459 replies to this topic

[aaCharley]

Life Extension Magazine - March 2015

 

Sweep Away Senile Cells

 

Main thrust seems to be on quercetin. 

Links to many studies on senescent cells.

 

Not sure why but I cannot create link to the article in this post.

Edited by aaCharley, 01 April 2016 - 02:14 AM.

[albedo]

Life Extension Magazine - March 2015

 

Sweep Away Senile Cells

 

Main thrust seems to be on quercetin. 

Links to many studies on senescent cells.

 

Not sure why but I cannot create link to the article in this post.

 

I think it is this article:

 

http://www.lifeexten...e-Cells/Page-01
 

[stefan_001]

In this abstract which is interesting for many positive things (neural outgrowth) I also noticed this about quercetin:

 

http://www.ncbi.nlm....pubmed/26936787

In addition, we found that quercetin, one of the active constituents, increased Vav3 mRNA expression.

 

because in this article VaV3 is a target for cancer drugs:

http://www.nature.co...icles/srep23100

VAV3 mRNA was markedly increased in breast cancer specimens and regulated biological parameters critical for the growth of breast tumors and their metastatic dissemination to the lung¹⁶. In addition, VAV3 was reported to be directly correlated with tumor recurrence and overall patient survival¹⁷. VAV3 expression was also elevated in androgen refractile prostate cancer cell lines and prostate cancer clinical specimens¹⁸. VAV3 knockdown greatly attenuated prostate cancer cell proliferation¹⁹ and inhibited breast cancer cell growth²⁰.

 

Might suggest caution with mega dosing?

[stefan_001]

found this study, perhaps senescent cells are not the reason for skin aging and these senolytics will have no or just limited effects:

http://www.ncbi.nlm....pubmed/27004597

[LeeYa]

@stefan_001

 

guess what the epigenome of senescent cells looks like?

[stefan_001]

@stefan_001

guess what the epigenome of senescent cells looks like?

You tell me. But it may be it doesn't matter because the study suggests that even if you get rid of them all you are stuck with cells that have undergone epigenetic drift that causes the aging phenotype.

@stefan_001

guess what the epigenome of senescent cells looks like?

You tell me. But it may be it doesn't matter because the study suggests that even if you get rid of them all you are stuck with cells that have undergone epigenetic drift that causes the aging phenotype.

[Fafner55]

Increased methylation heterogeneity does not appear to be independent of cellular senescence.  It has been associated with cellular senescence in cultured human epithelial cells.   “The senescent methylome and its relationship with cancer, ageing and germline genetic variation in humans” (2015) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574115/

[Logic]

The clearance of senescent cells goes hand in hand with the up regulation of autophagy.

ie: The up regulation of autophagy by upregulating mTOR and the inhibition of inositol monophosphate (IP3) levels with Lithium and Pterostilbene etc should be a big part of anyones Senolytics stack IMHO.

http://www.longecity...and-macrophagy/

Also important is circadian rhythm. Autophagy is upregulated during the fasted state at night just like the apoptosis of senescent cells IIRC.

http://www.longecity...ndpost&p=764866

NB: The upregulation of PARKIN by Nilotinib and the systemic effects that has:
http://www.longecity...ndpost&p=770820
 

 

 

 

 

 

[Kalliste]

 

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL 

Nature Communications 7, Article number: 11190 doi:10.1038/ncomms11190 Received 12 April 2015 Accepted 26 February 2016 Published Abstract

Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14^ARF. Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies.

 

http://www.nature.co...comms11190.html

Edited by Cosmicalstorm, 02 May 2016 - 06:06 PM.

[stefan_001]

 

 

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL 

Nature Communications 7, Article number: 11190 doi:10.1038/ncomms11190 Received 12 April 2015 Accepted 26 February 2016 Published Abstract

Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14^ARF. Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies.

 

http://www.nature.co...comms11190.html

 

 

In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.Because of its unfavorable pharmacologic properties ABT-737 is not appropriate for clinical trials, while its derivative ABT-263 has similar activity on small cell lung cancer (SCLC) cell lines and has entered clinical trials.

