Can Removing Zombie (Senescent) Cells Fight the Aging Process? Podcast with Paul Robbins

Aging is arguably the leading risk factor for chronic diseases in the modern world. People have historically thought of aging as an inexorable decline of function, driven by the passage of time – something that we simply have to accept, and that cannot be changed.

But what if aging were actually a modifiable risk factor?

Okay, so your chronological age, meaning the length of time that you have been alive, cannot be changed. Obviously. But we know that biological aging can vary significantly, even among individuals who are of similar chronological age. Most of us can think of some 70-year-olds who are remarkably vigorous and active – and on the opposite end, some 40-year-olds who seem comparatively tired and frail. Why is that?

Researchers have identified nine hallmarks that represent common denominators of biological aging in humans and other similar organisms. If you take a look, one thing you might notice is that each of these hallmarks are governed by genetic factors, but are also influenced by the environment, suggesting that they can and do vary from person to person…and that they could be modified.

This raises an obvious question. If we can better understand these fundamental mechanisms of biological aging, might it be possible to devise interventions that could prevent or delay age-related diseases?

Let’s examine one of those hallmarks: cellular senescence.

Zombie Cells: Senescence and Selolytics

One of the fundamental processes that contributes to age-related physical deterioration is cellular senescence. Cellular senescence is a phenomenon through which normal cells irreversibly cease to divide, typically in response to certain forms of stress (like genomic damage or oxidative stress).

Senescent cells accumulate in the body as we get older, and we used to think that their presence was largely coincidental with aging. However, we now know that senescent cells are metabolically active, and actually do a lot of bad stuff in the body. Senescent cells secrete an array of pro-inflammatory factors, like cytokines, and also increase levels of enzymes that break down structural proteins that make up our connective tissues (like collagen). This induces a state of chronic low-grade inflammation, collectively characterized as the senescence-associated secretory phenotype (SASP), and ultimately contributes to functional decline of tissues over the course of time. Researchers have convincingly demonstrated this by transplanting both senescent and non-senescent cells around the knee joints of mice. Rodents that received the senescent cells developed osteoarthritis.

But it gets even worse. These senescent cells can also drive other healthy neighboring cells into senescence, a phenomenon known as the bystander effect. So senescent cells are basically microscopic zombies!

That’s no good. But interfering with the process of cellular senescence itself might not be a great idea. Why not? Cellular senescence evolved as a protective mechanism, likely in order to stop the propagation of damaged (and potentially oncogenic, or cancerous) cells. We don’t really want to mess with that too much.

However, we do think that getting rid of the accumulated zombie cells might be a promising strategy. For example, Judith Campisi, whom we interviewed last year, found that removing senescent cells from the joints of injured rodents enhanced collagen repair and prevented the development of osteoarthritis.

Preliminary research like this has driven interest in identifying senolytics – compounds that can selectively kill senescent cells (while leaving normal cells alone).

And that brings me to our guest for this episode.

Guest

In this episode of humanOS Radio, Dan talks to Paul Robbins. Paul is the principal investigator at the Robbins Lab at Scripps Research Institute. His lab is focused upon developing novel approaches to treating autoimmune, inflammatory, and age-related degenerative diseases using biologics and small molecules. Notably, his lab has been screening for drugs that can safely and effectively clear out senescent cells.

This research has produced some remarkable results in animal models. For example, he and colleagues found that transplanting senescent cells into young mice induced physical dysfunction, which was reversed after they were treated with a senolytic cocktail. They also found that older mice that were given senolytics became faster and stronger, and experienced a 36% increased median post-treatment lifespan, compared to a control group. Wow!

Interestingly, several of the compounds that Paul and his team are investigating are polyphenols, which are commonly found in edible plants. In the paper described above, for instance, they used a mixture of dasatinib and quercetin – the latter being a flavonoid found abundantly in onions and tea.

Paul and colleagues are also investigating fisetin, a flavonoid that we find in a variety of fruits and veggies but is most highly concentrated in strawberries. Fisetin is perhaps best known for its effects on the spread of cancer cells, but it has also been shown that fisetin can selectively kill senescent cells. To that end, a clinical trial has started to determine if supplementation with fisetin can reduce inflammation, insulin resistance, and other age-related biomarkers in elderly women.

To learn more about this incredibly important work – that could literally affect every single one of us – please check out the interview below!

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Contributions

Dan prepared for and conducted the interview, Ginny wrote the draft for this blog post, and Paul continues to do all the hard work in the lab!

