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In what ways, if any, does administration of rapamycin *not* mimic calorie restriction?

In what ways, if any, does administration of rapamycin *not* mimic calorie restriction?


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Numerous sources like this say that rapamycin increases lifespan. And mTOR antagonism appears to be a large part of this (mTOR antagonism also appears to be a large part of calorie restriction's mechanism too).

Is the effect of calorie restriction equal to that of rapamycin treatment or are there differences?


Rapamycin specifically inhibits the mTOR pathway (mTOR = mammalian target of rapamycin), which has numerous downstream functions including protein biogenesis, regulation of cell cycle, immune function and apoptosis. The upstream effectors of mTOR include growth factors and amino acid availability, so you can certainly see that the lifespan enhancing effects of caloric restriction will be (at least in part) mediated by the mTOR pathway.

But there are key differences. mTOR also receives signals relating to DNA damage and inflammatory changes (to name just 2) that are essential for healthy survival. So any direct inhibition of this pathway will affect all the functions - I can't find the reference now, but I have definitel read in one of the numerous rodent studies that rapamycin treated mice have reduced immune function (i.e. the lifespan increased effects can only be seen in a controlled lab environment - in the wild mTOR-inhibition to this degree would be a disadvantage).

I think therefore it is fair to say that the effects of caloric restriction on longevity are mediated by mTOR, but administration of rapamycin is not an equivalent treatment.


Update

Really great review came out last month (http://www.ncbi.nlm.nih.gov/pubmed/22500797) - I recommend you give that a skim if you want detail!


In what ways, if any, does administration of rapamycin *not* mimic calorie restriction? - Biology

Can you relate to the following questions?

  • Have you worried about growing old, thinning hair, gaining weight, losing a step or forgetting someone’s name?
  • Did you used to work out or run but now you feel too tired?
  • Is high blood pressure or another medical condition preventing you from feeling your best?
  • Are you at risk for cancer or Alzheimer’s disease?
  • Are you too tired at night to go out and enjoy life?
  • Have you ever felt like the sun was setting on your life of health and vitality?
  • Have you thought how to live as healthy as possible for as long as possible?

Many of us have had these questions cross our minds. How do we prevent these types of things from happening? Are these the effects of the normal aging process? Many would argue that these complaints are indeed signs of aging. Are they reversible or treatable?

This last question will lead us to the topic of Rapamycin and mTor, and how to possibly fight back against the effects of aging.

Rapamycin is a natural antibiotic. It is also antifungal and immunosuppressant. mTor stands for "mechanistic target of rapamycin," and it essentially causes cells to deteriorate and age.


Introduction

Rapamycin (also known by the trade names of sirolimus or rapamune) is a macrocyclic lactone produced by Streptomyces hygroscopicus, which was isolated from soil samples collected from Easter Island by Georges Nogrady in the late 1960s [1]. Scientists at Ayerst Pharmaceuticals in Canada discovered that Streptomyces hygroscopicus produced a compound that would kill fungi, which they named rapamycin after the name of Easter Island, Rapa Nui. The initial interest in rapamycin focused on its antifungal properties. When it was found that rapamycin inhibited the growth of eukaryote cells, research on rapamycin turned to rapamycin’s immunosuppressive and anticancer properties. Rapamycin was approved by the FDA in 1994 to prevent organ rejection in liver transplant patients. In addition to being used as an antirejection drug, rapamycin or its rapalogs are being used today to prevent restenosis after coronary angioplasty, and they are being tested in many clinical trials as antitumor agents, e.g., FDA approved the use of rapamycin in treatment of pancreatic cancer patients in 2011.

Research in the late 1980s turned to identifying the mechanism by which rapamycin blocked the growth of eukaryote cells. Heitman et al. [2] discovered the protein, target of rapamycin (TOR), in yeast that was responsible for rapamycin’s ability to inhibit growth. Three groups in 1994 independently identified the mammalian counterpart, mTOR [3,4,5]. TOR, a serine/threonine kinase, was found to be a master-regulator in the response of eukaryote cells to nutrients, growth factors, and cellular energy status, and this is now known as the TOR pathway. Harrison et al. [6] in 2009 reported that rapamycin increased the lifespan of both male and female mice. This was a major discovery in aging because it was the first evidence that the lifespan of a mammal could be significantly increased by a pharmacological agent. The journal, Science, selected this study as one of the major scientific break-throughs in 2009 (Science 326, 1598–1607), the first discovery in aging to be selected by Science as a break-through. Over the past decade, there has been an explosion in the number of reports studying the effect of rapamycin on aging and age-related diseases, and there have been several reviews describing various aspects of rapamycin on aging [7,8,9,10,11]. In this article, we review the data collected over the past decade on the effect of rapamycin on lifespan and age-related diseases.


The Rapamycin Investigation

Rapamycin is already used as an FDA-approved drug in humans. (The Food and Drug Administration, or FDA, is a federal agency that approves medicinal drug use in the United States.) The medicine is sometimes known as sirolimus or by the brand name of Rapamune. At high doses, it suppresses the activity of the immune system. This ability is very useful in preventing the body&aposs rejection of tissue and organs transplanted from other people&aposs bodies. The drug is frequently given to people who have undergone a kidney transplant.

Rapamycin is believed to inhibit the immune system by interfering with the action of T cells. T cells are a vital component of our immune system. The system protects us from invaders such as bacteria and viruses. Unfortunately, the body considers medically transplanted tissue from another person to be an invader, too, and attempts to destroy the tissue.

Once inside the body, rapamycin inhibits mTOR. The abbreviation "mTOR" stands for "Mechanistic Target of Rapomycin". The protein plays an important role in T cell activation and reproduction. When mTOR is prevented from doing its job, T cells are hindered and transplanted organs are safer.


Practical Recommendations from David Sinclair’s Lifespan

Last week, I posted my summary and notes for David Sinclair’s thought-provoking book, Lifespan. In the book, the Harvard professor details his research into aging as a disease. Like any other disease, aging can be prevented, treated, and potentially cured. While Sinclair readily admits that more research and scientific inquiry is needed before we can cure aging—an audacious goal to be sure—there are a number of practical habits and behaviors available today that can forestall the effects of aging. This post highlights those recommendations.

Note that Sinclair is explicit that none of the ideas in his book constitutes health advice or should be substituted in lieu of professional guidance. The following is purely for informational purposes and does not constitute medical advice.

The Basics

Most of the practical recommendations for the book are found in three chapters:

  • Chapter 4: Here Sinclair discusses exercise, diet, cold exposure, and things to avoid (to maintain epigenetic and genetic health).
  • Chapter 5: Here Sinclair discusses molecules (pharmaceuticals and supplements) that mimic or amplify the benefits of health and diet.
  • Conclusion: Here Sinclair presents his personal habits in a short bulleted list.

The underlying cellular biology and metabolic reactions that are promoted by Sinclair’s recommendations are explained in detail in Part I of the book. The core principle is that we want to encourage cellular repair, reduce cellular inflammation, and encourage the recycling of old proteins (autophagy). Activities that promote these beneficial cellular processes are to be encouraged. Those that inhibit or impair these processes should be avoided. Activities like exercise and caloric restriction stimulate cellular survival and repair processes. This type of cellular “stress” (hormesis) is beneficial. It’s the same idea as the old aphorism “that which doesn’t kill you, makes you stronger.”

With that in mind, let’s look at the longevity-promoting actions and behaviors available to us today.

Diet: Eat Less

We might be tired of hearing about diet, but the fundamental role of diet where individual health is concerned is indisputable. Where longevity is concerned, “eat less” is the key recommendation. Studies suggest a strong link between calorie restriction and longevity. Moreover, caloric restriction stimulates many beneficial cellular processes noted above. Caloric restriction is also beneficial as a weight-loss strategy. There are two main approaches for eating less:

  1. Caloric Restriction (CR): Set a daily caloric target below the recommended daily allowance (RDA). Sinclair mentions 25% as a good target. He also cites human studies that show benefits with a 12% caloric reduction. There are different approaches for maintaining a CR diet over time. CR cannot be practiced indefinitely, you’ll need to maintain some level of BMI equilibrium at some point. Some practitioners cycle between CR periods and non-CR periods (e.g. one week on, one week off).
  2. Intermittent Fasting (IF): Practitioners only eat during designated feeding windows. Instead of 3 meals per day, an IF practitioner might eat 2 or only 1 meal per day. For instance, a 16:8 IF schedule means that 16 hours are spent fasting (no food) and 8 hours are spent eating (usually two meals).

Of course, there are a number of other ways one can eat less:

  • The 5:2 diet: Eat 75% fewer calories for two days a week.
  • Eat Stop Eat: Skip food a couple of days a week.
  • Quarterly fasting: Go hungry for an entire week every 3 months (Peter Attia does this).

Per Sinclair: “Almost any periodic fasting diet that does not result in malnutrition is likely to put your longevity genes to work in ways that will result in a longer, healthier life.”

Diet: Eat Healthy

Sinclair doesn’t go into great detail about what to eat, but does touch on some key points:

  • Eat less meat, eat more plants. Diets higher in plant-based foods reduce all-cause mortality.
  • Reduce sugar consumption: evidence suggests high blood sugar increases epigenetic clock.

If in doubt, look to the diets of people who live in “Blue Zones.” These are populations (like Okinawa) where the average lifespan is particularly high. Diet and lifestyle might offer hints to their longevity (genetics is another plausible explanation).

Source: Wikipedia.com

Exercise

Exercise offers many benefits including increased NAD levels (which activate the survival network). In addition, “longevity regulators like AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise.” Remember: the goal is benign stress.

Here are the book's recommendations:

  • Aim to raise the heart rate and respiratory rate.
  • Higher intensity is better than low intensity.
  • Breathing should be deep and rapid at 70-85% of max heart rate.
  • Should be sweating and unable to speak more than a few words without pausing for breath (aka the hypoxic response).

As for specific exercises, Sinclair mentions:

He doesn’t talk much about weight-lifting, except to say that he does do periodic weight-lifting of his own. Presumably strength, flexibility, and endurance are all desirable physical traits.

Lastly, he mentions two simple fitness tests that use bodyweight exercises (pushup and squat) to measure biological age:

  1. Pushup test: If you are over 45 and can do more than 20 pushups, you are doing well.
  2. Sitting-rising test (SRT): Sit on the floor, barefoot, with legs crossed. Lean forward and in one motion get up to a standing position. Fit people can do this without pushing off with their hands or an intermediate move to their knees. This is effectively a squat.

