Judith Campisi on Senolytics

As one of the authors of the initial SENS position paper, published many years ago now, Judith Campisi is one of the small number of people who is able to say that she was right all along about the value of targeted removal of senescent cells, and that it would prove to be a viable approach to the treatment of aging as a medical condition. Now that the rest of the research community has been convinced of this point - the evidence from animal studies really is robust and overwhelming - the senescent cell clearance therapies known as senolytics are shaping up to be the first legitimate, real, working, widely available form of rejuvenation therapy.

Why should we suddenly get excited about anti-aging drugs again?

There are now tools available to biomedical scientists that simply didn't exist when I was a graduate student or even a postdoc. So we're finally able to do experiments that were either considered impossible in some cases or were just dreams 20 or 25 years ago. The other thing that has changed is that the field of senescence - and the recognition that senescent cells can be such drivers of aging - has finally gained acceptance. Whether those drugs will work in people is still an open question. But the first human trials are under way right now.

How specifically does senescence contribute to aging?

The correct way to think about senescence is that it's an evolutionary balancing act. It was selected for the good purpose of preventing cancer - if cells don't divide, they can't form a tumor. It also optimizes tissue repair. But the downside is if these cells persist, which happens during aging, they can now become deleterious. Evolution doesn't care what happens to you after you've had your babies, so after around age 50, there are no mechanisms that can effectively eliminate these cells in old age. They tend to accumulate. So the idea became popular to think about eliminating them, and seeing if we can restore tissues to a more youthful state.

You've suggested that health care could be transformed by senolytic drugs, which eliminate senescent cells. That's a pretty broad claim.

If we think of aging as a driver for multiple age-related pathologies, the idea would be that a new generation of physicians - we call them geriatricians today - will take a much more holistic approach, and the interventions will also be more holistic. That's the idea-it would revolutionize the way we're thinking about medicine nowadays. And just to remind you, 80% of patients in the hospital receiving acute medical attention are over the age of 65. So the idea is that senolytics would be one weapon that geriatricians will have in their arsenal of weapons to treat aging holistically as opposed to one disease at a time.

Link: https://www.technologyreview.com/s/612284/finally-the-drug-that-keeps-you-young/

Comments

Too bad Unity's stock market cap is down $500 million from the recent CEO CNBC pump event

Posted by: stockzz at October 24th, 2018 5:57 AM

@stockzz: What event?

Posted by: Antonio at October 24th, 2018 7:22 AM

Q: Some Silicon Valley enthusiasts have been saying that life-span extension up to 500 or 1,000 years is feasible.

A: Well, it's religion. It's not science. I mean, that's all I can say. It's based on belief, not based on any data. People are certainly welcome to believe whatever they want to believe. But it doesn't make it true!

Again the highly confusing opinions of Campisi about SENS and SRF, supporting them a moment and ridiculing them the next moment, and back again.

And the next time she seems to support programmed aging:

And then if you go to a mouse, most of the really high-profile papers extend its life span maybe 20%, sometimes 30%. So think about the difference between a mouse and a human. We're something like 97% genetically identical, meaning we have the same genes. And yet there's a 30-fold difference in our life span.

So it seems to me that in order for evolution to evolve a 30-fold difference in life span with so few really clear genetic differences, evolution maybe had to tweak hundreds, if not thousands, of genes. It's unlikely at the present time that we will find a single drug that's going to be able to do what ­evolution did.

What a mess. I wonder what impression laymen readers get about all this.

Posted by: Antonio at October 24th, 2018 7:36 AM

Q: Some Silicon Valley enthusiasts have been saying that life-span extension up to 500 or 1,000 years is feasible.

A: Well, it's religion. It's not science. I mean, that's all I can say. It's based on belief, not based on any data. People are certainly welcome to believe whatever they want to believe. But it doesn't make it true!

I had a good chuckle at this because it's true. Some folks do treat the field and its potential like a religious cult. Judy is also likely mindful that putting big numbers on such things is foolish and leaves one open to attack from critics. Better to say nothing and let the data speak than make claims that cannot be proven. This is why radicals are not taken seriously and the field has been dismissed as sci-fi for years by many. The choice of language is super important in how you engage the public and there are plenty of studies (Harrison, Partridge, Pew etc...) that clearly demonstrate this.

Posted by: Steve Hill at October 24th, 2018 7:56 AM

On a more positive note, I was pleased to see Judy has become somewhat bolder in her statements about aging and doing something about it. This interview was significantly more bold in nature than the ones from 2-3 years ago. Scientifically cautious of course but certainly more bold.

