58 replies to this topic

[Fafner55]

The attached senolytic protocol combines grape seed extract (GSE) with either fisetin or, alternatively, dasatinib as effective senolytics for a wide range of cell types, including endothelial cells. This protocol builds reviews and assessments of the current state senescent cell (SnC) research, which I summarized in concise tables in the attachment. A review of therapeutic targets of SnC removal is also included.

This protocol is intended to improve the physical function of healthy individuals in middle and old age (45-80 years). However, for those who are frail or older, senolytic treatment might be dangerous due to the high percentage of SnCs these groups carry, along with their low levels of regeneration. For those younger than 40 or so, senolytic treatment is not expected to make much of a difference since this group has a low percentage of SnCs.

 

An exception to these age categories is smokers. While the effects of senolytics have not been studied in smokers, the well established associations between smoking, telomere attrition, DNA damage and cellular senescence suggest that removing SnCs will likely benefit those younger than 45 years in this group.

 

Protocol A (Primary): GSE + Fisetin

The doses listed here are calculated for a 70 kg individual and may be scaled by body weight.

 

For first-time SnC removal, as a precaution start by taking a half dose treatment cycle without food.

1. 2000 mg grape seed extract, 1x/day for 3 days.

2. 1000 mg fisetin, 1x/day for 3 days.

 

After the first SnC removal, wait about 4 weeks then take the following full dose treatment cycle once/month for 4 months. Thereafter, for maintenance repeat 1 or 2x/year.  

1. 4000 mg grape seed extract, 1x/day for 3 days.

2. 2000 mg fisetin, 1x/day for 3 days.

Attached Files

•  Protocol for Restoration of Physical Function in Aged Individuals by Removal of Senescent Cells_Fafner55_2022-01-03c.pdf   3.14MB   110 downloads

[Woody42]

Interesting I was already thinking about doing 3G of fisetin for 3 days later in the month but after reading this I may just do this 2 G of GSE and 1 G of fisetin instead.  I wonder if this would work even better if it was done right before , after or during a 3 or 4 day fast.

 

[Fafner55]

It makes sense to remove senescent cells before a fast. Longo's research on the fasting mimicking diet shows substantial regeneration and regrowth after a fast, and it well is established that senescent cells inhibit proliferation through paracrine signaling.

1. “A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan” (2015) http://www.cell.com/...4131(15)00224-7
2. “Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease” (2017) http://stm.sciencema.../377/eaai8700  
3. "Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reverse diabetes" (2017) http://www.cell.com/...74(17)30130-7  

[QuestforLife]

Does anyone know what the Procyanadine C1 content of standard Grape Seed Extract supplements is?

 

 

[Fafner55]

Does anyone know what the Procyanadine C1 content of standard Grape Seed Extract supplements is?

 

References are provided in the protocol. The key one is

“Polyphenolic Composition and Antioxidant Activities of Grape Seed Extract” (2008) https://www.tandfonl...42910701584260 

Attached Files

•  phenolic content of GSE.png   137.66KB   1 downloads

[Phoebus]

This is super interseting to me. I have been a believer in GSE for years and years. I have consistently taken it off and on for going on 20 years. According to this study "At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction." So considering I have always taken one capsule a day I assume I have created low concentrations in my biody of PCC1, enough to inhibit SASP (hopefully) but perhaps not enough to create the full senolytic effect. 

 

My question is what makes you think that 2 grams of GSE is enough to create a high enough concentration in the body to promote senolytic effects? That still seems like you would be getting very small amounts of PCC1, not to mention how much of the PCC1 is actually bioavailable? Procyanidins are water soluble substances. Perhaps a better method would be to make a tea of the GSE, let it sit over night and leach out the PCC1 and drink it in the morning. Problem with that is GSE tastes TERRIBLE! I mean this stuff is bitter, bitter bitter. 