Cold Temperatures

Exposing your body to uncomfortable temperatures activates longevity genes and “revs up” brown adipose tissue (aka brown fat). Once again, the underlying idea is inducing a tolerable level of stress. Remember: the goal of cold exposure is to induce benign stress NOT to cause hypothermia.

Examples noted in the book:

  • Exercise in the cold.
  • Wear fewer layers.
  • Leave a window open (day and night).
  • Sleep with a light blanket.
  • Turn off the heater.
  • Take cold showers.

It’s worth mentioning that one side effect of calorie restriction is that it reduces the body’s core temperature (bonus).

Sinclair also discusses heat (such as saunas). While he suggests heat therapies may be beneficial, there’s far less scientific research, vis a vis longevity, compared to cold therapies.

Things to Avoid (aka keep your cells healthy)

Recommendations that fall under this umbrella are all about AVOIDING situations that carry risk of increased cellular, genetic, and epigenetic damage. As Sinclair states “we can’t prevent all DNA damage. but we do want to prevent extra damage.”

  • Cigarettes. “There aren’t many legal vices out there that are worse for your epigenome than the deadly concoction of thousands of chemicals smokers put into their bodies every day.”

DNA-damaging chemicals that are part of modern life: pollution, PCBs, plastics, take-out containers.

  • Avoid microwaving plastic containers which releases toxins.
  • Azo dyes (such as aniline yellow) can also damage DNA.
  • Organohalides used in solvents, degreasers, pesticides and hydraulic fluid can damage genomes.
  • N-nitroso compounds are present in foods with sodium nitrite (beers, cured meats and bacon). These are potent carcinogens.
  • Natural and human-inflicted radiation: UV light, X-rays, gamma rays, radon, all damage DNA.

Pills: Drugs and Supplements

Certain molecules are capable of mimicking the benefits of diet and exercise. These are typically available as dietary supplements or controlled substances (prescription medications).

Rapamycin (aka Rapamune, Sirolimus)

  • What it does: Immunosuppressant. Inhibits mTor which may benefit longevity.
  • Availability (USA): Controlled substance, prescription needed.
  • What it does: Used to treat type 2 diabetes. Mimics aspects of calorie restriction.
  • Availability (USA): Controlled substance, prescription needed.
  • What it does: A sirtuan activating compound (STAC) that stimulates sirtuan activity (like DNA repair). Found in red wine.
  • Availability (USA): Available as a supplement.
  • What it does: Precursor to NAD (Nicotinamide adenine dinucleotide) which is a STAC.
  • Availability (USA): Available as a supplement.

NMN (Nicotinamide mononucleotide)

  • What it does: Precursor to NAD which is a STAC.
  • Availability (USA): Available as a supplement.

While there is some disagreement over the efficacy of NR vs. NMN, both are precursors to NAD. NR is, in fact, converted into NMN. According to Sinclair, “Give an animal a drink with NR or NMN in it, and the levels of NAD in its body go up about 25 percent over the next couple of hours, about the same as if it had been fasting or exercising a great deal.”

Note that supplements are poorly regulated compared to pharmaceuticals. Because of this, extra care must be taken to source supplements from reputable sources. Look for products with the “GMP’ label (Good Manufacturing Practices).

Sinclair’s Regimen

In the concluding chapter of his book, Sinclair shares his personal regimen:

  • Practices intermittent fasting daily. Usually by skipping breakfast (18:6) and often lunch (20:4).
  • Has increased ratio of plant to meat (but eats meat when exercising).
  • Restricts carbohydrate intake (avoid sugar, bread, pasta).
  • Maintains a BMI between 23-25.
  • Walks every day (high step count).
  • Exercises at the gym on weekends.
  • Workouts consist of weights and jogging.
  • Takes ice plunges and spends time in saunas.
  • Keeps ambient temperature cool throughout the day to keep his body on the cool side.
  • Prescription drug: 1 gram of Metformin per day.
  • Supplement: 1 gram of NMN per day.
  • Supplement: 1 gram of Resveratrol per day.
  • Supplement: Vitamin D, vitamin K2, and 83 mg of aspirin daily.

What I Do

I’m no paragon of youth or vitality, but per my most recent routine physical, blood test, and vitals were all good for a middle-aged man. Moreover, I’m happy to say I score well on the physical tests to measure biological age (I regularly do pushup sets of 30-40 reps and can perform the sit-stand test with no problem).

  • Intermittent fasting 16:8 schedule. My feeding window runs between 12pm and 8pm. I’ve been doing this for the last two months and one and off before that. Given that I’ve never been much of a breakfast person, this is no big sacrifice for me. I may restrict the window further since many days I effectively go 18:6 with no noticeable hunger pangs. The end-goal would be something more strict like a 20:4 schedule, but I’m not there yet.
  • Increased plant:meat ratio. I love meat in all its forms, so this is a challenging habit. When my daughter moved to a vegetarian diet at the start of 2019, I decided to support her and learn to cook more vegetarian dishes. These days, half of my meals are vegetarian. I still like meat and don’t anticipate giving it up entirely, but it is possible to move the needle and still enjoy a burger from time to time.
  • High daily step count. I aim for 10-12k steps which is made possible by my living in an urban environment where I walk to conduct many of my errands and daily tasks.
  • Cardio exercise: 3-4 times per week. I do a mix of running and HIIT. Usually for 30-60 minutes per session.
  • Resistance exercise: 3 times per week I lift weights (dumbbells or barbells) and/or perform bodyweight exercises. My preference is for the main barbell power lifts: deadlift, back squat, bench press and overhead press. I supplement those lifts with a variety of auxiliary exercises (e.g. rows, Romanian deadlifts, pushups, pull-ups, etc.). My goal is to hit the big muscle groups regularly: back, chest, legs, shoulders. In addition to strength, I believe flexibility and mobility are key: resistance training can help with this.

I have yet to try any of the prescription drugs or dietary supplements recommended by Sinclair. Were I to experiment with these, I’d likely try either NMN or resveratrol first.

Further Reading

This is a big topic and this post only considers recommendations from Sinclair’s book Lifespan. Naturally, there are many other scientists and researchers investigating and writing about human longevity. While I cannot claim expertise on this subject, I can point readers to other reliable sources of information—some will augment Sinclair’s ideas and others may contradict him.


Starvation pseudo-diabetes

In 1846, Claude Bernard detected glycosuria (glucose in urine) in a rabbit fed carrots after several days of fasting (cited in ref. 59 ). Later, Claude Bernard wrote: “If a man or an animal is fasted for some time, and then given a good meal with an abundance of carbohydrate, glucose will appear in the urine 59 .” This condition has been referred to as starvation diabetes, hunger diabetes, or pseudo-diabetes 59,60 .

During starvation or prolonged fasting, glucose utilization by nonbrain tissues is inhibited in order to feed the brain. Prolonged fasting is characterized by low insulin levels, gluconeogenesis, lipolysis, ketogenesis and ketosis (ketone bodies in the blood), glucose intolerance, and hepatic resistance to insulin (Fig. 2a). When a starved animal is fed with glucose, it cannot utilize the glucose (glucose intolerance), leading to transient glycosuria (glucose in the urine) and polyuria (high urine volume) (Fig. 3a).

Common alterations caused by prolonged fasting/starvation or chronic treatment with rapamycin (or everolimus). Green arrow—upregulation red arrow—downregulation

a Starvation causes glucose intolerance, but levels of blood glucose are low due to glucose deprivation. Resuming carbohydrate feeding causes hyperglycemia associated with glycosuria, which has been termed “starvation pseudo-diabetes.” b Chronic rapamycin treatment is accompanied by constant feeding, so glucose intolerance is associated with mild hyperglycemia, reversible by rapamycin discontinuation


Glucosamine instead of MetforminȊnd Rapamycin?

In it he gives sufficient evidence that Glucosamine extends life in nematodes, mice, and humans, by activating AMPK, and modulating mTor.

There is one caveat: The life extension benefits are lost if antioxidants are also supplemented at the same time.

There are two questions that come to mind:

a) If this supplement is readily available, cheap, and gives the same benefits as Rapamycin and Metformin combined, without the side-effects, and since this information is available for a long time, why all the fuss about Metformin and Rapamycin? Why bother? It seems to me like a no-brainer. Am I missing something?

b) I currently supplement with antioxidants NAC and Glutathione. How can I continue to take them and still reap the benefits of Glucosamine? I would assume some intermittent schedule. But no sure about the intervas.

Any ideas will be greatly appreciated.

I don’t think your #1 holds true. Efficacy of rapamycin for life extension is much higher and per dr Kaeberlein in reasonable doses rapamycin is no more dangerous than aspirin. Also per the research paper you have attached the average lifespan extension in mice is just 6% basically, no better than Metformin or berberine. This is quite lower than rapamycin or calorie restriction in mice, which can achieve

25% independently. Now human lifespan is much less pliable than mice, which means that 6% in mice may not extended human lifespan at all. Hence serious longevity researchers like Walter Longo don’t bother with such dubious therapies like Metformin and that’s why Glucosamine is not so exciting either. Now acarbose is much more interesting than Metformin and berberine or glucosamine as it extends an average lifespan in mice by 22%. Hence my suggestion would be to seriously consider acarbose , rapamycin and calorie restriction. These are heavy hitters and are very widely studied. Also I think your glutathione is actually a good and safe supplement although it doesn’t extend the lifespan.

In fact, I currently take Berberine, and every now and then Rapamycin. But I am trying to figure out if I should change. I am a bit scared of Rapamycin. Dr. Alan Green has mentioned that bacterial infections can be quite dangerous while on Rapamycin. In trying to extend healthspan/lifespan using Rapamycin, we risk dying very soon from bacterial infections.

In the link that I provided, there is a reference to an epidemiological study on about 77000 persons (age 50-76) which concludes that " the probability of death for those consuming glucosamine per unit time is 83% of that of controls". For the same group, the risk for Colorectal Cancer was reduced by 45%. It is true that epidemiological studies do not provide "proof" of causality. They do provide a strong indication.

In fact, I am more concerned that the benefits of glucosamine consumption disappear when at the same time antioxidants are consumed (I.e. NAC). Since I am also taking NAC, I would probably have to take both intermittently. I also wonder whether taking NAC while also taking Rapamycin, also negates the benefits of Rapamycin.

Here is a link to research that show decreased all-cause mortality among those who took Glucosamine. " A population-based prospective cohort study included 495 077 women and men (mean (SD) age, 56.6 (8.1) years) from the UK Biobank study."

