For many informed observers of anti-aging science and practice, rapamycin appears to be one of the most promising anti-aging treatments currently available.
Originally (and still) used as an immunosuppressant for transplant patients, it’s been found to increase lifespan in lab animals. (Ref.)
Side effects of rapamycin are a problem, but it’s since been found that a transient (3-month) treatment with rapamycin can extend life expectancy up to 60%. (Ref.) More studies are needed to determine the dosing regimen with maximal efficacy and minimal side effects. (Ref.)
Intermittent dosing at once every 5 days also extends lifespan in mice, and this “demonstrates that the anti-aging potential of rapamycin is separable from many of its negative side effects and suggests that carefully designed dosing regimens may permit the safer use of rapamycin and its analogs for the treatment of age-related diseases in humans. ” (Ref.) Note also that this dosing regimen wasn’t started until the mice were quite old, at 20 months, and it still extended lifespan.
The principal mechanism of action of rapamycin is the inhibition of the cellular nutrient sensor and growth regulator mTOR. In elderly humans, weekly dosing of an mTOR inhibitor (not rapamycin) increased immune function as measured by response to a flu vaccine. (Ref.)
Given all of this, rapamycin as it relates to the slowing or reversal of aging, is still an experimental drug. However, we will be waiting a long time, perhaps forever, for the FDA to approve rapamycin for anti-aging, and since it’s a generic drug, there’s little incentive for drug companies to pursue clinical trials. Meanwhile, many people have begun to realize that they could be dead before this treatment becomes recognized – again, if ever.
Alan S. Green, M.D. understood the potential of rapamycin and began, and continues, to take it himself. He began to use rapamycin as the basis of his medical practice, and has so far treated hundreds of patients with it. I first interviewed Dr. Green a couple of years ago (here), and I’m pleased now to present an updated interview to discuss his experience with over two years of practicing anti-aging medicine using rapamycin. Some of these questions below have been crowd-sourced from Twitter, and others are my own.
As before, I thank Dr. Green for taking the time to answer these questions. As a pioneer in the clinical use of rapamycin and other anti-aging interventions, his story and experience deserve to be more widely known.
Q 1. How have your patients fared? What have you learned from clinical practice with rapamycin (and other drugs) that you didn’t know when you started?
Dr. Alan S. Green: My first anti-aging patient drove from Ontario, Canada to my NYC office on 4/22/17. Your first interview which posted on 6/5/17 was of huge importance in increasing patient awareness. The second patient was seen on 6/16/17. At that point in time, the only person in the public domain who had taken weekly rapamycin for a year or more was me.
Now approximately 2 years later, this office has seen over 360 patients. In my opinion, the results have been spectacular. No patient has died and nobody has had a serious complication. It is still my opinion that rapamycin is the greatest new drug since the dawn of the age of antibiotics some ninety years ago.
Documentation of the long-term results, which I expect to be that very many patients live to 105 in good health with a lowered incidence of cancer, heart disease and Alzheimer’s disease, should be available in 30 years. However, the short-term results are excellent. Weekly rapamycin is a safe drug. Good to excellent results are frequently apparent within months. Subjectively, many patients note an improvement in function of their brain and heart. They feel better, think better, have more energy and get less tired with moderate or strenuous physical activity. Weight control is much easier. Insulin sensitivity, I consider the best indicator of good metabolic health, usually improves.
Q 2. As patient number one, how are you doing?
ASG: Prior to starting weekly rapamycin in January 2016, at age 73, I had been experiencing increasing shortness of breath and mild chest pain with moderate exercise in walking up slight hills for 2 years. These symptoms were consistent with early heart failure. At the time, I thought I was suffering from aging. With the experience I have now, I would have realized my cardiac symptoms were much worse than ordinary aging at age 73. However, after 4 months after starting weekly rapamycin, I was totally asymptomatic and felt great.
In March of 2019, I had an echocardiogram and discovered, to my great surprise, that I had an extremely rare autosomal dominant inherited heart disease (Apical Hypertrophic Cardiomyopathy). This genetic heart condition had killed my grandmother, killed my mother, and intended to kill me. While it was certainly a mistake to not have consulted a cardiologist in 2015; it was a fortuitous mistake. If I had seen a cardiologist and been told I had an inherited cardiomyopathy, I never would have started my study of aging or begun this rapamycin Odyssey.
It should be noted that although the condition was genetic, it behaved very much like a TOR-driven age-related disease and rapamycin was an excellent treatment. Of course, for best results, the treatment with rapamycin should have been started 10 years sooner. When I finally became aware of the true nature of my heart condition, I increased the dose of rapamycin from 6 mg to 12 mg once a week. Now, almost 4 years after starting rapamycin treatment, I feel much better than I did at age 70.