 

Best bet would be to buy PCC1 outright from a chemical supplier 

 

https://www.bertin-b.../procyanidin-c1

 

You could also make an alcoholic tincture out of the GSE but I think PCs are not fully soluble in alcohol? I don't know 

 

 

 

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice

 

• PMCID: PMC8688144
•  
• DOI: 10.1038/s42255-021-00491-8

Free PMC article

Abstract

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies

 

 

 

Also how much fisetin is bioavailable? Its very poorly soluble in water but is partially soluble in fat/oil. so you may want to eat some greek yogurt with your fisetin caps 

 

 

 

 

Solubility studies on resveratrol, fisetin or quercetin showed an increased solubility of these polyphenols in oil, but principally for the most hydrophilic ones (hydrophilic-lipophilic balance (HLB) >10) [23,38,39]. In the studies on lipid nanocapsules [22] and emulsions [23], it appears that quercetin and fisetin distribute, rather, at the oil/tensioactive interface. These compounds can then be qualified as neither fully lipophilic, nor hydrophilic, but, rather, amphiphilic, necessitating hydrophobic interactions, as well as hydrogen bond interactions with the aqueous medium to be encapsulated.

https://www.mdpi.com...923/5/3/457/htm

Edited by Phoebus, 07 January 2022 - 04:46 PM.

[Fafner55]

 

My question is what makes you think that 2 grams of GSE is enough to create a high enough concentration in the body to promote senolytic effects? 

 

Also how much fisetin is bioavailable? Its very poorly soluble in water but is partially soluble in fat/oil. so you may want to eat some greek yogurt with your fisetin caps 

 

 

Regarding your question about whether 2 g GSE is enough, the authors of 

“The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice” (2021) https://www.nature.c...5-021-00491-8  

were not specific about what grape variety the GSE came from or its PCC1 content. 

 

The measured PCC1 content of GSE from Riesling grapes ranges from 1.79 to 4.37% (8 samples, large measurement variation).

“Polyphenolic Composition and Antioxidant Activities of Grape Seed Extract” (2008) https://www.tandfonl...942910701584260

 

To arrive at 4 g GSE, I assumed a 3% PCC1 content and a 70 kg individual (the calculation is in the protocol).

The 2 g you refer to is a starting 1/2 dose, which I propose as a cautious approach for those carrying a heavy senescent cell burden.

 

Because the PCC1 content of GSE is uncertain, the 4 g is rounded up from the 3% calculation of 3784 mg. 

To give it a better chance of being effective, I extended the treatment to 3 days. That contrasts to the 32 hrs shown in the Figure 1 in vitro experiment for maximum effect.

Also, PCC1 is reported to have a serum half life of over 7 hrs.

 

Oral LD50 for GSE is > 5000 mg/kg (mice), so most people could safely increase the dose. Again, I was cautious. In my self experiment, I had no GI distress from taking 4000 mg GSE + 2000 mg fisetin, but I did experience fatigue.

 

The GSE and fisetin I consumed were in capsule form (400 mg/capsule GSE Bronson brand and 500 mg/capsule fisetin HumanX brand), so taste wasn't an issue. (I have no affiliation with either company and am not making a recommendation. I just purchased them randomly off Amazon.)

 

Pure PCC1 would be ideal, but it isn't generally available. The lab you referenced quotes €114.00 for 1 mg. I haven't looked into the chemistry of how it might be isolated from GSE.

 

As to your question about the bioavailability of fisetin, that doesn't matter here. The protocol is based on the human equivalent dose (70 kg individual) scaled from oral gavage in mice.

Edited by Fafner55, 07 January 2022 - 05:23 PM.

[QuestforLife]

Bioavailability of individual GS extracts appears to be poor; it might be better to take them together as a standard extract?

Encapsulating in liposomes may enhance absorption further.

From my admittedly brief skim of the paper on senolytic effects of PCC1, that specific extract didn't seem that much more effective than the standard GSE.

I agree that experimentation will be required to find the best dose.

It is encouraging more senolytics are being found amongst available nutraceuticals, particularly if they are shown to target different cell types.

[Phoebus]

If you want any of this to cross the BBB and address senescent cells in the brain then I would soak both in olive oil over night before taking

 

The fat will help make both more bioavailable and the oleic acid in the olive oil will help to open up the BBB 

 

 

 

Oleic acid reversibly opens the blood-brain barrier

https://pubmed.ncbi....ih.gov/1715805/

[DJSwarm]

Hi Fafner,

 

Very interesting paper on GSE. Thanks for posting it.

