459 replies to this topic

[sthira]

Mitteldorf: "This is a fast-moving field in which researchers are in a rush to publish and (presumably) pharmaceutical companies are taking pains to keep their results hushed up. Sharing of information and resources could push this research over the top and give us the first full decade of human life extension."

http://joshmitteldor...t-moving-field/

[LeeYa]

Long pepper as a senolytic agent:

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents
https://www.ncbi.nlm...les/PMC5191878/

[LeeYa]

Just a thought:

Induction of autophagy should support senolysis, but remember that senescent cells are a heterogenous group of cells.
Oncogene induced senescence (OIS) depends on autophagy*, for example. This type of senscent cells will escape an autophagy-based senolytic approach!

*http://www.tandfonli...1/auto.5.7.9444

[Rocket]

Is this a another new senolytic drug?

 

http://www.dutchnews...reverse-ageing/

 

 

 

 

[Visor]

Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence: Introducing the Perspective of Senolytic Effects of Phytochemicals

https://www.research..._Phytochemicals

[stefan_001]

Did round 2 of my regime experiment I started. Same dosing as before: http://www.longecity...-13#entry809871

I am now 24 hours after and there is definitely a noticeable effect in varying ways:
- teeth feel cleaner
- skin a bit softer
- total surprise, eye sight is better
- lungs feel cleaner
- etc

So lets see whether this holds up in the coming days. I am thinking that likely the regime was a temporary general beat down of inflammation, SASP etc that gives the body a break. I am hoping that this break will help the system to clean up and remove some "garbage" e.g. senescent cells. That may not be as dramatical of killing immediately senescent cells but when repeated regularly it should have impact...at least that is what I will try to find out with doing this weekly couple months.

Edited by stefan_001, 28 March 2017 - 08:45 PM.

[maxwatt]

Long pepper as a senolytic agent:

Discovery of piperlongumine as a potential novel lead for the development of senolytic agents
https://www.ncbi.nlm...les/PMC5191878/

 

If anyone thinks it's worth it, I have worked with a company with experience extracting this substance from the Asian Long Pepper, Piper Longum.

[pieter cloete]

Hi maxwatt, is this substance from the Asian Long Pepper available, if so where and pricing. Is it possible to make your own extraction.

Thanks

[maxwatt]

The company I have in mind collected the pepper and extracted piperlongumine for a client who was interested in its anti-fungal properties.  The project did not pan out, but the the company has the expertise, if not the inventory, to produce more.  If their is enough interest we can perhaps encourage them to produce a batch.  I don't expect this small group to need enough for large scale production.but there may be inventory or a lab intern to work on it.

 

There are a number of readily available senolytics to keep in mind:  quercetin, fisetin, tocotrienols.  Dasatinib I do not consider readily available, and am eagerly awaiting reports from those who participated in the group buy.  Any others?  I suspect genestein and even good old resveratrol will prove to be senolytics, though no one has tested them for that.

 

We should compile a list of known senolytics, and pin it to the head of the forum.

[Fafner55]

FOXO family of transcription factors is increased by multiple stress pathways, as one would expect since nature wants to keep cells alive under stressful conditions. In contrast, it is less easy to inhibit FOXO expression.

“Targeting FOXOs to slow aging” (2015) https://www.degruyter.com/view/j/motth.2015.1.issue-1/motth-2015-0003/motth-2015-0003.pdf

 

Here is more support that SIRT1 modules FOXO4, both up and down. Inhibiting SIRT1 should help tip the balance toward apoptosis.

“The interaction between FOXO and SIRT1: tipping the balance towards survival” (2004) https://www.ncbi.nlm.nih.gov/pubmed/15308206

 

 

[Logic]

Dasatinib I do not consider readily available, and am eagerly awaiting reports from those who participated in the group buy.

Yes Xmass, a personal loss, the chinese new year and impurities in the lab's LC-MS have all conspired to create that impression.
I will endeavour to get any other substances I do group buys for, to ...'researchers' more timeously in future, but price and purity are a higher priority to me.
You will be happy to know that the D has been tested and found to be as advertised at over 99% purity.  Now it's simply a case of waiting for the lab to do us the favour of posting it off at their convenience.