Transcript

Paul Robbins - 00:06: So it turns out that many anti-cancer drugs which target these pathways that prevent the cell from dying, which then leads to cell death, will kill a tumor cell but also kill a senescent cell.

Kendall Kendrick - 00:24: Human OS, learn, master, achieve.

Dan Pardi - 00:33: Welcome back everybody, I'd like to welcome Doctor Paul Robbins to Human OS radio. Paul is a professor in biology and aging at university of Minnesota department of molecular medicine. His work focuses on the role of inflammation in aging and the discovery of chemical agents that might influence the aging process. And as you are no doubt aware, humans are living longer than ever before but the incidence of chronic degenerative disease increases exponentially around the age 65. Why then? So for decades now medicine has been targeting symptoms of aging processes which are chronic diseases like diabetes etc, but what if we targeted the aging process itself rather than trying to treat individual diseases as they arise. Might we make more progress successfully dealing with these conditions if we think outside of the disease paradigm.

01:20: It is my opinion that the next major step function improvement in human health will come from the field of aging research, and the exciting thing is that real solutions seem near. In fact clearing Senescence cells using compounds known as senolytics has been shown to alleviate age related diseases and signs, think reversal of gray hair, and even extend life span in some animal models where it's been tested.

01:43: So Paul, welcome to Human OS radio. Thank you for joining us.

Kendall Kendrick - 01:45: Yeah, thank you, Dan. It's my pleasure to be here.

Dan Pardi - 01:48: I covered Senescence in an earlier show with Judith Campisi from the Buck Institute but as a quick refresher, tell our audience what Senescence cells are and how they form and why they're bad.

Kendall Kendrick - 01:57: Yeah. So, Judy is really the worlds expert on this and just joined the National Academy because of her work on Senescence but I'll try. What she mentioned was that Senescence is a process when cells become damaged or they start to grow uncontrollably or if they replicate too much, a system kicks on to cause that cell to go into irreversible growth arrest and then they will send out signals to the immune system to come get rid of it. So, it's like an alarm signal saying this cell's damaged, this cell's bad, this is a cell that's potentially cancerous and the immune system is supposed to come clear it. The problem is, is that as we age and our immune system starts to fail, we accumulate more and more damage, the Senescence cells percent starts to increase and our immune system doesn't clear them at the same rate so you have bad cells in your body releasing bad factors, telling the immune system to come get rid of them and the immune system is not and it appears that these bad factors that they've released can contribute to driving aging.

Dan Pardi - 02:52: What is a senolytic compound?

Kendall Kendrick - 02:54: There were several landmark papers published out of the Mayo Clinic by [inaudible 00:02:59] and Jim Kirkland using the transgenic mouse model where they could clear or eliminate these damaged cells, at least in the mouse model, using the genetic trick and in several papers, high profile papers, they showed that clearing these cells improved the health span of these mice and even improved the median life span, not maximal.

03:19: So, that led to a lot of excitement saying well, if this works in mice, can we identify drugs that mimic the genetic trick that was done by Jim and Jan. And so, my lab, actually in collaboration with Jim Kirkland and others, developed cell culture or laboratory models where we could now screen for drugs that might kill these damaged cells specifically and not affect the normal cells.

03:41: And so, in the screen of compounds, and we did this using a screen of compounds which are already used clinically, we actually identified a number of agents that could specifically lead to death of the damaged cells without affecting the normal cells, and so we turned those senolytics. We also identified compounds that may reverse or dampen some of these senescent type, [inaudible 00:04:07] type characteristics and we called these senemorphics because they kind of changed the morphology of the cells, and so senemorphics and senolytics we classified as what are called senotherapeutics, so targeting Senescent cells with therapeutic agents that either will kill them or suppress some of the bad factors that they're secreting that seem to be involved in driving aging.

Dan Pardi - 04:28: One of the reasons why the accumulation of senescent cells is bad is because they release factors into their surrounding and raise the general level of inflammation in the bodies.

Kendall Kendrick - 04:37: Yes. So, the senescent cells release inflammatory factors but they also release [inaudible 00:04:43], presumably to allow the immune cells to be able to infiltrate into the tissue and clear them, so they actually partially degrade the environment around them and so, between the [inaudible 00:04:53] and the inflammatory factors, this can lead to chronic inflammation with also tissue degeneration or lost homeostasis with age.

Dan Pardi - 05:01: Analytic compounds electively clear senescent cells, senetic [morphates 00:05:05] can revert what they're [crosstalk 00:05:07] environment and so either way you end up with a better situation than you had previously.