 

Fisetin's senescent effect seems to be very dose dependent. The Mayo clinic's run of fisetin with 70+ yr old fail people is 20mg/kg (about 1500mg). I'm guessing that was picked as the minimum needed to see a good effect. I've also seen 1200mg posited before. I've personally gone as high as 3000mg without issue. I don't plan to take it higher that that through. 

 

Also, take it all at once with oil and an emulsifier to aid absorption. Also, bromalin and pepper may also help with absorption. I've been shifting to liposomal preparations to also help with bioavailability.

 

If you're wondering; yes, fisetin is badly absorbed and not terribly bioavailable. This seems to be the case with all the bio-flavonoids and flavanols so rinse and repeat for things like quercetin, berberine, etc.

 

Fisetin is quickly broken down by the liver and has a short terminal life of 3 hrs before it is eliminated.

 

Also, take a break in any liver protectors like NAC, in particular, as they speed up elimination, a process we'd like not sped up.

 

Best wishes and I look forward to reports how it goes.

[DJSwarm]

After thinking about it, when they tested D, Q and D+Q they found that D(50-100mg)+Q(1000mg) was superior to either alone.

I might add Q with the D+GSE run. Or even combine them since D also seems to synergize with F (Details in the respective threads, trying not to get too side tracked).

[Fafner55]

The evidence listed in the protocol supports the idea that D+GSE will be more effective than fisetin+GSE, as summarized in Table 8. I described D+GSE as an alternative protocol to fisetin+GSE because D is not generally available. 

 

What I really like about GSE is that it is effective on endothelial cells. In contrast, D+Q was not effective. Now that GSE is shown to be an effective senolytic for endothelial cells, we can expect to see translational studies on its application to cardiovascular disease (CVD) over the next couple of years.

[Moondancer]

The evidence listed in the protocol supports the idea that D+GSE will be more effective than fisetin+GSE, as summarized in Table 8. I described D+GSE as an alternative protocol to fisetin+GSE because D is not generally available. 

 

What I really like about GSE is that it is effective on endothelial cells. In contrast, D+Q was not effective. Now that GSE is shown to be an effective senolytic for endothelial cells, we can expect to see translational studies on its application to cardiovascular disease (CVD) over the next couple of years.

 

Is there a reason not to combine D + GSE + Q?

[Fafner55]

Is there a reason not to combine D + GSE + Q?

 

Q and fisetin are similar in chemical structure, the signaling pathways they affect, and types of senescent cell they remove. Fisetin is a more effective senolytic than quercetin; that's why the protocol is organized around it. Both are relatively benign in terms of toxicity, and there shouldn't be a problem with adding Q to the mix. 

Edited by Fafner55, 26 January 2022 - 11:58 PM.

[Moondancer]

Q and fisetin are similar in chemical structure, the signaling pathways they affect, and types of senescent cell they remove. Fisetin is a more effective senolytic than quercetin; that's why the protocol is organized around it. Both are relatively benign in terms of toxicity, and there shouldn't be a problem with adding Q to the mix. 

 

 

Thank you Fafner. With regard to trying to target endothelial SC's. Is this paper and the suggestion of Bulavin et al not still a potential concern? 

In fact, I'm still not sure at all what we should conclude from this with regard to SC-removal. (And I say that while taking a course of Fisetin). 

https://www.scienced...64u_dZwbfPMEKhQ

 

Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan

"Highlights

 

•

p16High senescence is a slow process that manifests around 10–12 months of age

•

p16High cells in the liver of 12-month-old mice are LSECs and macrophages

•

Senescent p16High LSECs are structurally and functionally important

•

Elimination of p16High senescent cells induces liver and perivascular tissue fibrosis"

[Fafner55]

Interesting paper. Thanks for bring it to our attention Moondancer. It highlights a key concern in removing senescent cells - their acute removal in aged individuals who have a high percentage of senescent cells could be harmful, even lethal. For instance, my frail 92 year old mother is mostly held together by senescent cells. I don't doubt that a senolytic treatment would kill her within hours. The extreme aged are definitely not candidates for senolytic treatments.

