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mccoy

Dr Alan Green prescribing rapamycin

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The site contains a host of practical info on rapamycin use. It relates often to Blagoskonny's article: "Koschei the immortal", posted by Sibiriak in another thread and which we discussed there. Blagoskonny is a declared used of rapamycin.

Dr. Green takes 6 mg of rapa per week. All the rationale of his dosage is explained in detail in his site. Pls note he is 75 or 76 now and his health degraded after 70, so he doesn't worry excessively about collateral effects, as a matter of fact he proposes more drugs like metformin to  contrast insuline resistance and statins to contras hyperlipidaemia (both induced by rapamycin).

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I'm kind of surprised he is trying to market this, seems highly likely to result in lawsuits against him at some (perhaps distant) future point in time.  Also his blood tests show a huge increase in LDL, which he attributes to going off a dyslipidemia med, but it seems odd to me that he would be OK with such a change without intervention (?), this also indicates a confounding factor in his personal experiments.

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Gordo, I don't know what the law on medical practice is there in the US. Dr Green requires a signed informed consent plus only sees people in person in the East coast. Plus since he's about 75 might not be too interested in a distant future (although, if Rapa works then he might!).

 

We must understand it's all very empirical. He started at 3 mg per week, whereas the immunosuppressive effect is reached at 270-280 mg per week. about 1/100 the dose used in trasplant patients. Now I believe he's at 6 mg per week, but the starting point for an average patient seems to be 3 mg. If he proceeds with this practice he's probably going to elaborate a more precise empirical protocol.

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Today I spoke with the young pharmacist where I go, who is usually glad to humour my enquiries. Here they sell 1 mg capsules of Rapamycin at 580 Euros, about 640 US$ at the current exchange.

 

At the starting dosage, that means an amount sufficient for 33 weeks. The mantainance dose is 1-2 mg per day, evidently 30-40 mg d-1 is the dose given just after transplants. That means that the longevity dosage is about 1/10 the maintenance those for after-transplant immunosuppression. 

 

I must admit Rapamycin has its sinister attraction, like the potion concocted by the Witch Baba Yaga and drank by Koschei the immortal in Blagammoski's article.

 

It would be easy here to have Rapamycin prescribed by a friend or a relative who have a medical practice.

 

Not a hard thing: starting with 3 mg per week and checking parameters like blood glucose and blood lipids, eventually using metformin and statins to titrate them and in the process becoming a walking biological lab...

Edited by mccoy

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 I am turning 68 in August and think I need something to get me out of a perceived downward spiral. Parents and grandparents have checked out in their 70's and one early 80's.  Have a 76 year old brother who I am watching like the canary in the coal mine.  

 

I live not to far from Dr. Green. I am debating whether to become a patient.   I have a friend who has known him for years and has assured me he is a knowledgeable and  serious man.  

I am by nature a cautious person and I am trying to weigh the pros and cons.   I am thinking I should make a decision before my next birthday.  

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I hear you, pete533 - as the years encroach, it's harder and harder to resist going for some pharmaceutical interventions, because just good diet, exercise and lifestyle are all tapped out and you need that extra push. Unfortunately, it's a huge gamble, that might just as readily shorten your days as prolong them. So I understand the temptation perfectly. I've been debating rapa with myself for years now, and I'm feeling the heat as I'm getting older.

 

Consider that you may need more than one therapeutic modality. Rapa can elevate blood glucose and blood lipids. For that reason, there is speculation that it might be advisable, in humans, to have adjuvant medications like metformin, acarbose and prehaps a statin like simvastatin or the like. There might be melatonin depletion, so one may need to look into melatonin supps. Lungs can be affected, so one should be up on all the pneumonia shots etc. It's complicated. Meanwhile, the experiments in dogs are experiments in... dogs. We can hope they apply to humans, but I've been burned by the expectation of animal to human extrapolation often enough that I'm very reluctant to accept animal results, period.

 

I can't wait for the rapa+metformin studies in humans to start publishing results.

