Unity Biotechnology Starts First Human Trial of a Senolytic Therapy
The honor of running the first trial of a senolytic drug, albeit inadvertently, goes to one of the groups testing dasatinib or navitoclax back when those pharmaceuticals were first evaluated for cancer therapies. At that time nobody knew that these drugs could selectively destroy senescent cells, and were thereby far more valuable as a starting point for rejuvenation therapies than as cancer treatments. The first intentional human trial was started last year by Betterhumans, a non-profit organization. Now Unity Biotechnology has recently announced that their first human trial is underway, testing the ability of their initial candidate senolytic to treat osteoarthritis. You may recall that the evidence in animal models for the accumulation of senescent cells to be a primary cause of osteoarthritis is fairly compelling. We can hope that this holds up in humans; results will likely start to appear in a preliminary form next year.
UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to extend healthspan by slowing, halting, or reversing diseases of aging, today announced the treatment of the first patient in the Phase 1 clinical trial evaluating UBX0101 in moderate to severe osteoarthritis of the knee. "For many people, we believe that osteoarthritis is the main reason why it hurts to get old. By designing a treatment to selectively eliminate senescent cells in the joints of patients diagnosed with painful osteoarthritis, our goal is to alter the otherwise disabling course of this disease. This is an important milestone for UNITY. This is the first time we have treated a patient with a drug to eliminate senescent cells. While this study is designed to establish safety, we are also looking for the earliest signals of reducing senescent cell burden in this disease of aging."
The Phase 1 clinical trial of UBX0101 is a randomized, double-blind, placebo-controlled, single ascending dose study that will evaluate safety, tolerability, and pharmacokinetics of a single intra-articular injection of UBX0101 in patients diagnosed with moderate to severe osteoarthritis of the knee. Patients will be randomly assigned to receive UBX0101 or placebo in 3:1 randomization by dose level cohort.
Cellular senescence is a natural biological state in which a cell permanently halts division. Senescent cells accumulate with age and secrete as many as 100 different biologically active proteins, including pro-inflammatory factors, proteases, pro-fibrotic factors, and growth factors that disturb the tissue microenvironment. This collection of secreted proteins is referred to as the Senescence Associated Secretory Phenotype, or SASP. In addition to its effects on tissue function, the SASP contains factors that induce senescence in neighboring cells, setting off a cascade of events that culminates in the formation of the functionally aged and/or diseased tissue that appears to underlie a variety of age-associated diseases. UNITY believes that the elimination of senescent cells will remove SASP factors - addressing a root cause of diseases of aging. Senolytic medicines, or treatments designed to selectively remove senescent cells, target the SASP at its source, and may have a more durable impact on disease than current therapies.
They are in requirement state since May 1st. So there might be some preliminary results by the end of the year. If it turnes out to be safe and better than placebo it is will prove the concept of senolitics and more financing will be attracted to senolitics and they might even become a gold rush within big pharma.
However, i am afraid that most powerful senolitics will turn out to have nasty side effets. Four example , quercetin is often neurotoxic and might trigger diabetes, while beingng a week senolitic...
At last! Congratulations to them!
Dr. Michael Fossel states in the recent interview at the Life Extension Advocacy Foundation blog:
"Let's take this down to the cellular level and look at your knee joint. Let's say that ten percent of the cells are senescent. They've got SASP, gene expression that's actually causing problems to neighboring cells. The senolytic approach is to remove those ten percent of the cells that are causing damage, and that sounds good, and, initially, it would be. The problem is that the remaining 90 percent have to divide to make up for the missing cells, which means that you've just accelerated senescence in the remaining cells. So, next year, you have to kill another 10 percent, and every time you do that, you're increasing the rate of senescence of the remaining percentage of cells."
Is this a major concern?
Huh?? Why do you "just accelerated senescence in the remaining cells"? And why "next year"? I think he is talking without knowing the field of senescent cells.
@corbin I am no expert. But imo, no it does not makes sense. I do not believe cells dividing will significantly increase the rate of scenesence.