 

As to the focus of this paper - liver endothelial cells in mouse models for chronic and "acute" elimination of senescent cells - it identifies a concern but I don't see that it offers clarity on whether senescent cells can be safely removed. 

 

The authors' acute model used p16-Cre/R26-DTA mice to chronically eliminate p16+ cells. This chronic elimination not only removed age-related senescent cells, but also removed senescent cells that might have been involved in healing response. That removal disrupted the normal healing response and resulted in improper remodeling, i.e., fibrosis.

 

The "acute" model appears to me to be a shortened continuous model, and not truly acute. A tamoxifen (TAM)-inducible p16 knockin mouse line was used to remove senescent cells. TAM was added to the mouse diet for 1 month, then "we analyzed fibrosis in 1.5-year-old p16-CreERT2/R26-DTA mice 1 month after receiving a TAM diet."  That description is ambiguous, but I interpret it as meaning the mice were fed TAM for 1 month then analyzed after an additional month on a normal diet. In any case, inducing deletion of 100% of p16+ for a straight month is not "acute". I can't see that it would allow for a normal healing response.

 

Contrast that to administration of GSE, which is a 3 day protocol that removes 30-40% of senescent cells. The shorter duration and removal of fewer senescent cells in this protocol will more likely give tissues a chance to properly heal.

 

My protocol also suggests two steps: an initial clearance with a half dose of senolytics followed a month later by a full dose. For older individuals with a higher percentage of senescent cells, this approach is advised.

 

Further research is needed to determine the safety of and best approach to removing senescent cells. Certainly, it is a long way from FDA approval. However I can offer the anecdote that I have tried this GSE protocol and my blood pressure remains the same 120/80 before and after senolytic treatment. If there was large scale fibrosis of endothelial tissues, one would expect a reduction in the flexibility of blood vessels and higher blood pressure as a consequence. I don't experience that at all.

[QuestforLife]

 

 

In fact, I'm still not sure at all what we should conclude from this with regard to SC-removal. (And I say that while taking a course of Fisetin). 

 

 

You should conclude that senolytics are a risky proposition.

 

Dasatinib can cause endothelial dysfunction: https://pubmed.ncbi....h.gov/29867576/

Loss of fibroblasts is usually not accompanied by replacement with new cells: https://www.scienced...092867418313217

 

What all this is telling me is that we need to be sure that cells that are removed are replaced. In the first reference above they used a ROCK inhibitor to accomplish this.

 

If you think this is not required, then remember that the evidence that senolytics are beneficial alone comes from laboratory mice, whom tend to have very long telomeres and consequently enhanced regenerative ability in comparison to humans.

[Moondancer]

Interesting paper. [...] If there was large scale fibrosis of endothelial tissues, one would expect a reduction in the flexibility of blood vessels and higher blood pressure as a consequence. I don't experience that at all.

 

 

Thanks Fafner, I agree with you with regard to the fact that in Bulavin's study they call the senolytic treatment 'acute' but rather seem to continuously administer senolytics to the rodents for the duration of a month. "For TAM experiments, all mice were maintained on TAM-contained diet for 1 month before the analysis."

These rodents were 1.5 years old 1.5-year-old p16-CreERT2/R26-DTA mice. Albeit I'm not sure if we can conclude from that that administering the senolytics in a 'hit-and-run'-fashion would have avoided such a result. The domain of senolytics still seems like murky waters to me. I guess we ought to wait for more studies to be sure what we can conclude from this study. 

Edited by Moondancer, 27 January 2022 - 05:43 PM.

[Moondancer]

You should conclude that senolytics are a risky proposition.

 

Dasatinib can cause endothelial dysfunction: https://pubmed.ncbi....h.gov/29867576/

Loss of fibroblasts is usually not accompanied by replacement with new cells: https://www.scienced...092867418313217

 

What all this is telling me is that we need to be sure that cells that are removed are replaced. In the first reference above they used a ROCK inhibitor to accomplish this.

