459 replies to this topic

[Sanhar]

This falls directly under "destruction of senescent cells" as per the focus of SENS.

 

www.sciencedaily.com/releases/2015/03/150309144823.htm

[Bryan_S]

Just read the article myself in http://medicalxpress.com/.

 

Senolytics appears to be a new class of drugs that may one day help us eliminate senescent cells that just hang on.

This appeared in 2013 along the same lines.

http://www.ncbi.nlm....les/PMC3582125/

 

​Full article

http://www.uwaging.o...application.pdf

 

 

[Logic]

Great find Sanhar, but you need to advertise a bit more!  
 
New class of drugs dramatically increases healthy lifespan by killing of senescent cells:
"...The team suspected that senescent cells' resistance to death by stress and damage could provide a clue. Indeed, using transcript analysis, the researchers found that, like cancer cells, senescent cells have increased expression of "pro-survival networks" that help them resist apoptosis or programmed cell death. This finding provided key criteria to search for potential drug candidates.[/size]
Using these criteria, the team homed in on two available compounds -- the cancer drug dasatinib (sold under the trade name Sprycel®) and quercetin, a natural compound sold as a supplement that acts as an antihistamine and anti-inflammatory.
Further testing in cell culture showed these compounds do indeed selectively induce death of senescent cells. The two compounds had different strong points. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall..."

Dasatinib
http://en.wikipedia....Adverse_effects

Edited by Logic, 10 March 2015 - 02:24 AM.

[Sanhar]

Great find Sanhar, but you need to advertise a bit more!  
 
New class of drugs dramatically increases healthy lifespan by killing of senescent cells:
"...The team suspected that senescent cells' resistance to death by stress and damage could provide a clue. Indeed, using transcript analysis, the researchers found that, like cancer cells, senescent cells have increased expression of "pro-survival networks" that help them resist apoptosis or programmed cell death. This finding provided key criteria to search for potential drug candidates.[/size]
Using these criteria, the team homed in on two available compounds -- the cancer drug dasatinib (sold under the trade name Sprycel®) and quercetin, a natural compound sold as a supplement that acts as an antihistamine and anti-inflammatory.
Further testing in cell culture showed these compounds do indeed selectively induce death of senescent cells. The two compounds had different strong points. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall..."

Dasatinib
http://en.wikipedia....Adverse_effects

 

By advertising what do you mean?  I'm just posting links so people can read the Science Daily article as they might have missed it.
 

[Kalliste]

This forum turns various words blue for reasons that may be confusing at times. By advertise I think he meant you should post some juicy quotes. Promising news anyway, though I don't expect to be killing my senescent cells yet in 10 years at best.

 

A fix for senescent cells along with something to clean up AGE's might be the first two SENS components that arrive so we better keep an eye on them.

 

Pity these scientists are practically sleep-walking in terms of research speed. Imagine the panic if they were judging aging by the same standards as Ebola.

Edited by Cosmicalstorm, 10 March 2015 - 06:03 AM.

[ceridwen]

I wish they were aging kills far more people

[Sanhar]

Okay, I can quote more in the future.

[PWAIN]

Anyone know what sort of dose of Quercetin was used? Are we talking a super mega dose or just a typical amount? I am wondering why people using the stuff didn't have more profound effects.

[SearchingForAnswers]

I'm also curious as to the dosage and duration of Quercetin, and whether it was regular or dihydrate. If anybody can dig that up, please post!

[Danail Bulgaria]

In case you haven't found it already, the original article is published in the "Aging Cell" scientific magazine.

 

The official web site of the magazine:

http://onlinelibrary...(ISSN)1474-9726

 

The article abstract:

http://onlinelibrary....12344/abstract

 

The article full text in downloadable pdf:

http://onlinelibrary.../acel.12344/pdf

[ceridwen]

Before everyone gets too excited may I remind you that this experiment has been done on MICE! I have spent over a year trying experiments that have been done on mice only to be disappointed. Perhaps that's why quercetin doesn't seem so exciting. Alternatively perhaps it does work but does so so slowly in humans that it hasn't been noticed yet. What might happen is that it puts off serious illness before people get them. Has anyone had any miraculous cures on it recently? If so how long did they take it for?