Also; as senescent cells accumulate at a very slow rate, senolytics don't have to be on the shelf at the local 7/11 to be considered readily available!?  

Any others?  I suspect genestein and even good old resveratrol will prove to be senolytics, though no one has tested them for that.
 
We should compile a list of known senolytics, and pin it to the head of the forum.

A good place to start is to ask oneself why senescent cells build up in us, in the 1st place:

Pathogens and heavy metals:
There is a lot of evidence that pathogens, virii especially, are responsible for senescent cells not dying. Especially CMV:
https://www.ncbi.nlm...pubmed/15843887
(note the other papers on the right)
The effect of Quercetin on the common and apparently incurable cold and other virii, is further proof of this.
As such; its possible that Bavituximab and DRACO can be considered highly effective senescent cell killers..?

There is also a very good chance that the killing off of senescent/infected cells will release virii etc so precautions against this is a good idea IMHO.
Optimal vit D, VCO, BHT (CYP3A4 activator!!!), Olive Leaf Extract, Echinacea (possible senolytic), etc..?

There are a good # of papers pointing to heavy metals not only causing senescence, but stopping senescent cells from dying:
http://toxsci.oxford...t/99/1/126.full
https://www.ncbi.nlm...pubmed/20618956
https://www.ncbi.nlm...pubmed/23828460
https://www.ncbi.nlm...pubmed/25157103
When you combine this info with heavy metals being catalysts (Look catalyst up!) for AGE formation and just about all AGE breakers being chelators, I cant help but wonder what a properly researched chelation stack/therapy, prior to, or concomitant with senolytics, might do for one!?  Especially as AGEs play a large role in senescence.

SteveH of MMTP is exited about Apigenin:
https://www.ncbi.nlm...les/PMC2538676/
There is some promising research on improving the bioavailability of it too.

 

Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence?

https://www.ncbi.nlm...les/PMC3922784/
So a telomerase activation stack immediately after senolytics may be a bloody good idea.
Astragalus, Epitalon, Purslane, Fenugreek, Ginkgo Biloba, Korean Ginseng, BHT come to mind.

As the senescent cells are removed by autophagy/macrophagy and around 60 billion cells die each day due to apoptosis anyway:

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

I think research into the effect of D and Q etc on quiescent cells is very much reqd!
This is the state in which stem cells are kept in pristine condition before being deployed.
If D, N, Q oetc killing these off..!!!!?
 

[Logic]

@ 'Needs References':  

     
I count 8 references in that post.  On average that about 7 more than the other posts here!  
Then I like to think that my post count and ₮ points/rep means I can be trusted..?
So I can only assume that you are having some trouble stringing together a coherent search string, as you couldn't possibly be too lazy to do a bit of research yourself, could you!?

 

Googling 'quercetin cold  virus' gives

https://www.ncbi.nlm...pubmed/22465313

as the 4th result...

 

A search for 'quiescent cells dasatinib':

https://www.google.c...lls dasatinib&*

 

I'm going to stop there as; if you are in fact as useful as a one armed trapeze artist with an itchy arse, I dont know that the world would want you around for very long.

 

Edited by Logic, 31 March 2017 - 02:47 PM.

[Logic]

A lead?  (Scanned. not read)
Perhaps Beclin 1 regulation is a means of regulating  Bcl-2, Bcl-xL, BCL-w?

http://journals.plos...al.pone.0008755

 

...Although the Bcl-2/Beclin 1 interaction is clearly an important checkpoint in autophagy induction upon starvation or treatment with many different compounds, some other well-known autophagy inducers, like rapamycin (an mTOR inhibitor) and lithium chloride (inhibitor of inositol signaling), had less apparent effects on the displacement of Beclin 1 from Bcl-XL [25]. However, they induce autophagy in a Beclin 1-dependent manner...

https://www.ncbi.nlm...les/PMC3901098/

This ties in neatly with the, well referenced, autophagy thread I started:
http://www.longecity...ndpost&p=763863

I also have it on good authority that trolls live for ever and therefore have no need of senolytics!
But as usual, this needs references!

