Why does our body lose function when we get older? This is a staggeringly complex problem to understand. The good news, though, is that we’ve now made real inroads to grasp this phenomenon better. And the better we understand what is happening, the greater the likelihood we will be able to intervene in ways that make life better.
Much of the longevity discussion revolves around the possibility of extending the maximum human lifespan. But even if the main utility of this information only enables us to spend much more of our life with full-to-greater function (think 80-year-olds performing and looking like they are in their 40s), then that would be monumentally important. Of all the understanding we have gained in the aging process, few areas seem as promising for near-term impact as the work on cellular senescence.
When exposed to certain forms of stress (like DNA damage), normal cells enter a senescent state, in which they no longer divide. This, generally speaking, is a good thing – cellular senescence probably evolved as a protective mechanism to halt the development of cancers in the body.
However, this cancer-suppressive mechanism comes with some big tradeoffs.
First of all, once senescent cells are created, they don’t just go away quietly. Rather, they stick around, and they tend to accumulate as people get older. So, the more time we spend alive, the more time we have to defend against damage, and the more time we have to accumulate these cells.
Importantly, senescent cells are also metabolically active, secreting inflammatory molecules into the space that surrounds them. Over time, they promote a state of chronic low-grade inflammation throughout the body, which itself contributes to a wide range of diseases that are associated with aging, like atherosclerosis and type 2 diabetes. And if you remember from my conversation with Irina and Mike Conboy from UC Berkeley, inflammatory molecules prevent stem cells from becoming new healthy tissue. So, you can see now why many age-related diseases all start to happen at the same time: with enough senescent cells (and other important concurrent processes), you hamper tissues regeneration, and the signs of aging become evident.
Now, remember, the process of cellular senescence is critical in preventing cancer development. Therefore, we don’t want to inhibit cellular senescence from occurring. We do, however, want to clear senescent cells once they are formed (or at least that seems to be a promising solution, should we be able to create or identify interventions effective at clearing these cells).
In this episode of humanOS Radio, I interview Judith Campisi. Dr. Campisi is a Professor of Biogerontology at the Buck Institute for Research on Aging, and is best known for her work in advancing the field of cellular senescence.
Recently, she and a team of researchers found that selectively removing senescent cells from the joints of injured rodents had impressive benefits – the treatment enhanced cartilage repair in the damaged site, and prevented the development of osteoarthritis. It is likely that age-related joint degeneration is at least partially connected to the effects of local senescent cells.
What other age-related conditions might be responsive to this therapeutic approach? Listen below to find out more!
|Judith Campisi:||The SENS Foundation is now funding a project in my laboratory to see if we can get parts of the immune system to recognize senescent cells and clear them naturally.|
|Kendall Kendrick:||HumanOS. Learn. Master. Achieve.|
|Dan Pardi:||[00:00:30] Dr. Campisi, thank you so much for joining Human OS Radio. Give us a primer on senescent cells and senescence.|
|Judith Campisi:||Senescence, cellular senescence is the cellular process that refers to the way cells respond to certain external stressors. Some of those stressors can be things we would consider to be dangerous, for example, radiation or poisons [00:01:00] that we might eat or simply stress due to the oxygen that we breathe. As you know, that’s also a stress. Some of those stressors can be what we call physiological. For example, during certain stages of the embryo forming, there’s a wave of senescent cells that appear to fine tune certain structures, and we’ve shown that senescent cells also appear at the site of [00:01:30] wounds, where they appear to help heal the wound. They’re what we call an evolutionary trade off. That is, it’s a cellular response that can have good effects and bad effects.|
|The good effects is that they do things that help us respond to physiological stresses, like a wound. The bad side of it is that they can also respond to toxic stresses [00:02:00] like radiation or things that we eat or breathe, and in that sense they tend to not go away. They tend to accumulate, and we know now from many, many models that senescent cells accumulate with age. We now have good evidence that that accumulation can also help drive certain diseases associated with aging.|