Kendall Kendrick - 05:11: I think the only difference is, drugs that kill senescent cells could be taken intermittently. So, you could treat an individual, as we've shown in mice, you could treat an individual and then wait two or three months until the senescent cell burden comes back. Whereas with something that suppresses what the senescent cells are doing, you probably have to take chronically because you have to continually suppress that.

05:32: It may be that both approaches might be required to really get the optimal effect but that's to be determined in the clinic.

Dan Pardi - 05:39: What were some of the [inaudible 00:05:40] effects that you see when you implant these senescent cells.

Kendall Kendrick - 05:43: Right, so there's two ways to show senescent cells contributed to driving aging. One was the show if you cleared them, the mice or the rodent systems were healthier. The other approach, conversely, as you just mentioned, was that you could actually inject senescent cells into a young mouse and look and see what changes those senescent cells contribute to.

06:02: And what was shown, and this was mostly done by Jim Kirkland at the Mayo Clinic and published in a recent paper in nature medicine, if you inject senescent preadipocytes, so these are actually [inaudible 00:06:12] cells from fat that have been irradiated to cause damage to make them senescent. If you inject them, they actually would drive signs of frailty, you would see altered metabolism and you see changes in tissue histology. They're consistent with aging. So, this would show that the senescent cells are sufficient to actually drive aspects of aging and that's very exciting because for many years, it was thought these cells were more of a consequence of aging but not something which was driving aging.

06:41: But now it appears that these cells are playing a significant role, and the other interesting observation was made is that the senescent cells seem to lead to disfunction of indigenous stem cells. So, it's been reported that if you clear the senescent cells, the indigenous stem cells that are involved for repairing damaged tissues, these are adult stem cells that are found in every tissue in the body, these cells are healthier and they could actually facilitate repair of tissue more readily.

07:06: So, you might actually see, and I don't want to use regeneration or reversal of aging but if these stem cells become more functional, you might see improvement and not just slowing of the aging process.

Dan Pardi - 07:18: That's really exciting. I mean, one thing that seems clear with the aging process is the loss and degradation of healthy tissues, so [inaudible 00:07:24] as an example, that might be seemingly due to the increase in clematory burden that maybe is contributing to these stem cells not differentiating into new tissue. So, you just have a loss of [crosstalk 00:07:35] overall.

07:36: So, we definitely see that senescent cells increase with age but we didn't know to what degree they contributed or just epiphenominal to the aging process but because of your model of injection senescent cells in the younger animals, you could see that it was causative of age-related loss of function and that gave you more confidence to how much these are involved in the negative effects of aging itself.

Kendall Kendrick - 07:56: I think one of the important points I should make is that usually if you inject a lot of senescent cells into a mouse, it drives aging. One of the big questions is what senescent cells in an aging animal or aging human contribute to driving aging is a senescent kidney cell, a senescent muscle cell, a senescent liver cell, a senescent brain cell or, as I think some of our data is starting to show, it's actually senescent immune cell because they can trap it throughout the body.

08:24: So, if they're making bad factors, they actually can be all the places in the body where you might not want bad cells to be. So, it may be immune cells are doing this or it may be other types of cells. So, many groups are now going, research wise, just starting to clearing senescent cells in a tissue specific way or causing Senescence in a tissue specific way and what's the contribution. Not injecting cells, which is somewhat artificial, but can you increase Senescence or eliminate Senescence of specific cells types and that is going to be very informative. So, we then know what drugs we should be developing to target that subset of senescent cells.

Dan Pardi - 08:59: Yeah, that's a very interesting point and one that I hadn't thought of previously. I'd always thought about the senolytics as going into the body and then sort of replacing what the immune system was no longer doing as effectively, but if I'm understanding you correctly, the senolytics could have the potential of also improving the efficacy of the immune system. So, you could have the dual benefit of having a direct effect on senescent cells in the body but also making the immune system better at doing what it had done previously.

Kendall Kendrick - 09:22: Right and that may be even non-senolytic drugs, obviously for cancer therapies, there's a lot of [inaudible 00:09:27] are being developed to optimize or improve T-cell function or other components of immune response and so those, and it's still to be proven, but those also could have a potential benefit. If they can improve the [inaudible 00:09:40] of immune system to clear the senescent cells and it appears that senescent cells also, I won't say evolve in the body, but as we age, they seem to develop ways to avoid the immune system too. So, it's going to be a really interesting set of questions that need to be address about the roles of what cell types drive aging and then how the immune system either clears or doesn't clear them effectively with age and if we can really work out both of those areas, I think very effective drugs could be developed which probably would include senolytics but also other types and may also include using stem cells or some regenerative factors of stem cells it leads to.