I also love this answer here:

"Let's say we are successful at slowing down or reversing aging, or extending health span. Are there any social or cultural impacts that you have concerns about?

No. In my lifetime, the population of the earth has not quite doubled, but it's getting there. That's unsustainable. The truth of the matter is, not having people die is not going to add much to the population of the earth the way the current rate at which we're producing new people is ruining the earth. So I think that this is ridiculous.

So I really don't see a downside to this. There are problems, but I don't think extending health span is going to exacerbate those problems."

Posted by: Steve Hill at October 24th, 2018 8:00 AM

Campisi said: "That's aging, and that's terrifying. I am optimistic that we're on the cusp of understanding enough about that process to be able to intervene. And that people like us, who are not at that point, will benefit. But we're still going to die."

And what will we die of? If you cure aging, what remains are accidents, murders and the like, and that implies a life expectancy of a few thousand years, but you call that religion. So what? Will we simply fall dead from some sort of magic curse? Again, what a mess.

Posted by: Antonio at October 24th, 2018 8:14 AM

@Antonio

The CNBC "pump event" when they carted out their CEO to say "We can 'absolutely' create drugs that slow, halt or reverse diseases of aging"

Shot the stock up $300 million, and now it's down $500 million

https://finance.yahoo.com/quote/UBX/chart?p=UBX

Absent of real data, the only thing to move the stock are these pr announcements by the insiders

Posted by: stockzz at October 24th, 2018 8:23 AM

Ah, ok, thanks.

Posted by: Antonio at October 24th, 2018 8:29 AM

@Antonio: As Steve Hill rightly points out, people don't always express their feelings/thoughts 100% in interviews. It's all about spin, marketing and being mindful of investment and backing.

Also the majority of Silicon Valley enthusiasts are not that bothered about biology (although I'm sure they'd use any drug available to delay the inevitable), as they are looking to the long-term transhuman approach to extending life.

Posted by: Steven B at October 24th, 2018 8:29 AM

@Steven B: I'm not so sure. These days it's not a career killer to support radical life extension. And if she was so bothered, she could simply not sign that seminal SENS paper or not enter SRF advisory board. I think more probable that she simply has those contradictory views.

As for Silicon Walley enthusiasts, maybe they don't have enough knowledge, but thousand years lifespans follow straightforwardly from SENS. If you agree with the latter, you have the agree with the former, because:

1) If aging is damage and you eliminate that damage, only accidents, etc. remain, and that gives thousands of years.

2) If SENS classification of damage is correct, research gets easier and easier as you progress, since the damages that you first eliminate are the most abundant ones, and those are precisely the damages that accumulate faster, so you have more and more time to eliminate the damages that remain after you eliminate the first ones.

Posted by: Antonio at October 24th, 2018 8:41 AM

This is a critical point for all aging research, especially in a niche field that is not really a "darling" of Wall Street yet

And it hangs in the balance of Unity, a company that has tried to do everything the standard way, succeeding at what it has promised

If the Unity trial fails, or fails to impress, it could have a knock-on effect that bring down research for many years

Look at the history of gene therapy and anti-sense / RNAi

Little clinical troubles put a 30-year gap in between their revival in recent years

Posted by: stockzz at October 24th, 2018 8:52 AM

@stockzz: Would that stop, say, Jim Mellon? It doesn't seem so. Maybe he will move away from senolytics, but I don't think he will leave gerontology.

Posted by: Antonio at October 24th, 2018 9:17 AM

I have known about judy campisi for some time and most of the time she is extremely conservative when it comes to predictions in terms of lifespan. When Aubrey makes statements like the first 1,000 year old is likely alive today, one must be very careful to understand exactly what he means by that.

Posted by: Scott emptage at October 24th, 2018 2:52 PM

I'm an investor in Unity, so I am biased. Basically I like Unity's plan of small molecule drugs for individual organ systems, clearing senescent cells. Its not as radical as gene therapies or whole body clearance ideas, but I also view it as having a much better chance of succeeding in approvals.

Say you had a senolytic drug that cleared those cells from ailing kidneys. And the people given the senolytic drug in addition to the standard of care, died in an average of 7 years of kidney disease instead of in 5 years with only the current standard of care(making both numbers up).

That would easily be a multi-billion dollar a year drug. While that drug is still on patent Unity could be researching a version 2.0 kidney senolytic drug.

The same can potentially be done for all the organ systems in the body. Arteries, heart, liver, muscles, skin, etc.

