I've just finished my third Senolytic cycle.
Fisetin 1500 mgs on 2 consecutihve days repeated one month later
Dasatinab 180 mgs on 2 consecutive days + Quercitn 2250 mgs on the same days
I also take 4 mgs of Rapamycin once a week and 500 mgs of MetforminER twice a day.
65 years young.
that is fantastic your massage ! First time I find in internet this direct link between androgen dificiency and senolitic therapy. I was diagnosed 3 years ago with age related androgen dificiency. The doctor prescribe me trt . I was using gel patch and now I am near 1-2 year on nebido inj for every 12 weeks. During last 3 months I start only with fisetin Mayo Clinic protocol and made it 2 times. And this really so curiosity for me - that is already pass 16 weeks from the last inj and my testosterone level do not go down. I was doing blood analysis every week in a different labs, think that it might be the mistake. With androgen dificiency right level of testosterone is crucial important for me just to have a normal living and normal work. I depends very much from trt. Before trt my testosterone level was going down bellow then 250 ng/dL if I don’t use trt. Also long time of trt suppressing of my own body production of testosterone.
And now I do not to know what to do - stop trt or to continue any way? Because now my level is not ideal, is suboptimal (near 450 ng/dL). And I feel not enough..
Could you clarify little bit more how you could discontinue use of trt. How long you use senolitic to stop trt? How do you stop, immediately or any way continue some time with injection? How much in dynamics your testosterone level change?
As a rapamycin and metformin user, I'm unsure if senolytics will offer additional advantage when combined with mtor inhibition. The main reason for doubt is that in vivo tissue studies of mice (hepatic) and human (skin fibroblast) indicate rapamycin appears to produce a relative "clearance" of sensence as opposed to just inhibition of SASP and slowing senescent conversion. BiogerontologyJune 2019, Volume 20, Issue 3, pp 331–335, GeroScienceDecember 2019, Volume 41, Issue 6, pp 861–869|
Most impressively, the study of human skin showed probable clearance of senescent cells (by biopsy and staining) using a topical .001% rapamycin applied daily or every other day for 8 months. This concentration is like taking one milligram tablet rapamycin, crushing it, and mixing it with about 3.5 ounces (100 grams) of your favorite moisturizer.
It does appear that combining multiple anti-aging therapies can produce additive results such as the fruit fly study combining rapamycin, trimetinib and lithium Proceedings of the National Academy of Sciences, 2019; 201913212 DOI: 10.1073/pnas.1913212116. However, this drug combination affects the nutrient sensing network via three separate pathways which logically could be expected to be additive.
The issue with rapamycin combined with senolytics is: if rapamycin serves to clear senesence, then the addition of a senolytic therapy may not provide that much additional benefit. I have not seen any study which answers this question as it would require a rodent group with rapa, a rodent group with senolytics (and controls) and a combined rapa/senolytic group. Has anyone seen such a study?
Metformin is taken along with rapamycin to counteract some of the metabolic effects such as insulin resistance. I have no idea (nor does anyone) if the combo of these two drugs will be synergistic in terms of additive years to human life span.
Yes, genetically modifying the worm genome to manipulate insulin signaling and mtor systems lead to a 500% lifespan increase vs an expected 130%. Both of these pathways are distinct although perhaps somewhat convergent as they are separate parts of a nutrient sensing network. This synergy has also been shown in the fruit fly experiment by combining lithium (insulin signaling), rapamycin (mtor), and a tyrosine kinase inhibitor, all distinct paths of the nutrient sensing network showing a synergistic lifespan extension.
In the case of rapamycin combined with senolytics, they are both doing much of the same thing - decreasing senescent cellular burden. Much of the benefit of each may be acting on exactly the same endpoint and therefore not particularly additive. Study of this could be done as illustrated in a previous post.
For what it is worth, my opinion is that people using rapamycin at an appropriate dose earlier in life (pre-disease) will have markedly less senesence with aging. For those who are already progressed into the disease of aging without treatment, senscent burden will likely be higher. I surmise that people who start treatment later have greater probability of benefit from senolytics while those who have limited senscent burden (earlier treaters) will not benefit as much.
We don't know too much at this time so this seems logical - and this logic affects my personal decisions on my own treatments. Opinions like mine are not worth much until proven or disproven with the scientific method but it is all we can go on sometimes.