10:15: I think eventually it'll be a cocktail of agents and they're not all going to be small molecules, some may be biologic, some may be cells that you can administer every so often to improve or slow down the aging process.

Dan Pardi - 10:28: That's so interesting. It makes me think about the interview that I did with Mike and Irena Convoy from UC Berkeley where they had done [inaudible 00:10:36] of old and young mice. So, for the listener, that means sewing together an old and young mouse and what they originally found is that the young mouse became older, the old mouse became younger so this has given rise to this idea of young blood. Could young blood and factors that are contained within it, do something positive to an older [inaudible 00:10:54] to reverse it.

10:55: The most potent effect was actually the older mouse aging the younger mouse and they think that it might be some specific factors that are released from the senescent cells that are driving that process.

Kendall Kendrick - 11:04: So, there's factors that the old mice have actually drive aging in young mice but conversely, there are factors in young blood that flow aging in older mice and so we have the story about ready to publish where we show in the parabiosis, you put old and young mice together, you see less Senescence in the old mouse and and more Senescence in the younger one. So, you kind of get this intermediate [inaudible 00:11:26] and there have been clinical trials started at Stanford by Tony [inaudible 00:11:29] using young plasma into the [inaudible 00:11:33] depot with the least early stage Alzheimers and he's treated a certain number of patients, the phase one trial's been done and some of the data's been presented and I think they've seen some positive results, maybe not as effective as they had hoped but the question comes is how often do you have to give the young plasma? Is it once a month? Is how much? Age of the donor? There's a lot of questions and so, where a lot of groups are going is trying to identify what those good factors are in young serum that can reduce Senescence appear to improve stem cell function and as Tony [inaudible 00:12:03]

Paul Robbins - 12:02: ... appear to improve stem cell function. As [Tony's 00:12:03] wife [Corey 00:12:04] has shown, actually improve cognitive ability. That was what he has published in several nice papers was that young plasma or in heterochronic parabiosis improves cognitive ability of the older animal, which is very exciting.

Dan Pardi - 12:16: Absolutely. That speaks to a broader trend of what I'm seeing, which is there are promising aging compounds, rapamycin, and protocols, fasting. What is the frequency that you need to then employ these strategies, once a quarter, once a month? Obviously, we just haven't had the time to investigate all of these strategies and whether or not we found the perfect protocol for a person at a given age. Biomarkers are still gonna be a big part of this so that you can assess degree of improvement or change in this biomarker, then we're seeing the effect that we want. That's going to take some time to figure out.

Paul Robbins - 12:47: Yeah, we talked about young serum improving cognitive ability in older mice. There were actually two papers that have come out this last month that show that senolytics improve pathology and behavior in mouse models of Alzheimer's disease. There was a paper came out in Nature, this week from Darren Baker at the Mayo Clinic, showing that if you can clear these senescent cells either using a genetic trick or with a specific drug, and this is a drug called navitoclax, it's an anti-cancer drug that targets Bcl-2 family of antiapoptotic proteins, he saw dramatic improvement. In the month before, ran the [inaudible 00:13:21] from the Barshop Institute, that shown that the combination of drugs we identify with [Jim 00:13:26] Kirkland, dasatinib and quercetin, also shows a reduction Senescence in the brain and improvement in pathology in a mouse model of Alzheimer's.

13:35: I think that there are different approaches that can be taken to improve cognitive ability and potentially even treat Alzheimer's, which it's been very difficult to treat. Everything works in mice, but then doesn't work in humans. The preclinical data with both senolytics and with young plasma look very promising. There's hope that we're gonna see some positive results if this moves into the clinic.

Dan Pardi - 13:55: It seems like two different classes of compounds have merged, what are classically chemotherapy drugs, and then plant phytochemicals like flavonoids, particularly the fisetin. Judith Campisi studied apogenin and quercetin, of course.

14:07: Talk to us about the combination of fisetin and quercetin, that seems to have taken hold and has been studied now multiple times. Why that combo?

Paul Robbins - 14:15: The way these were identified, at least these two class of compounds, was by a bioinformatic approach. This started at the Mayo Clinic and then we picked up the project with Dr. Kirkland to demonstrate that the drugs really did work in the mouse model to eliminate senescent cells. The concept is he actually analyzed molecularly a senescent cell and compared it to a normal cell.