 

Venetoclax

 

Clinical trials studied the effects of venetoclax (ABT-199), a BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with chronic lymphocytic leukemia (CLL).Good responses have been reported. A phase 3 trial started in Dec 2015.It was approved by the US FDA in April 2016 for CLL associated with 17-p deletion. This is the first FDA approval of a BCL-2 inhibitor.

[corb]

I just read a paper that proposes a bit of caution when it comes to senolytic treatments.

It's a good paper to read for whoever is experimenting with senolytics right now. Some slight risks to consider.

 

 

Of more general interest is that a pre-senescent state in which stem cells express
senescence biomarker p16ink4a can be reversed. Expression of high levels of p16ink4a has
been considered a hallmark of senescence[19], though its clear that over-expression of
p16ink4a could sometimes be overcome[19]. Perhaps p16ink4a should be considered a
biomarker of deep-quiescence or pre-senescence rather than senescence, which may have
profound implications for basic and applied research

The idea that destruction of senescent cells, i.e., “senolysis,” will be of benefit to aging
mammals, such as mice and humans, has become quite popular. There are studies that
indicate that targeted destruction of p16ink4a expressing cells extends life- and health-span
or confers other anti-aging benefits [20] [21] [22] [23] [24]. Lifespan extension by ablation of
p16ink4a expressing cells remains controversial, as the reported 25% extended lifespan was
relative to a vehicle control group of mice that had a significantly shortened lifespan to what is
typically observed for the particular mouse strain studied[25]. However, if the results of
Garcia-Prat et al. are confirmed and extended to other stem cells, then senolytic approaches
that may provide some short-term health benefits, while unfortunately and simultaneously
destroying reservoirs of potentially recoverable regenerative activity, thus capping potential
health gains. To avoid such pitfalls, it may behoove anti-aging therapeutic drug designers to
develop treatments to first rescue pre-senescent stem cells, before destroying p16ink4a-
expressing “senescent” cells.

 

6.  Conclusion
Aging results in epigenetic changes that alter muscle stem cell function, resulting in loss of
self-renewal capacity or induction of senescence. The relative importance of each of these
mechanisms in humans remains to be elucidated. Both may be subject to therapeutic
intervention. The existence of potentially recoverable pre-senescent stem cells, should inform
the development of senolytic drugs in order to prevent unintentional reduction of regenerative
capacity.

 

http://www.ncbi.nlm....pubmed/27000748

 

It's falling into the trap of looking at senolysis as a therapy on it's own and not just a step in a full treatment. I've personally said it even in the beginning of the thread that this is pretty much the expected outcome and senolytics without stem cell implantation won't give the best outcome.

Also it hangs on potential benefits you could get from putting "quasi-senescent" cells back into "working" order, very fortunately for us the medicaments they use to this end are quite well known on these forums - rapamycin and spermidine - when it comes to efficacy we already have an idea how "effective" mtor inhibitors are in a human population (there was a paper on that recently) we can easily come to our own conclusions which could be more beneficial potentially.

 

Also an interesting thing to note is this paper looks at cells expressing p16. The paper posted previous looks at a mechanism which has not been discussed a lot as it comes to senescence p53 - although both p53 and p16 have been known players in senescence from cancer research.

p53 is antagonistic to p50/p52 (better known as NF-kB on these forums) and there is more than enough proof too much p50/p52 is not good for you and as we know it gets increases as we age.

I'm trying to give you a fuller perspective not just a quote from a paper, but maybe I'm just rambling a lot of these things should be common knowledge on the forum by now.

[albedo]

In case you missed Reason's article on the Ascentage Pharma and UNITY Biotechnology agreement:

 

"The combination of dasatinib and quercetin, for example, removes enough senescent cells in enough different tissues to produce meaningful benefits in mice. It isn't unreasonable to think that this type of result can be improved upon to the point at which it is a competitive option. Judging from recent news, it seems that UNITY Biotechnology will take the apoptosis-inducing drug development path, and, interestingly, is also setting up from the outset to deploy therapies outside the US in less heavily regulated regions:"

 

https://www.fightagi...cell-clearance/

[Fafner55]

Inflammation Markers as a Proxy for Measuring Senescent Cell Clearance

The following is speculation on my part.  Levels of inflammatory markers might serve as a rough proxy for accumulated senescent cells in the body.  Two possible markers are sedimentation rate and C-reactive protein level (hs-CRP) .  Comparing levels of these markers before and after an attempt to clear senescent cells might indicate if the attempt was in part successful.  My results are shown below.  My doctor commented that he had not seen such a low sed rate in individuals my age (61).