From Dr Greens website
In a 2018 paper Blagosklonny states, "It has been calculated than rapamycin slows geroconversion by approximately 3-fold". This means rapamycin slows formation of senescent cells three-fold. 
it seems that if true rapamycin is not getting rid of older senescent cells, just slowing progression of accumulation of new ones.
I would interpret that to indicate another method is needed to rid old cells. I suppose if you start rapamycin young enough then a senolytic treatment is not needed
I’m currently starting my first Dasatinib (compounded generic formula) - 100mg + quecertin (1,000mg) In split doses for 3 days prescribed by Dr. Green. This is in addition to my weekly Rapa (6mg), candasartan (16mg daily), and tadalafil (5mg daily). Dr. Green is following a similar regimen. He only prescribed me one course of treatment and wants to see labs 2 weeks post treatment. He feels this senolytics treatment is complementary to my other meds. This is somewhat consistent with Mikhail Blagoskonny’s research although he has recently posted on twitter that the senolytics research is much weaker. Dr. Green’s formulation of D+Q for 3 days is similar to a recent human study that showed some positive results for a small study. After day 1 I haven’t really had any side effects except for a slight headache towards the end of day 1.
Here is another Doctor Who prescribes rapamycin in Las Vegas.
- John Mcgough
I thought I would provide the name of my Doctor who does prescribes rapamycin but his practice is different from Dr. Green in New York.
I have found him to be veryknowledgeable and extremely helpful as he is versed and prescribes bio-identical hormones, PRP, peptides and other healing modalities. See below.
Julio L Garcia, M.D.
Regenerative Medicine Institute of Nevada
dedicated to helping patients with mesenchymal stem cell/ cytokine/ growth factor therapies and peptides for the treatment of acute and chronic medical issues
(855) 786-2356 toll-free
A new wide spectrum senolytic SSK1 in development. They imply that it works on all senescent cell types and works better than Dasatinib, Fisetin, and Quercetin.
In this study, we designed a new prodrug based on the major senescence marker — the elevated β-gal — to selectively target senescent cells. This prodrug, SSK1, specifically killed both human and mouse senescent cells independent of senescent cell types and inducers. In a mouse lung injury model, SSK1 cleared stress-induced senescent cells in vivo and alleviated associated symptoms. Importantly, SSK1 also effectively reduced naturally occurring senescent cells in aged mice, decreased the senescence- and age-associated gene signatures, down-regulated SASP both locally and systemically, and restored physical functions. These results demonstrated the robustness and specificity of our prodrug in reducing senescent cells.
We successfully developed a new prodrug strategy that directed gemcitabine to kill senescent cells in a highly selective manner. The foundation of our prodrug strategy was to select a highly specific senescence marker and identify an appropriate potent drug to efficiently kill senescent cells. First, the elevated enzymatic activity of β-gal, a universal senescence biomarker both in vitro and in vivo,18,52 was utilized to direct the prodrug to specifically target senescent cells. Second, through the screening of hundreds of FDA-approved drugs, we found gemcitabine to be one of the most potent agents in killing non-dividing senescent cells (Fig. 1a; Supplementary information, Fig. S1b, c, and Table S1). In addition, gemcitabine is a widely used FDA-approved drug with proven safety and short plasma circulation time.25,26 Our designed prodrug SSK1 is activated to release gemcitabine selectively in senescent cells (Fig. 1c), following which senescent cells were effectively eliminated (Fig. 1d). Our further study showed that gemcitabine activates p38 to induce apoptosis in non-dividing senescent cell (Supplementary information, Fig. S2a, b). As a nucleoside analog, gemcitabine could kill senescent cells through inducing mitochondrial DNA damage (Supplementary information, Fig. S2d), similar to a reported nucleoside analog, Ganciclovir.33 These results demonstrated that prodrug SSK1 is superior to current reported senolytics in terms of design strategy and specificity.