14:37: The first thing that came out was that molecularly there're many changes in the senescent cell that are similar to a cancer cell. If you think about it, these senescent cells have a lot of damage. What usually happens to damaged cells is they die. In our body that's how we thought that most of the damaged cells were eliminated is they just die. They induce kind of a self-death pathway called apoptosis. Senescent cells upregulate certain pathways that prevent them from dying. These pathways are actually very similar to a cancer cell, which when the cancer cell starts to proliferate it has to survive because usually there're systems, such as a senescent pathway, that tells it to stop. Kind of early stage tumor cells and senescent cells look very similar. It turns out that many anti-cancer drugs, which target these pathways that prevent the cell from dying, which then leads to cell death, will kill a tumor cell, but also kill a senescent cell.

15:33: Dasatinib is FDA approved, clinically used compound for lymphomas and leukemias. It's what you take if you fail Gleevec or for certain other indications as the first line treatment. Dasatinib, turns out, will kill tumor cells and will also kill certain type of senescent cells, not all, but some. Looking at the bioinformatic analysis, we identified the pathways which dasatinib targets, but there're other pathways which are also upregulated.

16:01: One of them has been shown to be targeted by quercetin, which is a flavonoid, which probably does a hundred different things. One of the things of it does is it targets and enzyme called PI 3-kinase delta, which was shown to be upregulated in the senescent cell type we were looking at. We showed that in those cells the combination was more effective inducing cell death, not true in all types of senescent cells. Some cells dasatinib was as effective alone. Other cell types quercetin was effective alone. We showed this combination among a broad spectrum of senescent cells was usually more effective.

16:33: Then we put this in the animals, we showed that this combination reduced senescent cell burden fairly dramatically. Which was somewhat surprising because I don't think dasatinib is the optimal senolytic. It was just the first one that we tested based on the bioinformatic analysis. I think it can be improved upon tremendously. What has been somewhat surprising and actually very pleasing is that in a number of different animal models that combination has shown to be the most effective combination as compared to navitoclax or some of the others that we've identified.

17:03: The reasons for that's still not quite clear, but it may be the specific targets for dasatinib may really turn out to be the best targets. These are receptors on the surface of the tumor cell or receptors on the surface of the senescent cell that seem to send survivor signals, so it helps the cell survive. If you block them the cells then die fairly quickly and fairly efficiently.

17:25: This combinations has been very interesting. It's been very successful in a number of different labs, number of different models. We know the safety profile because it's been given to hundreds of thousands of cancer patients, even some who take this chronically. I've met individuals who've been on dasatinib chronically for five, six years with I can't say no side effects, but limited side effects. I think it's a field in it's infancy, but dasatinib, quercetin, navitoclax, some of the other drugs, it's all very exciting.

Dan Pardi - 17:52: Do we have any resolution into the contribution of a senolytic effect from the two different compounds, quercetin and dasatinib, or do we really just know the total clearance that the combo induces?

Paul Robbins - 18:04: Yeah, I think again it depends on the type of senescent cell. I think we've gotta have tools to look at the different type of senescent cells carefully in vivo. Overall senescent cell burden is what you're looking at by markers that they secrete into the blood. The combination clearly seems to work better. I imagine there's some cells that dasatinib is killing more effectively, some quercetin. Then together the spectrum is even greater. These are experiments that we're doing to try to identify the targets and then try to optimize drugs or optimize a combination against those specific senescent cells.

Dan Pardi - 18:37: Let's talk about a compound that I am very interested in, have written about here and there over the last couple of years, which is fisetin. I've mentioned it before. It's like quercetin. It's a flavonoid found in the highest concentrations in strawberries, but also in apples, persimmons, onions and cucumbers. I know that you're doing a clinical trial with this, now. With the preclinical work, that made you excited to test this specific compound by itself as a monotherapy. Do we know anything about how it differs from, let's say, quercetin? [crosstalk 00:19:02] this gonna be [crosstalk 00:19:03] or bust.

Paul Robbins - 19:04: Quick question. We have published and we have a paper in press ... I don't want to talk too much about because it's still in press and there's supposedly an embargo on the press release. What have published was that fisetin seems to work more effectively that quercetin as a senolytic in certain cell types. We have confirmed that result that was published in The Journal of Aging last year and now have extended it into different mouse models of aging, both natural aging and accelerated aging. I can just say at this point we've seen very positive results, which have led to Jim Kirkland, at the Mayo Clinic, starting clinical trials, mostly to document that fisetin indeed eliminates senescent cells in humans. We've sort of taken age related diseases such as pulmonary fibrosis, individuals that have had high dose chemotherapy or radiation for cancer, that we know have a lot of damaged cells in their body, also chronic kidney disease, where you see accumulation of senescent cells in the kidney.