"Conclusions Regular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases."

"Regular glucosamine use is associated with a lower risk for total mortality (15%), CVD mortality (18%), cancer mortality (6%), respiratory mortality (27%) and digestive mortality (26%)."

My first thought was that users of glucosamine usually have painful joints and that they also take NSAID - aspirin etc. And that could explain some of the disease prevention. But they say "the associations between glucosamine use and all-cause and cause-specific mortality were not significantly modified by sex, age, ethnicity, obesity, current alcohol status, physical activity, diabetes, statin and aspirin use"

Yes Glucosamine is interesting.But does not have a long history of use in clinical settings like metformin. But according to the study I refer to it is not a shot in the dark.

My main question is: Am I already using substances that give me the benefits the Glucosmine will provide? In that case will there be a risk that glucosamine only will add the possibility of negative interactions.

The issue with Berberine is that it is just not as widely studied as Metformin and not fda controlled. It is probably ok and little bit beneficial for ldl-c and high blood sugar. If you take it do it just once a day 500 mg and cycle it on and off - 6 weeks on and 2 weeks off. With respect of nac and rapamycin I am not aware of any study investigating interactions between the two. That said nac being amino acid and rapamycin acting on mTOR, I suspect that they would counteract each other. I don’t see how staggering the treatments between the two be of any value. Now I think it makes for interesting lab experiment on mice but I wouldn’t try it on yourself. Idea is to minimize number of treatments and interactions as there are just too many unknowns.

With respect of rapamycin, I’m curious at what dosages the skin infections are observed? Can you find out from the doc who prescribed it to you?

Anyway the idea behind combing cr and rapamycin and acarbose is that you can achieve combined effect without having to resort to extreme intervention. That is e.g. instead of doing 40% cr restriction you do 15% and instead of taking 10 mg rapamycin you take 3 mg and you still a have the same benefit without incurring a high risk like skin infections (and yes you should be concerned about it as you don’t live in sterile lab) which comes with more extreme interventions.

I take Rapamycin and others w/o prescription. So, no doctor to ask. But Allan Green usually prescribes 5mg / week or less. So I assume that at this dosage he observed the problems with bacterial infections. This is the reason why I am a bit scared of Rapamycin, and I would much rather use something benign like Glucosamine, even if the effect is smaller than Rapamycin.

I agree with you that it might not be wise to take many supplements. Unfortunately, I end up doing the opposite. I find information about a supplement that presumable is useful. I add it to the stack. But do not remove something.

You seem to know much more than me, so maybe you can answer a question for me: For antioxidants, is it better to take them all the time, or intermittently? If intermittently, what would be the most appropriate on-off interval?

Zisos Katsiapis with rapamycin you need to have comprehensive lab work done before you start and then ongoing every six months. This needs to be reviewed by doc. To me the biggest concern with rapamycin is that it suppresses mtor effectively neutralizing the benefits of strength training. You need your muscles as you get older. Hence knowing a bit more about when and how much to take are big questions here. So rapamycin today as I see it is only useful as adjunct treatment to calorie restriction.

With respect to our question on antioxidants dosing. First of all I don’t recommend taking any antioxidant supplements (excepting some vitamins if you have low blood levels) as they shorten your lifespan perhaps excepting besides some vitamins and glutathione, which seem to be safe. The antioxidant precursors like sulforaphane make more sense to supplement and are more promising. These I would take either in low doses everyday or intermittently 6 weeks on and 2 weeks off. Now if we are talking about antioxidant vitamins then I would recommend obtaining rda doses everyday. For example you need vitamin c, which happens to be antioxidant, before your weight training to synthesize collagen afterwards. As you know other fat solvable vitamins like vitamin d don’t have to be taken everyday.

I'm curious about your statement that antioxidant supplements shorten your lifespan. I hadn't heard that. Would you expand on it, with some sources?

you stated. “me the biggest concern with rapamycin is that it suppresses mtor effectively neutralizing the benefits of strength training. ”


I have been taking rapamycin for 6 weeks on a weekly basis and have found that my workouts are more beneficial than before I started. My increased gains in muscle mass and have strength are noticeable so I don’t think your statement can be true. The only thing that has changed otherwise is I seem to have more energy to do workouts and so have been able to increase my number of workouts.

Stevan Lieberman Thanks so much for the n=1 post on Rapamycin and resistance exercise! I've been hesitant to add Rapamycin to my longevity intervention stack, due to concerns about exercise blunting. Metformin has been readily shown to blunt exercise.

I gained some comfort through some personal communications with THE Rapamycin guru himself, Blagosklonny.

He wrote "Amino acids do not make muscle stronger, exercise does. And Rapamycin potentiates strength"

It has been shown that there are MTOR INDEPENDENT pathways to MUSCLE hypertrophy in humans.

So I decided to take the plunge, waiting for my first Rapamcyin order to arrive.

May I ask what triggered your taking Rapamycin, and what is your dosing regiment?

MAC Dr. Nir Barzilai is a MD who is a medical researcher and expert concerning metformin. From the podcast notes, here is a summary what he said during a podcast interview by Dr. Peter Attis, MD.

  • He points out that while the metformin group had less muscle mass growth, the function was actually the same
  • Nir’s main points:
    • In this elderly population, metformin kept the young profile of the muscle
    • At the end, maybe you had less muscle, but you had the same function, and you gained by metformin protecting 500 transcripts that are aging transcripts

    David H Not swayed. I am 55 yo, very lean and fit, following a strict ketogenic diet, OMAD (one meal a day) time restricted feeding. Glucose and insulin signalling are not any metabolic concerns some days I am hypoglycemic. I am already doing some AMPK heavy lifting. I exercise daily 60-90 minutes, combined cardio (125 bpm/30 minutes) and whole body resistance training.

    Peter Attia has mentioned several times on various podcasts his concerns about metformin and exercise, and most especially for anyone who is very fit and far away from metabolic syndrome.

    Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial

    " In men and women aged 65 and older, 14 weeks of PRT induced the expected increases in muscle mass and strength. However, metformin administered along with PRT inhibited these gains. DXA showed that metformin gained significantly less total lean mass and less thigh muscle mass than placebo. Likewise, CT analysis indicated that normal density thigh muscle area increased following PRT, but metformin blunted this gain."

    Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults

    "Our findings in older adults at risk for T2DM demonstrate that compared to placebo, metformin blunted the improvement in CRF by

    50% after 12 weeks of AET. Since CRF and insulin sensitivity are primary predictors of age‐related morbidity and mortality, these data raise concerns about broad recommendations for the use of metformin as a treatment to target aging"

    Since CRF is the only proven longevity enhancement lifestyle intervention (DR and fasting have not been proven in human RCT, although in many other animal models) in humans, I wouldn't do ANYTHING that would blunt that intervention.

    MAC My parents started talking about taking anti-oxidants when I was in my mid 30's and convinced me I should take them too. Then the focus was on Vitamin C and the discussion mostly surrounded how ones body could not use vitamins as easily so one needed to supplement with higher amounts. It got me reading and I started adding on different supplements. I am now in my mid 50's an I have been able to tell that I didn't have the same energy or ability to heal for a while and ran across Dr. Green's website. After reading it I googled sirolimus and this site came up. I showed both sites to my primary care who then had a chat with Dr. Green and based on that both agreed to prescribe for me and has started taking the same dosage she has prescribed for me which is 4 mg once a week.

    Stevan Lieberman I’m glad that rapamycin is working for you. How much and how often are you taking? Also what brand and where are you getting it from? Also do you plan on doing before and after bloodwork? My personal experience is with the sirolimus 2 mg taken once a week obtained from Walmart. From my tests all I saw is that sirolimus succeeded in lowering my urine ph hence, putting me in the starvation mode. During 48 hrs after taking it, I could barely exercise.

    Joe smith I am taking 4mg once a week. It is prescribed so just getting it from cvs. I had a blood test before and then 3 months later. I have always worked out pretty regularly which I assume is why there was no difference between before and after. I will do another test in 6 months. All of my numbers are within norms. I felt like I had more energy the first couple of weeks taking it but since then not a significant difference. I am 55, not overweight and also take a number of supplements and have been doing so since my 30’s.

    Stevan Lieberman Also, I had no issues exercising after taking it, and in fact I found that I was able to work harder and since starting I am finding it easier to do more weight on weight lifting day

    Stevan Lieberman I’m 6 foot tall and about 160 pounds, thin and muscular. I exercise 5 times a week. I can do a single leg sit to stand. I’m about 5 years older than you are. I do take sirolimus with lithium, 500 mg berberine and 500 Metformin per day. As b and m are mtor suppressing together with lithium, they augment the effects of the sirolimus. This combined with my calorie restriction diet most likely suppress mtor to the point that I have to push myself to exercise within 48 hours of taking it. I also may be more sensitive to sirolimus than others.

    Joe smith You're strong. I've never been able to do a single leg to stand and only workout with 150 lb bench (I workout 3 days a week). I'm five foot 7 give or take and 165 pounds a little stocky. I take the lithium as well, 5mg. I don't really do calorie restrictions intentionally, I just don't get particularly hungry (my work has me sitting most of the day) so have a small breakfast of toast with a lot of olive oil and some nuts and blueberries and a lunch which is a full meal around noon and don't eat anything else for the rest of the day other than a spoonful of peanut butter around 5 sometimes (200 calories?). I am averaging between 1000 and 1500 calories unless I have a beer which is 2-3 times a week which I figure adds around another 150 calories. My weight hasn't changed by more than a couple of lbs in years. I also find I am not particularly sensitive to any drugs / supplements.

    I thought b & m did essentially the same thing, so why do you take both? I also understand they both give you loose stool. Do you have an issue there? I do not understand why suppressing mtor makes it harder to exercise. Can you or anyone else explain?

    Stevan Lieberman both berberine and Metformin are organic compounds but derived from different plants. Hence different mechanism of action. Berberine also lowers ldl-c and triglycerides, which you need when you take rapamycin. Berberine also counteracts negative side effects of Metformin.

    Mtor is basically growth regulator. You activate it more growth, bigger muscles, etc., you deactivate it then you stop/slow down the growth. Recovery from the strength training involves activating mtor in presence of amino acids and includes muscle hyperthropy and conversion of the stem cells into muscle fibers. Now if you suppress mtor then you slow down recovery from the strength training. So in my case when I take rapamycin it impacts my recovery as I train 5 times a week. So when I exercise next time within 48 hrs of taking rapamycin my mtor is suppressed, I’m not properly recovered and I can barely go through my routine.