|Dan Pardi:||I see. These are detectable during [00:02:30] embryonic development, they play an important role in life, but we do see an accumulation or an increase in senescent cells as we age. Is this increase uniform across the body, or do we see certain cells that are vulnerable to developing senescence?|
|Judith Campisi:||Probably all of the above. This is still at its embryonic stage in terms of our understanding, but yes, there are certainly cell-type-specific differences and tissue differences. Some tissues seem to accumulate more senescent cells [00:03:00] than others, and that can vary from individual to individual.|
|Dan Pardi:||Does there tend to be an inflection point where we start to see senescent cells rise? I guess it probably depends on the amount of damage that we put our body under. I’ll put that question to you.|
|Judith Campisi:||Yes. Some studies have been done, for example, looking at lung tissue in smokers versus nonsmokers. It’s obviously clear that smokers tend to accumulate more senescent cells faster [00:03:30] than nonsmokers but, in general, for most people, the inflection point is somewhere around the midpoint of our maximum lifespan. For humans, that’s around 50-60 years of age. Then, these cells tend to accumulate pretty quickly in a number of tissues.|
|Dan Pardi:||What is, then, driving the process of cellular senescence at all?|
|Judith Campisi:||During aging, you mean? During smoking, it’s obvious because [00:04:00] there are toxic chemicals that are made by cigarette smoke. Understanding what it is in normal aging in, say, a non-severely-stressed person, that’s a mystery. We still do not know what the major driver that drives cells into senescence during normal aging is. What we do know is that the cells do accumulate and, as they accumulate, they tend to affect neighboring cells. [00:04:30] That’s where we think that they are responsible for some of the diseases that we associate with aging.|
|Dan Pardi:||It’s a bit of a vicious cycle. The accumulation of senescent cells can drive the development of more senescent cells.|
|Judith Campisi:||Well, that’s true also. That’s the so-called bystander senescence, which is now, I think, pretty well established. It’s interesting because a single senescent cell that arises as a consequence of some kind of external stress can, [00:05:00] indeed, produce molecules that will cause a neighboring cell to become senescent; but that neighboring cell, the so-called bystander senescent cell, probably cannot transmit its senescent state to its neighbors. That makes sense because, if it were otherwise, you would imagine one single senescent cell would turn your whole body into a pack of senescent cells in a matter of time because it [00:05:30] would just propagate unlimitedly. That’s not what happens. We know that there’s a lot of variability. Even in very, very old people, senescent cells still do not comprise the majority of cells within any given tissue.|
|Dan Pardi:||What are some of the types of substances that are released, and then what is the net result of that in terms of the microenvironment surrounding the senescent cells?|
|Judith Campisi:||One of the characteristics of a senescent cell is that is secretes many [00:06:00] molecules, probably 100 or more. We really don’t know the exact number. Those molecules have various functions. Part of the function is, they produce growth factors. That, undoubtedly, is why senescent cells are beneficial during wound healing. Some of the factors are enzymes called proteases, which chew up proteins, and that may be both good and bad. It can be good during [00:06:30] wound healing. You need to chew up proteins in order to remodel the tissue, but it could be bad because chewing up proteins can also destroy a tissue.|
|Probably, the most important class of molecules that senescent cells secrete are called pro-inflammatory molecules, that is molecules that fuel a process known as inflammation. This has been known for decades, that aged tissues [00:07:00] have the capability or, rather, the property of being inflamed. Not grossly inflamed, which is what we call acute inflammation. This is what happens, for example, when you cut yourself and it turns bright red. That’s acute inflammation, but most aged tissues have the property that we term chronic inflammation that is low level, so much less than that bright redness that you see when you cut yourself. Low level [00:07:30] but chronic, meaning it’s there all the time.|
|For example, if a pathologist were to take, say, a liver biopsy from 16 year old and a 60 year old, that pathologist would probably be able to tell you which biopsy was young and which biopsy was old simply by looking for indicators of this low-level chronic inflammation. This is a property of aged tissues, and we know that senescent [00:08:00] cells attract the immune cells that cause low-level chronic inflammation. Why is that bad?|
