe not everybody listening to us today has also listened to all

00:22:14.280 of the other content over the years. So maybe just give folks a little bit of a primer on BDNF

00:22:19.340 as well. So BDNF is brain-derived neurotrophic factor, and it has been shown in the brain to really

00:22:27.540 be associated with even drive, but positive brain health. So intermittent fasting increases BDNF in the

00:22:35.460 brain. Exercise increases BDNF. If you give BDNF to the brain, the neurons function better. It's a

00:22:41.740 really good trophic factor for the brain. And it does remind one of clotho and effects of clotho.

00:22:48.460 And in fact, intermittent fasting simultaneously increases clotho in the brains of mice along with

00:22:54.340 BDNF. How long do the mice need to fast to get that effect?

00:22:58.680 So this work was done at the SOC. The mice fasted for 24 hours.

00:23:05.800 So not really something we can translate to humans given that that's, I mean, 24 hours in a mouse is,

00:23:12.700 that's half the distance to death. So that's, uh.

00:23:17.440 That's interesting.

00:23:18.800 But this is a real problem. This is a real problem with extrapolating from mice data, right? Is

00:23:23.460 even a 12-hour fast in a mouse is an overwhelming feat of calorie deprivation.

00:23:30.760 24 hours is staggering. We don't have a way to translate that to humans, but it could be that

00:23:35.960 that's on the order of weeks. So I just want to make sure people aren't listening to this thinking,

00:23:40.100 hey, all I got to do is skip breakfast and I'm getting the same amount of BDNF or clotho that I

00:23:46.160 would get from a 45-minute workout. My guess is those two are not even in the same zip code.

00:23:51.160 I think differently about it. So when I think about mouse time and mouse lifespan,

00:23:58.280 so they live to two to three years, but I believe that they're aging faster. They have a shorter

00:24:03.800 lifespan, but I think it's possible that their 24-hour lives are similar to our 24-hour lives.

00:24:10.980 But 48 hours of fasting will usually kill a mouse, right?

00:24:14.340 I don't know how long a mouse can go.

00:24:16.900 I used to be more facile with this literature, but I pay less and less attention

00:24:21.040 to mouse literature now than I used to. And maybe someone listening to this could write in

00:24:26.100 and correct me, but I don't think it's a stretch to say that 48 hours, put it this way, what I do

00:24:30.620 remember is an IRB would really scrutinize an investigator who's trying to get to 36 hours

00:24:39.080 of fasting in a mouse. It's a really big deal.

00:24:42.220 We don't do fasting studies in mice, but I would agree that in general, we have to be careful when

00:24:49.100 extrapolating from mice to humans. I do think that in the area of cognition and neurodegenerative

00:24:56.100 diseases, that studying mice and mouse brains and their neural circuits and their hippocampi and their

00:25:03.080 prefrontal cortices tell us fundamental things about the human condition, particularly because they have to

00:25:10.900 have very strong navigation strategies and memories for foraging, for coming back to their nests.

00:25:18.340 And these memory circuits are very, very fundamental and quite preserved up to non-human primates,

00:25:25.540 including us. But having said that, we do the majority of our work in mice.

00:25:30.140 We are always aware of, are we doing something that is important to the human condition? Is it relatable

00:25:37.440 to the human condition? Is it relevant? Who cares? Will any of this matter? These are always on

00:25:44.040 my mind, these questions, particularly as a physician scientist. And there are certainly

00:25:49.240 limitations. I also think that there are many strengths, particularly in studying memory and

00:25:55.820 neural circuits in the brain. But we don't stop there. And we have tested whether, I haven't talked

00:26:03.240 yet about what we have found in mice, but I'll just spill the beans and say that we found early on that

00:26:10.120 clotho enhances cognition in mouse brains. In a very recent study, we collaborated with biotech and Yale

00:26:18.960 University and found that actually clotho enhances learning and memory and cognition in old monkeys.

00:26:26.040 In a very complex brain, genetically diverse, anatomically diverse, functionally complex,

00:26:32.960 that in a brain like ours that clotho had very similar effects to what we see in mice.

00:26:39.600 There's so much I want to come back to on that topic because I've seen all of these data, of course,

00:26:44.640 and truthfully, they seem overwhelmingly positive. But let's go back and kind of use some of the mice

00:26:52.960 data to allow us to speak about maybe greater insights around the causal relationship between

00:27:00.000 clotho and brain health. So we've already established a few facts here. So you're going

00:27:04.820 back to the discovery of clotho in 97, which was based on effectively a knockout. We saw that that

00:27:10.620 is incompatible with a long life. And we saw that the reverse when clotho was enhanced, I believe you

00:27:18.180 said it enhanced lifespan by about 30%. Again, that's really remarkable in a mouse. There aren't

00:27:24.120 many things that enhance a mouse lifespan by that much. That's up there with the most draconian

00:27:30.500 caloric restriction, rapamycin administration under certain settings. That's a very reproducible and

00:27:36.680 robust finding. Let's talk a little bit about specifics to brain health, what you're talking about

00:27:43.240 with respect to not a disease state per se, but just enhancing cognition in an aging mouse or even

00:27:51.760 in a middle-aged mouse. This is where we started. And we started with the hypothesis that in these mice

00:27:59.480 that overexpress clotho, that live longer, that maybe these mice would be resilient to Alzheimer's

00:28:06.960 toxins. That was our starting point. And so we back-crossed Alzheimer's models with clotho overexpressing

00:28:15.560 models to create mice who have mausheimers and then have mausheimers plus lots of clotho. And then we had

00:28:25.760 normal mice and normal mice with lots of clotho. So there were four experimental groups. And to our

00:28:32.320 complete surprise, the normal groups, we're not talking about the mice that had Alzheimer's,

00:28:40.300 modeled Alzheimer's, but in the normal groups that had higher levels of clotho versus normal levels,

00:28:45.520 that group showed a remarkable difference, a remarkable statistically significant difference

00:28:52.660 across multiple cognitive tasks and across different ages. And that was that the mice that

00:28:59.900 overexpressed clotho that live longer were smarter. So you put them in a maze. They could map the room

00:29:07.200 better, escape quicker, not because they were swimming faster, not because they could see better,

00:29:12.540 but because they were remembering and learning more efficiently and better. And that was a complete

00:29:19.580 surprise. I remember the day, unblinding the data, analyzing it. It was unimaginable.

00:29:26.040 Dina, I just want to add a point. Sorry to interrupt, but it's so powerful.

00:29:28.820 You a moment ago said this was statistically significant, which of course it was.

00:29:34.080 And too often, I think people hear the term statistically significant. And I think they

00:29:40.040 can be forgiven for confusing it with clinically significant. But as you know, those are not

00:29:45.260 necessarily the same thing. And I almost think that in this case, Dina, stating that it is statistically

00:29:51.840 significant, which it is almost undersells what I think the magnitude of the differences are.

00:30:00.180 I have a friend who likes to point out that the really powerful stuff in biology is the stuff that

00:30:07.960 you don't actually need to do the statistics on. When the delta is so big that you don't need to whip

00:30:15.100 out the student t-test and calculate the p-value to make sure you're not being fooled, which by the way

00:30:20.680 is very important and you should be doing it every time, when it's actually just a formality because

00:30:25.940 the answer is so clear looking at the data, that's the really big aha moment. And I think I'd be safe

00:30:33.840 in saying that that was the case here, wasn't it? You're right. We tend to be really conservative.

00:30:40.020 We don't want to make an error. But having said that, you're totally right. I mean, I can imagine

00:30:46.780 the graphs now and there were non-overlapping data points. I didn't need to run the repeated

00:30:54.280 measures between subjects and NOVA to really know that it was statistically significant. It was that type

00:31:00.200 of a finding. So it's a point well made. Sometimes experiments will show you those differences and then

00:31:07.740 the next time you do it, they don't. Someone who runs the water maze is wearing a new cologne and the

00:31:15.020 mice get stressed out. They don't always repeat and are not always replicable. This is a case that it was

00:31:21.760 amazing, but was it going to replicate? Was it going to be true in different cognitive tasks? What would

00:31:28.460 happen in aging mouse? Like all of these questions opened up and we iterated and we did experiment

00:31:35.240 after experiment and the data held strong in mice that clotho overexpression really enhanced their

00:31:43.800 cognition in young mice, in aging mice, in mice that modeled Alzheimer's disease and also in mice in a

00:31:53.600 publication that's in peer review now, but also in mice that model Parkinson's disease, that overexpression

00:32:00.500 of clotho enhanced cognition. It is really a remarkable finding. I think it's maybe one of the most

00:32:07.080 important findings in my professional career. I would go one step further. I feel like it's one of

00:32:13.340 the most important findings in brain health period. I mean, on some levels, it's a bit of a mystery to me

00:32:20.400 why this isn't known by everyone. It's part of why I'm really, really happy to be sitting down with

00:32:27.400 you and why I've wanted to sit down with you for the better part of six months. And I know that between

00:32:31.960 my schedule and yours, it took a minute to get us on the schedule, but this is such a big deal.

00:32:37.880 I also want to reiterate something you said a moment ago, and I say this and we'll be linking to all of

00:32:42.700 these studies so people can see the data for themselves, but the reproducibility coupled with the

00:32:48.480 magnitude of the effect. So the consistent, enormous magnitude of difference across studies,

00:32:56.100 across labs, across investigators, that signals something is going on here. Again, not to bring

00:33:02.240 up rapamycin again, which people hear me talk about a lot, but people say, why are you so confident in

00:33:07.080 rapamycin's gyroprotective effects? The magnitude of benefit is enormous, and it doesn't seem to matter

00:33:14.360 who does the study. If it's done in this part of the country, or this part of the world, or with this

00:33:20.160 animal, or with that animal, it always seems to work. Now that doesn't guarantee it's going to work

00:33:25.860 in humans. I'd be the first to admit that. But boy, I feel a lot better when it works in every model

00:33:32.300 system, virtually every time, and when it passes the eyeball test. You don't need the error bars and the

00:33:39.160 p-values. So let's talk a little bit about, before we go to primates, and ultimately to the epidemiology

00:33:46.780 in humans, let's talk about mechanism of action. Tell me what you think is happening with this

00:33:53.120 soluble clothoprotein. I assume it's crossing the blood-brain barrier, or it wouldn't be having this

00:33:59.760 effect. Has that been easily demonstrated? It is a winding story, Peter. And one that's exciting,

00:34:08.980 and has led us to very unanticipated findings. I first wanted to mention, as we think about how

00:34:16.260 different interventions may converge upon the same biology, or relate to the same biology,

00:34:23.280 it is interesting that mice treated with rapamycin have increased clotho levels. So rapamycin,

00:34:29.660 either directly or indirectly, will increase clotho levels, just thinking about the convergence of

00:34:34.420 biology. Now, how does clotho enhance cognition in a young, aging, and diseased brain? And that

00:34:43.320 immediately became a major question for my lab and many other labs. And the very first thing that we

00:34:50.480 had turned to was a component of NMDA receptors. So NMDA receptors are really key in connections between

00:35:00.640 neurons. And when they're stimulated, they let in calcium into a neuron, and they allow essentially

00:35:09.200 a potentiation of a neuron for connections to form, for functional connections to form, and really for

00:35:14.660 the neural substrate of memory to form. So NMDA receptors are really key. And there's a component

00:35:21.080 of NMDA receptors called GLU-N2B. It's a subunit. I'm really going tiny and molecular here,

00:35:28.200 but it's very important because I had remembered that there was something called a Doogie Howser

00:35:33.880 mouse, affectionately called a Doogie Howser mouse.