Aside from my specific heart disease, the thing I noticed of general interest was the ease of losing weight on rapamycin. Prior to rapamycin, my best weight was 170-175 and great effort was required to prevent my weight increasing to 190 and above. After starting 6 mg once a week, my weight quickly decreased to 155 pounds and stayed at that weight for 2 years. When I increased dose to 12 mg once a week, I had another intentional weight loss of 10 pounds from 155 to 145 (5’10”).
An additional effect I noted, which is quite common, is improvement of chronic kidney disease.
Q3. Please address the risks of this drug. David Sinclair has expressed reservation of this drug due to risks.
ASG: Back in December 2015, when I contemplated being the first person to use weekly rapamycin using the Koschei formula, as outlined by Blagosklonny in his 2014 paper, I too had some reservations.
As regards David Sinclair, he is not a physician, he has never treated a patient with rapamycin and therefore it would be totally improper for him to say, “Use rapamycin, I have no reservations”. However, after taking rapamycin for close to 4 years and treating over 360 patients over the past 2 years, I have the experience and knowledge to say that weekly rapamycin is a safe drug.
As regarding the risks; the overwhelming risk is that tens of millions of people who could have been spared the ravages of age-related diseases such as Alzheimer’s disease, cancer, heart disease, blindness and premature death will not receive those benefits. Rapamycin is a generic drug and therefore there is no commercial interest in testing or promoting rapamycin. The risk people should really be afraid of is the risk of pain and suffering, of premature death from a heart attack, of terminal cancer, of dementia.
Q 4. What are the side-effects?
The side effects of daily rapamycin are TOTALLY different from the side-effects of weekly rapamycin. Daily rapamycin is used to reduce both mTORCl and mTORC2. Rapamycin was introduced in 1999 to reduce mTORC2 for organ transplant.
Reduction of mTORC2 has significant side-effects. People can review elsewhere the side effects of reducing mTORC2. Almost all the harmful side-effects of rapamycin use are from lowering mTORC2 and all the beneficial anti-aging effects are from lowering mTORCl.
Weekly rapamycin is designed to lower mTORCl and preserve activity of mTORC2. Dosing interval of one week is based upon the rapamycin half-life of about 65 hours.
It is required to delay the next dose until there is a low blood level of rapamycin so as not to interfere with production of new mTORC2.
There are side effects from reducing mTORCl. The major side-effect of lowering mTORCl is reducing the activity of the INNATE IMMUNE SYSTEM. The innate immune system is the first line of defense against bacterial infections and it involves neutrophils and macrophages, but not lymphocytes or antibodies. In my practice, everybody is warned of this danger and given a prescription of prophylactic antibiotics, (Z-pak) to have on hand and warned to aggressively treat fever or local signs of bacterial infection. My guess is 5-10% of patients might get a bacterial infection in a year and rapamycin increases the risk of serious bacterial infection. However, bacterial infections respond very well to prompt antibiotics.
On the other hand, the acquired immune system (lymphocytes) is improved as an anti-senescence effect and the risk of viral infection is reduced.
Very high levels of reduction of mTORCl may cause aphthous stomatitis. This is unusual at anti-aging preventive doses.
Aside from increased risk bacterial infections; there are minimal side-effects of weekly rapamycin as used in low doses to prevent age-related disease.
An off-target side effect of rapamycin is it’s an excellent anti-fungal agent. Longstanding cases of nail fungus (onychomycosis) are improved after prolonged treatment.
Q5. What do you make of the recent research that shows rapamycin increasing insulin resistance in muscle tissue?
ASG: The study you referred to I presume is “Chronic mTOR inhibition by rapamycin induces insulin muscle resistance despite weight loss in rats.” Deblon 2012. In this study they gave rats intraperitoneal injections 2 mg/kg/day. For a 70 kg human this would be a dose of 140 mg a day or 980 mg in a week. The typical dose I use is 3-6mg a week.
The dose in rat study above is designed to lower mTORC2; while my treatment is designed to lower mTORCl and preserve mTORC2.
In cancer therapy, rapamycin is used in very high dose to lower mTORC2. This is a good study to show the potential harmful side-effect of high dose rapamycin as used in transplant medicine and anti-cancer therapy. It has no relevance to use of rapamycin as an anti-aging medication.
Lowering mTORCl increases insulin SENSITIVITY in muscle while lowering mTORC2 increases insulin RESISTANCE.