    Joe smith Ok, that makes sense, but you say strength training. Does that apply to cardio as well? Yes, I know that also includes substantial muscles, but everything is a muscle, re heart, lungs, etc. Thoughts?

    Joe smith Just doing a bit of a deep dive on berberine. You say you take 500mg berberine with Rapamycin? I've read some papers and references that berberine and macrolides (of which Rapamycin is one), are contraindicated?

    The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides

    "Collectively, these results demonstrated that concomitant use of Berberine with macrolides may require close monitoring because of potential drug toxicities, especially cardiac toxicity"

    As well, find many articles indicating concern over long term effects of Berberine, much less well studied vs Metformin.

    I assume you are under care of MD, since metformin and Rapa are typically needing prescription?

    Do you take anything to help with bioavailability of berberine?

    Since I am strict keto/OMAD, my glucose and insulin are typically very low, so I wasn't thinking I'd need berberine to help dampen down any potential elevated glucose that might present itself when I start taking Rapamycin.

    Joe smith very strange. I take 10 mg a week and am an avid hiker and mountain biker. Ramamycin has no effect at all on my workouts

    MAC well yes rapamycin is micro-glide but the paper focused on antibiotics and it doesn’t appear to mention rapamycin. I think it would be a stretch to think that it covers it too. Berberine actually appears to be heart protective. and yes berberine is not as widely studied as Metformin hence, I only take 500 mg and only do it once a day. Berberine half life is about 3 hrs so I don’t overload my system with constant berberine drug pressure. I also cycle it on and off. To increase absorption I take berberine and rapamycin with fish oil.

    Paul Beauchemin well according to the research I reviewed it should impact resistance training in mice by 50 %. Anyway I wish Dr Green publish some studies to give us more insights here.

    Paul Beauchemin Must be placebo. Clearly from the literature that I recently attached to posts on this topic, mTOR inhibition is a no-no in terms of repairing muscle fibers after exercise. Use will also contribute to sarcopenia and frailty in seniors.

    In terms of Joe Smith's comment, fish oil stimulates mTOR in terms of muscle repair. It also inhibits mTOR in terms of preventing neurological diseases. Biology is complex.

    Peter H. Howe a brilliant personal attack!

    Peter H. Howe This is a really interesting debate. As it relates to aging and sarcopenia, it's now contested that it's actually OVER-ACTIVE mTOR which contributes to sarcopenia, and Rapamycin can reduce mTOR and geroconversion/senescence and actually REDUCE sarcopenia.

    I've already posted before on communication from Blagosklonny:

    “Amino acids do not make muscle stronger, exercise does. And rapamycin potentiates strength” The link explains the theory.

    A recent review paper from Cambridge University UK.

    Dietary protein, exercise, ageing and physical inactivity: interactive influences on skeletal muscle proteostasis

    I wrote to the author asking about the mTOR over-activation causing senescence and sarcopenia theory, and Rapamycin possibly ameliorating. He replied. "I have an on-going project grant also testing this hypothesis."

    I am intrigued on my n=1 response when I start taking Rapa. I am currently 55 yo male, in super cardio and skeletal muscular shape, daily exerciser, who also takes testosterone. What will rapa do to my daily bouts of exercise and cardio and muscular response with once weekly rapa?? The half life is 3-4 days in blood, but what is CELLULAR level?

    Paul Beauchemin I will review the article, I know it mentions 42 female mice of particular strain. At best this is enough to form a preliminary null hypothesis. I’m also familiar with newer research published in the same magazine, which draws different conclusions. Again until we have human data and larger sample size with longer duration, we just don’t know.

    Joe smith The fact that Rapamcyin, being a macrolide, is not specifically mentioned in the article hardly gives me scientific comfort. Surely they would not have listed every macrolide in existence, but common ones. But I think your heeding the safety of long term Berberine supplementation by limiting intake to 500mg/day is prudent measure of concern.

    Is the metformin and Rapamycin doctor scripted, or are you flying solo? And the berberine, although not needing a script, your own intervention or doctor approved?

    MAC Metformin and rapamycin is doctor prescribed. Berberine is really on my own that said I fully disclose to my doc what I’m doing and hasn’t heard any objections or concerns yet. I guess being conservative with the berberine helps. My doc wanted exhaustive blood and other tests before I started on rapamycin. As I mentioned, rapamycin has decreased my urine ph from an optimal range of about 6.2 down to 4.5. After I stopped taking rapamycin, it went backup to 6.2. hence word of caution you can get kidney stones at such low urine ph. I think that the explanation for the low ph is that rapamycin really induces “starvation” like state.

    Joe smith Thanks for sharing. I'm on strict keto, one meal day diet, and haven't had any issues, although to be honest, don't recall my doc asking for urine PH to be tested. My keto is plant fat based, not animal, and I don't overload oxalates (major cause of stones) and stay hydrated. My protein intake is max 20% macros of total calories, rest in plant fats. Been 4 yrs, no health issues so far. Duly Noted.

    So you're back on Rapamycin, and doing anything to address the urnine pH issue?

    Any significant change in your biomarkers baseline after Rapamycin?

    MAC no real change in my bio markers. A1c always around 5.2, hdl about 80, triglycerides 100 and ldl about 130. To address urine ph I take potassium citrate now foods supplement and eat lemons.

    Paul Beauchemin Response in kind.

    Joe smith The after lipids is with berberine and metformin correct, which would help blunt glucose and possibly lipids? Do you have results before/after with just Rapamycin? Sounds like you are hacking what comes your way!

    MAC without Metformin and berberine my a1c is 5.3 with Metformin and berberine after 6 months and longer, it is 5.1 - 5.2, Ldl without berberine is about 180 and after six month on berberine it is 122. Berberine doesn’t seem to affect my hdl and triglycerides much before and after hdl 80 and triglycerides about 100. When I take statins 20 mg Lipitor no berberine after 6 months my triglycerides go down to 70 and my ldl to about 65. Hdl stays at about 80.

    MAC The following is from an 80 yo who is trying to make it to a healthy 100 which has less than a 1 % probability. It gives me something to do and science is ever changing along with the multiple type 1 and type 2 errors in any scientific undertaking that has a very wide 95 % confidence interval. What can help me may be detrimental for someone else. With that said:

    In my opinion rapamycin is dangerous for a senior. Not considered so far is the potential adverse impact on a seniors immune system. You can ask Mr. Google and find that rapamycin inhibits the innate immune system. I am taking many steps to insure my immune system is properly stimulated and functioning, The last thing I need is interference.

    I saw your earlier reference to the Blagosklonny draft manuscript. I prefer to take a different path and it appears to be working for me. I am going to continue my 1 gm/kg protein/day with

    40 grams of that from whey protein which also stimulates my immune system. It also contains all the essential amino acids in the proper amounts. It is ( along with egg whites) natures best protein. As you probably found there a multiple peer reviewed papers on the need for seniors to get more protein in order to prevent sarcopenia, some suggest up to 2 gm/kg/day. .

    Before attaching several papers on the issue, you should know that I also consume

    5.5 grams/day of EPA/DHA (fish oil). I have been taking this for 25 years after I had an emergency bypass. It is a "miracle" drug that is critical in terms of me reaching the 100 mark. More on this latter.

    The following papers should explain my rational as to why I am going to stimulate mTOR in the interest of preventing sarcopenia and why I referenced my consumption of fish oil.

    The second reference is to a "sales pitch" article but it contains references to fish oil ,and the stimulation of mTOR in the interest of preventing sarcpenia.

    Another on fish oil and sarcopenia that references mTOR.

    You should be aware that maintaining your testosterone, estrogen and DHEA are also critical in preventing sarcopenia and also prevent osteoporosis, dementia and a host of other ailments. They blend in with fish oil, proper diet and exercise along with the ability to change your mind.

    I note that your previous post on metformin failed to mention that it inhibits testosterone production by inhibiting leutenizing hormone. I stopped its use about five years ago due to this problem. I also stopped a severe 5:2 diet with rigid 18:6 eating interval in May of this year after 2.5 years. It also severely limited my testosterone production. You can verify that calorie restriction and metformin impairs testosterone production with a simple google search.

    MAC You are apparently where I was 25 years ago after my emergency bypass. After an extensive search, I got lucky and found a cardiologist who integrated a statin with fish oil to prevent a future heart attack. I can assure that over the years, I have encountered a number of cardiologists who claim that fish oil is worthless.

    In this regard and in the interest of preventing dementia in your case, you might want to examine the attached review of fish oil benefits in preventing various forms of dementia by inhibiting mTOR ( 13 co-authors, 50 + pages

    250 references). Its introduction contains a extensive review of fish oil benefits. There are approximately 7,000 similar references on fish oil benefits. .

    Keep on truckin, keep your triglyceride/HDL ratio at

    1 and have a good new year. If those Brits publish that paper, please let me know.

    Peter H. Howe Healthy 80 yr old..you are way ahead of the game Peter! Less than 1% chance. depends, are you APOE 2/3, they are highly enriched for longevity vs. say APOE 4/4. I am APOE 3/4, so I have my work cut out. must work that much harder.

    ApoE e2 and aging-related outcomes in 379,000 UK Biobank participants

    Varying Effects of APOE Alleles on Extreme Longevity in European Ethnicities

    APOE2 is associated with longevity independent of Alzheimer’s disease

    Re Rapamycin and innate immunity. you missed that clinically, weekly intermittent dose ONLY impacts TOR1, and leaves TOR2 (innate immunity) unaffected. You are referencing chronic DAILY high dosing in transplant type scenarios. Many people taking intermittent Rapamycin are having their immune system checked, and in control. You can google this.

    I have been taking 3g/day DHA, and I eat wild sockeye 3x/week plus sardines. My last RBC Omega 3 blood test was 13%, very high. When I prick my finger for blood ketone measurement, the blood squirts out. I am aligned with you, I think DHA is super beneficial. DHA, keeping TG/HDL low, and very high cardio respiratory fitness are major interventions to prevent CVD.

    My philosophy at 55 yo is to PREVENT. and not wait for a chronic disease to manifest. Preventing a major mortality event is going to greatly increase my healthspan and mortality odds.

    I leave you with this 80yr old (at the time of the video) to consider what is truly the key metabolic lifestyle intervention to successful aging.