 

 

Edited by Logic, 01 April 2017 - 09:14 PM.

[stefan_001]

Round #3 of my experiment #426 is postponed to later in the week. 24-48 hours after round #2 I started to develop flu like sympthoms, since that has become a real flu that is now starting to go off. Somewhat interesting that it came on soon after round two, but I chalk it up to coincidence.

[Logic]

Trehalose supplementation In aorta of old mice supplemented with trehalose, the autophagy markers beclin 1, WIPI-1, LC3-II and LAMP-2a were restored to levels observed in young mice, and p62 levels were reduced

http://www.longecity...ndpost&p=765837

 

Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance
Alzheimer's disease (AD) is a neurodegenerative disorder associated with amyloid accumulation and autophagic changes. Parkin is an E3 ubiquitin ligase involved in proteasomal and autophagic clearance. We previously demonstrated decreased parkin solubility and interaction with the key autophagy enzyme beclin-1 in AD, but tyrosine kinase inhibition restored parkin-beclin-1 interaction.

http://www.longecity...ndpost&p=756876

 

phytic acid provided complete protection against amyloid precursor protein-C-terminal fragment-induced cytotoxicity by attenuating levels of increased intracellular calcium, hydrogen peroxide, superoxide, beta amyloid oligomers, and moderately up-regulated the expression of autophagy (beclin-1) protein

http://www.longecity...ndpost&p=688775

 

N-Acetylcysteine:

Our results reveal that NAC administration results in reduced muscle mRNA levels of several autophagy markers, including Beclin-1, Atg7, LC3, Atg9, and LAMP2.

https://www.hindawi....cl/2014/315896/

http://www.longecity...ndpost&p=713322

 

Ginkgo Biloba protects by upregulating genes Beclin-1

http://www.longecity...ndpost&p=698289

 

silibinin triggered the conversion of light chain 3 (LC3)-I to LC3-II, promoted the upregulation of Atg12-Atg5 formation, increased Beclin-1 expression, and decreased the Bcl-2 level. Moreover, we noted elevated reactive oxygen species (ROS) generation, concomitant with the dissipation of mitochondrial transmembrane potential (ΔΨm) and a drastic decline in ATP levels following silibinin treatment, which were effectively prevented by the antioxidants, N-acetylcysteine and ascorbic acid. Silibinin stimulated the expression of Bcl-2 adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), a pro-death Bcl-2 family member,

http://www.longecity...ndpost&p=777316

 

We show that 1,25-dihydroxyvitamin D3 (1,25D3), the active form of vitamin D, induced autophagy in human monocytes via cathelicidin, which activated transcription of the autophagy-related genes Beclin-1 and Atg5.

http://www.sciencedi...931312809002832

 

erein we demonstrate that autophagy is a novel mechanism by which MB can reduce tau levels. Incubation with nanomolar concentrations of MB was sufficient to significantly reduce levels of tau both in organotypic brain slice cultures from a mouse model of FTD, and in cell models. Concomitantly, MB treatment altered the levels of LC3-II, cathepsin D, Beclin 1, and p62 suggesting that it was a potent inducer of autophagy.

http://www.longecity...ndpost&p=513589

 

we found that melanoidins from Shanxi aged vinegar induced mitopahgy, the specific autophagic elimination of mitochondria, as assessed by up-regulation of the autophagy markers LC3-II and Beclin1 as well as degradation of the autophagy substrate p62 and mitochondrial proteins. Melanoidins reduced reactive oxygen species (ROS) in normal human liver cells and mouse livers through a mitophagy-dependent pathway, by the observation that the reducing ROS effect of melanoidins was partially lost when mitophagy was inhibited by chloroquine. Impaired Akt signaling was found in cells treated with melanoidins, which might explain the activation of autophagy induced by melanoidins. These results suggest that in addition to direct free radical scavenging activity, melanoidins decreased ROS levels through mitophagy in which damaged mitochondria, the source of ROS, were degraded.

http://www.longecity...ndpost&p=778081

 