How the public and private payers decide whether to fund drugs is based on QALY. Which is the cost per quality year of life gained. The number right now is if its under $50,000/year gained they will fund it. So an average of 2 years gain in my made up example, would be a $100,000 threshold(amortized to the net present value of that).

Then the patients would be taking that made up kidney drug for an average of 7 years. So say the drug was $4,000/year per pateint, that is $28,000 in cost over the 7 years. Which would be easily under the QALY and thus get funding approval.

If then 500,000 people with kidney disease in the US/EU/Canada/Aus/Japan & friends got put on the drug, that is 500,000 * $4,000 per year = $2 billion a year drug.

Posted by: aa3 at October 24th, 2018 7:46 PM

RNAi was only proved to exist in humans in 1998 so I don't know where the '30years of failure' figure is coming from. It was hyped around 2004, so maybe 10 years of failure would be more accurate.

There also seems to be a bit of confusion around the nature of technology, for instance gene therapy delivery. It doesn't matter how hard it was or how many years it took to crack a problem, once it is solved it is solved forever and will only get cheaper.

Posted by: Jim at October 24th, 2018 10:58 PM

@aa3

Everything in the biotech industry that succeeds in doing these things is a potential multi-billion drug

The issue is that the company is being hyped as a shite biotech penny stock with these pr blitzes with hundred million $$ swings over weeks

Posted by: stockzz at October 25th, 2018 3:00 AM

@Jim

Unfortunately that's not how the biotech industry works

Bio trends are very cyclical, and with the long development time lines, much gets lost

There is big difference between technology that works, and it getting to market in biopharma

PR pumping senolytics in this fashion to investors is a dangerous game for everyone if things don't pan out in an extraordinary way

Posted by: stockzz at October 25th, 2018 4:56 AM

I don't understand the optimism about senolytics in humans. Where are at least anecdotal accounts of significant benefits by self experimenters? Can't find 'em.

Posted by: Chris Zell at October 25th, 2018 7:15 AM

@Chris Zell: There is very abundant and solid evidence that senescent cells are harmful for humans.

Posted by: Antonio at October 25th, 2018 8:33 AM

@Chris Zell

There are none beyond the animal models

Most of these companies are banking on the general public investor being stupid / blind to the last 50 years of cancer cures in rats

It's all pretty much smoke and mirrors at this point until human data comes in

Posted by: stockzz at October 25th, 2018 8:35 AM

@ aa3: Except in rare cases, such as wound healing, the SASP generated by SC aging circulates as both a systemic and paracrine secretion. Local clearance of SCs, for example as you suggest in the kidney, likely has limited or no effect on the systemic SASP being generated by multitudes of other SCs in aged individuals. So the negative signaling effects of the systemic SASP will still inhibit regeneration and repair in organs like the kidney, absent systemic SASP clearance. This was clearly shown by Unity's data last year, where they ablated SCs in young and old mouse OA models, but only saw regeneration of cartilage in the young animals. The unsolved problem for small molecule approaches is finding one that kills SCs systemically without being toxic to non-SCs.

Posted by: Gary at October 25th, 2018 11:41 AM

@stockzz: There are different degrees of confidence one can have based on the established science prior to human trials. At this point it would require extraordinary new biology for systemic removal of senescent cells to fail to be very beneficial in humans.

Posted by: Reason at October 25th, 2018 3:27 PM

@stockzz, @Chris
For anecdotal cases you don't have to go too far. Just check the Helga's post on D+Q self experimenting.

Posted by: cuberat at October 25th, 2018 5:17 PM

@Reason

What are your opinions on Gary's comments regarding Unity's approach? If their osteoarthritis drug fails then that will be a big blow to this movement. We need investor enthusiasm to remain high.

Posted by: Nina at October 25th, 2018 7:03 PM

@Nina: Unity's study isn't the only one, and others are administering senolytics systemically. I'm not concerned. I think that all of the pharmaceutical approaches have the big challenge of the existence of dasatinib + quercetin, fisetin, and piperlongumine. If anything is going to sink them it'll be the inability to produce small molecules that are significantly better than a combination of the present widely available, very low cost options.

Posted by: Reason at October 25th, 2018 7:10 PM

Gary: I view that clearance of senescent cells locally will still be beneficial. A big problem in medicine in general is that drugs can work exceptionally well in a younger person, yet the benefits are more marginal in the elderly.

I think in that Unity study on cartilage senescent cells in mice, there still was benefits in elderly mice, just a lot less benefit as compared to younger mice.