[corb]

It's always great news to see a SENS concept translated to an experiment.

 

Before everyone gets too excited may I remind you that this experiment has been done on MICE! I have spent over a year trying experiments that have been done on mice only to be disappointed. Perhaps that's why quercetin doesn't seem so exciting. Alternatively perhaps it does work but does so so slowly in humans that it hasn't been noticed yet. What might happen is that it puts off serious illness before people get them. Has anyone had any miraculous cures on it recently? If so how long did they take it for?

 

That's a good sentiment, the compounds they used are just the first thing they've found to work, they're not a therapeutic option. Also there's still a lot more testing that needs to be done.

 

Effects of senolytic drugs on healthspan remain to be tested in chronologically aged
mice, as do effects on lifespan. Senolytic regimens need to be tested in non-human primates.
Effects of senolytics should be examined in animal models of other conditions or diseases to
which cellular senescence may contribute to pathogenesis, including diabetes,
neurodegenerative disorders, osteoarthritis, chronic pulmonary disease, renal diseases, and
others (Tchkoniaet al. 2013; Kirkland & Tchkonia 2014).

[Danail Bulgaria]

Plus there are many researchers, who disprove the existence of the "immortality elixir", e.g. the existence of a single compound, that to mend aging.

Edited by seivtcho, 10 March 2015 - 06:26 PM.

[Sanhar]

As there is no one cause to aging so can there be no one solution to it, be this involving drugs or not.

[corb]

Plus there are many researchers, who disprove the existence of the "immortality elixir", e.g. the existence of a single compound, that to mend aging.

SENS therapies are not supposed to give significant lifespan increases when only one of the therapies is used.

That doesn't mean they can't be effective as prevention for developing pathologies.
And I suspect senescent cells removal, followed by stem cells a week or so later might have quite the profound effect on overall health.

It doesn't need to be full rejuvenation for the effects to be noticeable and for it to affect life expectancy as well.

[Danail Bulgaria]

 

Plus there are many researchers, who disprove the existence of the "immortality elixir", e.g. the existence of a single compound, that to mend aging.

.....

That doesn't mean they can't be effective as prevention for developing pathologies.
And I suspect senescent cells removal, followed by stem cells a week or so later might have quite the profound effect on overall health.

It doesn't need to be full rejuvenation for the effects to be noticeable and for it to affect life expectancy as well.

 

 

And you are talking for at least two treatments here - 1) removal of the senescent cells and 2) replacing them with stem cells a week or so later. So it is not the usage of a single "immortality elixir" what you are talking about.

[niner]

 

Plus there are many researchers, who disprove the existence of the "immortality elixir", e.g. the existence of a single compound, that to mend aging.

 

SENS therapies are not supposed to give significant lifespan increases when only one of the therapies is used.

That doesn't mean they can't be effective as prevention for developing pathologies.
And I suspect senescent cells removal, followed by stem cells a week or so later might have quite the profound effect on overall health.

It doesn't need to be full rejuvenation for the effects to be noticeable and for it to affect life expectancy as well.

 

There's nothing about SENS that says individual therapies will not extend life.  I'd expect most of them to extend life on their own, but some would be better than others.   The use of a drug therapy to recover apoptotic competence in senescent cells is a huge breakthrough, one that I did not expect to see this soon.  I hope that it can be translated to humans.  Quercetin bioavailability in humans is fairly awful, but should be amenable to the same sort of formulation strategies that have been successful with curcumin.

 

Senescent cells are bad.  They pump out toxic crap all day long, poisoning the healthy cells around them and degrading the health of the organism.  Getting them to commit suicide as they should is a really really good thing.  With luck, we'll be able to develop an orally active cocktail of drugs with good PK and broad effectiveness, and perhaps take a yearly course of them.  Big Pharma may be interested; they can probably find an age related disease to serve as a work-around for the FDA's imbecilic "aging is not a disease" dictum.