00:35:37.040 We're kind of dating ourselves here because there's going to be a lot of listeners who don't

00:35:40.320 know who Doogie Howser is, but suffice it to say, this was a prodigious mouse.

00:35:45.520 Yes. So it was a mouse that was smarter. There are very few model systems where you can actually

00:35:50.720 pivot the system to make an engineer a mouse to be smarter. There are very, very few things.

00:35:55.760 Clotho is one of them. So this GLU-N2B overexpressing mouse or the Doogie Howser mouse showed a very

00:36:03.520 similar phenotype to the Clotho overexpressing mouse. When I looked at the behavioral data of

00:36:09.520 the GLU-N2B overexpressing mouse, in the very same test, it was performing very well, just like the

00:36:16.940 Clotho overexpressing mice. So I just wondered whether Clotho was acting through GLU-N2B to enhance

00:36:25.420 cognition. That was the hypothesis. In this case, the hypothesis, we gathered data that supported

00:36:33.040 the hypothesis. There wasn't a big surprise in that overexpressing Clotho caused an increase in

00:36:39.640 GLU-N2B at the synapse, at the area where brain cells connect, and led to a more efficient connection

00:36:48.240 and memory formation, synaptic plasticity at the level of the neural cell. So this GLU-N2B was really

00:36:55.500 important. When we blocked GLU-N2B with multiple pharmacologic inhibitors, we abrogated Clotho's

00:37:03.740 ability to enhance cognition. So that was one clue, but here's the major head scratcher.

00:37:09.620 So Peter, Clotho is expressed in the kidney, it's also expressed in the brain, secreted through the

00:37:16.720 chorid plexus, which also makes the fluid for the brain that the brain sits in. But Clotho does not

00:37:22.680 cross the blood-brain barrier. We have looked, others have looked through autoradiography, through

00:37:29.680 IP and Western blot, we've looked through many immunohistochemistry, we've looked through many

00:37:34.600 different methods and can see very clearly that it doesn't cross into the brain. However, when we give

00:37:41.920 a shot of Clotho to mice, to monkeys, in their arm or their belly, doesn't matter if we give them a shot

00:37:49.500 of Clotho, within four hours there is cognitive enhancement. And that cognitive enhancement lasts

00:37:55.720 for at least a couple of weeks. So how is it that giving peripheral Clotho is enhancing brain functions

00:38:04.060 if it's not actually crossing into the brain? That's been a major question that we and others have been

00:38:10.300 working on. And we have some clues that led us in unexpected places. I'm happy to talk about one of them

00:38:17.640 if this is a good...

00:38:19.300 I am all ears. To me, this is, I mean, I didn't want to get to this point yet, but this is the natural time to

00:38:26.640 talk about this. And then I think we should step back and talk about some other things. But yes, to me, this is

00:38:31.600 the jugular question, Dina. Why is it that when we inject a monkey peripherally with Clotho, it spends

00:38:41.600 the next 14 to 19 days in a state of cognitive superiority? And that Clotho isn't crossing the

00:38:50.980 blood-brain barrier. This is, to me, the jugular question.

00:38:55.980 You're right. And we have been working on this. I think I'll step back and say, it's actually amazing

00:39:03.580 that you give something peripherally. It has a central action. It's not crossing into the brain.

00:39:09.560 And it's something physiologic that our bodies are used to, that we have seen high levels of upon birth

00:39:16.740 and development. It does not have known side effects at physiologic levels that have been

00:39:23.020 observed yet. It's very remarkable. So what is it doing? We hypothesize. So I'll just say we don't

00:39:29.440 know yet. This is an area of fervent investigation for us and others. But we have one clue in a study

00:39:37.620 that we published recently in Nature Aging. And this is what we did. We started with the premise

00:39:43.920 that maybe Clotho was doing something in the blood that then would send a messenger into the brain.

00:39:51.880 So maybe there was this messenger of Clotho that was actually going into the brain when you gave it

00:39:56.860 peripherally. And so we did a very simple experiment. We injected mice with Clotho. And four hours later,

00:40:05.700 at the time of cognitive enhancement, we did an agnostic profiling of the proteins in their

00:40:13.620 plasma in their blood. And what we found was sort of unimaginable. It was unimaginable in that we

00:40:21.240 found that all of these platelet factors were increased with Clotho injection in the blood.

00:40:27.440 And Peter, I have to be honest, when I saw this agnostic data set, I turned to my postdoc and I said,

00:40:35.880 I'm really not interested in this. I am not interested in looking at platelets. They are involved in wound

00:40:42.880 healing. They're coagulation factors. This is weird. I had a postdoc, Kena Park, who was very persistent

00:40:50.600 and said, let me try. Let me just study this for a little bit. I said, go for it. I could see your passion.

00:40:58.240 One question, Dina, just to ask, in parallel, did you do the same multi-omic observation of the CSF in the mice

00:41:07.740 in parallel to see if there was something new that was showing up in the CSF to parallel the platelet

00:41:14.500 factors in the plasma? Yes, we did. We haven't published this yet, but we did. In the same mice,

00:41:21.420 we took their blood and we took their CSF. And what we found is that Clotho increased these platelet

00:41:28.140 factors. It was totally bizarre. I didn't believe it. I tend not to believe data. I need to see things

00:41:35.260 over and over again. I need to see functional studies. I need to see it matters. I tend not to believe data.

00:41:41.420 But there it was. She repeated the findings in many different ways. But ultimately, what she did

00:41:46.500 was a series of studies demonstrating that this biology is real, that Clotho is actually activating

00:41:54.200 platelets very modestly. And then when a platelet is activated, so let's first just step back.

00:42:01.320 What is a platelet? A platelet is an anuclear cell in our blood, and it contains little compartments

00:42:10.140 of bioactive chemicals, chemokines. And when a platelet is stimulated or activated, it actually

00:42:18.760 releases these factors. And it does so in a context-dependent way. So when there is a cut

00:42:25.680 or a wound, there is a huge activation of platelets and they release all sorts of factors that help with

00:42:33.680 clotting and help with the wound healing. So that's what they're traditionally known for. But it turns

00:42:39.780 out, Peter, that when we exercise, our platelets are activated and they're releasing factors that travel

00:42:47.880 into the brain. I mean, who would have thought that platelets could be messengers of brain health

00:42:53.760 and could take center stage as a messenger of brain health. So when we exercise, this was found by an

00:42:59.860 Australian group led by Tara Walker, that when we exercise, platelets are activated and certain

00:43:06.540 platelet factors, one of them being platelet factor four, is released and travels to the brain and actually

00:43:14.080 causes neurogenesis or the production of new neurons in the brain. That was very new data.

00:43:21.060 And with that data in mind, I felt too, like maybe there's something to this clotho platelet

00:43:27.000 connection. Maybe there's something to it. So Kena isolated platelets. She put clotho on them.

00:43:34.980 They released PF4, this platelet factor four, the same one that the Australian group had shown.

00:43:42.380 And then she gave this platelet factor four to mice, young, aging mice. She gave it to them as a

00:43:52.440 shot in the belly, just like we have given clotho. And she found that that platelet factor four

00:43:57.940 enhanced cognition in a young mouse and in an aging mouse. And it reversed cognitive deficits. And it was

00:44:05.580 totally remarkable. This is where it gets weirder and wilder. So I go to my colleague and close friend,

00:44:13.020 Saul Valeta here at UCSF. He's the young blood and old brain scientist. So he's really built a

00:44:19.340 really nice body of experiments and literature showing that if you give young blood to an old

00:44:24.940 mouse, it rejuvenates their brain. So Saul is studying brain rejuvenation through blood and I'm

00:44:30.460 having coffee with him. I said, Saul, we've found something so interesting. I have to tell you about

00:44:36.460 it. And I go on to tell him about PF4. Clotho stimulates platelets. Platelets release PF4. PF4 enhances

00:44:45.120 the brain. And he said, well, he was silent for a second. And he said, Dina, we found the same thing

00:44:51.560 with young blood. And that when we give young blood to old mice, that young blood is enriched for

00:44:59.160 platelet factor four, which declines in aging. And then we give platelet factor four, we rejuvenate

00:45:06.160 the old brain. And if you think that's a remarkable convergence of biology, wait till I tell you that

00:45:13.420 Tara Walker in Australia had found the same thing with exercise. And this is all at the same time

00:45:19.740 that exercise was increasing PF4. And that when she gave PF4 to old mice, it enhanced their

00:45:28.980 cognition. And so all of us who are close friends and colleagues now have an incredible convergence of

00:45:39.180 biology where clotho, young blood and exercise were activating platelets, releasing PF4. PF4 is enhancing

00:45:48.120 the brain. And as an aside, like the biology was just amazing. Each of us had our own unique

00:45:55.060 approaches and unique way of digging into the biology. But a practical question, Peter was like,

00:46:00.900 what are we going to do? Like, are we competitors now? Or are we going to hold hands and go through

00:46:07.180 the publication process together? Are you going to screw me? Am I going to screw you? How is this

00:46:12.860 going to come out? And what we did is, I think, a really nice example and model in biology where we

00:46:19.820 held hands and we said, let's just stick together. We went to editors. We went through a couple of

00:46:26.060 years of revisions and reviews. But at the end of the day, all three papers came out in the Nature

00:46:32.520 family of journals on the same day. It made for an impactful splash. And it also just highlighted the

00:46:39.940 convergence of the biology, the reproducibility of the biology. Again, this will never happen again in

00:46:45.740 my lifetime. But this was amazing and a complete surprise that platelet factors could play a role

00:46:52.280 here. So let's talk a little bit more about this. So platelet factor 4 is increased by all of these

00:47:00.000 three things. Do we believe that it's platelet factor 4 that is directly acting on glu-N2b then?