The final joint problems currently are treated by a replacement surgery. So for arthritis senolitic cleansing would be an improvement. Then we have stem cells that would divide and fill up the gap. Probably the number of senescent cells is much less than 10 % but even if it was that high, you would need years to get back to that sick state and reapply the treatment. Eventually you will exhaust the reservoir of the specialised stem cells, of course. But that could take many years, if not decades. By then you will need to have some stem cells replacement therapy. Probably culture them in vitro and inject the seeds back. Or some thelomere repair as a stop Gap. And in a few decades we could have organ printing to replace the parts and organs that are too worn out to fix with less invasive therapies
No. The percentage of senescent cells in tissue is very small, even for the aged. There could be a pathway limitation, say if they are targeting only p16 expressing cells, then it is possible that not all the bad cells would be removed
It begins!
The first rejuvenation therapies specifically designed against aging are in actual living humans.
This is a day that will be remembered.
@Corbin It is important to note that (at least some niches of) stem cells express telomerase, breaking one population-wide march towards senescence. While this division will increase the likelihood of mutations occuring, stem cells can usually self-replicate if they decrease in number - at least in stem cell popoulations i'm aware of.
Another important note: SASP deactivates stem cells, so it may have a net positive effect on stem cell activity.
Hi Patrick,
I was talking about the worst case scenario which can give you decades of improved quality of life , if not outright life extension
Thanks everyone for the input. I thought that statement by Dr. Fossel was odd, it was the first I've heard of anything like it. I'm so happy for Unity Biotechnology!
@corbin If the the accelerated aging of existing cartilage cells that Dr Fossell worries about does happen, this could possibly be addressed by injecting stem cells into the site after the senescent cells are cleared. Replacement cartilage would form from stem cells rather than older cells with shorter telomeres. There are other companies looking at stem cells to treat arthritis, so the best results might come from a combination therapy.
Of course Dr Fossell thinks telomerase is the answer, reprogam cells to act younger.
Maybe all approaches have merit. Clear out senescent cells, add stem cells to regrow cartilage, then finsh with a telomerase treatment to change the epigenetics of the cartilage cells to keep them youthful in the longer term.
Dr. Fosssel makes a relevant point
If the process of senescence is more than just about random cells that have "forgotten how to die" in the joint, but more of a tissue level problem that "produces" senescent cells, in the case of osteoarthritis as a downstream effect of friction forces, sheer stresses, visco-elastic changes in the synovial fluid, etc. etc. this does nothing to turn off the spigot
@Ira: That's not what he is saying.
Dr. Fossel does have a point. Increasing the turnover of cell replacement is increasing the demand for division and we already know that telomerase even in stem cells is not enough to keep pace with cell division thanks to the "pause" function that is incorporated into the replication process.
So Michael makes a valid point indeed and yes you would be accelerating senescence in tissue-resident stem cells due to increasing the demand for division wiping out 10% of the cells in tissue would cause. The stem cells would begin to divide to replace the senescent cells.
So yeah, he has a valid point here and we will not know the long-term implications until we run these clinical trials, anyone who says otherwise is kidding themselves. Biology works how it works not how someone with a pet theory wants it to work, so we will have to wait and see.
Where I think he goes wrong is that if one combines replacing stem cells periodically this could potentially redress the issue. The other possible approach is to make stem cell division more efficient by removing the "pause" function telomerase has during synthesis of DNA repeats.
[1] Chen, Y., J.D. Podlevsky, D. Logeswaran and J.J.-L. Chen (2018). A single nucleotide incorporation step limits human telomerase repeat addition activity. EMBO. J. 37: e97953, DOI 10.15252/emboj.201797953.
I also far more optimistic that rejuvenating the immune system is in the long-term the best solution to senescent cells. The work of Gudkov offers fairly compelling data to suggest the immune system failing is the reason senescent cells are there in the first place and not removed and that restoring the immune system to youthful levels could fix that issue. I am therefore more interested in the long-term potential of thymus rejuvenation and the comprehensive control of "inflammaging" to keep the immune system on track.
@Cuberat , do you know quercetin a) isn't senolitic per se and b) isn't "powerful". For sure they use specifically created molecules. Of course, and unfortunatelly they use small molecule, so they will get some side effects. That would be much better if they use immuno or gene threrapy like Oisin. https://www.fightaging.org/archives/2018/03/the-rise-of-oisin-biotechnologies
@Steve Hill, agree, -- even if his concern is real, we can always use cell therapy to replace them.
@Ariel - yes that is one potential solution though we will have to test that and see if it works as a co-therapy. There is reason to think it might but we cannot know yet.