 

Inflammation Markers, Before and After Attempts to Clear Senescent Cells                                                  

Test                                 Reference              Pre-Clearance 7/2004      Pre-Clearance10/2006     Post-Clearance 5/2016

Sedimentation Rate        0 - 20 mm/hr                      --                                       5                                    1

 

C-Reactive Protein                                                  1.75                                  0.87                                0.8

 

[mikey]

I bought some dasatinib and quercitin months ago from TLR. Now I find that their website is gone.

 

I haven't taken D & Q because I am cautious and I wonder what people experience.

 

Are there any adverse effects with a single dose of the two?

 

From what I've gathered a while back, dosing should be:

HED for D is:  0.4054054054054054 mg/kg - since I am 85 kg, my dose would be about 34 mg.
HED for Q is:  4.054054054054054 mg/kg - since I am 85 kd, my dose would be about 345 mg.

 

I welcome comments.

Thank you in advance.

Edited by mikey, 30 May 2016 - 03:30 PM.

[Logic]

Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis

http://www.longecity...point/?p=776917

 

So this may go well with D?

[Logic]

I bought some dasatinib and quercitin months ago from TLR. Now I find that their website is gone.

 

I haven't taken D & Q because I am cautious and I wonder what people experience.

 

Are there any adverse effects with a single dose of the two?

 

From what I've gathered a while back, dosing should be:

HED for D is:  0.4054054054054054 mg/kg - since I am 85 kg, my dose would be about 34 mg.
HED for Q is:  4.054054054054054 mg/kg - since I am 85 kd, my dose would be about 345 mg.

 

I welcome comments.

Thank you in advance.

 

IIRC a good # of people have taken TLRs D+Q with good results that were visible in senescent and pre cancerous skin blemishes.
I also think more Q was added due to its low bioavailability.
You will have to read the thread to find the reports.

Look for Fafner55's report especially.

http://www.longecity...ndpost&p=722708

[corb]

 

Senescence Can Be BETter without the SASP?
Maria Grazia Vizioli
1 , 2 and Peter D. Adams 1 , 2
1 Beatson Institute for Cancer Research, Bearsden, Glasgow, United King-
dom. 2 Institute of Cancer Sciences College of Medical, Veterinary and Life
Sciences, University of Glasgow, Glasgow, United Kingdom .
Corresponding Author: Peter D. Adams, Institute of Cancer Sciences,
College of Medical, Veterinary and Life Sciences , University of Glasgow,
Glasgow G61 1BD, United Kingdom. Phone: 141-330-2306; Fax: 141-942-
6521; E-mail: p.adams@beaston.gla.ac.uk
doi: 10.1158/2159-8290.CD-16-0485
© 2016 American Association for Cancer Research.

Summary: Global remodeling of the chromatin landscape occurs during senescence, although its functional
consequence is still unclear. In this issue, Tasdemir and colleagues show that the epigenetic regulator BRD4 is
required for expression of the proinfl ammatory senescence-associated secretory phenotype and immune clear-
ance of senescent cells in vitro and in vivo . Their results could be useful in the design of novel therapies to treat
aging-related diseases, including cancer. Cancer Discov; 6(6); 576–8.  © 2016 AACR.

See related article by Tasdemir et al., p. 612 (4).

 

[...]