00:47:07.700 And if so, what do you think is happening at the level of substrate and receptor?

00:47:13.080 Dr. That's where we went next with the biology and the experiments. And so one question was,

00:47:19.900 does platelet factor 4 actually cross into the brain? And we demonstrated that it does. We gave

00:47:26.400 it peripherally. We immediately looked into the brain and saw that it was ending up near neural cells or

00:47:35.220 even within neural cells. So it's crossing into the brain. And then does it act directly in the brain

00:47:41.380 was the next question? And what one of my lab members did is take hippocampal slices. So the

00:47:48.800 hippocampus is the area of the brain that is really executing the learning and memory and is targeted by

00:47:56.300 aging and diseases of aging. So he took hippocampus and then he put platelet factor 4 on it and saw

00:48:03.480 immediately within seconds, actually, there was a, well, I don't know within seconds, but quite

00:48:10.920 immediately, maybe seconds, maybe minutes, there was a change in the membrane potential and more

00:48:18.440 calcium was being let in. And we thought maybe this would be glu-N2b acting. And so we put on glu-N2b

00:48:26.260 inhibitors and platelet factor 4 no longer potentiated the synapse or enhanced the neural

00:48:33.960 function. So we do know that platelet factor 4, like clotho, is working through glu-N2b. And maybe

00:48:42.260 clotho is working through platelet factor 4 to change glu-N2b.

00:48:48.440 And sorry, has that same experiment been done, Dina, to look at the clotho that is derived from the

00:48:53.280 choroid plexus to say, when you dump clotho directly onto glu-N2b, you see an influx of

00:49:00.880 calcium. When you block glu-N2b, you abrogate the effect as well. So you now have two things,

00:49:08.040 platelet factor 4 and clotho, that can independently do the same thing. Is that a correct statement?

00:49:14.160 We haven't done that experiment yet. We've done transgenic overexpression in the brain,

00:49:19.500 and we've done clotho peripherally. We haven't dumped clotho itself onto the hippocampus

00:49:27.120 to see whether there can be a direct effect. Other groups have overexpressed clotho specifically in the

00:49:35.220 brain and seen cognitive enhancement. But I haven't seen studies seeing whether clotho is actually

00:49:42.960 directly influencing glu-N2b. We know that it indirectly influences glu-N2b. We know that we

00:49:49.520 can give it peripherally and it'll increase synaptic plasticity through glu-N2b, but we don't

00:49:55.820 know whether it can actually directly do that too. It may, based on other people's studies, it may. We

00:50:01.420 don't know. But here's something else that was actually quite disappointing, but the biology is the

00:50:06.800 biology. We then asked the question, does clotho rely on PF4 to enhance cognition? Is PF4 required

00:50:17.460 for clotho-mediated cognitive enhancement? And to do that, we generated a colony of mice with PF4

00:50:25.120 knockout. They just don't have PF4. And then we gave them clotho versus vehicle, always blinded,

00:50:32.700 always randomized, through a series of cognitive tests, water maze, large Y maze, one maze after

00:50:39.840 another, because you'd like to see the same effect reproduce. And what we found was that clotho

00:50:46.580 continued to enhance cognition, even in the absence of platelet factor 4.

00:50:52.660 To the same extent, Dina?

00:50:54.160 To the same extent. You might think there would have been a diminution, but to the same extent.

00:50:59.700 It just tells us that there's more than one factor. This has to be such an important pathway,

00:51:05.640 and it is so conserved that there is no way biology is going to let one thing be the messenger.

00:51:12.680 I'm making all this up, of course, but hypothesizing that if clotho is so important,

00:51:17.700 it can't be limited to one messenger. If it gets to the gate and it can't get through,

00:51:23.260 it has to have multiple messengers that it can deliver the message to,

00:51:27.240 PF4 being one of them. But clearly, this experiment would suggest that there's at least

00:51:31.620 one other messenger, right?

00:51:33.300 Right. That's the interpretation and conclusion, because PF4 is sufficient to recapitulate clotho-mediated

00:51:42.260 cognitive enhancement, but not necessary.

00:51:44.980 And so when you go back and look at the first experiment you did, the unbiased,

00:51:49.120 was that just a proteomic assessment or did you look at all omics? How broadly did you sample the

00:51:56.740 serum way back? And was there something else you missed because the PF4 was such a big signal?

00:52:03.440 Was there a smaller signal that was there perhaps as well?

00:52:06.500 There were many signals. There are many other platelet factors. There are many other proteins.

00:52:10.720 We are systematically marching through those. We're marching through not just proteins, but

00:52:16.880 metabolites. We are also asking in a cell-type specific way through a system called TurboID that

00:52:25.620 labels the protein as it's secreted from the liver, the kidney, the heart, from lymphocytes.

00:52:33.600 It's a really unique and elegant genetic manipulation that does a biotin label once a protein is secreted,

00:52:40.600 let's say from the liver. And we're asking when we inject clotho, what gets secreted out of the liver

00:52:47.640 and into the plasma? So we're doing like higher resolution studies to understand how clotho really

00:52:55.360 changes the systemic circulation in a cell-type specific way. And then asking which one of those

00:53:03.280 factors that comes from the kidney, the liver, the lymphocytes, the heart, which one of those factors

00:53:09.100 is necessary and required for clotho-mediated cognitive enhancement. And the answer at the end

00:53:15.840 of the day may be what you alluded to, that there may be many factors that have overlapping functions

00:53:23.120 of cognitive enhancement. Maybe they work together. Maybe they work independently. But you're right.

00:53:28.520 If this is a very important biologic function, it really shouldn't rely on just one factor. I think

00:53:36.120 that's a really important point to underline. Tell me a little bit more about this assay,

00:53:41.020 the in vitro assay that you were able to basically sprinkle on PF4, sprinkle on clotho to the glu-N2B

00:53:48.680 subparticle and witness the massive influx of calcium. It seems to me that if that assay is reasonable,

00:53:55.360 it could also become a great screening tool to identify, rather than having to do the experiments

00:54:01.800 to see if you can enhance cognition, at least do your first screen there. Now you run the risk

00:54:07.780 that if clotho is working through secondary mechanisms, you'll miss it. But at least as a

00:54:13.200 first screen, in as much as clotho is working through NMDA via glu-N2B, let's screen a whole bunch

00:54:22.160 of molecules on it, look for the activation, and then go back and search for those in a biased way

00:54:28.900 in our serum sample and sort of triangulate back and forth like that.

00:54:33.760 I love it. Let's do it. And we are doing it. And we're doing it with synaptic plasticity as a

00:54:42.060 measure, as a substrate of cognition. And we're also doing it in vitro at the cellular level using

00:54:48.000 live cell imaging, where we can isolate neurons from the brain, from a mouse brain, and then they

00:54:54.380 grow beautifully on a dish. They connect with each other, and they survive for weeks on end, actually.

00:55:02.860 And you can do live cell imaging to see whether if you put clotho on, I have a graduate student doing

00:55:08.260 this right now, Barbara Shariva, who is putting clotho onto neurons and these other factors that

00:55:17.460 we're seeing from the omics onto neurons, and seeing whether there is an increase in the neurite

00:55:23.340 outgrowth and the connections, the physical connections between neurons. Again, this isn't

00:55:29.720 cognition itself, but it's a substrate of cognition. It may be a distant biomarker for it, but it's a

00:55:36.920 really smart way to, when you're asking a question of this many proteins, which ones are important?

00:55:44.320 It's a way to screen. So with synaptic plasticity and with neurite connections, with the outgrowth

00:55:51.340 of the neurons' connections.

00:55:53.760 So all of this makes a lot of sense for a mouse model of Alzheimer's disease, where the primary

00:55:59.880 deficit is a cognitive deficit that seems disproportionately focused in memory. But you mentioned before I

00:56:06.880 distracted us down this rabbit hole that you are also seeing positive signals in a mouse model

00:56:13.320 of Parkinson's disease. Now, are you seeing them in the mild cognitive impairment that can accompany

00:56:20.580 Parkinson's disease? Or are you seeing it in the movement disorder? Are you seeing an improvement

00:56:25.300 in the primary issue associated with Parkinson's disease?

00:56:29.080 Part of this is published. Part of this is in the peer review process, but it's really,

00:56:34.240 really exciting to share. So these are the experiments. We took mice that overexpress alpha-synuclein,

00:56:43.840 which is a pathogenic player in Parkinson's disease. It disrupts the synapse and has a causative

00:56:50.900 role in Parkinson's disease because we know that people with mutations in causing overexpression of

00:56:58.000 alpha-synuclein will develop Parkinson's disease.

00:57:00.940 It's sort of like the equivalent of APP in people with Alzheimer's disease, where you have this,

00:57:07.300 it's not necessarily the dominant driver of the disease, but it's clearly playing a causal role

00:57:12.020 based on these mutation studies.

00:57:14.420 That's right. And then the mice that I've mentioned that we've used for our Alzheimer's,

00:57:18.720 our mouseheimer's studies were APP mutant overexpressors, just to pedal back to that.