|Well, the immune cells that are responsible for chronic inflammation are designed to protect our cells, our bodies, against invading pathogens. They are the first line of defense against an injury, and they’re very primitive. They’re very nonspecific. These are not what we think of when we think [00:08:30] of antibodies for specific T cells that kill specifically. The initial inflammation that we see in age and we see initially after an injury is designed to kill nonspecifically. That means these cells are producing toxic molecules like hydrogen peroxide or bleach. The idea is to kill, as quickly as possible, any invading pathogen. Well, that’s great if you have an invading pathogen. [00:09:00] It’s not great if it’s low level and chronic and there’s no invading pathogen. The type of inflammation we associate with aging is often called sterile inflammation, meaning there’s no evidence of an invading pathogen, but yet these innate immune cells are there producing these damaging molecules, and we know senescent cells are part of the reason why they’re there.|
|Dan Pardi:||Are there ways, then, to modify the production [00:09:30] of senescent cells in some way, or even the contents that are released by them, so we can potentially age better?|
|Dan Pardi:||Big question.|
|Judith Campisi:||Yes, there are. Let’s take the first scenario, where you modify what the senescent cells are secreting. Our lab and many other labs have identified the molecular processes that lead to their developing the secretory phenotype, the secretions that they produce. The good news [00:10:00] is that that research has led to very specific proteins that are important for causing the cells to secrete, and the other good news is that those proteins, in some cases, actually in a number of cases, already have drugs that had been identified by pharmaceutical industry to suppress their activity. That’s the good news.|
|The bad news is that the proteins that we’ve identified that cause the cells [00:10:30] to secrete are often proteins that are very important for basic life maintenance. For example, one of the processes we identified is the so-called DNA damage response, meaning when your DNA is damaged a bunch of proteins get activated, and some of those activated proteins make cells secrete the molecules that we think are damaging and causing aging. Now, the pharmaceutical industry has developed drugs [00:11:00] that make those proteins, those DNA damage response proteins, no longer active, but you surely would not want to go through life suppressing your ability to respond-|
|Judith Campisi:||… to DNA damage. That’s one problem is that the processes that drive the secretions of senescent cells tend to be basic processes that-|
|Judith Campisi:||… are important for life. The other problem is that you can apply these drugs, we’ve done this, at least in cell cultures, [00:11:30] shown that they suppress, but then as soon as you remove the drug, senescent cells starting secreting again. What that means is, you would need to take these drugs all the time-|
|Judith Campisi:||… to prevent them from secreting. Now, the drug companies don’t like when I say this, but the truth is, there is no such thing as a perfectly safe drug. You don’t want to be taking a drug that compromises an important system chronically, all the time.|
|[00:12:00] The best proposition, we think, is to maybe take a drug that works for some long period of time and then only take that drug every so often. It’s a lot safer thing to think about. That second class of drugs are called senolytics, that is drugs that have the ability to simply cause senescent cells to die and go away. There are some prototypes out there now that have [00:12:30] been discovered that can do that, that can cause senescent cells to undergo cell death and therefore to simply go away. The idea, then, is that you would not have to take this drug every day, but you take it once in a while and then slowly, as senescent cells build up, you take it again. You wouldn’t be taking that drug every day, and I think that’s the promise of the future. These drugs are not ready for prime time. They’re not in the clinic yet. They’re [00:13:00] being tested. A lot of testing goes into making sure these drugs are safe, but I think it’s a more reasonable wave of the future.|
|Dan Pardi:||It’s somewhat similar to a lifestyle intervention doing fasting. You would do an extended fast, perhaps, at some interval.|
|Judith Campisi:||That’s right, intermittent fasting as opposed to chronic fasting which, of course, is no fun at all. It’s the same idea.|