Here we show that a peptide, Tat–beclin 1—derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (HIV)-1 Nef—is a potent inducer of autophagy, and interacts with a newly identified negative regulator of autophagy, GAPR-1 (also called GLIPR2). Tat–beclin 1 decreases the accumulation of polyglutamine expansion protein aggregates and the replication of several pathogens (including HIV-1) in vitro, and reduces mortality in mice infected with chikungunya or West Nile virus. Thus, through the characterization of a domain of beclin 1 that interacts with HIV-1 Nef, we have developed an autophagy-inducing peptide that has potential efficacy in the treatment of human diseases.

https://www.ncbi.nlm...les/PMC3788641/

http://www.longecity...ndpost&p=765019

 

We find that Beclin and p53 genes are required to induce autophagy and concurrently reduce lipid storages and extend animal lifespan in response to frataxin suppression. Reciprocally, frataxin expression modulates autophagy in the absence of p53. Human Friedreich ataxia-derived lymphoblasts also display increased autophagy, indicating an evolutionarily conserved response to reduced frataxin expression. In sum, we demonstrate a causal connection between induction of autophagy and lifespan extension following reduced frataxin expression."

http://www.longecity...ndpost&p=556800

 

 

[Fafner55]

FOX04 serves to preserve tissue integrity under stress.

 

FOX04 is modulated by SIRT1. The activity of FOX04 is suppressed by SIRT1 inhibitors, such as nicotinamide, and enhanced by SIRT1  activators, such as resveratrol.

“SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress” (2005) https://www.ncbi.nlm.nih.gov/pubmed/16012755?dopt=Abstract

 

From this view, improvements to senolytic treatments could follow from

• Not fasting
• Not taking NR, resveratrol or pterostilbene
• Not engaging in vigorous exercise
• Inhibiting SIRT1 by large doses of nicotinamide, such as 2 to 3 gm.

 

Nicotinamide is a potent inhibitor of SIRT1. I would expect it to decrease FOX04 but don't have support.

1. https://www.researchgate.net/post/How_long_does_it_take_for_Niacinamide_to_inhibit_SIRT1_and_how_long_until_it_stops
2. “Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis” (2013) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789038/

 

Are there suggestions for other sirtuin and FOX04 inhibitors? I haven't yet found a good, direct FOX04 inhibitor.

 

On further review, I may have been mistaken in suggesting that taking nicotinamide to suppress SIRT1 is a good idea. It might actually promote cell survival instead of apoptosis.

 

The literature is consistent in stating that SIRT1 deacetylates (represses) FOXO4, but the effects of SIRT1 and FOXO4 on apoptosis appear inconsistent.

1. “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging” (2017) http://www.cell.com/cell/fulltext/S0092-8674(17)30246-5
2. “The interaction between FOXO and SIRT1: tipping the balance towards survival” (2004) https://www.ncbi.nlm.nih.gov/pubmed/15308206
3. “Mammalian SIRT1 represses forkhead transcription factors” (2004) http://www.cell.com/cell/fulltext/S0092-8674(04)00126-6

 

Nicotinamide represses SIRT1 and also promotes apoptosis, which appear to be inconsistent with the interaction between SIRT1 and FOXO4.

1. https://www.researchgate.net/post/How_long_does_it_take_for_Niacinamide_to_inhibit_SIRT1_and_how_long_until_it_stops
2. “Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis” (2013) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789038/

 

Could anyone with expertise in this area add clarity?

[Valijon]

Looks like we are barking up the wrong tree by consuming supplements to increase NAD+. Then we want a FOX04 inhibitor?

[Andey]

Maybe its a good idea not to overcomplicate things and put FOXO aside until more data available.

FOXO4-DRI peptide works very artificially not by downregulating but by blocking FOXO4 receptors completely. Its not designed to work this way by nature and whole pathway simply shutdowns. First - we certainly would not be able to duplicate very specific action of this peptide by unspecific means in our disposal, second - if we have access to peptide its very unpredictable intervention with possibility of dire consequences. I would give science a go to discover it further before jumping into actions.

 

Besides that there are a lot of other substances and practices available. What we lack now is a comprehensive and tangible measure of their effect. Activin-a blood test could be it BTW.