[proileri]

Before everyone gets too excited may I remind you that this experiment has been done on MICE! I have spent over a year trying experiments that have been done on mice only to be disappointed. Perhaps that's why quercetin doesn't seem so exciting. Alternatively perhaps it does work but does so so slowly in humans that it hasn't been noticed yet. What might happen is that it puts off serious illness before people get them. Has anyone had any miraculous cures on it recently? If so how long did they take it for?

 

Is it supposed to be a miracle cure, though?

 

As big mortality factors like CVD etc. take years or decades to develop, optimising your lifespan is more about keeping your body functioning and reducing risk of serious disease as efficiently as possible, IMO - 'proper maintenance', so to speak. In the maintenance sense, these 'senolytics' finds are quite promising - they may be another tool that you can apply to keep your system healthy over the years.

 

CVD causes up to 50% of old age mortality, so anything involved with cardiovascular health is good news.   

 

Someone asked about the doses, seems that with quercetin the optimal +proliferating/-senescent cells ratio was at 5-10 µM (some effect on senescent and minor effect on proliferating), and max. -senescent cells at 20 µM (large reduction of both cell types).

 

Edited by proileri, 11 March 2015 - 09:01 AM.

[nowayout]

Who's that guy again who did the longevity screening of many different dietary supplements in mice, whose work has been discussed here many times?  I can't remember enough details for google to help me with this.   Does anyone know if he tested quercetin?  He must have.  I remember all their results were negative for lifespan extension, at least all the ones they were willing to go public with. 

Edited by nowayout, 11 March 2015 - 01:46 PM.

[nowayout]

 

 

There's nothing about SENS that says individual therapies will not extend life.  I'd expect most of them to extend life on their own, but some would be better than others.   The use of a drug therapy to recover apoptotic competence in senescent cells is a huge breakthrough, one that I did not expect to see this soon.  I hope that it can be translated to humans.  Quercetin bioavailability in humans is fairly awful, but should be amenable to the same sort of formulation strategies that have been successful with curcumin.

 

 

FWIW, the quercetin was administered orally in the mice. 

[corb]

Quercetin, seems like the next big thing in self medicating I see in the future of the supplements forum.

 

http://www.ncbi.nlm....0?dopt=Abstract

 

 

Quercetin, glycosylated form of flavonoid compound, has potent antioxidant and anti-inflammatory properties. In this study, we have investigated the effects of quercetin on skin lesion, high mobility group box (HMGB)1 cascade signaling and inflammation in atopic dermatitis (AD) mouse model. AD-like lesion was induced by the application of house dust mite extract to the dorsal skin of NC/Nga transgenic mouse. After AD induction, quercetin (50 mg/kg, p.o) was administered daily for 2 weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for HMGB1, receptor for advanced glycation end products (RAGE), toll like receptor (TLR)4, nuclear factor (NF)κB, nuclear factor-erythroid-2-related factor (Nrf)2, kelch-like ECH-associated protein (Keap)1, extracellular signal-regulated kinase (ERK)1/2, cyclooxygenase (COX)2, tumor necrosis factor (TNF)α, interleukin (IL)-1β, IL-2Rα, and other inflammatory markers in the skin of AD mice. In addition, serum levels of T helper (Th) cytokines (interferon (IFN)γ, IL-4) were measured by enzyme-linked immunosorbent assay. Quercetin treatment attenuated the development of AD-like skin lesions. Histological analysis showed that quercetin inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells. Furthermore, quercetin treatment down-regulated cytoplasmic HMGB1, RAGE, nuclear p-NFκB, p-ERK1/2, COX2, TNFα, IL-1β, IL-2Rα, IFNγ and IL-4 and up-regulated nuclear Nrf2. Our data demonstrated that, the HMGB1/RAGE/NFκB signaling might play an important role in skin inflammation, and quercetin treatment could be a promising agent for AD by modulating the HMGB1/RAGE/NFκB signaling and induction of Nrf2 protein. This article is protected by copyright. All rights reserved.