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I re-read the article. The minimum starting dose is 2 mg every 10 days. most probably, according to the health status of his patiens, Dr. Allan Green is going to start with this dosage if the patient is in relative health. From there, he's going to monitor closely the possible occurrence of collaterla effects, like higher blood glucose, worsening of lipids profile, mouth ulcers and so on. This is a way to minimize risks. 

 

I'm not interested personally now since I'm in good health and 56. Should I develop something, or in 20 year's time, if health gets worse, I'd sure be tempted to consult a doctor or self-hack in lieu of proper docs.

 

@ pete 533: what if you take up an 'aggressive' natural prevention strategy: vegan regimen, lots of vegetables and protective phytochemicals, moderate carbs, lots of fiber, abundant nuts, 90 minutes daily physical exercise, 8 hours sleep, stress management....  It should stop the feeling of downward spiralling. 

Edited by mccoy

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Best to make one's peace --spiritually--with inevitable individual annihilation,  then carry on with a degree of detachment,  or "controlled folly",  to use a Castaneda term.

 

Another idea:  longevity is time alive--and time is, from one angle,  a psychological experience which can be extended experientially through specific practices.   I won't  say more, as these topics are beyond the scope of this forum.

Edited by Sibiriak

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Pete-

 

My perspective is closely aligned to the sentiments of TomB, McCoy ( and I think Sibiriak too - Sibiriak, not sure which practices you mean but acceptance, flow/immersion/mediation and sense of purpose can be powerful tools that enhance subjective quality of life and perception of progress through our finite timeline - would love to hear more ).

 

Al Pater recently linked to this 2014 reference below, which is symbolic and representative of the many unknowns of pharmacological agents that are truly bioactive like rapamycin, to say no less of the interaction between CRON and other fairly unconventional lifestyle practices common here with potential interactions with

Rapamycin

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458632/pdf/nihms855241.pdf( title: "Rapamycin reduces Drosophila longevity under low nutrition" )

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Al Pater recently linked to this 2014 reference below, which is symbolic and representative of the many unknowns of pharmacological agents that are truly bioactive like rapamycin, to say no less of the interaction between CRON and other fairly unconventional lifestyle practices common here with potential interactions with

Rapamycin

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458632/pdf/nihms855241.pdf( title: "Rapamycin reduces Drosophila longevity under low nutrition" )

 

I read the article linked by alPater, and the results after all are obvious, at least conceputally speaking:

  1. The flies are already under low nutrition. Low nutrition downregulates mTOr in all cells (decreases mTOR phosphorylation ratio)
  2. Rapamycin downregulated mTOR activity, even drastically with high doses
  3. Rapamycin acts on a system which is already downregulated. The sum effect is an extremely low mTOR phosphorylation ratio in all body
  4. All the metabolic activity governed by mTOR is nearly suppressed. There is almost no cellular growth. the immune system is compromised
  5. Death of the flies ensues.

If we administered Rapa to starving humans, probably the result would be the same.

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I

 

@ pete 533: what if you take up an 'aggressive' natural prevention strategy: vegan regimen, lots of vegetables and protective phytochemicals, moderate carbs, lots of fiber, abundant nuts, 90 minutes daily physical exercise, 8 hours sleep, stress management....  It should stop the feeling of downward spiralling. 

 

I think I will take a prudent approach as suggested by McCoy.  I will upgrade my diet that has been going off the rails of late, increase daily exercise that has been hampered by minor injuries.  + more sleep and stress management.  After doing this for a few months I will see my internist for blood work and reevaluate whether I want to try something as radical as Rapamycin + Metformin 

