Senolytic drugs under scrutiny

[TomBAvoider]

http://wtkr.com/2017/09/05/new-class-of-drugs-targets-aging-to-help-keep-you-healthy/

 

Scientists have long known that certain processes influence your body’s aging on the cellular level, according to the paper. Those processes include inflammation, changes in your DNA, cell damage or dysfunction and the accumulation of senescent cells.

It turns out that those processes are linked. For instance, DNA damage causes increased senescent cell accumulation, Kirkland said.

So an intervention that targets senescent cells could attenuate other aging processes as well, according to the new paper. That is, once such an intervention is tested for efficacy and safety.

[Michael R]

This is a good pop-press piece, hitting all the buttons you would hope them to.

 

The JAGS paper is subscriber-only, but Kirkland also wrote a very recent open-access piece on the same subject: Cellular Senescence: A Translational Perspective.

[TomBAvoider]

The translational perspective is a good overview, but I'd like to see human trials. My expectations are rock bottom. 

[Michael R]

Now you're just being bloody-minded . Seriously: the work on senolytic agents is just amazing: they seem to be damned close to panaceas, slowing or reversing an astonishing array of diseases of aging and all by themselves increasing median LS by up to 25%. It's certainly warranted to be at least skeptical of the translatability of a messing-with-metabolism intervention like CR or rapa, but much less so with an intervention that removes aging damage present "naturally" in aging members of both species.

 

In any case, you won't have that long to wait: I see that the pop press piece doesn't quite come out and say it, but UNITY Biotechnology has said that they expect to have their proprietary senolytic in human clinical trials for osteoarthritis by the end of this year (elsewhere, I believe they've said early 2018).

 

Edit: Meanwhile, Rescue Elders (with which CR Society President is now closely involved) is already now running an uncontrolled trial of dasatinib+quercetin as senolytic therapy: I'm not clear on what data they're collecting, and obviously it will be a lot less rigorous than an RCT done with $116 million in Series B funding and the involvement of many scientific hands deeply steeped in senescent cell biology — but it won't be nothing, and I'm hoping something concrete and/or self-evident will come of it.

 

If you aren't optimistic about this, you need more happy juice .

[TomBAvoider]

I would like to remind your optimistic self, that entropy is unidirectional as far as we know, that time is not reversible as we cannot travel faster than light, and that we cannot even stop time as we cannot travel even as fast as the speed of light. All this is to say that all my life I've heard promises, not one of which has come close to being fulfilled about any age-retarding drug (rapa being a possible exception - but note how it's possibly not compatible with CR and not superior to CR in effect, therefore in some sense superflous given our accessability to CR with fewer side effects). My suspicion, honed by a lifetime of experience with hype and promises, is that these senolytic drugs are more of the same - a big nothingburger for actual flesh and blood human beings living in the present and who will (hopefully) be alive in the next 20 years or so.

 

Old wine, new bottle:

 

"damned close to panaceas"

"amazing"

"reversing an astonishing array of diseases of aging"

 

I've heard it all before. The result has always been the same - equal to alchemists results with the philosophical stone. It's centuries, if not millennia old. I ain't buying.

 

If this were another 200 years into the future, I would be more optimistic. However, given the history of biomedical progress so far, based on that track record 1980-present, I suspect the chances of success within the next 20-30 years is somewhere between 0 and 0.000000000000000001%. Hence my expectations: rock bottom and scraping lower if possible.

[BrianMDelaney]

I'm so convinced by the evidence I've so far seen -- as well as by various theoretical reflections -- that I plan to try dasatinib + quercetin within a month or so. Details later.

 

Brian

[Saul]

I agree with you Brian. Keep me informed; I'll be happy to join you.

 

-- Saul

[Saul]

Please let me know the details when available.

 

-- Saul

[BrianMDelaney]

Saul, will do.

 

Meanwhile, you, or anyone who might be interested can sign up for whatever studies you want, here:

 

http://www.rescueelders.org/

 

Click on "Studies" at the top.

 

Brian

[Saul]

Thanks Brian!