[GreenPower]

From Science Daily.

Scientists have identified a new class of drugs that in animal models dramatically slows the aging process -- alleviating symptoms of frailty, improving cardiac function and extending a healthy lifespan.

 

Basically they have identified two drugs which kills of old cells and thereby "in animal models dramatically slows the aging process -- alleviating symptoms of frailty, improving cardiac function and extending a healthy lifespan".

 

This sounds much like the study performed on TA-65 which showed a decrease in the number of cells with short telomeres while the mean telomere lengths of all cells also decreased. The risk with this approach is that you will have a short term increase in health, while you will have a long term decrease in both health and life span.

[Kalliste]

Quote from other forum below. How long until people try this at home? We already have C60

From the paper you really want the combo of dasatinib (D) and quercetin (Q). Both D and Q are able to selectively kill senescent cells in two species albeit with distinct cell type specificity. We tested if D+Q administered by oral gavage was senolytic in vivo. We initially tested D+Q in old mice (>24 months-old). A single dose of D+Q (D: 5 mg/kg body weight and Q: 50 mg/kg by oral gavage here and in the following studies), reduced SA-βgal+ cells and p16 mRNA in fat from old mice within 5 days. D+Q also reduced p16-positive cells in liver from old mice. As with AP20187, the drug that activates selective killing of cells expressing p16 in transgenic INK-ATTAC mice (Baker et al. 2011), not all senescent cells were removed by D+Q.

[Kalliste]

Some quotes, do not have time to read the entire paper today.

 

 

We will probably have to wait for real killers of senescent cells that clear them all:

 

 

 

We view this work as a first step towards developing senolytic treatments that can be

administered safely in the clinic. Several issues remain to be addressed, including some that

must be examined well before the agents described here or any other potentially senolytic

agents are considered for use in humans. For example, we found differences in responses to

RNA interference and senolytic agents among cell types. Effects of age, type of disability or

disease, whether senescent cells are continually generated (e.g., in diabetes or high fat diet vs.

effects of a single dose of radiation), extent of DNA damage responses that accompany

senescence, sex, drug metabolism, immune function, and other inter-individual differences on

responses to senolytic agents need to be studied.

 

Might combination with fasting (IGF-1) or curcumin (targets P53) be feasible?

 

 

These receptors

include the insulin, IGF-1, androgen and nerve growth factor receptors, among others (Delloye-

Bourgeois et al. 2009; Goldschneider & Mehlen 2010). It is possible that more existing drugs

that act against the targets identified by our RNA interference experiments may be senolytic. In

addition to ephrins, other dependence receptor ligands, PI3K, AKT, and serpines, we anticipate

that drugs that target p21, probably p53 and MDM2 (because they regulate p21 and serpines),

BCL-xL, and related genes will also have senolytic effects. This is especially so since existing

drugs that act through these targets cause apoptosis in cancer cells and are in use or in trials

for treating cancers, including dasatinib, quercetin, and tiplaxtinin

Side effects seems like they will not be a big deal. Again, I would like to try this right now

 

Like all drugs, D and Q have side effects, including hematologic dysfunction, fluid

retention, skin rash, and QT prolongation (Breccia et al. 2014). An advantage of single doses or

periodic short treatments is that many of these side effects would likely be less common than

during continuous administration for long periods, but this needs to be studied.

 

 

 

D and Q are both approved for use in humans and appear to be relatively safe.

Interestingly, imatinib, which is very closely related to D, was not senolytic, at least in

preadipocytes (Supplemental Fig. 4). D and Q are promiscuous, like many drugs that affect

signaling pathway kinases either directly or indirectly. Despite this, they appear to have more

senolytic activity against some types of senescent cells than others and overall they appear to

work better in combination than individually. Thus one strategy to follow in developing future

senolytic agents will be to use promiscuous agents or combinations of drugs to target antiapoptotic

networks. Alternatively, additional senolytic agents could be developed by deconvoluting

the mechanisms through which D, Q or other senolytics exert their effects.