19:56: Now, he's comparing fisetin in some of these clinical trials with dasatinib, quercetin and others. It's more to really show that he's reducing the senescent cell burden. Then we'll be looking at therapeutic endpoints going forward. These trials are ongoing. I'm not a clinician, not directly involved with him, but I think there will be data, hopefully positive, coming out within the next six months to a year.

20:17: You asked about fisetin and quercetin. They're very similar. There's not much difference between them. It's very interesting. One of the things we're doing is we're doing medicinal chemistry on quercetin and fisetin to look at analogs and try to identify how these small differences influence the effect of fisetin on senescent cells. Minor changes in the structure of quercetin or fisetin can change its activity dramatically. We can increase the senolytic activity certain number of [inaudible 00:20:45] with small changes in the compound. We hope to be making better flavonoids, as we go forward, with a greater safety window, so lessen the effect on normal cells, but a greater effect on the senescent cell. That's our goal at this point.

Dan Pardi - 20:56: Give us a little overview of what's happening in biotech now on senolytics.

Paul Robbins - 21:01: It's been interesting in the biotech field in the aging space 'cause for many, many years nobody wanted to touch aging. It was not considered a disease. The FDA really wouldn't grant approval for a drug for aging. That's the reason a lot of nutraceuticals popped up sold on late night TV.

21:20: The FDA is starting to now appreciate that aging is the biggest risk factor for most diseases, so has reviewed and approved the first clinical trial for aging, which is a trial that's starting, run by Nir Barzilai at Albert Einstein, using metformin as the first potential anti-aging drug. They've designed a study to really show that metformin, which is used for type 2 diabetes ... There's data showing type 2 diabetics actually may live a little bit longer than age matched, non-diabetics not on metformin. Metformin's the first drug going forward. This is kind of opened up the space. People are saying, "Aha, we might be able to do clinical trials for aging."

21:58: Unity Biotechnology was the first company that sprung up in the senolytic space. Started out of the Mayo Clinic and out of the Buck by Judy Campisi and Jan van Deursen. They have started a clinical trial for osteoarthritis with the compound navitoclax, that targets this Bcl-2 family of antiapoptotic proteins. There're doing intra-articular injection for OA, which as been shown that actually be driven in part by Senescence. There are a lot of senescent chondrocytes that lead to cartilage damage.

22:26: With Unity having started and recently gone public, other companies are now springing up. What we have, probably four or five senolytic companies and probably others coming. Everybody has a compound they think might eliminate senescent cells, mostly in the laboratory, not necessarily in the animal models or in the clinic, yet. There's a lot of new companies that are thinking this is where the future's gonna be because we can treat not only a disease, we can maybe slow down or prevent onset of numerous diseases. The space is starting to take off.

Dan Pardi - 22:59: Just to surface that big point there, for the first time the FDA is [inaudible 00:23:02] a trial that is specifically in aging and not just on a chronic disease. That's opening the door for other studies and compounds to be tested specifically for aging. That's a big deal.

Paul Robbins - 23:14: That's correct. The metformin trial is called the TAME trial for targeting aging with metformin, which will be very interesting to see how that turns out. Then Unity's trial targeting osteoarthritis, again, with a senolytic. Then Jim Kirkland's trial using the compounds we spoken about for other age related conditions.

Dan Pardi - 23:30: Talk a little bit about rapamycin 'cause I know that's a very hot topic in this field and one that is being investigated. What do you know about the work that's happening there?

Paul Robbins - 23:38: Right, so rapamycin has received a lot of interest because it was the first compound shown by an NIH funded testing program, where three different laboratories around the country were testing certain number of compounds a year for ability to extend lifespan in male mice and female mice. The first hit that these three laboratories got was rapamycin, which was shown to extend life span in males and females. Many drugs-

Paul Robbins - 24:03: ... Was shown to extend lifespan in males and females. Many drugs might work in one sex and not the other for reasons we still don't understand. Rapamycin clearly extended lifespan, and then people have gone on the show that you don't have to give it chronically. You can give it intermittently, you can even start treatment towards end of life.