    His muscular physique didn't come from DHA or protein or pharmacology. It came from EXERCISE. that is THE key to skeletal muscle. That's what stimulates anabolic growth and is THE key to preventing sarcopenia. How many seniors are pounding the weights like he is? I've never seen a senior in the gym doing this type workout. I hope to continue this type resistance training as long as I can.

    Sarcopenia (barring some chronic disease that prevents exercise) in seniors is preventable. Seniors are not inactive because their bodies are falling apart, their bodies are falling apart because they are inactive.

    MAC Have differences of opinion on several issues--it is biology.

    I am well aware of the APOE issue and I am APOE3 homozygous. Women in my family have tendency for alzheimers. Men, if they make it past cardiac arrest, it is ministrokes followed by the big one. We have very little incidence of cancer, probably due to low levels of IGF-1.

    It is my opinion that the most important thing one can do in preventing mental illnesses related to the APOE gene is to follow the Bredesen protocol.

    As documented in this paper he reversed AZ in 9 of 10 patients and 6 of those returned to work. He has authored a book on the subject which goes into more detail. As I understand it, some enlightened neurologists are following it in terms of treating dementia.

    There are 3 steps which in general are:

    1. No simple sugars, no eating between 6 pm and 6 am to give microglia time to clean up and some calorie restriction

    2.Return hormones to youthful levels, supplement with fish oil and critical vitamins (D and B ) if they are low, and some additional supplements such as ashwagandha

    3. Remove toxins such as lead, mercury and pesticides.

    It is my opinion that the protocol is also an essential part of of an extended health span as it treats more than dementia. .

    Thank you for clarifying my issue with rapamycin and suppressing the immune system. I will however refrain from from it until I see a good risk assessment from some group like Forever Healthy. There are just too many unknowns.

    I recognize the need for senescent cell removal, and have initiated use of fisetin based on comments of a number of persons on this form, risk assessment by Forever Healthy and studies and current trials at Mayo. It is also a mTOR1 inhibitor . I follow the Mayo protocol, with some exceptions, and the intermittent use may suffice in terms of mTOR. Wish I had convenient way to measure effect levels as I have with blood test for statin and fish oil and cardio protection.

    In terms of fish oil my Omega Index is 9.16 %. Would like to get it somewhat higher, but if increase fish oil, I will start getting contusions. Had to stop baby aspirin due to the interaction of the two and almost daily bruises. Getting old. Cardiologist told me to stop the fish oil, not the aspirin, due to my history. Told him thank you but no thank you.

    Strongly suggest you incorporate EPA in your fish oil. It is the primary component that suppresses inflammation. Check your IL-6 and tumor necrosis factor alpha. It does not affect CRP according to the literature.

    That guy in the video looks old. Check out his face. Too much stress from all that weight lifting. Charles Atlas only lived to 82 as I recall. The average life expectancy of a male in the vegetarian Seven Day Activist community in La Jolla Ca. is 95.

    There is no question that exercise isn't important, but it cannot get you to 100 on its own. Most seniors simply do not have the ambition to do what you are doing, due in most part to a host of deficiencies.

    Thanks for the post. It keeps me alive along with the 110 deep knee bends with 2, 20 lb weights that I have to do next.

    Peter H. Howe apoe3/3 well that’s a better starting point, but still 60% of AD is 3/3. But apoe is NOT singularly causative, it’s a complex polygenic risk disease. My mom had AD, and maternal AD increases APOE4 risk. Sigh. So for me, my journey is neurological avoidance based. CVD or cancer death is not a known early mortality pathway in my family tree.

    Been on the Bredesen protocol for 4 yrs, started immediately after taking on a Functional Medicine Doctor. We push it to even farther ranges like overlaying keto/OMAD, DHEA/hormones, Vitamin D, toxins, iron dumping, much higher exercise (the protocol is lacking in exercise)

    Sedentary lifestyle and insulin resistance is the bane of western disease. Too many excuses and people waiting for “sick care” medicine to help them live longer AFTER you become chronically ill.

    But it did take discovering I was apoe 3/4 4 yrs ago to give me that “scare” self motivation to PREVENT disease while I still have window.

    Exercise is my #1 lifestyle intervention for longevity. Will keep running and lifting weights as long as I can!

    Will keep you posted on my n=1 Rapamycin experiment. I haven’t even told my doc yet I plan on adding this hack! I did ask him to explore it with me earlier this year, and he was open to it.


    Rapamycin for longevity: opinion article

    From the dawn of civilization, humanity has dreamed of immortality. So why didn’t the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.

    “If you wait until you are ready, it is almost certainly too late.” Seth Godin

    In one short-lived mutant strain of mice, the mTOR inhibitor rapamycin (known in the clinic as Sirolimus) extends maximum life span nearly three-fold [1]. Albeit less spectacularly, rapamycin also prolongs life in normal mice as well as in yeast, worms and flies, and it prevents age-related conditions in rodents, dogs, nonhuman primates and humans. Rapamycin and its analog, everolimus, are FDA approved for human use and have been used safely for decades. In 2006, it was suggested that rapamycin could be used immediately to slow down aging and all age-related diseases in humans [2], becoming an 𠇊nti-aging drug today” [3].

    But rapamycin was unlucky

    Rapamycin known in the clinic as Rapamune or Sirolimus, was unlucky from the start, however. Twenty years ago, it was labeled an immunosuppressant and used to treat renal transplant patients. If rapamycin had been labeled an immunomodulator and anti-inflammatory drug instead, it would sound much more appealing now. At anti-aging doses, rapamycin 𠇎liminates hyperimmunity rather than suppresses immunity” or, more figuratively, it “rejuvenates immunity” [2]. This enables rapamycin and everolimus, a rapamycin analog, to act as immunostimulators [4𠄶], improving immunity in cancer patients [7] and the elderly [8,9]. For example, rapamycin reduces the risk of CMV infection in organ transplant patients [10�], improves antipathogen and anticancer immunity in mice [13�], prolongs lifespan in infection-prone mice [16] and protects aged mice against pneumonia [17]. Rapamycin also inhibits viral replication [18,19]. As a noteworthy example, rapamycin inhibits replication of the 1918 flu virus (the deadliest flu virus in history) by 100-fold [19], and also protects against lethal infection with influenza virus when administered during vaccination [13]. Still, as Dr. Allan Green advises, patients taking rapamycin should be carefully monitored for skin and subcutaneous bacterial infections, which should be treated with antibiotics https://rapamycintherapy.com.

    Twenty years ago, it was thought that rapamycin might increase the risk of cancer (see a forthcoming review “Understanding the side effects of rapamycin”). Despite that concern, it was revealed that rapamycin actually prevents lymphoma and some types of cancer in transplant patients [20�]. Currently, in fact, rapamycin analogs, everolimus and temsirolimus, are widely used in cancer therapy. Furthermore, rapamycin is the most effective known cancer-preventive agent in mice [25,28�] extending the lifespan of cancer-prone mice [33�]. It has even been suggested that rapamycin extends lifespan by preventing cancer [37].

    Nevertheless, social media often warn that although rapamycin prevents cancer, its use to prevent cancer may come at the cost of getting cancer. This self-contradiction miscites a twenty-year-old warning by the FDA for all drugs marketed as immunosuppressants (including rapamycin and everolimus): “Increased susceptibility to infection and the possible development of malignancies such as lymphoma and skin cancer may result from immunosuppression.” This statement does not say that rapamycin or everolimus cause malignancies. (Just read it again). Although rapamycin and its analogs are now approved by the FDA for treatment of cancer and lymphomas, the rumors that these drugs may cause cancer persist. To my knowledge, no study has shown that mTOR inhibitors cause cancer.

    At this point, most scientists agree that rapamycin is not counterindicated because of concerns about immunosuppressive effects. But a new objection against rapamycin has emerged, namely that rapamycin may cause diabetes. As discussed in detail [38], the new wave of �r of rapamycin” is groundless. So, what are the metabolic effects of rapamycin?

    Metabolic effects or rapamycin and starvation

    When it is over-activated by nutrients and insulin, mTOR acts via S6K to inhibit insulin signaling, thereby causing insulin resistance [39�]. Acute treatment with rapamycin abrogates insulin resistance in cells and animals including humans [45�]. One study showed that chronic treatment with rapamycin may also prevent insulin resistance [52]. However, in some (but not all) rodent models, chronic treatment with rapamycin can also cause glucose intolerance and even insulin resistance [53�]. This was interpreted as a deleterious side effect or even type 2 diabetes (T2D). Actually, however, these metabolic changes are features of benevolent starvation pseudo-diabetes (SPD), which was described 170 years ago in fasted animals and later in humans [57,58]. During prolonged fasting, utilization of glucose by non-brain tissues must be suppressed to ensure an adequate supply to the brain. When a fasted animal or human is then given a meal, glucose appears in the urine (glycosuria), which is a canonical symptom of diabetes. But this is because prolonged fasting (starvation) leads to decreased insulin secretion and to insulin resistance, and subsequent re-feeding then causes transient hyperglycemia and glycosuria. This SPD can be caused not only by prolonged fasting, but also by severe restriction of calorie and carbohydrate intake [38]. For example, severe calorie restriction can cause diabetes-like glucose intolerance [59]. Despite that, very low calorie diets are the most effective treatments for type 2 diabetes [60�]. Some researchers re-discovered SPD in obese patients on strenuous weight loss program and erroneously warned that low calorie diets cause type 2 diabetes [63].

    The obligatory symptom of starvation is ketosis, as ketones substitute for glucose as the main fuel for the brain. The ketogenic diet, a promising treatment for diabetes and obesity in humans, can cause symptoms of SPD in rodents (see for references [64]). Once again, some researchers warned that the ketogenic diet can favor type 2 diabetes [65]. As discussed, such warnings may not be justified [64,66�].

    Rapamycin can be viewed as a partial starvation-mimetic [69�]. It is therefore predictable that, under some conditions, prolonged treatment with rapamycin may lead to the emergence of SPD [72]. This has been confirmed in rapamycin-fed mice, which developed insulin resistance, glucose intolerance and mild hyperglycemia [54]. Nevertheless, rapamycin-fed mice lived longer and thus were healthier than mice fed a standard diet [54]. It is not completely clear why SPD was observed in only some studies and was not observed in other studies (see for references [38,73]).

    Importantly, SPD is reversible and does not lead to complications. Furthermore, rapamycin reduces the incidence of diabetic complications such as diabetic nephropathy in rodents [42,74�]. In healthy elderly humans, chronic treatment with rapamycin or everolimus did not cause hyperglycemia [8,9,86]. On the contrary, the risk of hyperglycemia was lower in the mTOR inhibitor treatment group than the placebo group [9].