-- Saul

[Michael R]

I would like to remind your optimistic self, that entropy is unidirectional as far as we know

That's true, but that doesn't bear the implications you seem to be drawing. Entropy doesn't prevent us from undoing aging processes. Here, we're not talking about simply reducing the rate at which cells become senescent, but about removing them from the aging body after they've formed. We aren't violating the Second Law of Thermodynamics when we maintain old Model Ts or hippie-era VW buses in the same tip-top shape they were in when they rolled off of the assembly line, or even when we restore them to such order after they've broken down.

 

This is the crucial distinction between messing-with-metabolism approaches like CR and rapa (which seek to force the body to generate less aging damage and thus slow down the degenerative aging process) and the repair-based heuristic of SENS. By removing, repairing, replacing, or rendering harmless the inert molecular and cellular damage whose accumulation underlies the slide into frailty that is aging, we can return those essential biomolecules to their youthful fidelity, creating a body that is once again structurally and functionally young.

 

You need to read this book.

 

All this is to say that all my life I've heard promises, not one of which has come close to being fulfilled about any age-retarding drug (rapa being a possible exception

But >90% of that was BS from the outset, or showed itself to be non-viable early on. This is a robust body of research, and it's headed to the clinic.

 

 

I've heard it all before. The result has always been the same - equal to alchemists results with the philosophical stone. It's centuries, if not millennia old. I ain't buying.

You have never heard it before about a damage-repair based therapeutic, and you have really only very rarely seen work this promising on any messing-with-metabolism, age-retarding interventions — most of which have never been turned into a therapy. Other than rapa (which is, again, not in the same class and is inherently less likely to translate and clearly questionable in terms of safety), I challenge you to name a single "packagable" intervention (like a pill or injection) that has ever gotten anywhere near this far in terms of documented effects in normally-aging mammals.

[BrianMDelaney]

 

But >90% of that was BS from the outset, or showed itself to be non-viable early on. This is a robust body of research, and it's headed to the clinic.

 

It's actually in the clinic now, in a loose sense: "in the clinic" means, of course, very small, "phase 0" human trials are underway. We'll have results in a matter of weeks, I'm pretty sure. (I'm not in a position to give more details yet.)

 

Exciting times!

 

Brian

[Gordo]

Quit teasing us Brian  

 

Regarding entropy/2nd law - it only applies to closed systems, which definitely does not apply to the human body (or any other living organism) considering these systems have unlimited amounts of input energy, and virtually no end to outside tinkering including but not limited to, replacement parts.

[KHashmi317]

Seriously: the work on senolytic agents is just amazing: they seem to be damned close to panaceas, slowing or reversing an astonishing array of diseases of aging and all by themselves increasing median LS by up to 25%. 

TTBOMK, cellular senescence is a good thing for tumor suppression in younger organisms. In fact, that (in and of itself) may be a big reason cancer rates are relatively low until the org. reaches late-middle to old age. Is this correct? (not sure which age-range animals were in senolytic experiments).

If correct, why would a person less than senior age mess with senolytic agents ?

[KHashmi317]

In any case, you won't have that long to wait: I see that the pop press piece doesn't quite come out and say it, but UNITY Biotechnology has said that they expect to have their proprietary senolytic in human clinical trials for osteoarthritis by the end of this year (elsewhere, I believe they've said early 2018).

UNITY's CEO shares some basic info in this Nov. 2016 video:

 

 

Not sure how much is hype ... but it is a slick presentation . The kind that catches the eye of Sand Hill VC's and seed investors. Hence that big $116Mil. infusion. 

[BrianMDelaney]

Not sure what UBX0101 can do that navitoclax or dasatinib+quercetin can't do. Lots of people are already doing group buys on those at Longecity and elsewhere. I'm waiting a few weeks, but then I'll be trying d+q, to start.

 

My strategy will be to target all the SCAPs (Senescent Cell Anti-apoptotic Pathways) possible, as long as there's reasonable rodent safety data. I wouldn't recommend this for others, of course. Waiting for human data would be the cautious approach.

 

(TTBOMK? To The Blumpkin Over Ma Kardashian?)