 

Edited by Andey, 08 April 2017 - 07:18 PM.

[Logic]

Expressing the genes that  keep healthy cells healthy will protect senescent cells and even 'repair' them to a certain extent.

ie:  Clearing out senescent cells and a stack to keep healthy cells healthy are at complete opposite ends of the spectrum!  

 

Fortunately clearing out senescent cells is basically a one-off procedure that does not need to be repeated for a long time.
At a guess I would say that that senescent cell clearance is a 1 to 2 day long procedure, that only has to be done once a year, to once every six months.
This should clear out senescent, pre/cancerous cells, including senescent, pre/cancerous stem cells, with gene and other defects, leaving the fitter, more youthful cells to replace them and generally do their youthful thing.

The procedure should be followed by a more conventional daily stack and should also include a course of telomerase activators and stem cell activators like Epitalon, Astragalus, Purslane etc.
This way you end up repairing and protecting only the fitter healthier cells with less DNA etc damage, decreasing the chances of immortalising cancer etc.
 
So basically:
Senolytics = bad for all cells, but especially senescent cells which it kills.  Done very intermittently.
Then telomerase activators and a protective daily stack to repair and protect the healthy cells, without immortalising old, trouble causing cells.

 

What to take daily gets confusing because we co evolved, over billions of years, with plants.
ie:  We co-opted the protective constituents of these plants which often do the same for us when eaten.
Due to this long process of co-evolution nature, in its wisdom, has come up with molecules that are good for healthy cells, but help to kill of and get rid of cells that are past redemption.

There are a large # of such substances.  Off the top of my head; low dose Lithium, pterostilbene and resveratrol metabolites like piceatannol have this effect.
ie:  There is a good long list of substances that give the best of both worlds and can be taken daily.  Especially if you keep circadian rhythms in mind.
Here is a good starting point:

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

 

[Florian E.]

 

FOX04 serves to preserve tissue integrity under stress.

 

FOX04 is modulated by SIRT1. The activity of FOX04 is suppressed by SIRT1 inhibitors, such as nicotinamide, and enhanced by SIRT1  activators, such as resveratrol.

“SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress” (2005) https://www.ncbi.nlm.nih.gov/pubmed/16012755?dopt=Abstract

 

From this view, improvements to senolytic treatments could follow from

• Not fasting
• Not taking NR, resveratrol or pterostilbene
• Not engaging in vigorous exercise
• Inhibiting SIRT1 by large doses of nicotinamide, such as 2 to 3 gm.

 

Nicotinamide is a potent inhibitor of SIRT1. I would expect it to decrease FOX04 but don't have support.

1. https://www.researchgate.net/post/How_long_does_it_take_for_Niacinamide_to_inhibit_SIRT1_and_how_long_until_it_stops
2. “Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis” (2013) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789038/

 

Are there suggestions for other sirtuin and FOX04 inhibitors? I haven't yet found a good, direct FOX04 inhibitor.

 

On further review, I may have been mistaken in suggesting that taking nicotinamide to suppress SIRT1 is a good idea. It might actually promote cell survival instead of apoptosis.

 

The literature is consistent in stating that SIRT1 deacetylates (represses) FOXO4, but the effects of SIRT1 and FOXO4 on apoptosis appear inconsistent.

1. “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging” (2017) http://www.cell.com/cell/fulltext/S0092-8674(17)30246-5
2. “The interaction between FOXO and SIRT1: tipping the balance towards survival” (2004) https://www.ncbi.nlm.nih.gov/pubmed/15308206
3. “Mammalian SIRT1 represses forkhead transcription factors” (2004) http://www.cell.com/cell/fulltext/S0092-8674(04)00126-6

 

Nicotinamide represses SIRT1 and also promotes apoptosis, which appear to be inconsistent with the interaction between SIRT1 and FOXO4.

1. https://www.researchgate.net/post/How_long_does_it_take_for_Niacinamide_to_inhibit_SIRT1_and_how_long_until_it_stops
2. “Nicotinamide-mediated inhibition of SIRT1 deacetylase is associated with the viability of cancer cells exposed to antitumor agents and apoptosis” (2013) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789038/

 

Could anyone with expertise in this area add clarity?