00:57:26.180 So we took these Parkinson's model mice and they have both motor deficits, meaning that they walk

00:57:34.700 across a balance beam and they'll fall. If they're put on a spinning rod, they're discoordinated and

00:57:41.120 they'll fall. They have motor difficulty. They also have cognitive difficulties, which are not as

00:57:48.100 severe as the Alzheimer's model mice, but they do have cognitive difficulties and their ability

00:57:53.180 to map a spatial environment and to hold memory in their mind with working memory. So they have these

00:57:59.840 deficits. We did two things. We injected them with clotho and remarkably saw that clotho treatment

00:58:10.680 improved their cognition. It didn't normalize, but it improved, if I'm thinking about the data

00:58:17.680 correctly by maybe 70% or so, their cognitive abilities. So nearly normalized their cognitive

00:58:24.600 functions. It didn't do anything to their motor functions. So they continued to have motor dysfunction

00:58:31.440 and clotho did not help that. That was also true with the transgenic overexpression of clotho all over

00:58:39.680 the body and brain. That boarded the cognitive deficits induced by Parkinson's toxicity, but it did

00:58:47.740 nothing for the motor problems. And I've spoken to my Parkinson's colleagues about this. There's a lot of

00:58:55.400 interest in potentially using clotho as a treatment for Parkinson's disease because they tell me in our

00:59:03.780 clinics, you know, we can treat the tremor and the rigidity, but people complain over and over again

00:59:11.780 consistently about the cognitive deficits that we now know are a part of Parkinson's disease, not just later in

00:59:19.280 the disease, but even as part of the disease. And those deficits specifically are problems with executive

00:59:27.180 function, which is the ability to focus, to shift attention, to make certain judgments, to think

00:59:36.320 quickly. And it is mediated by the prefrontal cortex, an area that became important when we looked at

00:59:44.400 human studies. So the bottom line was that in mice, clotho really enhanced, again, cognition, but didn't do

00:59:51.880 anything for motor functions. Is there a mouse model that fits between the Alzheimer's model and the

00:59:59.880 Parkinson's model that is more akin to a Lewy body dementia model where it has some of that alpha

01:00:05.420 synuclein pathology, but also has a much more significant cognitive component? There are so many mouse

01:00:12.760 models, Peter. I think that a good mouse model for Lewy body would be alpha synuclein and maybe more in the

01:00:21.120 brainstem and the hippocampus and cortex. I bet there is one, but I'm not clear. But a reasonable

01:00:28.460 hypothesis would be, again, that it would probably provide some relief of the cognitive symptoms,

01:00:37.060 though not necessarily the movement symptoms. That's right. So that's what we're seeing consistently.

01:00:43.560 One of my friends and colleagues had an interesting analogy of thinking about clotho as a helmet for

01:00:49.140 neurons, that whatever came crashing the cell's way, whether it was alpha synuclein, tau, amyloid beta,

01:00:58.120 aging stresses, that the neuron was protected. It remained resilient against multiple toxicities.

01:01:06.520 And the effect of clotho is really in cognition itself, in hippocampal and frontal cortical circuits,

01:01:13.780 it's that these neurons and glia and other cell types are really protected against multiple

01:01:19.640 toxicities. If we want to jump into clinical trials, I think this is the time to really

01:01:24.620 move clotho toward human clinical trials. Wouldn't it be amazing if we had a cocktail for Alzheimer's

01:01:31.620 disease, in addition to lacanumab or denanumab that's removing the amyloid beta from the brain?

01:01:39.440 What about adding something like clotho that can really help shore up the functions of the cells?

01:01:48.000 Because we know that Alzheimer's disease is a multi-proteinopathy. It's not just one protein

01:01:54.000 that's causing the disease. We need factors in our treatment. We need cocktails that can really resist

01:02:01.860 multiple protein toxicities. So I just have this dream that people might be able someday to benefit

01:02:09.940 from clotho, this factor that naturally circulates in our body, that helps with longevity, that helps

01:02:16.720 with other organ systems and enhances the brain. As we know from our monkey studies, for weeks at a

01:02:23.220 time, at least a couple of weeks, if not more, there was funding for a certain amount of time, but it has

01:02:29.800 a long-acting action. We need to put helmets around the neurons to really stave off multiple

01:02:38.000 toxicities. And this is clotho. This is what clotho does. This is the new job of the Greek fate

01:02:44.480 that spins the thread of life. It's to protect our brains.

01:02:49.000 Yeah. You're preaching to the, not just the choir, but the fully converted. And obviously in my other

01:02:54.520 activities, this is something that a lot of my energy goes into. I want to come back to a couple other

01:02:59.720 questions on the mouth study that are going to factor into, I think, when we start to talk about

01:03:05.640 the humans more. Has the following experiment been done where you take a mouse that is genetically

01:03:11.940 susceptible to Alzheimer's disease, so the equivalent of your APP mouse or something like that, and you

01:03:18.200 take a control group, maybe just from my own knowledge, if you took an APP mouse, at what point in its

01:03:25.060 life, how many months old before it starts to develop a clinical disease? So maybe two questions.

01:03:31.520 At what point would it start to be accumulating amyloid in the CSF? And how many months of age?

01:03:36.700 And then how many age when it starts to show cognitive impairment? What are those two numbers roughly?

01:03:41.980 It depends on the mouse model. And there are so many mouse models of Alzheimer's, including APP

01:03:49.240 models. The one that we've used consistently is called the J20 model. It expresses human APP,

01:03:57.100 which produces amyloid beta in mutant forms. And it's a more aggressive model, Peter. And it causes

01:04:04.700 synaptic loss, that connection between cells. It really disrupts that connection between cells

01:04:12.080 really early, before three months. And then it starts producing cognitive deficits at around

01:04:19.620 three to four months. And that's the J10? The J20 model. J20. Okay. So here's my question,

01:04:26.820 Dina. Has the experiment been done where you give those mice clotho starting at birth at a high dose?

01:04:35.200 And does it delay the onset of the inevitability? We know that through overexpression throughout the

01:04:44.920 brain and body, that those mice, those APP mice will have almost normalized cognition. But we don't

01:04:53.820 know whether it's delaying the onset. There are others that have done human population clinical studies.

01:05:00.100 I want to make sure I understand what you just said. You're saying if you take the J20,

01:05:05.280 the APP mutant, and you also cause a mutation that overexpresses clotho, are you saying that

01:05:12.380 you've done that in the same mouse? Yes.

01:05:14.920 Tell me about that mouse's lifespan. Is it normal? And is it cognitively normal? Or does it still get

01:05:21.120 Alzheimer's disease? That mouse that has the APP mutation and overexpresses clotho by about

01:05:28.480 three to four-fold? That mouse will live much longer, number one, so it extends its lifespan.

01:05:38.240 Number two, it will normalize its cognition.

01:05:43.440 Across its lifespan?

01:05:44.620 Across its lifespan. At three months, seven months, eight months, yes, it normalizes its cognition. It's

01:05:51.720 very remarkable. And then when you look in the brain, Peter, when you look at levels of amyloid beta

01:05:59.540 and of tau, they're not different from the mice without high levels of clotho.

01:06:07.280 That is unbelievable.

01:06:10.280 In other words, their brains are still riddled with the Alzheimer's toxins,

01:06:14.740 but they've been able to really thwart the effects of those toxins because they show normal

01:06:22.560 cognition. And if you look at their synapses, this work was done in collaboration with Leonard

01:06:29.300 Muki and Eliezer Maslia, who's at the NIH now. When Maslia looked at the synapses in these mice,

01:06:37.000 he saw that the synapses were all preserved. So again, like this analogy where clotho is really

01:06:44.640 providing a helmet around each neuron, it really allowed the synapses to be preserved. But there

01:06:51.740 was a whole bunch of amyloid and tau still there. And that is resilience. These toxins are present.

01:07:00.080 They won't necessarily go away with clotho, at least in mice. The story may be different in humans,

01:07:05.940 but clotho provided resilience and thwarted the toxicities of Alzheimer's disease.

01:07:13.740 Okay. So I'm going to plant the seed with you, which we'll come back to. But the reason I'm

01:07:18.660 asking this question, Dina, is I do believe that at some point we will have clotho as a drug.

01:07:25.840 I think it's going to come to market.

01:07:27.620 We're absolutely going to be injecting people with clotho. Where we'll go is,

01:07:32.580 do we believe this is a drug we will only want to give to people once they have MCI for the listener,

01:07:40.640 right? So early, early, early stages. Or do we believe that we'll take anybody who's susceptible

01:07:47.040 and just be giving them clotho even before there is a demonstrated disease risk? So that's where I

01:07:53.840 want to go with this is kind of thinking three or four moves ahead on the chessboard.

01:07:57.480 Now let's go back and talk about the primates because we've talked about this incredible body

01:08:03.360 of literature in mice. And again, I think it's reasonable to be circumspect around mice literature.

01:08:10.620 But again, when you start to talk about the volume of literature here and the breadth of mouse models

01:08:16.580 and the number of investigators that consistently find the same results and the magnitude of the

01:08:23.060 results, again, it passes the eyeball test. You don't need to do ANOVA tables all day long to get

01:08:28.960 the answer and squeak at it. This looks incredible, but it would be nice if we had a more convincing

01:08:35.180 model. So let's talk about the single best thing we can ever do before we get to humans and that's to

01:08:40.700 look at primates. So let's talk a little bit about primate brains and the body of literature around

01:08:47.020 clotho in that brain. This is an area that I wanted so much to get into. I don't work with monkeys.

01:08:56.580 I think it's a very, very specialized field to test cognition in monkeys. And so I'll just take us back

01:09:04.080 a long time ago, maybe eight years ago, when I really wanted to know, Peter, whether clotho can enhance

01:09:13.280 a more complex brain than a mouse brain. And like you said, mice are really important in scientific

01:09:19.700 discovery, but there are so many examples of what worked in mice and cured Malzheimer's disease

01:09:27.060 failed in humans. And that's the valley of death. Works in mice doesn't translate to humans. It's not

01:09:34.560 true for everything. And mice have been very, very important for fundamental scientific discovery and

01:09:40.120 for medicines, but I didn't want to spend my career on something that was not going to be relevant to

01:09:47.300 humans. And that might not be that big and important thing that Stephen Hauser challenged me on when I was

01:09:54.440 a resident. I was pitching this want to test clotho and primates all across Silicon Valley to biotech

01:10:01.860 and pharma. And people were curious and enthusiastic about it, but one individual really got this,

01:10:09.920 Ned David, who had started a company, Unity Biotechnology, to attack aging. And we joined forces.

01:10:20.060 They fundraised, they found really great collaborators at Yale, and really made this happen to test clotho

01:10:29.640 and cognitive enhancement in a brain like ours. And people would tell me, if it doesn't work,

01:10:36.640 it's going to kill your research program. And I would say, let it die then. I don't want to spend

01:10:42.420 my career on something that's not important. If it's done well, well, no. And so this collaboration

01:10:48.720 between biotech, me and Yale was one in which a lot of thought, a lot of money went into the design

01:10:56.300 and the execution. So why non-human primates? Rhesus macaques are incredible organisms.

01:11:05.040 They have very complex brains. They are more genetically diverse than humans. And that genetic

01:11:12.540 diversity is something that often trumps effects, can often really influence whether an effect is

01:11:19.060 able to survive genetic diversity or not. So having a lot of genetic diversity is very important to

01:11:24.900 really challenge and test the biology. Mice are inbred. They all have the same genetics, just to say.