 

Brian

[Sibiriak]

TTBOMK,    tocotrienols + quercetin  hasn't been been mentioned.

 

 

Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence

https://www.researchgate.net/publication/281588707_Pleiotropic_Effects_of_Tocotrienols_and_Quercetin_on_Cellular_Senescence_Introducing_the_Perspective_of_Senolytic_Effects_of_Phytochemicals

Abstract

The possibility to target cellular senescence with natural bioactive substances open interesting therapeutic perspective in cancer and aging. Engaging senescence response is suggested as a key component for therapeutic intervention in the eradication of cancer. At the same time, delaying senescence or even promote death of accumulating apoptosis-resistant senescent cells is proposed as a strategy to prevent age related diseases. Although these two desired outcome present an intrinsic dichotomy, there are examples of promising natural compounds that appear to satisfy all the requirements to develop senescence-targeted health promoting nutraceuticals.

 

Tocotrienols (T3s) and quercetin (QUE), albeit belonging to different phytochemical classes, display similar and promising effects "in vitro" when tested in normal and cancer cells. Both compounds have been shown to induce senescence and promote apoptosis in a multitude of cancer lines. Conversely, they display senescence delaying activity in primary cells and rejuvenating effects in senescent cells. More recently, QUE has been shown to display senolytic effects in some primary senescent cells, likely as a consequence of its inhibitory effects on specific anti-apoptotic genes (i.e. PI3K and other kinases). Senolytic activity has not been tested for T3s but part of metabolic and apoptotic pathways affected by these compounds in cancer cells overlap with those of QUE. This suggests that the rejuvenating effects of T3s and QUE on pre-senescent and senescent primary cells might be the net results of a senolytic activity on senescent cells and a selective survival of a sub-population of non-senescent cells in the culture. The meaning of this hypothesis in the context of adjuvant therapy of cancer and preventive anti-aging strategies with QUE or T3s is discussed.

Cf.  Tocotrienols, health and ageing: A systematic review

PMID: 27889054

http://sci-hub.cc/10...tas.2016.11.003

 

Abstract

 

OBJECTIVES:

A systematic review of studies was undertaken to evaluate the potential effect of intake of tocotrienols or circulating levels of tocotrienols on parameters associated with successful ageing, specifically in relation to cognitive function, osteoporosis and DNA damage.

 

METHODS:

Following PRISMA guidelines a systematic review of epidemiological observational studies and clinical trials was undertaken. Inclusion criteria included all English language publications in the databases PubMed and Scopus, through to the end of July 2016.

 

RESULTS:

Evidence from prospective and case-control studies suggested that increased blood levels of tocotrienols were associated with favorable cognitive function outcomes. A clinical trial of tocotrienol supplementation for 6 months suggested a beneficial effect of intake on DNA damage rates, but only in elderly people. Regarding osteoporosis, only in vitro studies with cultures of human bone cells were identified, and these demonstrated significant inhibition of osteoclast activity and promotion of osteoblast activity.

 

CONCLUSIONS:

Research in middle-aged and elderly humans suggests that tocotrienols have a potential beneficial anti-ageing action with respect to cognitive impairment and DNA damage. Clinical trials are required to elucidate these effects.

 

Modulators of cellular senescence: Mechanisms, promises, and challenges from in vitro studies with dietary bioactive compounds

https://www.researchgate.net/publication/260609445_Modulators_of_cellular_senescence_Mechanisms_promises_and_challenges_from_in_vitro_studies_with_dietary_bioactive_compounds

 

 

 

 

[Michael R]

 

Seriously: the work on senolytic agents is just amazing: they seem to be damned close to panaceas, slowing or reversing an astonishing array of diseases of aging and all by themselves increasing median LS by up to 25%.

TTBOMK, cellular senescence is a good thing for tumor suppression in younger organisms. In fact, that (in and of itself) may be a big reason cancer rates are relatively low until the org. reaches late-middle to old age. Is this correct? (not sure which age-range animals were in senolytic experiments). If correct, why would a person less than senior age mess with senolytic agents ?

 

They've been tested in long-term studies starting in early middle aged and in old mice.