24:18: There are now clinical trials starting with rapamycin for certain indications, a lot of effort put into developing what are called rapalogs. These are compounds that work similarly to rapamycin but which may not have some of the side effects of rapamycin.

24:33: I think one of the important studies that was done by Novartis several years ago was a study where they showed that rapamycin treatment for a short period of time in the elderly led to a better immune response to the flu vaccine.

24:47: They actually could stimulate the immune response by treating with a low dose, certain dose, high doses wouldn't do this, of rapamycin showing their immune system was now better. This has ramifications for more than just the flu vaccine. They're now extending these studies I think to look at more age related phenotypes.

25:06: Rapamycin is a drug that potentially has a large role in this aging space, it's just rapamycin's had some side effects affecting metabolism. Then in males, it's been shown in some cases at high doses to cause testicular atrophy, which is not something that you want to develop if you take rapamycin chronically.

25:24: They're going to be better rapalogs developed and then find the right dosing regiment. I think those are going to be identified.

Dan Pardi - 25:31: A lot of men who are on testosterone replacement therapy live with that side effect regularly. If it causes that, without pathology, I bet a lot of people would live with it. If you can avoid it, that's great.

25:43: If we look out at the next 12-20 years with all the work that's happening, if you were a gambling man, where do you think that we're going to see the first approval? Then what do you think are the most promising areas given what we know now about affecting the aging process directly?

Paul Robbins - 25:57: I'm always an optimist, so I'm always wanting to think it's going to happen faster and maybe to a greater extent in the [inaudible 00:26:03]. This field is just taking off, so I think clearly senolytics, the ones that we've identified now or more likely more optimal ones, clearly will play a role in treating age related conditions.

26:15: This can go anywhere from skin creams to slow aging, of the appearance of aging, to systemic treatments for a whole spectrum of conditions, as well as starting maybe at mid-life to a little bit later in age individuals to slow the aging process itself.

26:30: I think that's there's going to be no one type of drug that's going to have a huge effect, it's all going to be somewhat incremental. It's really going to be coming as we talked about earlier, a cocktail of therapeutics. I think things targeting senescence cells, maybe suppressing the factors they secrete; if you don't kill them all, get rid of the bad factors. Things improving mitochondrial function, things which may promote regeneration.

26:56: I mentioned that there's evidence that stem cells could be improved if you treat mice with senolytics. We've also shown if you inject young stem cells in younger mice, it slows their aging and improves certain functions. I think that stem cell based therapies, or at least stem cell factor based therapies with senolytics, with potentially antioxidants, potentially other classes of drugs; eventually you're going to have the right cocktail.

27:19: Again, it will be one pill or a set of pills you take every so often that's really going to make you healthier, extend health span. Then the big question is if you extend health span, how much is that going to extend lifespan? That's going to a big question.

27:32: I think health span is clearly going to be extended, so we're not in the nursing homes, we're not in the emergency rooms, we're not bedridden. Hopefully we're out playing golf and tennis, or whatever else we want to be doing.

Dan Pardi - 27:43: You mentioned that in the beginning when we were talking about how some of the animal models, the medial lifespan increased without changing the maximum lifespan. When we think of the science fiction possibilities of therapies that can actually make us live beyond maximal human lifespan, that is estimated to be around 125 years.

27:58: If the conditions were absolutely perfect, that's about the extent to which humans could live. Some therapies could maybe take us to 150. That is maximal lifespan. Median lifespan just means, how would you translate an improvement in median lifespan?

Paul Robbins - 28:11: I think the extension of median lifespan really reflects the extension of health span. That hasn't always been shown, but that's the way we interpreted it and there's some data to support that. If you look at these mice, they're living a little bit longer. They're all living longer and a little bit healthier.

28:24: Having said that, in the recent paper we published in Nature Medicine with Jim Kirkland, this combination of dasatinib and quercetin given to mice starting at two years of age, which maybe equivalent of 65-70 in humans, somewhere in that range; that actually extended their maximal lifespan.

28:41: It wasn't a huge effect, it was only 10%. That extended both the median and maximal lifespan, and improved readouts such as treadmill endurance, grip strength, just a variety of measurements of physical function. We're now trying to see if there is improvements in cognitive ability, that was not measured in the first study. That's now being looked at, and I assume we're going to see improvements there too.

29:03: I think we can extend maximal lifespan as well as health span, the question's how much. The key is we want to compress this time of morbidity. We don't want to just delay this period of morbidity, we want to compress it. Again, you're playing golf and die of a heart attack at 110 sort of approach.