01:11:32.220 So the rhesus macaques are incredibly genetically diverse, more than humans. They have a functional

01:11:38.880 complexity that's very similar to humans in terms of the even more of the neural circuits, the hippocampus,

01:11:47.060 the prefrontal cortex. And they have an anatomic complexity that's pretty similar to us.

01:11:53.200 So by testing clotho and non-human primates, the idea was to jump over this valley of death.

01:11:59.460 If it worked in primates, let's look toward humans. If not, let's do something else.

01:12:07.860 I want to pause there for a second, Dina. I mean, I think obviously the listener can imagine where this

01:12:13.240 story is going, but that's a huge burn your ships moment. I want to just spend a minute probing that

01:12:21.400 a little bit more. And you were a wildly successful investigator before this. I don't think it's an

01:12:29.000 obvious step that you would take to push that much further, because let's be clear, if clotho had

01:12:35.720 failed miserably in primates, how many PhDs and postdocs and students do you have in your lab?

01:12:42.340 We're a group of around, it fluctuates between seven to 11.

01:12:46.920 Yeah. And obviously you probably have a very well-oiled machine at generating R1s and

01:12:53.300 all sorts of grants. It's not easy to start all over again if all of that dries up, right?

01:12:58.840 Well, that's why it was so risky. And some people just go to a human trial. You can do biomarkers,

01:13:05.340 but this is risky. And it is risky if it's not done well, but it's super informative even if it's

01:13:12.960 negative. If it's good negative data, and not because the experiments were done in a sloppy way,

01:13:18.960 it's good negative data, then it really tells you something. And we have other projects on longevity.

01:13:26.960 We study why women live longer than men. What does the second X chromosome have to do with it?

01:13:32.620 And there are other longevity factors. So it was really important to push forward and to push

01:13:39.480 forward in a rigorous way. And also with the knowledge that the results could really change

01:13:45.400 the direction of what we're doing. But we have times in our lives where we reflect on what we're

01:13:52.280 doing, how we're spending our time. Is it with people that we appreciate? Is it doing things

01:13:58.480 that are meaningful? And it may be deeply philosophical, but from day to day, I really

01:14:04.980 want to be doing something that I have a lot of faith in, and that potentially has meaning for the

01:14:11.800 human condition to improve human health. And if we've done a really great experiment that's negative,

01:14:17.620 and there's really reason to believe that this isn't going to go forward, then that's fine. We will

01:14:24.400 mourn it, and we will still move forward with something else. But we just don't have lifetimes to devote

01:14:31.500 to 100 different scientific projects. So we have to be very choosy. And I really, really wanted to make

01:14:37.460 sure that this is something really worth putting time, energy, resource, passion, constant thought,

01:14:44.580 training, fundraising. I think the reason I'm pointing this out, Dina, is I want to publicly

01:14:51.600 commend you for something that honestly, I don't think most scientists would be willing to do. And I

01:14:55.960 wouldn't even hazard a guess at the fraction, but I think there are a lot of scientists who have lost

01:15:02.080 sight of what you just said, and they think the job is doing science. But it's not. The job is

01:15:08.900 knowledge creation. The job is knowledge creation for the purpose of making lives better. And those

01:15:15.560 are very different things. They overlap. The former is a process to the latter. But it's very easy. And

01:15:25.080 it's very easy to lose sight of that in the weeds. So I only call it out to say, I don't think everybody

01:15:32.120 would have come to the same conclusion you did. So with that said, let's talk about how you and your

01:15:38.820 colleagues at Yale and basically thought of the right question to ask, and then the right design

01:15:47.520 of an experiment to ask the right question. First, I just want to say thank you. And that is very well

01:15:54.140 said. Monkeys undergo cognitive decline in a very similar parallel fashion to humans. They have

01:16:03.120 synaptic loss, the connection between neurons with aging, as do humans do. And the circuits that are

01:16:12.240 affected in aging are really similar to the human circuits. So they are the hippocampal frontal circuits,

01:16:20.500 the hippocampus, and the frontal lobes. And aging will preferentially target working memory and also

01:16:29.120 spatial memory and other types of memory. But this working memory, holding something in your mind,

01:16:34.360 you go to the refrigerator, you open the door, and you think, why did I come here? What was holding that

01:16:39.620 immediate memory in your mind is something that aging really targets. And monkeys undergo this very

01:16:45.960 similar cognitive decline to humans. And there are ways to test monkeys that interrogate those circuits.

01:16:55.320 In this case, a spatial delayed task was used. Graham Williams and Stacey Kastner conducted the studies.

01:17:03.160 And Clotho actually preferentially targets those circuits that aging erodes. So here is a model system.

01:17:11.080 It's genetically, anatomically, functionally complex. It undergoes cognitive aging parallel to humans.

01:17:18.200 And there are really well-developed tests by these exceptional scientists who are very experienced and

01:17:26.020 adept at conducting these tests. So it was a really excellent setup to ask, can Clotho enhance

01:17:33.640 cognition in these aging monkeys? What was done is something called a spatial delayed response.

01:17:42.440 And the monkeys presented with a bin of multiple wells. And sometimes there's a few wells, and

01:17:49.220 sometimes there's a lot of wells. And it's harder when there's a lot of wells to find a treat. So a treat

01:17:54.960 is placed in a well, and they can see you place the treat. And then a screen drops. And then all the wells

01:18:02.440 are covered, you cannot see where the treat is. And then the blind is opened, and they are tested

01:18:08.880 where to choose, because they're basing this on spatial memory and on working memory, where that

01:18:15.800 treat was. Again, it's a little easier if there's only three wells. It's easier to choose one out of

01:18:21.600 three and get it correct. It's harder when there's nine wells to remember spatial and working memory where

01:18:27.660 that treat was. It was done very rigorously, I must say. The study was largely blinded.

01:18:34.100 And it was done in a way in which the injection of Clotho wouldn't interfere with causing stress

01:18:41.660 in memory so that everyone got a baseline. They then got a vehicle, and then they got vehicle or Clotho.

01:18:48.660 It's a really well-designed study.

01:18:51.280 And just for folks listening, vehicle is placebo, so that they understand what we mean by that.

01:18:55.180 Thank you. So the monkeys that got a Clotho treatment, again, largely blinded,

01:19:02.820 performed better than the ones that got vehicle treatment.

01:19:06.100 Sorry, Dina, how did you guys decide how to raise the dose? So first of all, when you obviously did

01:19:12.520 all the mice experiments, you're dosing like you probably do based on a certain number of milligrams

01:19:17.580 per kilogram or milligrams per gram of animal. What did you use to dose escalate that? Did you just

01:19:24.360 assume the same dose per unit body weight or did you make other adjustments?

01:19:29.660 Well, we went with two things in mind. One is we really wanted to stay at least with one dose

01:19:37.460 in a physiologic range. So with something that the body has been exposed to and has seen over its

01:19:44.520 lifetime. And so in one dose, we wanted to go somewhere up to like maybe four to five.

01:19:51.000 Correct. Yep. Yep. You're still just below what they would have been born at.

01:19:55.680 Right. A very youthful level of Clotho. It's a rejuvenating dose. And then the other doses were

01:20:03.640 higher and were meant to test, could you really push the system to improve cognition even more

01:20:11.860 than what is observed with that physiologic dose? By the way, that physiologic dose, that sort of natural

01:20:18.900 dose is what we have always used in mice. I should say, we've also given mice huge, huge doses that

01:20:28.140 were way beyond what they would ever see or used to. And it's still enhanced cognition in mice. And

01:20:33.880 that's going to be different than the monkey story. By the way, when you gave the supraphysiologic

01:20:39.560 doses to mice, so presumably 10 fold and beyond, did you run into any problems? For example, did the

01:20:48.660 mice ever develop antibodies to the protein? Did anything else arise that would suggest that more

01:20:54.960 is not always better? We didn't see signals in mice. But having said that, we didn't systematically

01:21:02.160 study whether doses of 100 micrograms per kilogram was doing something different. We didn't observe

01:21:10.800 differences in their normal behaviors or like in their basic blood work, but it worked. It didn't

01:21:17.600 work better. So I should say like those super low doses were just as well as the super high doses in

01:21:24.600 mice. And super low doses mean well below 3x normal. So if we could just call 6x the peak physiologic

01:21:34.820 dose, what was the minimum effective dose in mice relative to that? More than five times less,

01:21:42.200 a very, very small dose that still worked. I'm thinking if we gave mice 10 micrograms per kilogram,

01:21:47.800 I'm remembering something like 0.5 or 1 enhanced cognition, 82 micrograms enhanced cognition. So

01:21:57.320 very, very low, just a touch more, just a boost enhanced cognition. Our strategy was to stay within

01:22:05.820 a physiologic dose and make sure that that was represented in the monkey studies. I mean, I really

01:22:11.340 thought about this, consulted with people that have taken drugs to market. Tom Boone is one of them and was

01:22:17.680 very instructive and taught me a lot in terms of thinking about relevantly dosing in monkeys.

01:22:26.040 And then there were higher doses that created much higher doses than the body has seen,

01:22:30.540 which is maybe 10 times higher and beyond, 10, maybe 20 times higher and beyond. And what we found

01:22:37.600 is that the low physiologic, that natural dose of clotho enhanced cognition in the monkeys. And it did so

01:22:47.040 within four hours. And then that cognition stayed better. Their ability to think, remember stayed

01:22:54.680 better for at least three weeks, 14 to 21 days. And some were even tested out to a month.

01:23:02.840 I saw 28 days. Yeah.

01:23:04.580 And then at some point the study had to be stopped. It's a million dollars or more. And so,

01:23:09.500 but it was remarkable that one sub-Q dose, like a shot of Ozempic would be given, a sub-Q dose that

01:23:18.660 was low physiologic had an immediate effect on cognitive enhancement that lasted for a very long

01:23:25.480 time. Now, there were a few different types of tests done. One was for normal memory load and one

01:23:33.380 was for high memory load. And the high memory load was a test with a lot of different bins where they had

01:23:39.140 to remember which one among seven or eight wells was the treat hidden in. It's just more taxing with

01:23:46.920 more choices to remember. And they did even better in that study of high memory load.

01:23:53.980 With a low dose.

01:23:55.260 With a low dose. So the effect was particularly pronounced. They were particularly smarter when

01:24:02.840 the task became harder. And again, why this task? Why monkeys? Why clotho? It all came together

01:24:11.200 because clotho works on these circuits that are tested in the monkeys that decline with aging and

01:24:18.020 with neurodegenerative diseases like Alzheimer's and Parkinson's.

