Enthusiasm for Rapamycin and Polypills in the Search for Ways to Slow Aging

The author of this paper is one of the more outspoken advocates in the research community when it comes to mTOR and rapamycin as a path to slowing the progression of aging. He keeps up quite the output of position papers, such as this one, which calls for immediate human trials of polypills made up of rapamycin and a brace of other drugs broadly used in treatment of age-related conditions, such as statins and metformin. I have to think that the evidence to date suggests this will be less effective than hoped, while still very plausibly being better than doing nothing, even considering the side-effects of the drugs involved. Effects in animal studies usually tend to be much more pronounced than effects in humans when it comes to slowing or preventing specific age-related diseases through pharmaceuticals.

If it was the only game in town, I'd be all for it, but there are far more effective ways forward towards the effective treatment of aging as a medical condition - approaches that aim at rejuvenation, not a mere slowing of aging. Still, I think the author here has the right general idea, in that the research community should move faster, the sooner plausible approaches are trialed the better, and that we should all pitch in to help, it is just that he is advocating a poor approach with a limited upside in comparison to other methodologies.

Inhibitors of mTOR, including clinically available rapalogs such as rapamycin (Sirolimus) and Everolimus, are gerosuppressants, which suppress cellular senescence. Rapamycin slows aging and extends life span in a variety of species from worm to mammals. Rapalogs can prevent age-related diseases, including cancer, atherosclerosis, obesity, neurodegeneration and retinopathy and potentially rejuvenate stem cells, immunity and metabolism. Here, I suggest how rapamycin can be combined with metformin, inhibitors of angiotensin II signaling (Losartan, Lisinopril), statins, propranolol, aspirin and a PDE5 inhibitor. Rational combinations of these drugs can maximize their anti-aging effects and decrease side effects.

At first, the discovery of anti-aging properties of rapamycin was met with skepticism because it challenged the dogma that aging is a decline driven by molecular damage caused by free radicals. By now, rapamycin has been proven to be an anti-aging drug. In contrast, anti-oxidants failed in clinical trials and the dogma was shattered. In the last decade, anti-aging effects of rapamycin have been confirmed. Anti-aging doses and schedules can be extrapolated from animal studies. Well-tolerated doses with minimal side effects can be deducted based on clinical use of rapalogs. So optimal anti-aging doses/schedules can be suggested. Given that rapamycin consistently extends maximal lifespan in mice, rapamycin will likely allow mankind to beat the current record of human longevity, which is 122 years. Yet, rapamycin will not extend life span as much as we might wish to. Now is the time for anti-aging drug combinations. For example, metformin is currently undergoing re-purposing as an anti-aging agent. Several other existing drugs can be re-purposed. Now we can design an anti-aging formula, using drugs available for human use.

Rapamycin (or another rapalog) should be a cornerstone of anti-aging combinations, given its universal anti-aging effect and the ability to delay almost all diseases of aging. Rapamycin and metformin: Both drugs extend lifespan in animals and have non- overlapping effects. In addition, they may, in theory, cancel possible metabolic side-effects of each other. Rapamycin and statins: Rapamycin promotes lipolysis increasing blood levels of fatty acids. This, in turn, increases levels of lipoproteins produced by the liver. Rapamycin-induced hyperlipidemia is benevolent and reversible. Still, statins are already used to prevent rapamycin-induced hyperlipidemia.

The 7-drug combination can be tested in mice, especially in mice on high fat diet and in cancer-prone mice. If started late in life, the experiments will take just several months to evaluate the effect on lifespan and cancer incidence as well as weight, blood pressure, glucose, insulin, triglycerides and leptin. In humans, the treatment program can be initiated regardless of any pre-clinical studies, because all 7 drugs are approved for human use and some of them such as aspirin and statin are widely used for disease prevention anyway. The only what is needed is to watch for side effects. Especially, heart rate, blood pressure, and glucose levels should be monitored.

The anti-aging formula is ready for human use. If one will wait until the life-extending effect will be shown in others, this individual will not be alive by the time of the result. Human clinical trials are needed to optimize the doses and schedules. However, unless we participate in clinical trials ourselves, we will not know how long participants will live because they are expected to outlive non-participants. If we want to live longer we should be participants in clinical trials. In the best scenario, this might allow us to live long enough to benefit from future discoveries of anti-aging remedies.

Link: https://doi.org/10.18632/oncotarget.18033

Comments

Completely agree. Every weapon we have should be used against aging. Sure we may not be able to achieve LEV with this combo, but will it buy us some time and reduce the cost of an aging population? You bet it will.

Posted by: Mark Borbely at June 21st, 2017 10:36 AM

Maybe exploring all the possibilities is a good way to do science, but it's one of the worst ways to do engineering. And medicine is engineering, not science. When you have a reasonable plan, you must follow it, instead of pursuing all possible plans at the same time, even the least reasonable ones. That's why America's manned space program has been stagnating for half a century now.

http://www.nationalreview.com/article/383100/why-nasa-stagnant-robert-zubrin

If half the money spent buying supplements (or on CR research) had been spent on SENS research, we'd probably reached LEV by now.

Posted by: Antonio at June 21st, 2017 11:28 AM

@ Antonio

True, if we could have spent $X more on SENS we'd be closer to LEV for sure, but there are some problems with getting revenue from people buying currently available treatments...

Those wishing to see LEV have a choice:

Spend money on currently available treatments (Rapamycin (reduce senescence), Angiotensin inhibitor/blockers (mitochondrial QC)), which will extend our own, personal life by some small amount (to be determined) and make it more likely we will survive to see a better treatments in the future; or

Spend money on research, which will help everyone still alive, possibly including ourselves, a great deal at some unspecified point in the future, but do nothing for us right now.