However, the present study also has other more positive translational implications: It establishes small-molecule inhibition of BRD4 as a candidate therapeutic strategy to suppress the pro-aging and protumorigenic activities of SASP. Because senescent cells accumulate with age and are present at sites of aging-related pathologies, the ability of BET inhibitors to prevent or ameliorate the pro-aging and protumorigenic effects of senescent cells should be explored. Notably, mice lacking CXCR2 (the receptor for multiple SASP factors CXCL1, CXCL2, CXCL5, and CXCL8) are resistant to spontaneous and inflammation-driven cancer ( 7 ). Therefore, BET inhibitors might exhibit chemopreventative/tumor
suppressive activity by suppressing inflammation-driven cancer. More speculatively, BET inhibitors might suppress the proaging effects of SASP outside of a cancer context. Also, in linewith the potential of BET inhibitors to promote healthy aging, Myc-heterozygous mice were recently shown to exhibit extended healthspan and lifespan ( 8 ). A major caveat here though is that, although BET inhibitors likely act in part by repression of MYC expression, MYC is by no means their only target. Given this complexity, it will be essential to carefully evaluate and test all the pros and cons of clinical application of BET inhibitors. Initially, BET inhibitors will continue to be tested for their anticancer activity in clinical trials, both alone and in combination with other agents. If a molecule in this class is ultimately approved for treatment of cancer, it will then be possible to assess other activities, such as suppression of inflammation, in large numbers of humans receiving BET inhibitors as anticancer agents.

 

 

Short paper. Paywalled too.
There's another paper talking more about BRD-4  in the same issue of Cancer Discovery. Much more indepth.
 I'll try to get that one.

 

 

[Wilberforce]

@mikey same. I've got two TLR doses in the fridge but I'm no longer convinced to try. Haven't seen any positive reports. The c60 does the trick wrt skin tone (and I'm presuming other organ tissue health) but it the datasnib 'feels' wrong


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[Logic]

My Nilotinib Supplier does Dasatinib if anyone is interested?

It would be easy/cheaper to have both sent to the lab for testing in round 3 of the Nilotinib buy.

 

gamesguru posted about galangin here:

http://www.longecity...ndpost&p=777892

A quick goole search brought up some very interesting info!:

 

...Galangin treatment inhibited cell proliferation and induced autophagy (130 μ mol/l) and apoptosis (370 μ mol/l). In particular, galangin treatment in HepG2 cells caused (1) an accumulation of autophagosomes, (2) elevated levels of microtubule-associated protein light chain 3, and (3) an increased percentage of cells with vacuoles. p53 expression was also increased...

http://www.ncbi.nlm....pubmed/22507894

 

Galangin: autophagy inducing flavonoid

http://www.sigmaaldr...ng=en&region=ZA

 

...Galangin is a flavonol, a type of flavonoid. It is found in high concentrations in Alpinia officinarum (lesser galangal)[1] and Helichrysum aureonitens.[2] It is also found in the galangal rhizome (Alpinia galanga)[3] and in propolis.[4] Galangin has been shown to have in vitro antibacterial[5][6] and antiviral activity.[7] The flavonol also inhibits the growth of breast tumor cells in vitro...

https://en.wikipedia.org/wiki/Galangin

 

I post this here in case anyone is interested in further researching this easily obtainable substance.

 

Edited by Logic, 23 June 2016 - 09:34 AM.

[MidwestGreg]

So I woke up this morning and I felt an unexpected effect.  My breathing feels easier and my lungs feel lighter.  It has led to a few peculiar coughs.  It feels like the type of cough and breathing you get when you go outside into freezing air and the first breath in overwhelms your lungs and you cough a bit, but it feels good.  I have no idea if that is a side effect of the drug or whether or not the senolytic cleared out some senescent cells in my lungs.  I'm not sure if lung tissue is among the tissues affected by this drug combination, but there you go; that's what I've noticed.  

 

Decimus,

 

Are you continuing the experiment? Any updates? I am very curious if you have seen any continued improvements to your lungs. Thanks
 

[Logic]

Dasatinib group buy?

 

I am currently busy with the 3rd, very successful, buy of Nilotinib and would like to get myself some Dasatinib, which they also stock.

It could easily be added to the same parcel.

 

I can get 99% pure Dasatinib for , $ 2310.00 for 500g from the Nilotinib supplier.  )

That's $ 4.62 per gram, untested.

 

3rd party testing will add $ 600.00 to the price, bringing it up to $ 2910.00 for 500 grams.

That's $ 5.82 per gram, tested.

Postage via USPS Priority Mail Small Flat Rate Box differs depending on where you are in the world.  Its $ 6.80 in the USA.

 

I have not searched to see what people are paying for Dasatinib, so have no idea how this price compares? 