01:24:22.060 So what about the high dose?

01:24:23.620 Right. So the high dose did not work. The high doses that gave the monkeys clotho

01:24:30.160 way beyond what they've seen in their lifetime. They didn't harm. They did not impair cognition,

01:24:37.100 but they didn't help cognition. And it's not too much of a stretch to think that too much of something

01:24:44.580 that does multiple things in the body and maybe multiple pathways that could just create an imbalance

01:24:51.340 that doesn't support cognitive function. Again, it wasn't harmful with the measures that we tested,

01:24:58.000 but it didn't help to take so much more than the body has seen and is used to. And that again was

01:25:05.080 different from the mice. With the mice, and this may be a big difference between mice and a more complex

01:25:09.700 brain with a non-human primate. In mice, we saw continued cognitive enhancement. And in monkeys,

01:25:16.940 we really got a window into, before going into clinical trials, that if we're giving clotho,

01:25:23.660 probably should be thinking about a specific therapeutic window, one that the body knows,

01:25:29.600 one that the body is used to.

01:25:31.080 So Dina, why do you think the effect lasts for so long? This is also a little counterintuitive.

01:25:41.500 When you consider the hourly variation of clotho naturally, when you consider the transient

01:25:53.240 effects potentially of things like exercise, where you see these large boosts over a short period of

01:26:01.060 time following a bout of exercise. But it seems hard to imagine that the benefits of an hour of

01:26:06.440 exercise persist three weeks later, the way a subcutaneous injection of clotho did. So

01:26:13.040 what do you think accounts for that?

01:26:15.340 I don't know the answer, but I'll speculate. First, I'll just say it's remarkable, isn't it?

01:26:20.720 It's particularly remarkable as we imagine therapeutics in that maybe this is the type of

01:26:29.680 treatment of rejuvenation that could be administered maybe once a month, once every

01:26:35.940 three months as a shot in the arm, for example. So I think it has really important therapeutic

01:26:41.420 implications. Mechanistically, this means that clotho has not just an acute effect of immediately

01:26:50.080 enhancing NMDA receptor functions, synaptic plasticity, cognitive function at four hours,

01:26:55.980 but it has an organizational effect. It's doing something to, in the longer term, really help

01:27:04.040 to, for example, remodel a synapse. So I would imagine that, for example, with GLU-N2B being trafficked

01:27:13.040 to the synapse and to promote better functions that those sort of synaptic organizational effects

01:27:21.260 are happening for and staying put for a longer period of time. I think the biology of this

01:27:29.060 organizational effect of clotho has yet to be discovered, but it's something that's happening

01:27:35.620 being at the synapse. I have a very strong sense of something that's happening organizationally,

01:27:42.020 structurally at the synapse.

01:27:44.240 As much as I want to go deeper into that and talk about the conformational changes that could

01:27:49.480 be occurring, we'll have to save that for another discussion because where we have to really go next

01:27:56.020 is what do we think about in humans? And what evidence do we have, because we do have some

01:28:03.200 really interesting evidence, even absent a single experiment, that everything we've talked about

01:28:09.300 so far might indeed also be relevant to the species of interest. And no disrespect to the mice and the

01:28:16.280 macaques, but there aren't too many people listening to this whose mind isn't already wondering,

01:28:22.340 okay, enough about the animals already. Tell me, is this going to make a difference for my mom

01:28:28.680 or for my dad who are in the early stages of dementia? Is this going to make a difference for me

01:28:35.120 because of my risk factors, even though it's 20 years from now? And so tell me a little bit about

01:28:43.500 a particular SNP associated with the clotho gene called KLVS and what its significance is to this

01:28:52.060 story. None of this matters, Peter, if it doesn't have potential to help the human condition. It

01:28:59.400 just doesn't matter. It's interesting, but the big and important is if it's relevant and may work in

01:29:07.300 humans. I don't know whether we've done anything big until we test clotho in humans. So with that said,

01:29:15.800 back in the early days, and I think it was 2012 or so when these are 2011, 2012, when these first

01:29:24.760 clotho studies, we were doing them in mice and discovering these cognitive enhancing effects.

01:29:30.200 I went to, and again, I'm a physician scientist. I always have humans in mind. I have my patients in

01:29:35.320 mind. Alzheimer's disease, 50 million people around the world. This is going to triple by 2050.

01:29:41.720 Cognitive decline is our biggest biomedical challenge. Always have humans in mind. I went

01:29:48.400 to my friend and colleague, Jennifer Yokoyama at the Memory and Aging Center here at UCSF,

01:29:53.340 and I told her that there was this genetic variant of clotho that had been found. We can talk more about

01:30:00.100 what that is, but was there a way, because she's a geneticist, and she and others at the Memory and

01:30:06.600 Aging Center, Joel Kramer, Bruce Miller have built this incredible population of individuals and

01:30:13.940 patients. Alzheimer's disease with normal aging, with frontotemporal dementia, and they really

01:30:19.580 carefully characterize them, their genetics, their blood biomarkers, et cetera. So I went to Jennifer

01:30:25.580 and I said, is there any way we can know whether this genetic variant of clotho, KLVS,

01:30:33.660 has any association with cognition? Because that would mean that this clotho is important to brain

01:30:40.440 health. It would mean that there was some link with humans and brain health. So what is KLVS that

01:30:46.220 you mentioned, and what does it associate with? As we've discussed, we all have clotho circulating in

01:30:53.860 our blood and around our brain. But some of us, about one to four, one to five of us, will carry a gene

01:31:03.800 for clotho, a genetic code for clotho that leads to higher levels of production. And KLVS refers to two

01:31:14.100 single nucleotide polymorphisms that cause a difference in the coding of the protein itself.

01:31:23.860 Again, so about one to four, one to five of us will have KLVS. Other people are non-carriers.

01:31:31.040 And those people with KLVS will genetically have higher levels of clotho circulating in their blood.

01:31:38.080 Now, interestingly, it's only the people with one copy of KLVS, the heterozygotes. And very rarely,

01:31:46.900 there are homozygotes of KLVS. And those people end up having multiple disadvantages in lifespan

01:31:54.900 and vulnerability to different diseases. So when we talk about KLVS, we're talking specifically about

01:32:01.880 heterozygosity carrying one allele of it.

01:32:04.740 What are some of the health consequences of being homozygous? And what is the prevalence

01:32:11.800 of homozygosity?

01:32:13.560 It's really rare. So if the prevalence of heterozygosity is around 25% in populations,

01:32:21.040 homozygosity is so...

01:32:22.620 It's probably about one to 2% because actually it would kind of mirror APOE4, where the heterozygosity

01:32:31.320 is about the same. It's about 1 in 4, and the homozygosity is about 1 in 50 to 1 in 100.

01:32:40.700 Yeah, that's about right. It's pretty rare, but it exists. And those people have shorter lifespans.

01:32:47.300 They have much lower levels of clotho, and they are at risk. For anything that the heterozygosity

01:32:53.860 helps with, the homozygosity hurts. But the heterozygosity has been a really interesting

01:33:00.700 window into clotho and natural experiments.

01:33:05.560 How much higher is their clotho level?

01:33:08.100 Well, we did this study. Jennifer and I took this serum from individuals here at the Memory and Aging

01:33:15.020 Center, a few hundred, and tested the ones that were non-carriers that just have the typical clotho

01:33:22.060 gene versus the KLVS heterozygote carriers. And the heterozygote carrier status increased clotho

01:33:30.640 levels by about 15%, 15, maybe 20%. And just to give you context, if you're wondering, am I a carrier?

01:33:40.360 And some people are, and some people aren't. I don't want people to forget that exercise is thus

01:33:46.160 far one of the more powerful modulators of clotho expression. And exercise increases clotho on average

01:33:53.280 by 30%, so much more than what the genetic influence is. But nonetheless, KLVS increases clotho levels by

01:34:02.400 about 15%. So for example, if an average number, let's say a non-carrier had 800 picograms per

01:34:10.340 mil of clotho circulating in their serum. A KLVS carrier might have like 950 or so picograms per mil.

01:34:19.620 That's what I'm remembering from our graphs. There's reason to believe that it increases clotho

01:34:24.520 because those two amino acid changes that translate into a different amino acid in the protein itself

01:34:33.820 influences secretion of clotho from cells. There's a biologic reason that this variant is probably

01:34:42.960 changing clotho levels. The other piece to this story, Dina, that's just so fascinating

01:34:48.400 is now when you take those data, the prevalence of heterozygosity of KLVS, and you cross it with

01:34:58.560 APOE4. So now we have listeners of this podcast are absolutely not strangers to the population-based

01:35:06.120 risk of APOE4. Of course, we always want to remind people that at the individual level,

01:35:10.480 very difficult to make that statement. But at the population-based level, we know that having

01:35:16.020 an APOE3 and an APOE4 is at least a doubling of risk, maybe even slightly more. And homozygosity for

01:35:24.180 APOE4 could be an 8 to 12-fold increase, so call it a log order increase in risk. So tell me,

01:35:32.260 what did you find in people who are homozygous and heterozygous for APOE4 who also happen to be

01:35:40.920 heterozygous, i.e. have the favorable variant of KLVS, single copy?

01:35:45.780 This is really remarkable data. I first want to go back to that original experiment

01:35:51.180 that we published in 2014, I believe, with Jennifer, and that those people that carried

01:35:58.460 the KLVS allele did better across cognitive testing. And this is a normal aging. This was

01:36:05.940 not an Alzheimer's disease, but carrying that variant, carrying KLVS associated with better

01:36:12.580 cognition across the board. I'm often asked, well, how much smarter were those individuals? And

01:36:18.880 I would be careful about smarter and happier, and we don't know, but the cognitive test showed us

01:36:25.060 that they did better. And they did better to the same extent that APOE4 carriers would do worse.

01:36:32.840 So it was a sort of a similar amount of change in cognition in which KLVS was improving and APOE4

01:36:41.080 was decreasing. With that in the background, since then, many groups and many people have

01:36:48.040 looked at KLVS looked at KLVS in their populations. And that association has held largely in most

01:36:56.000 studies, not in all, but in most studies, there is an association of KLVS and better cognition

01:37:02.880 with heterozygosity. So then the question comes that you asked about APOE4, Alzheimer's risk,

01:37:11.220 and clotho in KLVS. We initially did a study in collaboration, actually led by Oziamo Konkwo and

01:37:19.240 his group at Wisconsin, that showed that in individuals with APOE4 that were carriers of KLVS,

01:37:29.460 that they just had less of the effects of APOE4 in terms of less A-beta deposition, less cognitive

01:37:37.980 problems. It was a smaller study of a few hundred people at risk for Alzheimer's disease, but

01:37:43.880 it was a good study. But I'll tell you the study that I'm most excited about that we were not a part

01:37:49.740 of. That came from Stanford, led by Mikael Belloy. He's one to watch. He just established a lab at WashU

01:37:58.800 and his senior PI, Michael Grisius, and they're wizards at doing genetic population studies.