Q6. The new study showing epigenetic reversal of aging with HGH, DHEA, metformin, vitamin D and zinc, was of great interest. But I felt that volunteers might have done better without HGH. What do you think?
ASG: I recently had 78 year old patient who had an epigenetic age test one year after starting rapamycin therapy. Epigenetic age was 66, 12 years less than chronological age.
This put him in top 99 percentile of lowest epigenetic age vs chronological age. Another person at 75 had an epigenetic test done before starting rapamycin and 1 year after treatment his epigenetic age was lowered 6 years.
In above study change was @ 2 years. This is a modest change. I would be very disappointed with this very small change for rapamycin. I think 12 years less than chronological age after 1year rapamycin is probably a typical result.
Metformin is known to lower TORC1 and would be expected to lower epigenetic age.
HGH raises mTORCl and accelerates aging and cancer and other age related disease. I would expect metformin to have a better result without HGH.
The take away from the study is that the epigenetic test was able to show modest effect of metformin, probably blunted by HGH.
However, in my opinion, this study does nothing to rehabilitate the well-deserved reputation of HGH for being a very harmful drug that accelerates aging, cancer, and risk of death from heart disease.
Q7. For your upcoming interview, can you ask Dr. Green how the lay person can be prescribed rapamycin? I have a hard enough time to convince my NP to give metformin as it is.
ASG: The best argument is the 2018 Blagosklonny paper, “Disease or Not, Aging is easily treatable”. This paper avoids arguments about the nature of aging. The focus is that rapamycin has been shown to increase lifespan in all animals tested and decrease risk almost all age-related diseases.
20% of people are ApoE4 positive. These people have 3 times the risk of Alzheimer’s disease and get AD 10 years sooner than the general population. The 2019 paper by Kaeberlein and Galvan, “Rapamycin and Alzheimer’s disease: time for a clinical study?” presents a huge body of literature showing rapamycin prevents Alzheimer’s disease. If you are ApoE4 positive, this paper is a great argument that you need rapamycin.
Q8. Can we access data online to see for ourselves? What studies have been conducted?
ASG: The above two papers cited in question 7 present long lists of life-span extension studies and age-related diseases references. Review these papers and the references.
Q9. At what age would he recommend someone start rapamycin? Are there more common molecules that have a similar effect, i.e. berberine is similar to metformin with a lesser effect?
ASG: By age 40-45 I suggest people start thinking about aging as a disease they need to consider. The Blagosklonny 2009 paper, “TOR-driven Aging, Speeding Car Without Brakes” provides the best introduction. The basic theory is TOR-driven aging is the same thing as TOR-driven age-related disease, just an earlier and treatable stage.
The Einstein equation E=MC squared is that energy and mass are the same matter. The Blagosklonny theory is that TOR-driven aging and age-related disease are the same disease.
To slow down TOR-driven aging; start with diet and exercise, avoiding overeating, overweight and pay close attention to your waist:hip ratio.
Monitor insulin sensitivity: Measure fasting insulin, fasting glucose (a lab test), then go to “Calculate HOMA-IR score” website, plug in fasting glucose, fasting insulin and site calculates HOMA-IR score. 0.5-1.4 is healthy; above 2 is early insulin resistance; above 3 is significant insulin resistance. Type 2 diabetes is a preventable disease. If you avoid insulin resistance you avoid type 2 diabetes and the increased risk for most age-related disease. Knowing your HOMA-IR score is very important as this is best indicator of good metabolic health. High HOMA-IR score causes increase in insulin, increase in TOR and accelerated aging.
Dietary ways to reduce TOR are caloric restriction, intermittent fasting, and keto diet. Moderate alcohol reduces TOR. Metformin reduces TOR.
Rapamycin is the most direct way and most effective way to reduce TOR.
By about age 55-70 most people can benefit by starting on rapamycin.
QlO: Effect of rapamycin on skin, hair?
ASG: Rapamycin has a beneficial effect on skin aging. However, for skin and hair best results would come with topical application. Topical rapamycin ointment is available in a few countries; but not in U.S.A.
Qll: What is the major difference between TOR-driven aging and other aging theories? Your approach and classical medicine ?
ASG: Slowing TOR-driven aging is about preventing age-related disease in the 55-100 year old age group. It is about how aging causes the common age-related diseases. The mechanism of TOR-driven aging is hyperfunction. The diseases are frequently driven by hyperfunctioning senescent cells. TOR reduces production of senescent cells. Senolytics, drugs which kill senescent cells, ca n be used as part of the treatment for TOR-driven aging.
Most aging theories are not about age-related disease. They are about the ultimate causes of death. Why 115 is about the apparent maximum age for humans. The ultimate cause of death in the very, very old is not hyperfunction; but rather accumulation of damage which is not repaired. Blagosklonny calls this post-aging syndrome.