 

If you think this is not required, then remember that the evidence that senolytics are beneficial alone comes from laboratory mice, whom tend to have very long telomeres and consequently enhanced regenerative ability in comparison to humans.

 

Interesting QFL. I stumbled on this paper weeks ago, that I posted in another thread wherein I asked what you are now discussing: whether we should perhaps combine senolytics with a ROCK inhibitor. 

Can a combination of senolytics with ROCK inhibitors and 5-LOX inhibitors contribute to tissue rejuvenation? from Dmitry Dzhagarov.

 

Admittedly it was way above my head to be able to answer that question myself, but I had also ran into the paper you cited yesterday. In fact out of concern I took 10mg of Rovustatine yesterday, which in studies appears to be rather effective in ROCK-inhibition. I'd prefer to use Fusadil, but this was all I had access to now. (I had also added curcumin and boswellia serrata as I hoped it may potentially have an additional effect on 5-Lox and ROCK inhibition). 

But it made me wonder: how long does it take before we can see an effect in ROCK-inhibition after taking a statin such as Rovustatine? I saw a study wherein they noted ROCK-inhibition after 11 days of taking two different statins, but then again: this was the first moment they tested. 

 

Edited by Moondancer, 27 January 2022 - 05:23 PM.

[QuestforLife]

Interesting QFL. I stumbled on this paper weeks ago, that I posted in another thread wherein I asked what you are now discussing: whether we should perhaps combine senolytics with a ROCK inhibitor.
Can a combination of senolytics with ROCK inhibitors and 5-LOX inhibitors contribute to tissue rejuvenation? from Dmitry Dzhagarov.


Admittedly it was way above my head to be able to answer that question myself, but I had also ran into the paper you cited yesterday. In fact out of concern I took 10mg of Rovustatine yesterday, which in studies appears to be rather effective in ROCK-inhibition. I'd prefer to use Fusadil, but this was all I had access to now. (I had also added curcumin and boswellia serrata as I hoped it may potentially have an additional effect on 5-Lox and ROCK inhibition).
But it made me wonder: how long does it take before we can see an effect in ROCK-inhibition after taking a statin such as Rovustatine? I saw a study wherein they noted ROCK-inhibition after 11 days of taking two different statins, but then again: this was the first moment they tested.

Conditional reprogramming in vitro is when they use a ROCK inhibitor to 'simplify' the shape of the cells (otherwise stuck to the dish) and telomerase (usually from murine feeder cells but it's also possible to do this with a form of gene therapy) to 'conditionally' immortalise the cells. They can proliferate indefinitely in a state akin to progenitor cells, but have a normal karyotype and revert back to their normal state when the rock inhibitor and telomerase are removed.

Dimitry is proposing to do this in Vivo. I'm less than convinced a purported LOX inhibitor like botswellia will provide the required telomerase, but it is otherwise a good idea.

I used a low dose statin and a Sartan for a month (then off for 3 months) a couple of times and reduced my epigenetic Methylation age by 2 years. So there may be something to it.

[Moondancer]

Thanks QLF, I believe Dmitry Dhzagarov suggested among others Baicalein may be used for 5-Lox inhibition. I could not find a supplement with Baicalein (most supplements I found had Baicalin). 

[Dallasboy]

Thanks QLF, I believe Dmitry Dhzagarov suggested among others Baicalein may be used for 5-Lox inhibition. I could not find a supplement with Baicalein (most supplements I found had Baicalin).

https://liftmode.com/baicalein-powder/

[Moondancer]

Concerning using a stating for potential ROCK-inhibition:

 