It is clear from this tradeoff calculation that more money will go to the first option than the second; it is simply how humans think - small but more certain benefit now beats much larger, more speculative benefit later. The best we can hope for in getting more money to the second option is that enough people will take a punt on the long range option.

It may help that currently available treatments will soon include senolytics, and some of the funds from this may be reinvested in further rejuvenation research.

Posted by: Mark at June 22nd, 2017 4:11 AM

There is no such tradeoff. There is no indication that those "treatments" are really treatments, i.e., will produce any measurable LE on humans. Quite the opposite, using evolutionary arguments, it's likely that they will produce very tiny LE if at all. And the more strict experiments with antioxidants and supplements indicate that some of them are actually detrimental rather than beneficial, and the rest has no positive effect, unless you have some dietary defficit.

Posted by: Antonio at June 22nd, 2017 6:27 AM

@Antonio

Firstly, I should make clear I totally agree SENS is the way to go if we want to achieve LEV, and putting as much money as possible into the 2nd option is the best way of getting there.

But on your discussion against currently available therapies, you are wrong and undermine your own arguments for LE in making such claims - rapamycin has extended life in pretty much every species it has been tried in, and shows every indication of extending life in humans, even if it is only a mean rather than max lifespan extension (it does both for mice).

Anti-oxidants are a more mixed story, the jury is still out, though note I mentioned angiotensin inhibitors/blockers, which work through mitochondrial QC, which is not the same thing.

Definitely rejuvenation research is required as a priority, if we are to get to LEV, but we shouldn't pretend that there is no trade-off to be made in the minds of potential donors.

Posted by: Mark at June 22nd, 2017 7:27 AM

I didn't deny rapamycin life extension in mice. I totally agree that it does that. What I said is that its effect on *human* LE will be minimal or not measurable. The effects of rapamycin and other therapeutics based on CR research (mTOR regulates nutrient sensing) on lifespan are dependent on the natural lifespan of the species it's used on. The effects on short-lived species are bigger than the effects on long-lived species. This has been observed and is what one would expect from evolutive considerations.

Posted by: Antonio at June 22nd, 2017 9:19 AM

Agreed humans will not get anywhere near the LE from rapamycin that mice get, as you say from a evolutionary point of view: humans develop for much longer before maturity so their MTOR will be set lower, but rapamycin treatment and CR don't equate exactly. Rapamycin inhibits MTOR far more strongly than any kind of achievable CR, especially if you start late in life. Of course CR also does things rapamycin doesn't.

But this is besides the point, rapamycin has already shown a lot of potential in delaying the diseases of aging in humans - and is available now - so even if this is only a healthspan effect, it will increase mean human lifespan and will be of benefit.

Sure we are going to hit hard limits on max lifespan only SENS can address, I'm not contesting that, but let's not pretend there is nothing we can do right now.

Posted by: Mark at June 22nd, 2017 9:36 AM

What are the proofs of that "lot of potential in delaying the diseases of aging in humans"?

Posted by: Antonio at June 22nd, 2017 10:44 AM

I'll post the links to some papers when I'm back in the office in Monday.

Posted by: Mark Williams at June 23rd, 2017 1:53 AM

@ Antonio

You make some great points here! I totally agree with you!

Posted by: BigB at June 23rd, 2017 11:05 AM

Found some papers doing a few searches. Really Blagosklonny is the authority on rapamycin. Not saying i agree with everything he says, but he makes some very good points. Anyways, Some papers on rapamycin effects on cancer
In transplant patients
https://www.ncbi.nlm.nih.gov/pubmed/16434506
https://www.ncbi.nlm.nih.gov/pubmed/15233824
General overview papers on cancer and rapamycin/MTOR
https://www.ncbi.nlm.nih.gov/pubmed/16039868
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552905/
On restenosis (CVD)
https://www.ncbi.nlm.nih.gov/pubmed/16630986
Some discussion on possible benefits for Alhzeimer's
https://www.ncbi.nlm.nih.gov/pubmed/25481271

Definitely some potential for considerable healthspan benefits in humans, maybe even more.

Posted by: Mark Williams at June 23rd, 2017 3:31 PM

Just started Rapamycin therapy, in combination with Metformin. 3mg x1 week; short term observations, probably placebo after 4 days of first dosage;

Loads and loads of energy. I just feel great.
Oddly, my OCD seems to have tamped down a significant degree. Fewer circular thoughts. I have no clue as to why this is occurring. Again, probably placebo.

Mental clarity seems greater.

Lost about 5 lbs. Of course, that could be from the marathon weekend drive to NY with two kids and my wife to get the prescription!

Ain't the placebo effect wonderful? Well, even if that's what it is, I'll take it!

Posted by: bmack500 at August 22nd, 2017 9:41 AM

I have been on Metformin 850 mg. twice per day for the past yr. Now looking for a Dr. to perscribe 3mg doses of Rapamycin to start for longevity puropses. I was diagnosed with sorsoris 4 years ago and now because of somewhat watching my sugar in foods levels, plus taking Metformin I no longer exhibit signs of sorsoris.
Now looking for a Doctor in 17363 area code+,MD. or PA. to prescribe Rapamycin for me, as any extension of life would be great at age 76 and the effects of less other medical problems ie: arthritis, loss of muscle mass, etc. would be greatly appreciated.

Posted by: David Sherrer at October 10th, 2017 10:49 AM

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