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I would be super careful in extrapolating results from flies, yeast and the like, to humans. To take just one obvious question wrt. rapa and flies - the claim is that rapa shortens lifespans for the flies that are "low in nutrients", and "under low nutrition". What in the world does that mean? CRON, to take the most obvious example is Caloric Restriction Optimal Nutrition. CRON does not imply "low in nutrients" or "under low nutrition" - it could imply quite the opposite, many CRONies have superior nutrient content in their diet than ad-lib. So since CRONies are not "low in nutrients", then this result is irrelevant. If however this is just another way of saying "low energy" or "low in calories", then that's another ball-game. This is hard to tell in organisms where the separation between "low energy diet" and "low nutrient diet" is very slight. If the organism consumes mostly sugar, then cutting back on sugar automatically cuts back on both the nutrient and energy aspects. How do you disentagle those two in flies, yeast etc.? It's easy in humans, not so easy in those lower lifeforms. If it's all about mTOR downregulation, then that's what should have been looked at. In which case the title might have been "In organisms which already have mTOR downregulated, the addition of rapamycin shortens the lifespan". That would've been far, far more useful than "Rapamycin reduces Drosophila longevity under low nutrition" - perhaps "Rapamycin reduces Drosophila longevity when mTOR activity is already suppressed through other interventions, including CR".  As it stands now, the paper's relevance to humans is questionable. 

Edited by TomBAvoider

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I think I will take a prudent approach as suggested by McCoy.  I will upgrade my diet that has been going off the rails of late, increase daily exercise that has been hampered by minor injuries.  + more sleep and stress management.  After doing this for a few months I will see my internist for blood work and reevaluate whether I want to try something as radical as Rapamycin + Metformin 

 

Pete, remember that exercise needs not to be strenuos, mishaps and nagging pains may occur but often we can work out around them. Walking on a treadmill plus light upper arms exercise  is enough, providing it's done on a daily basis and with a minimum duration (90 minutes is an optimal figure which comes from Dr Greger's elaborations). If we have access to machines we can do such a multitude of exercises that some of'em will bypass pain.

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Tomb, Re: drosophila and Rapa. The article reports some details on the flies' diet: 

 

 

All stocks were maintained and conducted under standard conditions (25 °C, 12 h light:12 h dark) on normal media (2% yeast, 11% sugar, 5.2% cornmeal, agar 0.8% w/v in water and 0.2% tegosept -methyl 4-hydroxybenzoate, from Sigma- St. Louis, MO, USA)....

For starvation studies flies were maintained in a 0.8% Difco bacto-agar in water. 0.1X SY food was prepared as described in (12)

 

As far as I understood, that's a macronutrients CR (yeast % has been varied)

 

 

As expected, dietary restriction of yeast at 2, 3, or 4% diet causes a repeatable extension of longevity relative to 1% yeast, in two independent experimental blocks separated by 6 months (Figure 1, A and B).

 

The results are evident from the survival curves

 

post-7347-0-26681600-1497333557_thumb.jpg

 

in both blocks, on severe CR (1% yeast)  the control group lives much longer than Rapa group. At moderate CR (2% yeast) control and rapa are the same. In the E graph, at both 2% and 8% yeast Rapa increaseas life (that's the second block of flies). There are more graphs in the articles on Rapa concentration and mean lifespan and so on.

 

Extrapolability to humans is valid, IMO, only at the conceptual framework. the mTOR pathway is highly conserved from yeast to humans thru flies. The CR severity and Rapa concentration of course cannot be extrapolated directly, but the concepts we outlined I believe stand true for humans (emphasis mine), with a proviso on the short duration of the life of flies:

 

 

In summary, there are three conclusions from these experiments: 1) Under limited nutrition, rapamycin decreases the longevity of two Drosophila strains in a dosage-dependent manner (Figure 3) in two independent low-nutrition diets (1% yeast and 0.1X SY food). 2) Rapamycin does not consistently extend longevity of Drosophila melanogaster under unrestricted diets (Figure 1 and 2). 3) The detrimental effects of rapamycin are not observed in two Drosophila strains when under starvation conditions (Figure 4). The lack of a detrimental effect of rapamycin under starvation suggests that the pharmacological effects of rapamycin depend upon the nutritional state of the fly. Thus, as a dietary restriction mimetic, the addition of rapamycin to a diet that is already low in nutrients may exacerbate malnutrition and reduce longevity. It may be that decreased longevity is not observed under starvation because rapamycin cannot further restrict dietary nutrients. 