 

 

 

I think that normal body operation is to switch between SIRT1 and PER2 (autophagy) through circadian clock.

If i get this correct, both SIRT1 and PER2 expressions decrease while aging by circadian clock regulation according to environmental factors.

And degradation is mainly caused by mitochondrial damage, decreased cysteine/glutathion levels, dna damage, lysosomal damage, (others ?)

 

So imho, nothing wrong with NR (sirt1 activators). As long as you allow the body to also perform PER2 expression at a different time (?). And stop NR while doing senolytics.

Edited by Florian E., 13 April 2017 - 06:58 PM.

[Authentic]

Is this a another new senolytic drug?

 

http://www.dutchnews...reverse-ageing/

Rocket I've been trying to find out more information about their compound "Proxifim" but have not yet been able to locate any information.

[Authentic]

Is this a another new senolytic drug?

 

http://www.dutchnews...reverse-ageing/

 

Rocket I found the information in CELL

 

http://www.cell.com/...8674(17)30246-5

 

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging

 

Highlights

• •A modified FOXO4-p53 interfering peptide causes p53 nuclear exclusion in senescent cells
• •This FOXO4 peptide induces targeted apoptosis of senescent cells (TASC)
• •TASC neutralizes murine liver chemotoxicity from doxorubicin treatment
• •TASC restores fitness, hair density, and renal function in fast and naturally aged mice

[stefan_001]

Senescent cells may not be relying on glycolysis like cancer cells do:
http://rd.springer.c...1010-017-3005-1

That could mean that cancer drugs targeting various pathways in that area have no effect. Energy transfer paths may be a target.

[A Better World]

Age 45, male, weight 225 lbs.

 

I've experimented a few times with D + Q for senolysis and have had results:  http://www.longecity...althspan/page-8.  Since I posted this, I have tried just the combo of D + Q with no curcumin and have noticed effects on energy and skin.  I also added in milk thistle, which was found in the original D + Q study to have mild senolytic effects; I included it on the off chance that it might have synergistic effects with D and Q, which were found to synergize with one another in that original study. 

 

You have all undoubtedly seen the latest findings regarding fisetin:  https://www.fightagi...rug-candidates/.  

 

So 72 hours ago, inspired by these findings regarding fisetin, I downed 2 grams of fisetin (20x 100mg Doctor's Best Fisetin) on the way home from work, along with a small meal high in lipid content.  

 

Effects were interesting.  As reported by others in experiments with D + Q, there was a fever-like thermogenic effect.  In this case, it was quite pronounced.  It was accompanied by mild tingling in extremities, and what I can only describe as a mild buzz.  This latter effect was unexpected, but hey, this stuff does cross the blood-brain barrier. When I got home an hour later, I took the remaining gram of fisetin and added in dasatinib 50mg, quercetin 4 grams, and milk thistle 3 grams.  I could have gone for a higher dose of dasatinib, but it was a weekday and when I have taken 100mg the next day is no fun. 

 

Anyway I woke feeling good.  Energy level was definitely increased.  The next night I only got a couple of hours of sleep but had a pretty normal work day the next day, not only not feeling wiped out, but with a spring in my step.  Today, day three, I feel really good.  Stronger, more energetic than usual.  I can feel my muscles as I move in a way that is new. None of the usual aches and pains. 

 

Am next going to try 3 grams of fisetin all at once, unaccompanied by anything else, and then will give it a few months to see if I can see a lasting effect.  In general, my unscientific experiments with senolytic substances have left me with the impression that it is making a difference.  This latest run with fisetin so far seems to have had the most pronounced effect of all in terms of how I feel.  I sort of feel maybe 5 years younger in terms of energy level, etc. Don't think it is placebo.  

[Andey]

Age 45, male, weight 225 lbs.

 

I've experimented a few times with D + Q for senolysis and have had results:  http://www.longecity...althspan/page-8.  Since I posted this, I have tried just the combo of D + Q with no curcumin and have noticed effects on energy and skin.  I also added in milk thistle, which was found in the original D + Q study to have mild senolytic effects; I included it on the off chance that it might have synergistic effects with D and Q, which were found to synergize with one another in that original study. 