    In some cancer patients, high doses of rapamycin or everolimus can cause hyperglycemia, which is usually mild (grade 1-2) and reversible, and does not lead to treatment interruption [87�]. Hyperglycemia is a common side effect of many oncotargeted drugs and is not a manifestation of diabetes. Everolumus, for example, can cause hyperglycemia by decreasing insulin production [89].

    To summarize, chronic treatment with high doses of rapamycin may cause symptoms of reversible SPD. Diet-induced SPD, at least, is beneficial and therapeutic. Rapamycin-induced SPD is a relatively rare side effect and probably can be avoided by administering the drug intermittently or at lower doses, and if SPD does occur, it can be reversed by discontinuation of the drug.

    In some studies in transplant patients, rapamycin (sirolimus) and everolimus did not increase the risk of diabetes [90�]. In one study, no patient, out of 21 patients treated with rapamycin, developed diabetes, while the incidence of diabetes was 7% in patients treated with either cyclosporine or tacrolimus [96]. Most importantly, cyclosporine- or tacrolimus-induced diabetes resolved in 80% of patients after conversion from tacrolimus/cyclosporine to rapamycin (sirolimus) [96].

    On the other hand, a large retrospective study reported an association between Medicare billing for diabetes treatment and rapamycin use, implying that rapamycin may increase the risk of diabetes [97]. However, this association was explained by the interaction between rapamycin and calcineurin inhibitors, which increase each other’s levels [96,98,99]. Consequently, it remains unclear whether rapamycin per se increases the risk of diabetes in transplant patients [96]. Moreover, this is further complicated by the fact that most transplant patients develop type 2 diabetes spontaneously without rapamycin treatment [100].

    Rapamycin is not much more dangerous than ordinary drugs

    If used properly, rapamycin is not much more dangerous than ordinary aspirin. Aspirin, one of the most widely used nonprescription medications, may cause numerous side effects, including life threatening gastric bleeding. The manufacturer lists as possible side effects: ringing in ears, confusion, hallucinations, seizure, severe nausea, vomiting, bloody stools, coughing up blood, fever and swelling. Still, millions of people take aspirin daily to prevent cardiovascular disease and cancer. It was calculated that the benefits of aspirin are greater than their risks [101,102]. I believe the benefits of the anti-aging effects of rapamycin/everolimus may even be greater ( Figure 1 ).

    Potential risk vs benefits of rapamycin-based anti-aging therapy. Pros and Cons: Potential benefits of rapamycin may outweigh its risks.

    In the case of rapamycin and everolimus, the most worrying side effects have not been confirmed. At low doses [8,9,86], or when administered as a single high dose [103], no side effects have been detected so far in the elderly. At high doses, rapamycin and everolimus slow cell proliferation, which decreases blood cell counts. As a result, mild and reversible thrombocytopenia (low platelet count), anemia and leukopenia are their most common side effects. But a mild reduction of platelets may be beneficial. In fact, one of the intended effects of aspirin is a decrease in platelet function.

    There is one crucial reason why the side effects of rapamycin are exaggerated. The frequency of rapamycin side effects has often been estimated in studies lacking a placebo group. In cancer and transplant patients, numerous effects ascribed to rapamycin, such as fatigue (asthenia), for example, are often caused by the disease itself. In a placebo study of healthy volunteers, the placebo group reported more side effects such as fatigue than did the rapamycin group [104]. In recent placebo-controlled studies in healthy elderly people, no side effects were noticed as compared to placebo [9,86].

    While aspirin may cause gastric ulceration and bleeding, rapamycin may cause stomatitis and mycositis (ulceration of the mucous membranes of the mouth and the digestive tract) when used at high doses or chronically. A rare side effect of rapamycin is noninfectious interstitial pneumonitis [105]. And by inhibiting neutrophil function, rapamycin may increase the severity of bacterial infections [106]. These side effects require rapamycin’s discontinuation. For antiaging purposes, however, rapamycin may be used either intermittently (e.g., once a week) or at low daily doses and can be discontinued if any unpleasant effects occur.

    From a single dose to intermittent schedules

    Although nearly all drugs, including nonprescription drugs such as aspirin, can be fatal at sufficiently high doses, there are no known fatal cases of acute rapamycin (sirolimus) overdose [103]. For example, in a failed suicide attempt, an 18-year-old woman ingested 103 rapamycin tablets (103 mg), and the only detected effect was an elevation in total blood cholesterol [103]. In rats, rapamycin’s LD50, a measure of drug lethality, could not be determined because it is higher than 2500 mg/kg. While a single dose of rapamycin is safe, it is sufficient to extend life and decrease obesity in several rodent models [1,107]. Furthermore, transient treatment with rapamycin can be long lasting, extending the lifespan and preventing obesity long after drug discontinuation [107�]. The magnitude of life extension by rapamycin depends mostly on reaching a high peak blood level [113]. A similar conclusion was reached by a study of rapamycin use in obesity [112]. It was suggested in 2008 that a pulse (intermittent) schedule of rapamycin administration would improve regeneration of stem cells [114] while avoiding mTORC2 inhibition [54,115].

    Therefore, to avoid side effects and maximize anti-aging effects [110], a feasible approach would be to prolong intervals between rapamycin administrations while keeping the total dose constant. For example, instead of daily administration, a weekly administration of a higher dose can be suggested to achieve a high peak blood level, followed by drug-free period to avoid undesirable effects. Still, everyday treatment of the elderly (1 mg/day for several weeks) was not associated with side effects and has been shown to be safe [86]. Similar results were achieved with low doses of other mTOR inhibitors [9]. Another option is an alternating schedule for example, a 3- month course of weekly rapamycin alternating with a rapamycin-free month. Finally, anti-aging schedules can be very flexible to fit an individual patient. The optimal anti-aging dose is a personalized maximum dose that does not cause side effects in a particular patient ( Figure 2 ).

    Optimal dose of rapamycin for maximal net benefits. Life extension by rapamycin is dose-dependent in rodents. The higher the dose, the higher the anti-aging benefits, including cancer prevention and life extension. In humans, side effects are dose-dependent and net benefits could potentially decrease at very high doses. This point of the highest net benefit is the optimal dose. The optimal dose varies in different individuals due to the variability of potential side effects. Thus, the optimal dose in a particular individual is determined by the emergence of side effects. The treatment can be viewed as life-long phase I/II clinical trial.

    In conclusion, the side effects of rapamycin are well-known and reversible. When used on an anti-aging schedule, side effects may be absent but, if not, they may be mitigated by combining rapamycin with other anti-aging drugs (metformin, statins) or by temporarily discontinuing it.

    Noteworthy, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging. And by living longer, our generation will benefit from future anti-aging discoveries ( Figure 1 ).

    But the fear of nonexistent side effects is not the only reason the use of mTOR inhibitors for life extension has been questioned. The second reason is that there is rightful skepticism about any claims made about anti-aging drugs because thousands of anti-aging remedies have already failed. What then makes rapamycin different?

    The history of mankind: empty promises of immortality

    On the one hand, from the dawn of civilization humans have dreamed of immortality. On the other hand, from the dawn of civilization a myriad of anti-aging remedies turned out to be empty promises. Even worse, they often shorten lifespan. Two notable examples are antioxidants and human growth hormone. The idea that free radicals, or reactive oxygen species (ROS), cause aging was based on a “wild guess,” as Harman, a father of the ROS theory, acknowledged when he titled his paper, “I thought, thought, thought for four months in vain and suddenly the idea came” [116]. The idea is simple and intuitive, and it was widely accepted based on circumstantial evidence. In fact, ROS are inevitable products of metabolism, and they do damage biomolecules. Moreover, excessive ROS can shorten lifespan. Similarly, the atomic bomb can shorten life span. Yet this does not mean that either atomic bombs or oxidants are the cause of normal aging as we know it.

    Numerous experiments support the ROS theory. However, key experiments ruled the ROS theory out (see for references [2,117�]. To make a long story short, antioxidants could in theory prolong lifespan if mTOR-driven (quasi-programmed) aging were suppressed and we lived long enough to die from ROS-induced post-aging syndrome (I will discuss the nuances in the forthcoming article “ROS and aging revisited”). Indeed, ROS will kill any organism eventually. However, organisms normally die from mTOR-driven, age-related diseases (aging as we know it) before ROS can kill them (see for discussion [2]). As an analogy, consider most of the passengers on the Titanic. Would antioxidant treatment have been useful to them for life extension? The best way to extend life for members of that group would have been to carry more life boats. Only after their safe rescue could one expect antioxidants to potentially increase their life further. Similarly, only after rescue from the quasi-program of aging may antioxidants potentially have an impact.

    Not surprisingly, antioxidants did not extend lifespan in any clinical trials and were detrimental in some [122�]. As Ristow put it, they were “worse than useless” [119]. For example, in two very large randomized controlled trials, antioxidants increased the incidence of cancer, especially of lung cancer in smokers [131�]. Antioxidants also increased all-cause mortality. The results were so disturbing that two trials were stopped earlier than planned [131�]. Also disturbing is the finding that antioxidants accelerate cancer progression and promote metastasis [134�]. But despite their uselessness, antioxidants continue to be a multibillion-dollar business. They are widely sold as natural products in the forms of nutritional supplements and in foods “rich in antioxidants.”

    Another example is human growth hormone (HGH), which is widely used for rejuvenation and longevity. Yet, it actually accelerates aging and shortens lifespan [137,138]. Growth hormone is a pro-aging hormone because it indirectly activates mTOR [139]. Notably, the hype around growth hormone is based on a single publication [140], which misinterpreted its acute effects [141].

    Given that all previous anti-aging remedies have failed to meet expectations, it is not surprising that the discovery of the anti-aging effects of rapamycin are being met with skepticism too. But unlike HGH, the effects of rapamycin are not based on one single paper as were HGH, nor is it based on a wild guess as were ROS.