 

Again, you have to draw a bright-line distinction between interventions that inhibit the metabolic drivers of aging damage, and interventions that remove, repair, or replace existing aging damage. Preventing the activation of the senescence program in precancerous cells is absolutely risky at any age, because it gives those cells the chance to keep replicating and eventually acquire all the "Hallmarks of Cancer" and become full-blown metastatic disease. But removing cells after they've become senescent allows the original anti-cancer benefit of inducing senescence in such cells to happen, but then reduces the cancer risk to zero by eliminating them altogether, and eliminates the baleful effects of their ongoing presence.

 

 

In any case, you won't have that long to wait: I see that the pop press piece doesn't quite come out and say it, but UNITY Biotechnology has said that they expect to have their proprietary senolytic in human clinical trials for osteoarthritis by the end of this year (elsewhere, I believe they've said early 2018).

UNITY's CEO shares some basic info in this Nov. 2016 video

 

Not sure how much is hype ...

Not much: look at the published science.

 

Not sure what UBX0101 can do that navitoclax or dasatinib+quercetin can't do.

It's proprietary, so one thing it can do is create the IP needed for a viable route to financing proper clinical trials.

 

But on the pure biomedical side: we don't know its exact MoA beyond involving apoptosis, but it is evidently one of the UNITY compounds that UNITY CEO Ned David stated "are 300 times more poisonous to these cells than to non-senescent ones.” Navitoclax/ABT263 has EC50 values for senescent vs normal cells ranging in different in vitro models from 8.69 to 21 (PMID 26657143, Supplemental Fig. 1(e)). Unfortunately, no one has done actual EC50 calculations for D or Q; per Kirkland, "N is senolytic in HUVECs [human vascular endothelial cells], IMR90 [human lung] cells, and [mouse embryonic fibroblasts], but not in senescent human primary  preadipocytes"; D is effective against preadipocytes, Q against HUVECs. We don't know anything about cell-type selectivity of UBX0101.

 

Campisi/UNITY have also published that Navitoclax is effective in fibroblasts induced into senescence by multiple means; we have no equivalent published data on any of the other agents.

 

I'm aware of two labs (neither of them Campisi/UNITY) that have tried to independently replicate the reported senolytic effect of quercetin, and neither has been able to do so: one group got inconclusive results and is trying a second round on different cell types, while the other got a mild inhibition of one component of the senescence-associated secretory phenotype (SASP) but no selective killing. It may be significant that the Mayo group did not report in vivo results with quercetin alone, but only in combination with dasatinib; the reported results could therefore be attributable to dasatinib alone, or quercetin might enhance dasatinib's effects but have no benefit as a monotherapy.

 

Two rodent lifespan studies using quercetin have come to less than promising results: the redoubtable Steve Spindler found there was no effect in a study using a dose of quercetin similar to that used by the Mayo group,(1) while it shortened life rather than lengthening it in the other, using about twice that dose.(2) The protocol in these studies was not ideal for testing a putative senolytic agent — one would want periodic cycles of administration rather than chronic dosing — but these results add to doubts of the benefits or wisdom of decades of high-dose self-experimentation.

 

Lots of people are already doing group buys on those at Longecity and elsewhere. I'm waiting a few weeks, but then I'll be trying d+q, to start.

I'm glad you at least have some oversight ...

 

My strategy will be to target all the SCAPs (Senescent Cell Anti-apoptotic Pathways) possible, as long as there's reasonable rodent safety data.

The downside of all of these agents is that they selectively induce apoptosis by suppressing the activity or expression of cell-survival genes involved in cell survival, on which senescent cells heavily rely — but those same survival pathways are also needed for normal cells under stress. Inhibiting those genes does have some known and unknown negative side-effects, even if the overall effect (as seen in the studies above) is quite positive. Because they've only been tested for short periods in cancer patients and for longer periods in mice in the lab, we don't know if they aren't (for instance) somewhat depleting stem cell pools used for repair of ordinary injuries or for immune function that aren't drawn down as much by mice living in safe cages with no risk of injury or infection.