Cellular senescence is a highly heterogeneous process due to the different cell origins and stimuli,6,53 whereas the key feature of SSK1 is the ability to efficiently clear senescent cells with a broad spectrum of cell types and senescence inducers, including replication, irradiation, oncogene and genotoxic stress (Fig. 2a, c). In this study, we compared SSK1 with other reported senolytics on HEFs, human preadipocytes and HUVECs, which were used to test senolytics. ABT263 (a classical anti-apoptosis BCL-2 inhibitor) eliminated senescent HEFs and HUVECs, but showed little effect on human preadipocytes (Supplementary information, Fig. S3b, f, j), which was also reported by other previous studies.12,13 The combination of dasatinib (a pan-tyrosine kinase inhibitor) and quercetin (a plant flavonoid) killed all three types of senescent cells in a dose-dependent manner (Supplementary information, Fig. S3c, g, k), but had a high toxic effect on non-senescent cells in consistence with others’ results.11,16,36 Another natural flavonoid fisetin, reported as a potential senotherapeutic agent,15 showed modest effect on eliminating senescent HEFs and preadipocytes even at higher concentrations (Supplementary information, Fig. S3d, h) which was comparable to other’s results.54 Most importantly, SSK1 could overcome these limitations, including cell-type dependency, high toxicity on non-senescent cells, and low efficiency on senescent cells (Supplementary information, Fig. S3a, e, i). Therefore, SSK1 possessed a better senolytic activity regarding of specificity and efficiency on a wider range of cell types, demonstrating the superiority of β-gal-based prodrug strategy to target senescence.
Moreover, we found SSK1 exerted its elimination effect on senescent cells in vivo. SSK1 eliminated stress-induced senescent cells effectively and decreased different senescence markers in bleomycin-induced lung injury model, highlighting its effectiveness in vivo (Fig. 3). SSK1 treatment also relieved lung fibrosis (Fig. 3d; Supplementary information, Fig. S4c, d) and attenuated the impaired physical function as tested by treadmill assay (Supplementary information, Fig. S4f). In this study, we also treated naturally aged mice with SSK1 and tested its effects on senescent cells, chronic inflammation and physical function. First, SSK1 could remove senescent cells in multiple tissues and decrease the senescence-associated signatures as shown by the GSEA analysis (Fig. 4b–g). Second, SSK1 could decrease the expression of SASP-associated genes in aged livers and kidneys and reduce chronic low-grade inflammation in the blood (Fig. 5a, b, e–h). Third, SSK1 ameliorated the impaired motor function, balance, exhausted exercise, muscle strength, and spontaneous exploration in aged mice (Fig. 6a–e). Most importantly, the performance of rotarod and beam balance in the SSK1-treated group was improved compared with that in the initial pretreatment condition (Supplementary information, Fig. S8e, f). Collectively, our prodrug SSK1 targeting β-gal-positive cells exerted very significant biological effects in naturally aged mice.
While SA-β-gal is widely used as a marker of cellular senescence,20,21,22 its elevated activity can be found in some other cells such as activated macrophages.48,55 These SA-β-gal-positive macrophages can be harmful and have been found to accumulate in injured and aged tissues contributing to chronic inflammation.44,45 Importantly, we have shown that SSK1 decreases the number of SA-β-gal-positive macrophages in injured lungs and aged livers (Supplementary information, Fig. S6g–j), which is consistent with our observation of reduced secretion of chronic inflammation-related cytokines. Therefore, eliminating macrophage accumulation by SSK1 might reduce chronic inflammation and benefit aged organisms. In addition, activated macrophages play crucial roles in acute inflammation and cytokine storm,56 especially those induced by virus infection. During virus-induced acute inflammation, macrophages produce pro-inflammatory factors and trigger initiation of cytokine storms.57 For instance, the depletion of macrophages could protect mice from coronavirus-induced lethal infection.58 Accordingly, activated macrophages could be potential targets for treating acute inflammation and cytokine storms via SSK1. The future potential for SSK1 in treatment of acute inflammation, injury, and age-induced chronic inflammation is promising.