01:38:06.820 So Peter, they did this remarkable study of 22 different cohorts that were normal cognition,

01:38:15.560 MCI, mild cognitive impairment that you mentioned earlier, and Alzheimer's disease, over 20,000

01:38:21.200 individuals, a very large meta-analysis. And they looked at if there was a relationship between

01:38:28.520 KLVS carriers and APOE4. And the bottom line of what they found was that if an individual

01:38:36.160 carried KLVS, the APOE4 didn't matter. So let me break down what that actually meant in their

01:38:45.160 experiment. That meant that in those people that carry APOE4, if they were also heterozygote for

01:38:54.640 KLVS, they had a decreased risk for developing Alzheimer's disease that was pretty close to the

01:39:03.240 normal population. They had a decreased conversion from MCI to AD, and they had decreased Alzheimer's

01:39:12.380 biomarkers, both in their CSF and in their brain. They just had less amyloid beta. It's a really

01:39:19.460 striking study. Again, because it has the power of statistical analysis. It holds across many,

01:39:26.620 many cohorts, and it's many, many people. And KLVS essentially blocks and abrogates the APOE4

01:39:34.860 toxicity by this genetic association. It's really remarkable.

01:39:39.960 Did the double E4s, did the homozygotes, reduce to a completely normal 3-3 risk? My recollection,

01:39:48.300 but it's been a while since I looked, there's a graph that demonstrates all of this that's a great

01:39:52.480 summary. My recollection, which could be wrong, that's why I'm asking, was that the 3-4s were

01:39:58.060 completely abrogated to a 3-3 risk, and that the 4-4s ended up coming way down, but they still looked

01:40:06.340 like more of a 3-4. Am I misremembering that? They didn't actually publish that. They excluded

01:40:12.740 the homozygotes from the analysis, and it might be in a supplement somewhere, but I actually reached

01:40:19.180 out to Mikael, and I asked him about the 4-4. I had the same question. And so this is just by verbal

01:40:26.300 communication. He indicated that the 4-4 also associated with the protection from the KLVS

01:40:34.620 heterozygosity, so that the effect of having one APOE4 wasn't different than having two APOE4s

01:40:43.200 in terms of KLVS protection. It protected in both heterozygosity and homozygosity of the APOE4

01:40:50.160 allelo. Again, it's just through verbal communication. It might have been in a supplement

01:40:54.060 somewhere.

01:40:55.420 So did they find anything negative? So going way back to the mechanism of this, which at least

01:41:00.280 in part is communicated through a platelet factor, was there anything that might have

01:41:06.740 been unwarranted, such as an increase in stroke risk? I mean, I know that it's actually the

01:41:13.000 opposite, but I'm just trying to say, is there anything with an increase in a platelet factor

01:41:17.200 that could have led to an increase in DVTs or something? I mean, when you have a sample size

01:41:21.900 as large as they did, presumably you would find something that was negatively associated with

01:41:28.420 the KLVS. I'm not aware of increase. As you were saying, it's actually the opposite. The KLVS

01:41:36.100 heterozygosity actually associates with the protection against stroke risks, cardiovascular

01:41:41.520 risks. Even metabolic risk.

01:41:44.700 And metabolic, yeah, metabolic diseases. I've searched for something that could be negative. And I did find

01:41:52.960 that in the cancer literature, KLVS heterozygosity has a poorer prognostic, indicates a poorer prognosis

01:42:02.180 in BRCA1 carriers with breast cancer. There are examples where it's not helpful. And one is in BRCA1

01:42:12.560 positive breast cancer. Dina, going back to the human homozygotes for KLVS, do we know how much of an

01:42:22.980 increase in clotho they produce? So if the heterozygotes are producing 15 to maybe 20% more, how much more

01:42:31.420 clotho is being produced by the homozygotes? And does that give us an insight into toxicity in humans that

01:42:39.180 was not observed in mice and not even observed in the primates? Because in the primates, when you gave too

01:42:45.960 much, you just didn't get a benefit, but you didn't get a harm. In the mice, you actually got more and more

01:42:51.180 benefit. As the organisms get more and more complicated, it seems that the therapeutic window is getting narrower

01:42:56.240 and narrower. Do the homozygotes give us any insight into that?

01:43:00.320 With Jen here at the Memory and Aging Center, we have access to homozygote serum. And we actually looked at

01:43:07.620 several homozygotes compared to non-carriers and heterozygotes. And what we found is that

01:43:14.160 their clotho levels are actually lower than normal. And we think that has something to do with,

01:43:21.020 I'm going to get a little deeper into this, because I think it's really important when we

01:43:25.760 think about therapeutics, actually, that many genetic variants won't cause a change in the

01:43:32.420 protein sequence itself. If a nucleotide change is in an intron, it's just not going to change the

01:43:40.640 structure or function or anything of the protein. But in KLVS, there are two nucleotide changes and

01:43:47.800 they translate into different amino acids in two places of the clotho protein. And so what we think

01:43:55.060 is happening, this is speculation, but what we think is happening, based on in vitro studies that

01:44:02.520 Arking did in 2002, that in the clotho heterozygote in which one allele is making a mutant protein,

01:44:12.420 we think that there's an overcompensation for that mutant protein by increasing wild type levels.

01:44:19.980 Because what that variant does is it mucks up clotho secretion from the cell. So just to be

01:44:27.720 clear, carrying one variant is likely changing the structure and function of clotho, but there's

01:44:34.620 probably an overcompensation from the wild type allele, causing higher levels of the wild type clotho.

01:44:42.140 First of all, that is an unbelievable, I would not have guessed that, and I can't believe I didn't

01:44:48.040 think to ask such an obvious question, which is, do the KLVS individuals produce the same protein?

01:44:56.780 I took it for granted that they produced the same protein and just made more of it. But to be clear,

01:45:04.140 if you assay those individuals, are you finding two proteins in them? A protein that mirrors the

01:45:11.820 wild type, that's the one that's elevated 15 to 20% and an actual mutated protein or a protein that

01:45:19.620 has two different amino acids, which again, to many people sounds like big deal. You've got a thousand

01:45:25.460 amino acids in the full protein. You've changed two of them. How much can it matter? Well, unfortunately

01:45:30.580 in biology, it can always matter. Ask a patient with sickle cell anemia. So is that what you're seeing?

01:45:36.440 You're seeing two different proteins and it's the wild type one that is overexpressed?

01:45:42.060 At this point, it's the hypothesis that the wild type one is really compensating, overcompensating

01:45:49.180 by increasing levels for what may be a mutant protein. But in reality, and we've done ELISA's on

01:45:56.740 the enzyme linked immunoassays on thousands and thousands of individuals, but the ELISA itself

01:46:03.780 doesn't distinguish between a KLBS protein and a normal wild type clothoprotein. It doesn't

01:46:12.300 distinguish between the two. And so the answer to that question is not known.

01:46:17.560 ELISA is just too blunt an instrument to figure that out.

01:46:20.080 If we take that a step further and say, what's happening in a clothopomozygote,

01:46:27.180 they're expressing a mutant protein from one allele that mucks up secretion,

01:46:32.140 and they're expressing a mutant protein from another allele that mucks up secretion. And so

01:46:38.480 they don't have wild type clotho. All of their clotho is the KLBS form, and it's very low.

01:46:46.280 How much lower is it, Dina?

01:46:48.040 In our studies, it was, I'm trying to visualize the graph. If there was a 15% increase with

01:46:54.800 heterozygosity compared to non-carriers, there was probably a 30% decrease with homozygosity.

01:47:02.140 Compared to non-carriers. So to give you a sense of numbers, if a non-carrier was at 800,

01:47:10.060 a KLBS homozygote carrier was below 600, something like that. This is why this matters.

01:47:18.000 It matters for many reasons, but there have been some really large-scale studies recently,

01:47:23.340 Peter. One is called the NHANES study published in 2022, I believe. And what this study showed us

01:47:32.040 is that clotho levels as measured by this immunoassay by Eliza, that the clotho levels

01:47:38.960 really correlated with mortality. I want to make sure I get this right. So it was over 10,000 people

01:47:45.900 in the United States. Clotho serum was measured on everyone. The mean age was about 56 years.

01:47:54.500 And if the mean clotho level was around 800, then something less than what they defined as 666 by

01:48:03.280 their study, picograms per mil, associated with a 30% mortality over five years. And that was replicated

01:48:12.120 in another study called in Chianti, that lower levels of clotho. And again, this isn't like half

01:48:18.180 the levels. This is maybe it's like 30% of a decrease of levels associated with a 30% mortality

01:48:25.400 over five years. And that mortality was primarily in cancer and cardiovascular disease. I think levels

01:48:34.040 are going to matter. As we think about our human aging, as we think about our organismal health,

01:48:39.980 heart health, brain health, cancer health, the levels, at least by association right now,

01:48:46.640 matter. And lower levels are really associated with more diseases of aging.

01:48:52.360 It's just like, can we even scratch the surface of this? I mean, we've just sat here and talked for

01:48:57.360 two plus hours about the limits of our understanding of clotho and brain health. And yet, this NHANES

01:49:04.640 study is actually looking at something totally different, which is all-cause mortality.

01:49:08.760 And saying basically, if you're in your 50s, and your clotho levels are 30% below what would be

01:49:16.480 expected for somebody your age, it's associated with a 30% increase in all-cause mortality over

01:49:22.140 the next five years. If that turns out to be causal, and you're saying that the manner in which that

01:49:29.340 death was distributed was cardiovascular and cancer, so it doesn't even have to do with more

01:49:35.840 dementia, which of course wouldn't be kicking in in your 50s, it suggests that clotho is doing even

01:49:42.440 more than just protecting brain health, which if it did nothing else, would still be arguably the most

01:49:48.180 important thing that we should be trying to get into humans for clinical trials. So I know that your

01:49:53.980 area of expertise is not oncology or cardiovascular medicine, but I'm just curious as to what your

01:49:58.440 thoughts are as to how that could be happening.