Today, 99% of people die from TOR-driven aging. It is only when TOR-driven aging will be prevented; perhaps sometime in the future, that aging in the post 100 year age group may take on some clinical significance.
The main point is TOR-driven aging is garden variety disease and most aging theories are about cause of death when 110 years old. This is reason that most aging theories are ignored by medicine as totally irrelevant; they are not the cause of typical age-related disease, such as atherosclerotic heart disease.
Classical medicine treats established clinical disease. The approach is one medication for one disease.
The TOR anti-aging approach is the same prevention for all age-related disease and treatment must be started before clinical disease. This is what Blagosklonny calls “pre-pre-disease a nd pre-disease”.
Q12. What is the reception from other physicians?
ASG: I recently reviewed my last 100 patients and found 10% were physicians. These are frequently very prominent physicians, heads of departments, physicians at very prestigious hospitals, a president of the county medical society; but the interest is generally for their own use.
Most physicians are very reluctant to treat patients with rapamycin due to lack of human clinical studies.
Q 13. Does he have metabolically and physically fit patients? If so, what are their ages and what have been their clinical results with rapamycin ?
ASG: Many of my patients are exceptionally healthy, some are elite middle-age athletes. Some recent patients included a former Olympic runner, a Boston marathon sub 3 hour runner, a world class 50 mile trail runner, and many very excellent cyclists. These are people are very healthy and want to stay that way. The age range of top athletes is 50-70. They were top athletes before I saw them and they intend to remain top athletes.
Q 14. There’s a good diagram in this paper showing exponential rise in disease with age. Can you speak to how rapamycin affects this?
ASG: TOR driven aging is not a risk factor for these diseases; TOR driven aging IS these diseases. Cancer, CHF, COPD, Ml, stroke, dementia, diabetes are all the late end stage manifestations of TOR-driven aging. Slow down TOR-driven aging at the molecular level, the cellular level, the pre-pre-disease stage, the pre-disease stage and you decrease end-stage disease. Rapamycin slows down TOR-driven aging and it can be expected to decrease all these age-related diseases.
Q15. What would you estimate might be a typical lifespan/healthspan extension for an otherwise healthy person who began taking rapamycin in late middle age?
ASG: In my opinion, 100 will be the new 80.
Q16. Mikhail Blagosklonny’s latest paper compares rapamycin to the ketogenic diet. Do you think that rapamycin and ketogenic diet work in similar ways?
ASG: Rapamycin acts by direct inhibition of TOR. The ketogenic diet works by some backdoor pathway to inhibit TOR. However once they pull the trigger the downstream effect is the same. The main different is degree of inhibition. The potential degree of inhibition of TOR by rapamycin will be much greater than the fairly limited inhibition of TOR that can be achieved by keto diet.
Q17 . Do you think taking a regime such as this (including the metformin etc) has any adverse effect on the liver?
ASG: No. In particular Rapamycin is excellent drug for treatment of NAFLD (non alcoholic fattly liver disease).
Q18 What are his views on the anti-aging effects of EGCG as found in green tea?
ASG: I don’t think green tea has a significant effect on the TOR system to be considered an anti-aging drug. The criteria for anti-aging drug is increases life span in animals, especially mamma ls and prevents most age-related disease. Have not seen such evidence for EGCG.
Q19 I believe there was a study of alcohol having similar effect as rapamycin. Would be interesting to know more and if small doses of red wine could be used instead of rapamycin. Feels like a safer option, taking rapamycin (or any drug when you are healthy) feels too radical.
ASG: Both alcohol and rapamycin are drugs.
Both alcohol and rapamycin can be used to inhibit mTORCl. The main question appears to be which is better for anti-aging ?
Rapamycin is a very specific and very powerful inhibitor of mTOR. Alcohol is a weak inhibitor. Also alcohol has many off-target effects not related to inhibition of mTOR.
If your primary goal was anti-aging, you would choose rapamycin.
If your primary goal was cerebral intoxication; but you also wanted an anti-aging effect, then would choose alcohol.
If you wanted to slow mTOR-driven aging; but you did not have access to rapamycin, you did not like caloric restriction or intermittent fasting; but you did like cerebral intoxication; then alcohol is perfect for you. Moderate alcohol has a modest but significant anti-aging effect.
It was long known that moderate alcohol had a modest effect to prolong life span and prevent heart disease and dementia to a modest degree. However, the mechanism was unknown. The demonstration that alcohol interacts with the TOR pathway to lower TORl is very interesting.