An understanding of the toxicological effects of SSK1 in vivo is critical to clinical applications. Importantly, our data showed that high concentration (100 mg/kg) and high frequency SSK1 treatment had no apparent systemic toxicities (Supplementary information, Fig. S9). This provides strong evidence for the in vivo safety of SSK1. This safety profile is further supported by comparison to gemcitabine, an SSK1 effector and approved clinical drug. First, our effective in vivo dosage of SSK1 was approximately 60-fold lower than the clinical dosage of gemcitabine (30 mg/kg) and implies a greatly reduced risk of in vivo toxicity of SSK1.24 Second, gemcitabine is a nucleoside analog that potently affects rapidly dividing cells and the off-target effects of gemcitabine could be shown in different proliferating cell types.59,60 SSK1, however, targets only β-gal-positive cells. Notably, in addition to macrophages, we found that the majority of non-senescent β-gal-positive cells are rapidly dividing epithelial cells (Supplementary information, Fig. S10a, b). As a result, the potential types of proliferating cells with SSK1 sensitivity are greatly narrowed relative to gemcitabine. Even though small numbers of β-gal-positive epithelial cells are targeted by SSK1 treatment, these cells have robust self-renewal ability.61 Consistent with this self-renewal property, we found that epithelial tubular cells in the kidney with elevated β-gal activity had a high percentage of Ki67-positive cells (Supplementary information, Fig. S10c). Following SSK1 treatment, we observed only a few cells of this tubular cell population undergoing apoptosis (Supplementary information, Fig. S10d), and such low-level impairment could be easily repaired by the rapid self-renewal of tubular cells during SSK1 treatment. Moreover, the short duration of SSK1 treatment might avoid significant impairment in related tissues and further minimize its side effects. In summary, our study demonstrates the superiority and safety of this prodrug strategy by targeting β-gal to selectively remove senescent cells of multiple cell types. These findings open a new avenue for the treatment of age-associated diseases and provide a clinical opportunity for intervention into the aging process.
this is what Dr Green lists:
Dasatinib 100 mg dose for 3 days.
Quercetin 1000 mg for 3 days
Fisetin 1500 mg for 3 days.
I get diarrhea every time I take more than 500 mg of quercetin and I imagine the antibiotic would affect me the same
I never had aches and pains but I read others report flu like symptoms the first time they take Dasatinib
Just received my order for Fisetin 50 grams and Dasatinib 5 grams from China. No problems with Customs was shipped via Fedex. Fisetin was $2.50 gram including $25 Fedex. Dasatinib was $20 gram + $25 shipping. I received exactly 50 grams of Fisetin, and 5.6 grams of Dasatinib. Over paid for Fisetin, better to order online. Dasatinib and Rapamycin also are such small amounts that they can ship in an envelope and less likely to have a problem with customs. Dr. Green is now recommending to take Fisetin and Dasatinib together and you can skip or not quercetin because Fisetin works better. Green recommends 1500 mg Fisetin x 3 day x quarterly for anti ageing. I prefer to use Mayo clinic's formula of 20mg/kg. On July 01, 2020, I will take Fisetin 1700 mg x 3(with olive oil) + Dasatinib 100 mg x 3.(quarterly) The next week will take 250 mg Zithromycin x 6 days (quarterly) Will try taking Vitamin C, 500 mg with all of the above. These 3 drugs target 3 of the 4 senescent putrid cells, (aka, zombie) WIll be waiting for a treatment for the 4th. cell type.
Paul Beauchemin said:
attacking senescent cells is evolving as the #1 treatment for aging
In my view, clearing senescent cells is the first step (but by no means the last) in treating aging. The cell's internal programming has declared senescent cells to be too damaged to replicate, and that decision should be taken seriously. One should clear them before any other intervention. After that, if quasi-embryonic pluripotent stem cells are available, they should be provided to replace the cleared cells. (Apparently, given the recent Unity Bio trial failure, this is important.) Then, if an intervention is available to reset the epigenetic programming of the remaining cells (e.g., by AAV delivery of DNA or liposome delivery of mRNA to cause OSK Yamanaka factor expression), this should be done. In principle, we know how to do all of these steps right now. However, FDA roadblocks and the expense of human testing put access to these therapies far down the road, at least in the USA.
I wouldn't put any money on it. Essentially, the flawed approach of Unity Bio involves repurposing a highly toxic anti-cancer drug that they call UBX-0101 and have patented for senolytic applications. UBX-0101 cannot be used as a general senolytic because of its toxicity. To avoid whole-body toxic effects, they inject UBX-0101 into relatively isolated body systems like the knee capsule or the eye capsule. The problem with this approach, in my opinion, is that the cleared senescent cells need to be replaced with healthy one, they are not clearing nearby senescence outside the capsule, and the SASP effects of these neighboring senescent cells are preventing replacement by stem cells.
In my view, one needs to use a general non-toxic senolytic that clears all senescent cells. Oisin Bio's DNA plasmid/liposome technique does this. The recent Chinese paper describing a new synthetic small-molecule senolytic called SSK1 that targets the senescence-marker beta-galactosidase seems to promise to do the same. However, the toxicity of SSK1 under all conditions has not been well established, it has not been tested on humans, and all senescent cells do not express beta-galactosidase. Both such treatments should be followed up by providing a supply of pluripotent stem cells to replace the cleared senescent ones.