Dan Pardi - 29:20: My grandma had a pretty good life, she died at 102.

Paul Robbins - 29:23: Good for her.

Dan Pardi - 29:24: She had most of her hobbies with her until she was probably 98. She was a painter, so her eyesight really failed her so she couldn't paint as well as she liked. I think some of her zest for life started to go. She had a long life of good health, and then it was sort of a rapid decline relatively versus decades of disability.

29:40: She's my hero in a lot of ways, but that's what I would want for myself and for most people, just a long healthy life. I'm so glad that this work is going to be contributing to that. I'm really confident that it will.

Paul Robbins - 29:51: You look at someone that's 102, there's a good chance that she had some, you don't use the word mutations, but variants in certain genes that contribute to that. We actually have a study where we're trying to do genomic analysis of centenarians and super centenarians to identify what those variants are. It's being done in collaboration with people at Albert Einstein.

30:11: Then trying to develop drugs that mimic the effects of the variants, that's kind of a long term goal. It may mean that you may have actually inherited some of those beneficial variants. You might enjoy that same longer lifespan too.

Dan Pardi - 30:23: Go grandma.

Paul Robbins - 30:24: Yes, go grandma. You have to hope it was passed down the right way, you got the right genes and not the wrong ones.

Dan Pardi - 30:30: Totally. Well, maybe to the degree that mitochondria is super important and that comes from the matrilineal line, then again, go grandma.

Paul Robbins - 30:38: Go grandma.

Dan Pardi - 30:39: A question real quick and then I'll let you go. This has been fascinating. In that mice study that you mentioned with giving the dasatinib and quercetin starting later in life in the mice, was that given on a daily basis, or was it more pulsatile fashion?

Paul Robbins - 30:51: It was given intermittently. If I remember correctly, it was every two weeks. Again, it's something that they did consistent with a mechanism of action of the drugs given at that time is by eliminating something. If that wasn't the case, you'd have to give the drug more chronically so it appears that [inaudible 00:31:08] senescence cells starting even at two years of age provides benefit, which means there's still hope for us who are a little bit older than you are.

Dan Pardi - 31:15: Yes. If you look in diet and nutrition, one thing that consistently seems to be a part of longer lived communities is diet that is higher in vegetables and fruit that have lots of phytochemicals. One interesting idea is now looking at these phytochemicals pharmacologically and with a combination of other drugs, but what about a lifetime of high intakes of these phytochemicals and that having a similar effect? It's just harder to discern, it's an effect that accumulates over decades.

Paul Robbins - 31:42: Yes, I think those questions, long term administration of these agents and what the effects are going to be, those are really unknown. Right now they're just short term studies. Those are things that we'll learn going forward, maybe that you can get away with giving these drug combinations very infrequently. It could be once a year might be sufficient. As we develop biomarkers to measure the senescence cell burden, we'll know who needs the treatments earlier than others and how effectively they're working. That's what we really need, you mentioned biomarkers earlier. That's an area that has not been that fruitful in the aging space, but I think there are now hints that there are potential biomarkers that really can determine biological age and not chronological age.

Dan Pardi - 32:22: There's a whole new field of digital markers looking at our markers of physiological health status, which is a newer but growing field that I think can contribute meaningfully to the dialogue. I'm excited to see the biomarker space expand in that way as well.

Paul Robbins - 32:37: It's kind of an aside, but I heard Brian Kennedy, who used to be the CEO of the Buck; he gave a talk about a collaboration that's ongoing with somebody in Singapore that's using face recognition to see if they can predict age. There's just certain facial characteristics that really let the AI that's involved with this project predict the biological age.

32:58: He was talking about using facial recognition as a potential biomarker for looking at efficacy of certain drug treatments. There's going to be a lot of stuff coming that's going to allow us to predict who needs to go on more aggressive treatments and who doesn't, then who's responding and who's not.

Dan Pardi - 33:15: Most people have a smart phone, so we can just do that assessment really easily. More people might be able to access that.

Paul Robbins - 33:21: This is an exciting time. I just wish I was starting off in this field and not further along. I think the next 15-20 years is going to be really exciting.

Dan Pardi - 33:29: Paul, thank you so much for your time. It fascinates me and really appreciative of the work you do, we all are, also taking the time to come chat with us.

Paul Robbins - 33:36: I really enjoy myself Dan, enjoyed chatting with you.

Kendall Kendrick - 33:41: Thanks for listening and come visit us soon at humanos.me.