Even more marginal benefits in the elderly still make for successful drugs. Like in my hypothetical example of the person dying of kidney disease in an average of 7 years with treatment, versus 5 years with no treatment.

Posted by: aa3 at October 25th, 2018 9:34 PM

stockzz: Its been sort of funny watching the panic selling on Unity over the last month. A lot of short term traders bought in during the pumping on CNBC, while the stock was rising on high volume.

Weeks later those same short term traders had to hold their heads in shame and sell for horrific losses.

Posted by: aa3 at October 25th, 2018 9:59 PM

@ aa3: I don't mean to suggest local clearance will have *no* effects, just that they may be underwhelming to many of us looking for one of the magic bullets to help reverse damage accumulation and its resulting systemic aging phenotype. For example, there may be local effects that produce reduced pain in OA after ablating SCs, which would be huge as a benefit to sufferers, even it it has no healthspan or lifespan benefit due to lack of regeneration. Also, if Unity recruits principally from a younger population for their trials (the trial recruits between ages 40 and 80, I believe) they may see sufficient regeneration to still make their approach the standard of care for a disease like OA that is refractory to most other treatments; if so, they'll make money. (Speculation alert: I have no evidence what their population ages in the current clinical trial may in fact turn out to be.)

Posted by: Gary at October 26th, 2018 12:34 AM

This is really the core issue that Unity will need to keep their fingers crossed on

https://endpts.com/mixed-data-doesnt-stop-this-biotech-unicorn-from-plotting-a-looming-phiii-showdown/

Cartilage regeneration is not a "given", and pain / function improvement is not enough to win in this market - Chondrogenesis is an extremely complex form of bio-morphologic regeneration in humans, and the hope that new pristine cartilage will just miraculously start churning out is a leap of faith

To date, there has never been a "disease-modifying osteoarthritis drug" (DMOAD) approval

In this recent Phase 2b Samumed study there was no DMOAD activity seen at 24 weeks - now they will try for 52 weeks

Will be interesting how this will compare to whatever happens with the Unity Biotechnology senolytic drug approach

Posted by: Ira S. Pastor at October 26th, 2018 4:15 AM

I read stuff at Longecity and it didn't sound very impressive. Helga sounds OK as to some improvements.

My other question is, can removal by senolytics possibly get rid of lipofuscin laden cells with some selectivity or preference? That might be very useful, if we can get heart muscle involved.

Posted by: Chris Zell at October 26th, 2018 8:59 AM

Just finished my 3rd course of D&Q. And have blood test results.
My cc is totally resolved, no more problems, just as I mentioned in my last comments.
I can't detect any improvement in my arthritis, I am really trying hard! Maybe slightly less pain???
Blood test very interesting. Had elevated CEA for years, creeping up to over 10, last test earlier this year 9.2. Todays result: 0.2
The only explanation is D&Q.
Could that be used as a bio marker? Just thinking.

Posted by: Helga at October 26th, 2018 9:55 AM

@Helga
Thanks for the update. Great news about your CEA levels. The reduction may be due to quercetin alone (possibly via lowering PGE2):
https://www.ncbi.nlm.nih.gov/pubmed/16846595

Posted by: CD at October 26th, 2018 3:45 PM

Gary: I too am hoping the more revolutionary goal of wiping out senescent cells from all around the person works out. I think both paths are worth pursuing at this point.

My thinking is the Unity scientists and pharma people must feel that if the results seen in mice in OA are repeated in humans, then it will be enough for approval and at least some re-imbursements.

Of course the timelines are depressing for futurist thinkers.. like assuming it gets approved, we are talking 2023 for approval. Then it takes a few years to scale up sales, even if you have a good drug.

Posted by: aa3 at October 26th, 2018 7:09 PM

@CD I doubt it. Had taken daily 800 -1000 mg of Q several years ago, for duration of 3 months at a time, 3 months on, 3 months off - suggestion of LE - But did not notice anything.
If anything, CEA kept creeping up.

Posted by: Helga at October 27th, 2018 3:44 AM

@CD and @ Cuberat D&Q self - experimentation I feel utterly foolish! The email copy was barely legible. My hard copy has CEA as 8.2 NOT 0.2. Pls. ignore the above.
However, using "agingai" and their 33 input parameter, my biological age came back with 28 years. I had double checked all input and units, no mistake made. Earlier in the year it was 40 years. My chronological age is 80 years.

Posted by: Helga at October 27th, 2018 7:49 AM

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