Regards quercetin it appears not to be senolytic per se but in fact masks some elements of SASP, what some people are calling a "senomorphic" rather than a Senolytic. I would also add that quercetin is a pro-oxidant that provokes an antioxidant response from the cell by a hormesis effect.
http://www.isoquercetin.net/neuroprotection/
@Steve Hill - Janko Nikolich-Zugich, who presented at the SENS 5 conference, recently got a 10 million grant to rejuvenate the Thymus, however he thinks it will also be necessary to rejuvenate the lymph nodes:
https://uanews.arizona.edu/story/ua-lab-seeks-holy-grail-gerontology
https://www.fightaging.org/archives/2017/10/will-rejuvenation-of-the-thymus-require-rejuvenation-of-the-lymphatic-system/
I think Fossel is right and senolytics on their own will not be as good in humans as they are in mice. We will need to replace those cells. However we might find for specific cases with severe inflammation that senolytics helps to break that cycle.
@Mark, senolytics is just a part of the SENS rejuvenation panel. They cannot be "enough" on their own. There are another sources like glucosepane and lipofuscine. However, the number of senescent cell is very low, and experiments on animals is very promising, we can assume patient own stem cells will recover quickly when we make level of chronic inflammation even half low.
Let's just see what the data shows us.
In the case that fibrosis of the lymph nodes does turn out to be a blocker to immune rejuvenation via thymus rejuvenation, surely some group out there must have a project to create lymph nodes either via tissue printing or in vivo?
@Steve Hill, pure observation shows nothing -- do you know that space travel is possible? Why? Because you use it or because engineers proved it a 100 years ago using classic physics? Many spacecrafts failed but it did not make aerospace engineering false conception. They were just bad implementation of the good proved conception. Likewise in bioiengineering, we all know for 20 years that scenescent cells are bad so removing them is good. If someone youse poor implementation it is not the problem of the conseption.
I have no knee or other joint pains despite 6 miles/day of steps and running. But a couple of my brothers and my mother had cataract surgery, so I would be more interested in getting rid of the senescent cells that might cause that rather than arthritis. I read where a mice study using senolytics delayed cataract development.
@Biotechy Marcks, could you please send me a link or any information re the study using senolytics to delay cataract formation. And Is it related to the studies using lanosterol to reverse already developed cataracts?
@ Ann Coppola: The reference in mice is: Nicholas Wade, Nov. 2, 2011, Science, Purging cells in mice is found to combat aging ills. I also came across lanosterol but those must be more recent studies.
@Ariel - The trials will test for efficacy and that will show if that candidate works or it does not in humans. Nothing to do with false equivalencies and everything to do with rigorous clinical testing and observation.
I still believe Gudkov et al. is correct and that senescent cells only lead us to the real issue, the dysfunctional immune system. Fix this and we do not need senolytics ultimately. I see senolytics as a short-term fix and repairing the immune system as the long-term solution.
Note: My comment above does not mean that I see no value in senolytics, as we cannot rejuvenate the immune system yet, so clearly they may be potentially useful if they work in humans as they do in mice. However, we cannot know this until they are tested and the data is in. It is good news but the race has only just begun.
@Steve Hill, there are many ways to kill senescent cells -- a) small molecules (Unity), b) gene therapy (Oisin), immunotherapy (SIWA). It is up to you what you choose, by the way, you may need all of them for efficacy. Of course, some concrete approach may not work, but we are talking about whole conception -- since senescent cells produce SASP and chronic inflamation -- then we need kill them. What for immune system reload -- the idea is nice, it is not separate idea in SENS programme because immunosenescense is decomposed into other known problems. Immune cells become senescent on its own and to use immunotherapy properly we need firstly clear out such "wrong" cells and "reseed" immune stem cells. It's like chicken and egg problem.
@ariel the immune system is the likely long-term solution vs senolytics. It gets messed up, at least in part, because of "inflammaging" and there is a very strong chance the origin point of that inflammaging is the gut microbiome that sets it all off.
As I have already said twice now, I am happy senolytics are here but in the longer term fixing the immune system is in my view the way forward. We should be looking not only to repair but improve on our biology and engineer resilience in the coming decades ahead.
Senolytics would still be needed to get rid of senescent immune system cells. If the immune system couldn't produce enough replacement cells in time, the SCs might need to be be more gradually culled or non-senescent immune cells would simply be injected back into the patient. Trying to reprogram a-few-steps-away-from-turning-into-cancer, senescent immune system cells without repairing their cancer-prone mutations doesn't sound like a good idea.