Importantly, since we found that senescent cells originating from different types of cells vary in

susceptibility to RNA interference and pharmacological interventions, it may be feasible to

design drug strategies focused on specific indications by clearing senescent cells arising from

particular cell types or in specific organs.

 

 

 

Edited by Cosmicalstorm, 12 March 2015 - 05:37 AM.

[pone11]

Here is full text to the study in question:

http://onlinelibrary.../acel.12344/pdf

 

@Greenpower, this study looks at lifespan and healthspan.   They recorded increase in healthspan and no decrease in lifespan.   So how can you possibly hypothesize shortened telomeres from that experimental outcome?   Shortened telomeres should decrease lifespan, and you would think that it would also decrease healthspan by rapidly increasing disease incidence in the last 10% of life.   None of that happened here?

 

And if shortening of telomeres does not affect lifespan or healthspan, then what would that say about our understanding of the importance of telomere shortening in aging?

 

I think you have not called out the really amazing part of this study.    They got six months of benefit from this therapy by taking the drug ONCE!!!   In other words, they induce senescent cell death very rapidly using these drugs, then the organism is allowed to regain its internal environment without interference from drugs.   That's an extremely attractive tactic since it avoids long-term side effects from continuous use of the drugs that the study may not have seen.

 

It looks like the drugs had an effect of lowering proliferating (healthy) cells as well senescent cells.  But the remaining tissues have a higher percentage of healthy cells, so presumably once the organism fully recovers from the treatment that is the reason they see better health.

 

Can someone guide us what is the human-equivalent dose of Quercetin corresponding to 10 uM in a mouse?   Does Quercetin survive digestion if you take it in pill form?   It looks like the mice were dosed orally about 50 mg/kg of Quercetin.

 

The other drug they studied is a chemotherapy drug.   That would be a bit crazy to self-administer, even if you could obtain it.

 

The whole discussion online about telomerase-activating and telomerase-inhibiting substances is just confused.   There is a big difference between saying a substance activates or inhibits telomerase in vitro, and actually measuring longer or shorter telomeres after therapy in vivo.   Reading many of the studies, you get the distinct impression that the actual biology is way more complex than our understanding of it.   You can read 10 studies on Resveratrol and Quercetin and end up not having a clue about what the actual end result will be on telomeres in vivo.  

 

Edited by pone11, 12 March 2015 - 08:22 PM.

[niner]

I merged GreenPower's senolytics thread with this one, which also has been moved to BioScience, a more applicable forum.  Pone11's post above is a response to GreenPower's post, which it was adjacent to in the old thread.

[tunt01]

Who's that guy again who did the longevity screening of many different dietary supplements in mice, whose work has been discussed here many times? I can't remember enough details for google to help me with this. Does anyone know if he tested quercetin? He must have. I remember all their results were negative for lifespan extension, at least all the ones they were willing to go public with.

Stephen Spindler

[nowayout]

 

 

Like all drugs, D and Q have side effects, including hematologic dysfunction, fluid

retention, skin rash, and QT prolongation (Breccia et al. 2014). An advantage of single doses or

periodic short treatments is that many of these side effects would likely be less common than

during continuous administration for long periods, but this needs to be studied.

 

 

 

FWIW, their sentence is confusing, so I should be noted that the side effects listed are those of D.  These are not side effects of Q as far as I know.  The paper by Breccia et al. cited is about D. 
 

[Kalliste]

How dangerous would it be to do this in a human? Looking at some cancer forums people seems to be eating this day in and day and while complaining about prices and so on. I guess there would be some side-effects, I know cytostatica can be a real boring thing for many.

But both Q and D seems like nothing that would be too bad in one single dosing.

 

Why isn't this forum going crazy over trying this? It's the dream of all supplements so far IMO. A

[Razor444]

Apropos this thread: Kill Senescent Cells Before They Kill You (Josh Mitteldorf's blog).

 

 

The Bottom Line

I’m betting that the search for strategies that differentially kill senescent cells will soon lead to better drugs than quercetin or dasatinib.