    Rapamycin is a proven anti-aging drug

    The evidence that rapamycin can function as an anti-aging drug is the product of thousands of scientists working independently all over the world, studying mTOR and its inhibitors for a variety of different reasons in diverse organisms, ranging from yeast to humans. Studies in model organisms, such as yeast, worms and flies, have revealed components of the TOR signaling pathway [142�]. It was predicted in 2003 [146] that conversion from quiescence to senescence (geroconversion) is driven by growth-promoting mediators, such as mTOR, when the cell cycle is blocked [147]. Figuratively, geroconversion is “twisted” growth that occurs when actual growth is completed [2], [147]. In cell culture, mTOR is maximally activated and geroconversion lasts 3-6 days, whereas in the human body it may take decades. mTOR drives geroconversion, rendering cells hypertrophic and hyperfunctional (e.g. senescence-associated secretory phenotype), which eventually leads to the development of age-related pathologies [2]. Working independently, clinical researchers have studied rapamycin for the prevention and treatment of nearly every age-related disease, including cancer, obesity, atherosclerosis and neurodegeneration. If a drug is indicated for all age-related diseases, it must be an anti-aging drug in that it targets a common driver of age-related diseases – that is, aging (see for references [2]). This is because aging is the sum of all age-related diseases, which limit lifespan [148�]. Does rapamycin suppress aging and extend lifespan by preventing diseases, or does it prevent diseases by slowing aging? Actually, both reflect the same process.

    By 2006, an extensive body of work from several independent fields all pointed to rapamycin as an anti-aging drug [2]. According to hyperfunction theory, aging is an unintended (not programmed but quasi-programmed) continuation of the developmental growth program, driven in part by mTOR [2,120,121,151,152]. Testable predictions have been formulated [2,153] and confirmed in numerous independent studies (see for references: [150,154]).

    In two dozen studies using different strains of mice, rapamycin extended life span. Starting from a thorough study by Harrison et al. [155] and followed by nearly simultaneous studies by others [33,108], the anti-aging effects of rapamycin have been confirmed many times (see for references: [113,150,156,157]). Importantly, rapamycin and everolimus are indicated in most, if not all, age-related diseases, from cancer to neurodegeneration [2,158].

    Conventional drugs as anti-aging agents

    Several conventional drugs used to treat age-related diseases (e.g., hypertension, ischemic heart disease, diabetes, cancer, prostate enlargement) can be viewed as somewhat anti-aging drugs [150,154]. First, these drugs extend lifespan in the same model organisms (see for references: [159]). For example, metformin extends lifespan not only in mice, but also in the worms, which do not suffer from human diseases [160,161]. ACE inhibitors prolong life not only in hypertensive rats, but also in healthy normotensive rats [162]. If these drugs were not ordinary drugs for human diseases, then gerontologists would call them anti-aging agents.

    Second, these drugs prevent or treat more than one disease. For example, metformin is indicated to treat type 2 diabetes as well as pre-diabetes, obesity, metabolic syndrome, cancer, and polycystic ovary syndrome [163�]. Aspirin not only reduces inflammation (a hallmark of aging), it also reduces the risk of cardiovascular disease, thrombosis and cancer. Low-dose aspirin prevents one-third of colorectal, gastric, and esophageal cancers [169]. PDE5 inhibitors such as Sildenafil and Tadalafil, which are widely used for erectile dysfunction, are also effective against benign prostatic hyperplasia (BPH) and pulmonary arterial hypertension in humans and suppress inflammation-driven colorectal cancer in mice [170]. Aging is the sum of all these age-related diseases. Given that humans and animals die from age-related diseases, life can be extended by treating multiple pre-diseases and diseases. Rapamycin and these drugs may complement each other in an anti-aging formulation by further extending life and/or by mitigating each others possible side effects [159]. For example, metformin may counteract rapamycin-induced hyperglycemia [171].

    Not taking rapamycin may be as dangerous as smoking

    Strangely, the fear of tobacco smoking is less intense than the fear of rapamycin. But whereas smoking shortens both the healthspan and lifespan, rapamycin extends them. Smoking increases the incidence of cancer and other age-related diseases. Rapamycin prevents cancer in mice and humans. Heavy smoking shortens life expectancy by 6-10 years. In other words, simply not smoking prolongs life by 6-10 years. In middle-aged mice, just 3 months of high-dose rapamycin treatment was sufficient to increase life expectancy up to 60% [109]. When taken late in life, rapamycin increases lifespan by 9-14% [155], despite the dosage being suboptimal [111]. This possibly equates to more than 7 years of human life. By comparison, smokers who quit late in life (at age 65 years), gain between 1.4 -3.7 years [172]. Considered in those terms, one could say that in the elderly, not taking rapamycin may be even more �ngerous” than smoking. Finally, rapamycin may be especially beneficial to smokers and former smokers. While the carcinogens from tobacco cause lung cancer in mice, rapamycin decreases tobacco-induced lung cancer multiplicity by 90% [28].

    Diet and rapamycin

    Calorie restriction (CR) and intermittent fasting (IF) extend both the lifespan and healthspan in diverse species. However, CR is of little benefit when started in old age [73,173�]. Fasting inhibits the mTOR pathway in young but not old mice [179,180]. By contrast, rapamycin strongly inhibits mTORC1 at any age. It extends lifespan, whether started late or early in life [108,155,181], even if used transiently [109]. So, whereas CR is more beneficial early in life, rapamycin may be indicated later in life. In addition, the beneficial effects of rapamycin and CR may be additive, given that they are exerted through overlapping but distinct mechanisms [182�]. Intermittent rapamycin and CR (24-48 hours after) can be combined, to avoid potential hyperglycemia. Physical exercise may be most beneficial starting immediately after rapamycin use, to take advantage of rapamycin-induced lipolysis as a fuel for the muscles. By itself, chronic rapamycin treatment does not compromise muscle endurance [187] and even prevents muscle loss [188�].

    Do we need new or safer rapalogs to start aging prevention?

    Despite the metabolic side effects seen in some mouse models, mice treated with rapamycin live longer and are healthier. Humans also may want to live longer and healthier lives, regardless of whether one calls the means unsafe. Some basic researchers believe that rapamycin cannot be routinely used to treat aging in humans because of its metabolic effects and call for the development of safer analogs. First, rapamycin and everolimus are FDA-approved drugs, safe for human use. Since 1999, rapamycin has been used by millions of patients with no unexpected problems. One may suggest that rapamycin/everolimus are safe enough for very sick patients, not for healthy people.

    First, healthy elderly people chronically treated with rapamycin or other mTOR inhibitors showed no ill effects (e.g. hyperglycemia) [8,9,86]. Logically, more threatening adverse effects could be expected in cancer and transplant patients, who are often heavily pre-treated and terminally ill than in healthy people. Second, there are no truly healthy people among the elderly otherwise, they would be “immortal”, given that all humans die from age-related diseases, not from healthy aging. And the sooner they would be treated with anti-aging drugs, the longer they would remain relatively healthy.

    That said, it is, of course, important to develop new rapalogs, but not because current rapalogs are unsafe. It is important because such research will help us to learn more about mTOR and aging and may lead to the discovery of agents capable inhibiting the rapamycin-insensitive functions of mTORC1. These future drugs could potentially complement current rapalogs to further extend lifespan. Non-rapalog rapamycin analogs will also be developed [191]. The limitation of current rapalogs is not that they are unsafe but that their ability to extend life is limited. The goal should be to develop new drugs that extend life span further.

    Rapamycin is a natural anti-fungal antibiotic produced by soil bacteria of Eastern Island. The patent on rapamycin has expired, and pharmacological companies have developed other rapalogs such as everolimus. (I use the term rapalogs to encompass both rapamycin, everolimus and any other analogs). At equipotent doses, rapamycin and everolimus exert almost identical therapeutic and adverse effects although, everolimus is weaker and has a shorter half-life in the organism compared with rapamycin.

    All current rapalogs exhibit the same side effects as rapamycin and everolimus. Their real side effects are mTORC1-dependent. Inhibition of mTORC1 decreases cell proliferation and function, which is manifested as lower blood cell counts and insulin levels, especially when rapalogs are chronically administered at high doses. We could develop weaker rapalogs, which would have no side effects if used at the same dose as rapamycin. But then why not just use a lower dose of rapamycin? (I will discuss elsewhere how safer rapalogs are probably weaker rapalogs.) Given to mice at the same doses as rapamycin, weaker analogs would have neither side effects and no therapeutic effects. Consequently, their metabolic effects would be diminished and so would their therapeutic effects. However, the same negative result can be achieved simply by decreasing the dose of rapamycin. While waiting for silver bullets, we need to use the currently available rapalogs, such as rapamycin and everolimus, to live longer. When “safer” rapalogs are clinically available, we may use them too.

    The time is now unless it’s too late

    The overwhelming evidence suggests that rapamycin is a universal anti-aging drug – that is, it extends lifespan in all tested models from yeast to mammals, suppresses cell senescence and delays the onset of age-related diseases, which are manifestations of aging [discussed by me in [148,149,158,192]. Although rapamycin may reverse some manifestations of aging [181,193], it is more effective at slowing down aging than reversing it. Therefore, rapamycin will be most effective when administered at the pre-disease, or even pre-pre-disease stages of age-related diseases [150]. For example, Carosi et al. suggested that mTOR inhibitors could be useful in Alzheimer disease, but only in the earliest stages [194,195]. In addition, rapamycin and everolimus are more effective for preventing cancer than treating it. They may also be useful for treating osteoporosis, though not a broken hip after an osteoporotic fracture. Rapalogs may slow atherosclerosis, thereby preventing myocardial infarction, but they are unlikely to help reverse an infarction. In other words, anti-aging drugs extend the healthspan ( Figure 3 ) and are most effective before overt diseases cause organ damage and loss of function.

    Effects of standard and anti-aging medicine on health- and life-span. (A) The relationship between health- and life-span. Aging is a sum of all age-related diseases, pre-diseases and pre-pre-diseases. Before overt age-related diseases become apparent, there is a seemingly healthy period of aging (so-called healthy aging). Starting from adulthood, pre-pre-diseases progress towards pre-diseases and then towards overt diseases. Unless treated with modern standard medical practice, the diseased stage is relatively brief. From (A) to (B) Standard medical treatment is usually started when overt diseases are diagnosed. Standard medicine extends life span mostly by preventing death from diseases, thus extending “unhealthy” phase of life, especially terminal stages of diseases, characterized by organ damage, failure and loss of functions. Standard medicine extends lifespan. From (B) to (C) Anti-aging medicine is most effective at the stage of pre-diseases and initial stages of diseases, characterized by increased functions before complications and organ damage occur. In terminal stages of deadly diseases, anti-aging therapy may not be useful. Thus, anti-aging medicine increases both health span and life span. Anti-aging medicine and standard medicine are additive when aging becomes unhealthy. The schema is simplified because, in reality, age-related diseases start at different ages (presbyopia vs sarcopenia), progress at different paces (atherosclerosis vs cancer), and most are not lethal, and some are well treated (cataract). Therefore, healthspan is an abstraction.