01:50:00.280 I couldn't agree with you more. And my expertise is as a neurologist and neuroscientist is really on

01:50:06.680 the brain. But having said that, the side effects of clotho increasing it may be much more than

01:50:15.480 helping brain health. It clearly has a very strong association with protection against cancer,

01:50:22.940 cardiovascular disease, and kidney disease. There is, Peter, a very, very, very large literature

01:50:30.360 on clotho and organ health, a very strong one. In the cancer field, there are many preclinical models,

01:50:39.200 again, in rats and mice that show that giving clotho the soluble hormonal form actually stopped

01:50:48.160 and reversed cancers in mice, like pancreatic cancer, for example. And then there are association

01:50:55.260 studies in humans too, but there is so much more to the biology of clotho than only what it's doing

01:51:01.360 in the brain. In kidney disease, clotho is going to come to market and maybe the kidney people beat

01:51:08.220 the brain people. If clotho comes to market, I think people are going to benefit no matter what. But

01:51:13.480 in chronic kidney disease, there is a decrease in clotho secretion and decrease in clotho in the

01:51:20.760 blood and the kidney folks, the kidney specialists are really developing clotho as a diagnostic

01:51:27.420 biomarker to understand when the kidney starts failing. The idea there is that right now the measures

01:51:35.260 are glomerular filtration rate, urea, and these are not as sensitive as they would want biomarkers to be

01:51:45.080 in detecting kidney dysfunction. As soon as the kidney starts having trouble, clotho declines.

01:51:52.800 As soon as it starts having trouble, so there's a fervent interest in developing clotho as a biomarker

01:51:58.200 for kidney function. And I would say, again, if we think in a broader sense about clotho, maybe someday

01:52:05.720 and maybe someday soon, we would have our clotho levels checked just as we do our blood pressure and

01:52:12.600 our cholesterol and we get breast exams and we have colonoscopies. Why not have a clotho level

01:52:19.900 checked? Everyone's will be different.

01:52:22.380 Now, how do we get around the issue that it has this diurnal effect? That's the only thing that jumps

01:52:27.240 to my mind when you're talking about a marker of EGFR, because I know in our practice, we're

01:52:33.220 fanatical about monitoring EGFR. I mean, we look at cystatin C, we look at creatinine, we're triangulating

01:52:40.760 them. At least to our ability, these don't depend terribly on time of day. So do you think that the

01:52:47.520 answer for clotho is you have to have it done 60 minutes after you wake up in the morning, it's

01:52:52.960 non-negotiable. Don't ever let somebody check your clotho level at two in the afternoon.

01:52:57.240 Otherwise, we can't interpret it. Is that how you think it's going to factor in?

01:53:02.100 I think that is going to give us the best and more accurate level of clotho. And in fact,

01:53:07.500 I mentioned that we've done thousands and thousands of clotho measurements and human serum and human

01:53:14.420 CSF, cerebrospinal fluid. And I always make sure that whoever we're collaborating with and who has

01:53:21.000 collected the specimen did it in a morning fasting manner so that the individual or patient hasn't

01:53:28.960 eaten and it's first thing in the morning. Why do you know that eating impacts clotho levels?

01:53:34.920 I don't know that. And I don't know that it's really been tested per se, but in the spirit of

01:53:42.140 what one does, for example. Just being incredibly consistent and rigorous.

01:53:45.620 With less confounding factors in the background. But having said that, the decline over the course

01:53:53.480 of a day isn't dramatic. The decline by age is more relevant than the decline by time of day?

01:54:01.720 I would say that the decline by age is a consistent decline, but the time of day does matter because it

01:54:09.620 can decrease by almost 40% by midnight. And this is done with, I have to say, I've looked through the

01:54:15.300 literature, the diurnal rhythm of clotho has been shown in a small number of people, but the data

01:54:20.140 look good. That it's not really statistically different until like afternoon, but it's starting

01:54:27.540 to decline. I had to design the time and day. And I would say that we need a clotho test that people

01:54:34.700 take in the morning fasting, like they do with their cholesterol, just get it along with the

01:54:40.020 cholesterol, draw. And most importantly, we need a standardized assay.

01:54:45.980 Yeah. I was about to say, is there a CLIA-based assay for this?

01:54:48.880 No. Nope. I think it's coming given how many people and how many samples. Levels haven't been

01:54:55.460 coordinated between institutions and labs. So everything we do in our lab is consistent to our

01:55:01.760 methods and standards and we standardize everything to, and I include my own samples in there,

01:55:08.280 but it's all standardized. But then my lab may have slightly different values than what is going on in

01:55:15.340 another lab. And then of course, so if I woke up in the morning and I checked my level and I was at

01:55:21.220 800, is it picograms per milliliter? Is that the unit? Yeah.

01:55:24.960 If I did my test at six o'clock in the morning and I'm 800 picograms per milliliter, and then

01:55:30.640 from seven o'clock to nine o'clock in the morning, I'm in the gym, I could easily be 1200 picograms

01:55:37.560 per milliliter after. So how does that impact our understanding of what's going on?

01:55:43.400 I think that's a really good, important point. I do want to emphasize that the human studies show

01:55:48.560 chronic exercise increases clotho by after a few months, after three months. And there's been a

01:55:54.420 mouse study that shows an acute bout of exercise can really nearly double clotho. But I think we

01:56:00.720 would be interested again, we're imagining a not so distant world. It would be important to get a

01:56:06.560 baseline level. Where are you living? So just to be clear, you're saying you do not have human data

01:56:12.660 that demonstrate that acute bouts of exercise dramatically. I have not seen that. I have not

01:56:19.240 seen that. I know a person who might be willing to do that experiment for you. We could discuss that

01:56:25.040 offline. Sure. Okay. So final question on this, Dina, because I know it's come up for us a lot in our

01:56:33.420 practice. So I'm hoping you have a better solution for us. We do like to test our patients, especially

01:56:40.160 those who are higher risk for Alzheimer's disease. We do like to test to see if they have the KLVS

01:56:47.160 polymorphisms. It is very difficult to get that information. Are you guys doing that work

01:56:54.220 yourselves? Are you outsourcing that? How are you guys getting that information on your own? I mean,

01:57:00.480 I realize that much of the research you're doing is on a database where that's been done.

01:57:04.000 But are you aware of any commercially easy ways for individuals to determine their KLVS status?

01:57:12.320 Should they choose to know? I don't know the exact answer to this. I know that the information is

01:57:17.760 represented somewhere on 23andMe. We can't seem to get it out of 23andMe, even when we use Prometheus.

01:57:26.000 Yeah, we can't seem to do it. Hopefully somebody listening can say, no, you're wrong, Peter. You just

01:57:29.680 got to do this. But we haven't figured it out. Yeah, I have to say that in our case, when we

01:57:35.300 collaborate with the clinical researchers, they have their populations completely genotyped for

01:57:42.880 CLOPO, APOE4, and most other genes out there with the polymorphisms. There's been a really deep

01:57:49.880 sequencing and genetic screen of all of those individuals. But I'll have to circle back to you

01:57:54.840 about that. Okay. Well, Dina, this has been an, I mean, I think at the risk of being hyperbolic,

01:58:01.660 just an insanely fascinating discussion. And I'm so happy to be able to have discussed your work

01:58:08.340 with you and then by extension to be able to put this in front of so many people. Because I do think

01:58:13.660 that for a disease like Alzheimer's disease, that if we're being brutally honest, of all the what I

01:58:19.480 call the four horsemen of death, if there's one that we have very, very little to offer patients

01:58:25.540 once they're in the throes of the disease, this is the sad poster child for it. It is unfortunately

01:58:32.360 today, I don't need to tell you what you see every day, but I think people watching this understand

01:58:37.640 that even with the advent of anti-amyloid therapies, they have barely, barely been able to put a dent in

01:58:44.940 this enormous problem. It's for that reason that I'm very excited about this and just applaud you

01:58:51.120 on your career. I think this is only the beginning. We have to get this into human clinical trials.

01:58:57.160 That's what's next. Thank you so much for this invitation. It's been really, really fun talking

01:59:03.460 to you. Alzheimer's disease is one of our biggest biomedical challenges. Our entire world is aging. It used

01:59:11.920 to be the US, Japan, Sweden, but it's the entire world. China, India, Africa, all continents are aging

01:59:20.540 and we're aging rapidly. Again, this is one of our biggest biomedical problems. We really do not have

01:59:26.200 effective therapies. And I'm hopeful that with multiple shots on goal right now, something will

01:59:32.760 come to market that provides that resilience. In addition to anti-amyloid therapies, that is a cocktail

01:59:39.580 that provides resilience for the suffering that really erodes our memory. It destroys families,

01:59:47.580 economies. It's just a devastating problem. We're glad to be working on it and we hope that we can

01:59:54.080 do something big and important, but that remains to be seen. I also just wanted to say I'm so lucky to

02:00:00.360 be doing what I love to do, really, really love to do. And I am also lucky enough to have a very

02:00:08.260 diverse portfolio of being funded by the NIH, by foundations and in the past by biotech and also

02:00:16.380 by philanthropy. I can't emphasize enough how much friends and supporters of our lab have enabled

02:00:24.040 really risky science, have enabled us to just take a leap, ask big questions, take a big risk and see

02:00:32.540 what happens and win or lose to really see what happens when we go down that route. And I think

02:00:37.580 that's so important to progress in science is to do something risky, to take a risk. So I'm very

02:00:45.800 grateful to be doing what I'm doing. I'm glad you mentioned that. I do think that philanthropy

02:00:50.920 can have an enormous impact in science when philanthropists come in with the right attitude,

02:00:57.280 which is I want to fund something that is asymmetric in the following way. It is too risky

02:01:06.600 for say the NIH to fund or too risky for industry to come in and fund, but yet it has enough biologic

02:01:14.300 plausibility and enough potential upside that if it works, it's a game changer. And look, the reality of

02:01:20.360 it is I think Clotho is a poster child for that type of work. And at least as of this moment,

02:01:26.960 it looks like it's actually paying off. So I and countless others are grateful for what's been

02:01:32.220 done. Dina, thank you so much for your time today. Really, really appreciate it.

02:01:38.160 Thank you. This is wonderful. Thanks.

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The Peter Attia Drive - May 27, 2024

#303 - A breakthrough in Alzheimer's disease： the promising potential of klotho for brain health, cognitive decline, and as a therapeutic tool for Alzheimer's disease ｜ Dena Dubal, M.D., Ph.D.

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