 

You have all undoubtedly seen the latest findings regarding fisetin:  https://www.fightagi...rug-candidates/.  

 

So 72 hours ago, inspired by these findings regarding fisetin, I downed 2 grams of fisetin (20x 100mg Doctor's Best Fisetin) on the way home from work, along with a small meal high in lipid content.  

 

Effects were interesting.  As reported by others in experiments with D + Q, there was a fever-like thermogenic effect.  In this case, it was quite pronounced.  It was accompanied by mild tingling in extremities, and what I can only describe as a mild buzz.  This latter effect was unexpected, but hey, this stuff does cross the blood-brain barrier. When I got home an hour later, I took the remaining gram of fisetin and added in dasatinib 50mg, quercetin 4 grams, and milk thistle 3 grams.  I could have gone for a higher dose of dasatinib, but it was a weekday and when I have taken 100mg the next day is no fun. 

 

Anyway I woke feeling good.  Energy level was definitely increased.  The next night I only got a couple of hours of sleep but had a pretty normal work day the next day, not only not feeling wiped out, but with a spring in my step.  Today, day three, I feel really good.  Stronger, more energetic than usual.  I can feel my muscles as I move in a way that is new. None of the usual aches and pains. 

 

Am next going to try 3 grams of fisetin all at once, unaccompanied by anything else, and then will give it a few months to see if I can see a lasting effect.  In general, my unscientific experiments with senolytic substances have left me with the impression that it is making a difference.  This latest run with fisetin so far seems to have had the most pronounced effect of all in terms of how I feel.  I sort of feel maybe 5 years younger in terms of energy level, etc. Don't think it is placebo.  

 

 

  Thanks for sharing. Very encouraging.

 

Edited by Andey, 27 April 2017 - 09:33 AM.

[Andey]

Very informative interview of Judith Campisi by Dr. Rhonda Patrick.

Escpecially on interaction of mTor pathway, fasting and senescent cells.

Judith Campisi, Ph.D. on Cellular Senescence, Mitochondrial Dysfunction, Cancer & Aging

 

Looks like a good idea to subscribe to Rhonda`s channel to support content like this.

 

Edited by Andey, 29 April 2017 - 03:05 PM.

[stefan_001]

From a lung cancer research paper. Seems to have the right properties to be a senolytics treatment as well:

Carnosic acid and fisetin combination led to apoptosis in lung cancer cells. Caspase-3 signaling pathway was promoted in carnosic acid and fisetin co-treatment, which was accompanied by anti-apoptotic proteins of Bcl-2 and Bcl-xl decreasing and pro-apoptotic signals of Bax and Bad increasing. The death receptor (DR) of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was enhanced in carnosic acid and fisetin combined treatment.

https://www.spandido...2/ijo.2017.3970

[stefan_001]

It seems CA does the same sensitizing in combination with Tamoxifin:
Carnosic acid cooperates with tamoxifen to induce apoptosis associated with Caspase-3 activation in breast cancer cells in vitro and in vivo
https://www.ncbi.nlm...pubmed/28282784

and also in carcinoma cells:
https://www.ncbi.nlm...les/PMC4359314/

ofcourse remains to be seen can it do the same trick in senescent cells. I will try to buy some to combine with Fisetin.

[stefan_001]

Interesting, bit of topic but CA is also useful for AD. So a combination of F, which has its own anti AD properties, and CA may have multiple anti-aging effect. Will send some CA to my parents too.

Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer's disease models.
https://www.ncbi.nlm...pubmed/27906174

[Bryan_S]

Drug 'reverses' ageing in animal tests (BBC News website)

The link:  http://www.bbc.com/n...health-39354628

I just read this a hour ago. The team at Erasmus University Medical Center, in the Netherlands, are planning human trials for what they hope is a treatment for old age.

If this is true I want to be the first on the human trails.

 

 

I think this was another article on the same study http://www.sciencema...igns-aging-mice

 

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging http://www.cell.com/...8674(17)30246-5