However, rapamycin may need more time than only a few days to modulate longevity and its effect under starvation might be hindered by the short longevity of starved flies.

 

 

Takeaway lesson from this study seems to be that, when administering Rapa to humans, a careful evaluation is needed on the current macronutrients intake of the patient and the balance: rapa dosage-CR.

 

AFAIR, Dr. Green was in CR when he started self-administering Rapa.

 

 

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A further qualitative consideration. From the conceptual framework discussed above and discended from the drosophila article (Villa-Cuesta et al., 2014) CR and Rapa seem to have a synergic effect. So in humans CR might be usefully employed to decrease Rapa dosage needed to improve longevity and healthspan, at least theoretically, with ensuing lesser hazard from collateral damage.

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A recent article from Blagosklonny (Oncotarget, 2017) , proposing a multi-drugs approach to longevity. That looks more and more esimilar to Baba Yaga's concoctions, to which on the other side the author freely inspires.

 

The hyperfunctions model is also an interesting POV. Blagoskonny illustrates some inhibiting signals to the hyperfunctions/aging mechanisms, among which CR and exercise. 5 drugs are considered to be most effective: Rapalogs, metformin, lysonopril, aspirin and statin. 2 additional drugs, propanolol and PDE5 inh are allegedly subordinate.

 

The above would constitute Baba Yaga's 7-ingredients cocktail, drunk by Koschei the immortal, the mythical figure which inspired blagosklonny.

CR is the 8th ingredient.

 

post-7347-0-33054100-1497517502_thumb.jpg

Edited by mccoy

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My personal feelings is that Blagosklonny here is overextending himself with the amount of drugs. At least, as far as healthy individuals are concerned. From his same words, hyperglicaemia and hyperlipidaemia from Rapamycin are often irreversible and can be monitored, or counteracted with CR.

 

The 7-drugs cocktail sounds hazardous, for those who have not nothing to loose.

Edited by mccoy

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Once I saw Baba Yaga naked in a field of rhodiola, gorging herself on  sea buckthorn and blue honeysuckle berries.

 

I hope she was in her younger version !!!

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A recent article from Blagosklonny (Oncotarget, 2017) , proposing a multi-drugs approach to longevity. 5 drugs are considered to be most effective: Rapalogs, metformin, lysonopril, aspirin and statin. 2 additional drugs, propanolol and PDE5 inh are allegedly subordinate.

 

This cocktail is almost identical to that used by the crowdfunded "I am a little mouse, and I want to live longer"  pilot study in 2013, which gave everolimus (rapalog) + metformin + Ramipril (ACE inhibitor) + aspirin + simvastatin + metoprolol (beta blocker) to mice in their food, all at the same daily dose shown to retard aging in the case of rapa and to exert modestly positive effects in at least some studies in the others (albeit none other than possibly rapa that would make it at all rational for an otherwise-healthy but aging human to take them). The result, still not properly reported, was a shortening of lifespan in some subgroups and no lengthening in the others.

 

On the other hand, it should be noted that metformin seems to enhance the anti-aging effect of rapamycin, particularly in males, despite having no effects on its own — apparently by reducing the negative effect on glucose tolerance.

 

Much of the rest of the thread has been taken up by discussion of various phytochemicals. Much of the research being discussed is in vitro, and/or is purely mechanistic, or is in vivo but in models that don't reflect the conditions of normally-aging humans (coadministration of hideous toxins, severe genetic disease models, high levels of imposed oxidative stress, etc). None of these substances has been shown to extend lifespan under proper testing conditions.

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Much of the rest of the thread has been taken up by discussion of various phytochemicals.

 

 

It might be desirable to move the phytochemicals discussion to a separate thread.

 

(Agreed: done. Thanks, Sibirak! -MR).

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A little late to the thread but very thankful to have found it.

The more I read about some of the choices we have in the start of the 21st century I feel we are all truly lucky to be alive at this time. Then again you don't need to hear me say that as Ray Kurzweil says it in just about every personal appearance.

Thanks again for making the forum. So looking forward to reading what you all have to say

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