|Dan Pardi:||That does make sense. I can see how either a drug or fasting [00:13:30] or both could occasionally clear out an amount of senescent cells that have developed, and that could put you at a better state in terms of the amount of inflammatory molecules that are being secreted by accumulating senescent cells. You reduce them, you’re in a better inflammatory condition. What about the lifestyle approach, because exercise, getting adequate sleep, there was recently a study by Judith Carroll at UCLA that showed one night of sleep deprivation enhances the senescence-associated secretory phenotype. That makes sense to me, that’s a powerful stressor. Then, also, flavonols, [00:14:00] things like quercitin, fisetin. I know that you had a study on Apogen. Since those are, oftentimes, less powerful than pharmaceutical drug molecules, would the regular consumption of flavonols, for example, do a job at reducing senescent cells?|
|Judith Campisi:||That, undoubtedly, will help. The complication is that this senescence-associated secretory phenotype is very complex. As I said, it’s probably 100 molecules, maybe more. We really don’t know. [00:14:30] Each of those interventions, adequate sleep, things like quercetin or other flavonoids, apigenin, they do suppress some parts of that secretory phenotype. They don’t suppress it all. We simply don’t know, at this point, whether what those compounds do are sufficiently penetrant, meaning they sufficiently suppress enough of the secretory phenotype to be really beneficial longterm [00:15:00] for multiple indicators of health as opposed to one or two specific indicators of health. That’s a big unanswered question at the time. The safest bet would be to get them to die, the cells to die, so they’re not secreting anything. These are early days. We really have to interrogate those potentially safer, meaning natural-product-type or lifestyle-intervention- [00:15:30] type interventions to know how complete they are in what they can do or whether we really do need a “drug” that will cause senescent cells to die. It really still needs to be determined.|
|Dan Pardi:||We probably don’t want to be preventing cellular senescence, since it has an important role in cancer prevention, so it’s really about clearing them.|
|Judith Campisi:||Yes, precisely. I should have mentioned that early on. The whole purpose of the stress response is to prevent cells that are stressed and damaged [00:16:00] from undergoing cell division, because those cells, then, are potential cancer cells. It’s a very important process for preventing cancer. You don’t want to prevent it. You want them to go ahead and do their little thing and undergo senescence, but then you would like those cells to go away.|
|Dan Pardi:||Are there human trials happening now that are looking at clearing senescent cells in some form?|
|Judith Campisi:||To my knowledge, there are no human trials yet. They’re still in the stage of being tested in multiple [00:16:30] animals. This is required by the FDA, for good reason that, before you go to humans, you want to make sure that it works in a number of different animal models. I think some of the tests are at that stage. They’re not yet in humans. The hope is that there will be something in humans relatively soon. Some of the estimates are within a year or so.|
|Dan Pardi:||That’s exciting. Tell us a little bit more about your collaboration with SENS. I’ve had Aubrey de Grey on the show in the past, and we’ve discussed his model of aging, [00:17:00] and also your work with UNITY Bioscience. I’d love to hear more about those relationships.|
|Judith Campisi:||Yes. Let me start with SENS. I’ve been an advisor to SENS for a long time. The SENS Foundation is now funding a project in my laboratory to see if we can get parts of the immune system to recognize senescent cells and clear them naturally. That would be ideal, right, not to have to take a drug at all but to get your natural body’s defenses to clear [00:17:30] these cells? It’s still a big unknown whether this will work and how it will work, but this is something that the SENS Foundation is funding my lab. We’re very excited and very grateful to the foundation for the opportunity to explore this somewhat risky arm of a potential intervention that we hope will, at least, shed light on what we can do about [inaudible 00:17:55] accumulation of senescent cells with age.|
|UNITY Biotechnology is a [00:18:00] relatively new company. I’m one of the scientific founders, although I really had very little to do with actually setting up the company; but it has a stellar cast of CEO, president and medical officers who are steering the company toward developing drugs that will cause senescent cells to die. Again, the idea is not that you would take these drugs all the time but that you would take them intermittently. As you know, [00:18:30] the FDA has not recognized aging as a disease, so in order to get a drug to be approved for something like eliminating senescent cells, the drug has to be targeted to a specific disease. That’s what UNITY is doing now, targeting a few very specific age-related diseases with the hope that they’re successful, it can then be expanded to other diseases of aging, and there are dozens [00:19:00] of such diseases. We’ll see whether these drugs are effective in humans, and also how many diseases they might be effective against.|