I do know that there is 95% pure D available at a much lower price..?

 

If anyone is interested; please post the # of grams you would like, tested or untested?

 

 

[SearchingForAnswers]

I would be interested, but tested only. However, I haven't caught up with this thread; For a 220lb 55yo male, how much would I need for a run along with quercetin? How many days x how many times per day x dosage?

[Logic]

I would be interested, but tested only. However, I haven't caught up with this thread; For a 220lb 55yo male, how much would I need for a run along with quercetin? How many days x how many times per day x dosage?

 

Thx for replying SearchingForAnswers.

IIRC the HED was 300 mg of D and 3000 mg of Q per day, but people have been playing with dosages and getting interesting results, so reading the thread is a good idea.

We need to get to 500 grams for this to happen. I will start a new thread.

How many grams would you be interested in?

Edited by Logic, 28 July 2016 - 08:47 PM.

[mikey]

 

I would be interested, but tested only. However, I haven't caught up with this thread; For a 220lb 55yo male, how much would I need for a run along with quercetin? How many days x how many times per day x dosage?

 

Thx for replying SearchingForAnswers.

IIRC the HED was 300 mg of D and 3000 mg of Q per day, but people have been playing with dosages and getting interesting results, so reading the thread is a good idea.

We need to get to 500 grams for this to happen. I will start a new thread.

How many grams would you be interested in?

 

 

Why bother with plain quercetin when we can buy both liposomal quercetin and micelized quercetin, which each are taken into circulation many times better than plain quercetin?

 

I haven't had time to read this entire thread, but I don't think that I've seen anyone mention these more efficient delivery methods.

Edited by mikey, 29 July 2016 - 04:06 AM.

[Logic]

 

Why bother with plain quercetin when we can buy both liposomal quercetin and micelized quercetin, which each are taken into circulation many times better than plain quercetin?

 

I haven't had time to read this entire thread, but I don't think that I've seen anyone mention these more efficient delivery methods.

 

 

I believe I did mention them earlier in this thread Mikey and also believe them to be way better choices.
IIRC one wants the aglycone metabolite of Q, so something that produces more of it would be a nice find.

Its been a while since I've read this thread too.

Edited by Logic, 29 July 2016 - 03:31 PM.

[Logic]

Group Buy

 

I have interest in 50grams so far.

Only 450 grams to go for the 500 gram minimum!  

 

I think the main group buy thread should be this one for now:

http://www.longecity...buy-from-nyles/

[PWAIN]

Logic, how much to ship 10grams to Australia? Just regular post (usps) in an envelope.

[Logic]

Logic, how much to ship 10grams to Australia? Just regular post (usps) in an envelope.

 

Have a look at USPS's price calculator here PWAIN:

https://postcalc.usps.com/

 

Please post group buy related posts here everyone:
http://www.longecity...buy-from-nyles/

[ClarkSims]

Count me in for 20 grams of tested.

Thanks

[Fafner55]

 p19ARF appears to be another target.

 

Elimination of p19ARF-expressing cells enhances pulmonary function in mice (2016)

Senescent cells accumulate in many tissues as animals age and are considered to underlie several aging-associated pathologies. The tumor suppressors p19ARF and p16INK4a, both of which are encoded in the CDKN2A locus, play critical roles in inducing and maintaining permanent cell cycle arrest during cellular senescence. Although the elimination of p16INK4a-expressing cells extends the life span of the mouse, it is unclear whether tissue function is restored by the elimination of senescent cells in aged animals and whether and how p19ARF contributes to tissue aging. The aging-associated decline in lung function is characterized by an increase in compliance as well as pathogenic susceptibility to pulmonary diseases. We herein demonstrated that pulmonary function in 12-month-old mice was reversibly restored by the elimination of p19ARF-expressing cells. The ablation of p19ARF-expressing cells using a toxin receptor-mediated cell knockout system ameliorated aging-associated lung hypofunction. Furthermore, the aging-associated gene expression profile was reversed after the elimination of p19ARF. Our results indicate that the aging-associated decline in lung function was, at least partly, attributed to p19ARF and was recovered by eliminating p19ARF-expressing cells.