 

Future therapies can do much better by using cell-surface markers, the unusual cell-to-cell communication system of senescent cells, or targeting cells with components of the senescence program actively engaged to more selectively target senescent cells (this last being the strategy of Oisín Biotechnologies, a startup targeting the clearance of senescent cells from aging tissues using a transient kind of gene therapy, which was launched  with funding from SENS Research Foundation and the Methuselah Foundation and with some intellectual property match-making also from the Foundation:

 

https://www.fightaging.org/archives/2016/02/the-sens-rejuvenation-biotechnology-companies/

 

https://www.fightaging.org/archives/2016/02/an-interview-with-gary-hudson-of-oisin-biotechnologies-senescent-cell-clearance-startup/

 

http://www.leafscience.org/gary-hudson/

 

(TTBOMK? To The Blumpkin Over Ma Kardashian?)

Google, Brian. There's even a public radio show ;) .

 

TTBOMK, tocotrienols + quercetin hasn't been been mentioned.TTBOMK, tocotrienols + quercetin hasn't been been mentioned.

 

On quercetin, see above. The reviews you cite on T3s are really irresponsible speculation: there is, at present, zero evidence that they are senolytic, or even that they selectively hit Bcl family members known to be selectively induced in senescent cells.

 

The figures you reproduce all illustrate a range of compounds that either inhibit the formation of senescent cells, or might do so on the basis of mechanistic speculation: there is no suggestion here that any of them ablate existing senescent cells.

 

References

1: Spindler SR, Mote PL, Flegal JM, Teter B. Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice. Rejuvenation Res. 2013 Apr;16(2):143-51. doi: 10.1089/rej.2012.1386. PubMed PMID: 23432089.

 

2: Jones E, Hughes RE. Quercetin, flavonoids and the life-span of mice. Exp Gerontol. 1982;17(3):213-7. PubMed PMID: 7140862.

[Sibiriak]

Michael Rae:  The figures you reproduce all illustrate a range of compounds that either inhibit the formation of senescent cells, or might do so on the basis of mechanistic speculation: there is no suggestion here that any of them ablate existing senescent cells.

 

 

 

The figures I reproduced were only meant to give a taste of the article, not represent its entire content.    If you actually read the article you will see that it does in fact deal with ablation of senescent cells, as well as immunosurveillance  "clearance" of SCs.  True, the focus is primarily on  in vitro studies and mechanistic speculation, but there was no claim otherwise--hence the title "Modulators of cellular senescence: Mechanisms, promises, and challenges from in vitro studies with dietary bioactive compounds."   Not surprisingly then,   when it comes to ablation  the article does not go beyond discussion of potential mechanisms and candidate bioactive dietary compounds. 

 

The authors posit six categories of cellular senescence modulators: SASP modulators, immunosurveillance enhancers, inducers, delayers, rejuvenators, and ablators.

 

 

[BrianMDelaney]

Michael,

 

Agree that Oisín Biotechnologies' approach is extremely promising (and well-done, SENS and Meth. Foundation, for helping to fund them!).

 

For now, I'm impatient enough that I'm going to start trying some of the Rescue Elders protocols even though the evidence for efficacy and safety isn't immense. D+q seems most promising to me (cheap, likely safe, probably at least a bit helpful).

 

Off-target effects are a concern, of course, but loss of some stem cells, and indeed any other cell type, can probably be remedied/offset within 10-15 years, with the exception of neocortical neuron loss, of course, which is the trickiest age-reversal problem we face. But I doubt d or q would knock out neocortical neurons, but of course we don't know....

 

 

Lots of people are already doing group buys on those at Longecity and elsewhere. I'm waiting a few weeks, but then I'll be trying d+q, to start.

I'm glad you at least have some oversight ...

 

To the blumpkin over Ma Kardashian, there is no oversight involved in any of the group buys (aside from the obvious "oversight" of quality control: all the people involved agree about the need for careful assays of whatever we purchase (whether or not it comes from China...).

 

Perhaps you just mean I'll be guided, in the case of d+q, by results of the small trials we're doing using diff. dosing protocols. Yes, I will be.

 

Brian