"Accordingly, we enrolled 30 men with stable atherosclerosis (low-density lipoprotein [LDL] ≥100 mg/dL) in a randomized, double-blind study comparing equivalent LDL-lowering doses of a hydrophilic statin (rosuvastatin 10 mg once a day) with a lipophilic statin (atorvastatin 40 mg once a day) for 28 days. We assessed the change in lipids, ROCK activity, and flow-mediated dilation (FMD) of the brachial artery before and after statin therapy. Both treatment groups exhibited comparable 30% to 32% and 42% to 45% reductions in total and LDL cholesterol, respectively. Only atorvastatin reduced triglycerides, and neither statin altered high-density lipoprotein cholesterol. Whereas both statins inhibited ROCK activity (p <0.0001), the extent of inhibition was greater with rosuvastatin (18 ± 2% vs 8 ± 2%, p = 0.0006). Statins also improved FMD from 7.4 ± 0.6 to 9.3 ± 0.4 (p = 0.003) with rosuvastatin being slightly better than atorvastatin. The inhibition of ROCK activity by statins did not correlate with reductions in LDL (p = 0.57) but was associated with improvement in FMD. In conclusion, these findings provide direct clinical evidence that statins, at clinically relevant doses, could differentially inhibit ROCK activity and improve endothelial function by cholesterol-independent mechanism." https://www.scienced...00291490801878X

 

But this was after 28 days on 10mg of daily Rosuvatin or 40mg of daily Atorvastatin in males with stable atherosclerosis. 

And: 

"128 patients with stable coronary heart disease were selected in our hospital from June 2014 to November 2015, and divided into four groups (control group, experimental group A, B, C) according to the random number table, 32 patients in each group. According to the clinical medication guide, patients in control group were treated by giving nitrates, anti-platelet aggregation, anticoagulation, lowering blood sugar, controlling blood pressure and other conventional treatment according to the patient’s condition, patients in experimental group A, B, C were treated by different doses of 5, 10, 20 mg rosuvastatin on the basis of conventional treatment, the frequency of medication was once a day, the time of comparative treatment was lasting for 8 weeks. The level of hypersensitive C reactive protein (hs CRP), Rho kinase (rock) activity, endothelium- dependent vasodilator function of the brachial artery, total cholesterol (TC) and adverse reaction of four groups were detected and compared. Results: Before the treatment, the index levels of four groups have no significant difference (P>0.05). After treatment, the hs-CRP level in control group was (3.13±0.67) mg/L, and experimental group A, B, C were respectively (2.67±0.73), (2.15±0.44), (1.87±0.32 ) mg/L, the hs-CRP level in experimental group A, B, C were all significantly lower than control group (P<0.05), and the level of hs-CRP reduced as the dose of rosuvastatin increasing; the Rho kinase (ROCK) activity in control group was (62.73±12.67)%, the Rho kinase (ROCK) activity in experimental group A, B, C were respectively (53.71±10.98)%, (41.63±9.61)%, (35.46±9.24)%, the Rho kinase (ROCK) activity in experimental group A, B, C were all significantly lower than those in control group (P<0.05), and the ROCK activity was lower as the dose of rosuvastatin increasing;" https://lcbl.csu.edu...wFile/5823/6284

 

This was in 128 patients with stable coronary heart disease after 8 weeks of doses of 5,10 and 20mg Rosuvastatin. 

 

But the question remains: how long would you have to take Rovustatin to experience such lowering of Rho Kinase (ROCK) activity. Any idea, Questforlife?

I'd prefer not to use statins for too long given potential side-effects, but wanted to add them to my senolytic protocols, just in case. 

 

Edited by Moondancer, 27 January 2022 - 08:46 PM.

[Moondancer]

https://liftmode.com/baicalein-powder/

 

Thank you, Dallasboy. Nice find! It's quite inexpensive also. I wonder what doses we'd be looking at. Unfortunately, living in Europe, I'd have to see if they ship overseas.

[QuestforLife]

https://liftmode.com/baicalein-powder/

I found boswellia as a bioavailable alternative to baicalein for 5-Lox inhibition (if you buy a form like apres flex/5-loxin etc.), but this powder is a good find and could probably be put in liposomes fairly easily.

I'm still not sure we're covering the telomerase base adequately, but it's a start. Moreover in this study they found feeder cells release telomerase when irradiated (peaking after a couple of days), so that suggests this kind of protocol should be taken within a few days of the senolytics.

https://ajp.amjpatho...e/S0002-9440(13)00594-4/fulltext

Particularly fig 8.

[QuestforLife]

But the question remains: how long would you have to take Rovustatin to experience such lowering of Rho Kinase (ROCK) activity. Any idea, Questforlife?[/color]
I'd prefer not to use statins for too long given potential side-effects, but wanted to add them to my senolytic protocols, just in case.