@Florin Clapa and yet the youthful immune manages to do so just fine without senolytics. Nope, I ain't buying that explanation. A youthful working immune system would remove truely senescent immune cells as it does other cells.
Macrophages act in a contextual way, they work properly given the correct signals and that has been demonstrated numerous times. The macrophages I am speaking of are not senescent per se, they are influenced by the inflammatory signaling which guides them towards a certain polarization, removing that signaling makes them work properly again. Gudkov and others have demonstrated this and that they can be rescued from their dysfunctional state and work properly.
No one knows for sure if a youthful immune system can actually keep the level of SCs low enough to prevent pathology. But even if this was true, senolytics would still be needed.
Whether macros are real SCs or not is still an open question, but since they are otherwise dysfunctional, they could be treated like SCs, namely: kill'em all and let metabolism sort it out. Even without the cancer problem, reprogramming dysfunctional (for who-knows-what-reason) cells seems more risky (How long will they remain functional? Is a systemic anti-inflammatory needed?, etc.), and it remains to be seen if it's even possible in vivo.
If inflammaging is the actual cause of macro dysfunction rather than senescence, that kind of inflammation would need to be eliminated by removing the aging damage that is the cause of the inflammation. However, that might not be possible unless SCs are killed off using senolytics, since they are a cause of chronic inflammation. And there are other causes of chronic inflammation besides just SCs and gut bugs. After all of the causes that contribute to macro dysfunction were eliminated, perhaps there would be no further need for senolytics, but that's a long way off.
And...uh-oh, some guy named "Michael" just threw cold water on the idea that messing around with macrophage polarization could eliminate SCs. ;-)
https://www.fightaging.org/archives/2018/07/just-how-dynamic-are-cellular-senescence-levels-in-old-tissues/#comment-32420
As I have said many many times, inflammaging is caused by various known sources: Microbial burden, immunosenescence, cell debris, senescent cells etc. However, the initial origin point of inflammaging is looking ever more likely to be the gut and failure of the gut membrane. This then likely leads to the constant activation of the immune system due to the inflammation it causes and bingo the vicious circle begins. You get dysfunctional immune cells, a chronic background of inflammation, senescent cell accumulation and cell debris as the spiral continues.
We also know that germ-free mice do not experience the same dysfunction of macrophages which is caused by inflammation. The case for restoring the immune system by managing chronic inflammation is perfectly plausible and reasonable. So once again, managing that background of inflammaging is the likely long-term solution here. That may initially require senolytics but that is not as good as restoring the immune system to working order.
Anyway last I am saying here, as this conversation will just keep going around and around and lead nowhere. I am a busy person so let's leave it there and we will see what the data shows us down the road.
You (Steve) and Gudkov seem to have implied that macrophages kill SCs, but apparently, that's not the case as Michael has pointed out (NK cells actually kill SCs, not macros). So, your other claim (the one I also mistakenly reinforced) that rejuvenating macros could somehow replace senolytics doesn't seem likely either.
https://www.leafscience.org/long-term-solutions-to-senescent-cells/
https://www.leafscience.org/dr-andrei-gudkov/
Let's ask.what causes degenerative immune system.it could be as a result of senescence cell making various component of immune system being less efficient.i bet senolytics therapy will not be selective and will remove senescence cell in immunity tissues and organs rejuvenate them and increase Immunity. At this point the high immunity starts also removing senescence cell as well as senolytics.they are now attacked from both quarters.it is like using a stone to hit two birds.and then the rough cells removed from the body even faster
I'm a bit late to this discussion, but I remember reading several papers indicating that an injection of senescent cells into young animals caused degenerative disease. Below is the first article that came up on a search. This implies that a presumably functioning immune system is not protecting the animal from degeneration brought on by injection of senescent cells. So, while the immune system may be important, it does not seem that senescence is unimportant. This may be a case where "those who can't do it should get out of the way of those who are doing it"...
https://academic.oup.com/biomedgerontology/article/72/6/780/2630057
@Dan
Yes, clearly the immune system doesn't clear the SC efficiently, especially in the old individuals. That was discussed in FA fortune a couple of months ago. While very important and very promising the senolytic treatments will not solve all the issues of an old age.
We have to keep that in mind
That in mind...