|Dan Pardi:||It’s such a shame the FDA doesn’t recognize aging as a disease, yet it affects so many age-related diseases. Hopefully, there’s a paradigm shift here.|
|Judith Campisi:||The National Institute on Aging doesn’t require that the FDA recognize aging as a disease in order for it to … NIA, the National Institute on Aging, to fund basic research in aging. [00:19:30] What is difficult, right now, is that the NIA is a relatively underfunded institute within the NIH despite the fact that many of the other institutes are dealing with diseases that are actually diseases of aging. There are two-|
|Judith Campisi:||… infrastructure problems. One is that NIA is relatively underfunded, and the other is that the FDA, for the purposes of developing therapies, [00:20:00] doesn’t recognize aging as a bona fide disease.|
|Dan Pardi:||Can somebody now determine the amount of senescent cells that they have in their body, or at least some sort of global measurement?|
|Judith Campisi:||Very, very indirectly. We cannot … we meaning the biomedical industry, cannot take biopsies of many of your tissues. You would probably not want to submit to a brain biopsy or a heart biopsy. The two biopsies that [00:20:30] are feasible in humans are blood, a simple blood sample, or maybe a skin biopsy or little prick that removes a little bit of skin cells. It is possible to determine the burden of senescent cells in blood and skin by some of the biomarkers that we have for senescent cells. That’s good in the sense that it gives you a snapshot of those two compartments of your body, but we’re not at the point yet of having a very good biomarker that [00:21:00] predicts, say, the whole body burden of senescent cells. We’re just not there yet. A lot more research needs to be done.|
|Dan Pardi:||If you were to simply track blood or skin and you were to look at the trajectory of senescent markers, that might be an indication of how much you’re accumulating over a period of time?|
|Judith Campisi:||It’s a very loose correlation. Those studies have been done, that is, serial biopsies of people throughout different parts of their age and also even horizontally, meaning bunch [00:21:30] of people that are young, bunch of people that are middle age, bunch of people that are old. You do get a correlation, but there’s a lot of individual-to-individual variation, which is, of course, what you might expect, right? We all know 50 year olds that look like they’re 30 and 50 year olds that look like they’re 70. We don’t yet have the means to be very precise in taking one person’s skin or blood sample-|
|Judith Campisi:||… and say, this is your “biological [00:22:00] age” as opposed to your chronological age. We’re just not there yet.|
|Dan Pardi:||Do you also see a lot of within-person variability?|
|Judith Campisi:||You do, from tissue to tissue, that’s correct. That’s part of the complication is that not all-|
|Judith Campisi:||… tissues and not all individuals accumulate senescent cells at the same rate.|
|Dan Pardi:||This is such exciting research because of how far things have come, seemingly quickly, and also the fact that there seems to be compounds and strategies that, at this point, are untested but are promising [00:22:30] to affect this.|
|Judith Campisi:||There are. The other thing I should point out that the field is just growing enormously. I just returned from the fourth international cell senescence meeting, which was held in Paris. The first one had maybe 80 or 90 participants, and this one had nearly 300 participants, and all this occurred in four years. The field is-|
|Judith Campisi:||… exploding. There’s lots of very good labs working on this. It holds promise for at least [00:23:00] increasing the health span of humans, if not lifespan. We don’t know about lifespan, but certainly health span, meaning living longer, healthier.|
|Dan Pardi:||Dr. Judith Campisi, thank you for your time and your commitment to this field. I’m 43, so I wonder if, within my lifetime, we’ll see therapies that actually modify my health span and potentially my lifespan. I think the answer might be yes.|
|Judith Campisi:||I think you have reason to be optimistic, absolutely.|
|Dan Pardi:||Well, I [00:23:30] appreciate your time, we all do, and again, your work. Thank you so much for joining me on humanOS Radio.|
|Judith Campisi:||My pleasure. Thank you.|
|Kendall Kendrick:||Thanks for listening, and come visit us soon at humanOS.me.|
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