Unfortunately I think the answer is about 1 month. I covered this all on my thread some time ago.

This is the relevant paper, doi: 10.1089/rej.2015.1722

Note they weren't looking at ROCK activity, but saw significant benefits to FMD, C-reactive protein, etc and fluvasartin was synergistic with valsartan (I don't think the specific statin matters much, they all have these 'pleitrophic' effects, i.e. benefits unrelated to chloresterol reduction).

So you might want to take a statin and a sartan for a month and then do senolytics at or near the end of treatment.

[Moondancer]

Unfortunately I think the answer is about 1 month. I covered this all on my thread some time ago.

This is the relevant paper, doi: 10.1089/rej.2015.1722

Note they weren't looking at ROCK activity, but saw significant benefits to FMD, C-reactive protein, etc and fluvasartin was synergistic with valsartan (I don't think the specific statin matters much, they all have these 'pleitrophic' effects, i.e. benefits unrelated to chloresterol reduction).

So you might want to take a statin and a sartan for a month and then do senolytics at or near the end of treatment.

 

Thanks, QFL, that's helpful. 

I'd personally not feel comfortable to take a statin for a month each time I'd want to do a senolytic treatment. I assume it is impossible to try to obtain Fasudil and we have no other potent Rho Kinase inhibitors? 

[Moondancer]

Any thoughts about this study: "Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal."

https://pubmed.ncbi.nlm.nih.gov/33832488/

[QuestforLife]

Thanks, QFL, that's helpful.
I'd personally not feel comfortable to take a statin for a month each time I'd want to do a senolytic treatment. I assume it is impossible to try to obtain Fasudil and we have no other potent Rho Kinase inhibitors?

Note that taken for 1 month only, the statin and Sartan combination was highly beneficial.

I identified bacailein, boswellia, phloretin and tongkat ali (Eurycoma Longifolia) as natural ROCK inhibitors. The first I dismissed for bioavailability reasons. I tried the other 3. All had various side effects - but several reduced my BP quite quickly, so may have been effective for ROCK.

I got distracted and moved onto other things. But I'd recommend those supplements as a starting point for research.

Pharmaceutical ROCK inhibitors like fasudil are very hard to get hold of, and I suspect fasudil would be an intravenous treatment.

Incidentally, here is a summary of my research on ROCK inhibition from 2019: https://www.longecit...e-6#entry883118

Edited by QuestforLife, 29 January 2022 - 09:32 AM.

[Moondancer]

Note that taken for 1 month only, the statin and Sartan combination was highly beneficial.

I identified bacailein, boswellia, phloretin and tongkat ali (Eurycoma Longifolia) as natural ROCK inhibitors. The first I dismissed for bioavailability reasons. I tried the other 3. All had various side effects - but several reduced my BP quite quickly, so may have been effective for ROCK.

I got distracted and moved onto other things. But I'd recommend those supplements as a starting point for research.

Pharmaceutical ROCK inhibitors like fasudil are very hard to get hold of, and I suspect fasudil would be an intravenous treatment.

Incidentally, here is a summary of my research on ROCK inhibition from 2019: https://www.longecit...e-6#entry883118

 

 

Thanks again, QFL. I had been using Boswellia (LEF's 5-Lox-inhibitor) while taking senolytics. I've been taking this specific type of Boswellia twice per day for years. Not sure about its effectivity - never noticed any subjective changes or changes in my blood work after I started taking it. I may add Tongkat Ali to my next round of senolytics.

 

Do we have any studies that indicate how selective Dasatinib really is in targeting senescent cells? I read a comment on another forum that Dasatinib supposedly also kills off a good amount of healthy cells, without research to support that suggestion. But it made me wonder if any studies have been discussed with regard to the selectiveness of Dasatinib in targeting SC's? 

 

Did anyone try to add grapeseed extract to their senolytic compounds meanwhile, and any observable results thus far? 

 

I did a round Fisetin and Theaflavins weeks ago, and want to do a round of Fisetin, Dasatinib and potentially grapeseed extract next month.