    So, is it too late to take rapamycin once aging reaches an unhealthy stage? Actually, it is not too late. Even if one or a few age-related diseases renders aging unhealthy, other potential diseases are still at pre-disease stages, and anti-aging drugs may delay their development. And they may slow down further progression of existing overt diseases.

    In addition to rapamycin/everolimus, the anti-aging formula metformin, aspirin, ACE inhibitors, angiotensin receptor blockers and PDE5 inhibitors, each of which can prevent or treat more than one age-related disease [159]. Note that I mention only clinically-approved drugs because they can be used now. Later, perhaps, we may be able to consider further life extension through the use of low doses of pan-mTOR [196,197], mdm-2 [198,199] and MEK inhibitors [200,201], lithium [201,202], as well as next-generation rapalogs.

    There is currently no consensus around the short-term markers of anti-aging effects. Therefore, rapamycin trials should be focused on its potential side effects rather than anti-aging effects. We must be sure that the therapy is safe. In the future, the treatment should be conducted as a life-long phase I/II trial, with dose escalation of rapamycin/everolimus until the side effects are reached in an individual patient. The tailored optimal dose (see Figure 2 ) should be determined individually for each patient and may vary widely. Doses and frequencies should be limited by the side effects: stomatitis/mucositis, anemia, thrombopenia, leukopenia, edema, and pneumonitis. To be safe, even mild hyperglycemia should be avoided or mitigated with metformin. Treatment is intended to be life-long, unless discontinued due to side effects.

    Self-medication (even by physicians themselves) should be avoided and strongly discouraged. Instead, we need anti-aging clinics that implement the entire anti-aging recipe, including a complementary low carbohydrate diet and life style changes. Blood levels of rapamycin should be measured, as the rapamycin concentration in blood varies greatly among individuals taking the same dose. Doses of rapamycin should be tailored: personalized dosing and schedules. There is no shortage of potential patients who unfortunately already employ self-medication with rapamycin, but there is a shortage of physicians to treat them. Fortunately, a prototype clinic already functions in the USA, demonstrating that it is feasible from a regulatory standpoint (see Alan Green’s practice, Little Neck, NY). We cannot wait for results from others if we want to live longer and healthier ourselves. The time is now.


    J.H.J.H., W.P.V., H.v.S., and M.E.T.D. performed conceptualization. M.B.B., D.J., W.P.V., and M.E.T.D. designed and wrote the manuscript. All authors contributed to editing the manuscript. R.M.C.B., S.B., N.v.V., S.I., C.T.v.O., B.N., W.P.V., and M.E.T.D. performed and analyzed the mouse cohorts. S.I. performed FACS analysis of nuclei and S6 related western blotting. E.P.F. and A.J.M.R. quantified vascular function. D.J., R.M.C.B., S.B., N.v.V., and W.P.V. performed and analyzed phenotypical scoring and behavioral analysis. M.B.B. and D.J. characterized neuropathological changes. J.L.A.P. and W.P.V. performed transcriptomic analyses. J.A.F and W.P.V. performed statistical analyses with body weight and life span data. R.M.C.B. and Y.E. performed the genetic interventions. D.J., J.H.J.H., W.P.V., and M.E.T.D. carried out supervision.

    This article has been awarded <Open Data, Open Materials> Badges. All materials and data are publicly accessible via the Open Science Framework at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149029.


    Crossing the Thin Line to Starvation: Caloric Restriction

    In the creepy dystopian future of Max Ehrlich’s The Edict (1971), the population has burgeoned out of control because there is no longer any cancer or cardiovascular disease. The average age in its "Senior City" was 100 many lived until 125 and some as long as 150 years because older people were "a patchwork of other people's parts." (p. 74) There was, however, not much food—only algae and plankton—and the average daily calorie allotment, scientifically calculated based on the ratio of births to deaths, was 652 calories. As a result, 90 percent of all deaths were due to "simple malnutrition."

    For entertainment, the population went to titillating films called "Foodies," where they would watch vintage footage of old time supermarkets filled with fresh vegetables and fruits. The only part of the film this severely malnourished audience could not fathom was the diet section of the supermarket where there were shelves of low or no calorie items. But as the audience watched scenes of people eating real food like enormous pieces of roast beef or "a great slice of chocolate cake" with "a sticky bouquet of chocolate frosting," they would salivate and let out a collective moan, as if watching a pornographic movie, as their mouths "opened and closed in symbiotic union." (p. 133)

    Throughout history, there have been many devastating famines, particularly in times of war and political conflict. During the Dutch famine of World War II, for example, the official rationing went from 1,800 calories a day in 1943 to 619 calories in the first quarter of 1945. (Keys et al, Biology of Human Starvation, Volume I, 1950, p. 25) It was even worse for the victims of the Lodz and Warsaw Ghettos (Weisz and Albury, Israel Medical Association Journal, 2013) and Nazi Concentration Camps: the official daily ration at Auschwitz was one liter of watery soup 250 grams of bread 20-25 grams of margarine or sausage or imitation honey. Explains Lucie Adelsberger, a Jewish physician imprisoned there, "These quantities became in time insufficient to support life, and the German camp doctors admitted that a prisoner could not hope to survive on them much longer than six months." (Adelsberger, The Lancet, 1946) In Belsen, technically a detention camp and not an organized extermination camp, where the daily caloric intake was under 800 calories a day, if that, (Lipscomb, The Lancet, 1945) the average male survivor weighed 44 kilos (97 pounds) and the average female survivor weighed 35.3 kilos (77.8 pounds) at the time of the camp's liberation, with an average loss of almost 40 percent of body weight. (Mollison, British Medical Journal, 1946.)

    Most people can tolerate a weight loss of about 5 to 10 percent "with relatively little functional disorganization" but humans do not survive weight losses that are greater than 35 to 40 percent. (Keys et al, 1950, p.18, Vol. I) With war-ravaged Europe in mind, Ancel Keys and his colleagues at the University of Minnesota designed an experiment with a group of 36 conscientious objectors to assess the effects of caloric restriction that mimicked the malnourished diet (e.g. mostly potatoes, turnips, dark bread) of Europeans. The brochure proclaimed, "Will You Starve That They Be Better Fed?" The investigators' results were published in a meticulous two-volume tome, Biology of Human Starvation (1950.) Beginning in 1945, these men went from about 3,200 calories a day to about 1,800 calories, but continuously titrated down so that the men were to lose about 25 percent of their body weight (and walk 22 miles a week) in semi-starvation conditions over six months prior to a three-month rehabilitation period. The men became completely preoccupied with food, as they developed depression, nervousness, social withdrawal, anemia, fatigue, apathy, extreme weakness, irritability, neurological deficits, edema, loss of sexual interest, and inability to concentrate. Keys et al called the constellation of symptoms, a "semi-starvation neurosis." (p. 909, Volume II) Though the men found the experience grueling, when interviewed years later, they were proud to have participated. And unlike the conditions in Europe, said one participant, "We were starving under the best possible medical conditions. And most of all, we knew the exact day on which our torture would end." (Kalm and Semba, Journal of Nutrition, 2005.)

    Keys et al noted that there is an important difference between a prolonged period of inadequate caloric intake and total fasting: With under-nutrition, the feelings of hunger get worse over time, whereas with total abstinence, hunger sensations dissipate in a few days. (Keys et al, p. 29, Vol. I)

    What happens, though, when calories are restricted but there is adequate nutrition? Since the 1930s, researchers have questioned the value of restricting caloric intake, while maintaining adequate protein, fat, and carbohydrates, to benefit health and even to extend life. Caloric intake depends on our age, level of activity, and whether male or female. For example, adult men (before the age of 50) who are very active (e.g.walking quickly for more than three miles a day for more than 40 minutes, as well as usual activities) require about 2,400 to 2,800 calories a day very active adult women may require about 2,200 calories a day. As we age, we require fewer calories. (Health and Human Services, NIH) The Institute of Medicine suggests the following ranges: 10 to 35 percent calories from protein 20 to 35 percent from fat and 45 to 65 percent from carbohydrates. (Dwyer, Chapter 95e, Harrison's Textbook of Medicine, 19th Edition, online.)

    For years, researchers have found that many species (e.g. fruit flies, rodents), though not all (and even depending on strain of rodent) have not only substantially lengthened their lifespans through caloric restriction while maintaining adequate nutrition, but have also decreased their incidence of cancers as well as metabolic and immunological abnormalities. (Sohal and Forster, Free Radical Biology & Medicine, 2014) In an attempt to extrapolate their findings to humans, researchers have undertaken several major, long-term studies in non-human primates (e.g. rhesus monkeys) to assess the effect of caloric restriction (CR) on longevity. The results have been inconsistent: a study from the University of Wisconsin found a significant positive effect of CR on lifespan while a study from the National Institute on Aging did not find CR increased lifespan, though both groups found substantial health benefits. Allison and his colleagues, who conducted the statistical analysis for both studies, (Mattison et al, Nature Communications, 2017) explained the discrepancies in outcome: there were fundamental differences in each study's design and implementation. For example, there were different feeding schedules different diet compositions including different amounts of protein and vastly different amounts of sugar in the diets different age ranges for the initiation of the intervention of CR, and even different genetic strains of monkeys. Further, they acknowledged "the minimum degree of food restriction for maximum benefit has not been identified." And at a certain point, caloric restriction can go from being beneficial to being detrimental. (Roberts and Speakman, Advances in Nutrition, 2013)

    Since non-human primates, though, share our "catalogue of pathologies" typical of our own aging, Allison and colleagues (Mattison et al, 2017) believe that there is a likely benefit of CR with adequate nutrition for lowering age-related morbidity in humans as well. This is the concept of healthspan-"maintaining full functioning as nearly as possible to the end of life." (Rowe and Kahn, Science, 1987) Explain Allison et al (Smith et al, European Journal of Clinical Investigation, 2010), ". the academic or esoteric question of whether lifespan can be truly extended by CR in humans may not be as important as the potential prolongation of healthspan." Further, say Kirkland and Peterson, (Journal of Gerontology: Biological Sciences, 2009), who also emphasize the importance of healthspan, "It is not clear whether increasing lifespan will be associated with a pushing of morbidity out until near the end of life (compression of morbidity) or with increased disability and health care costs for society (expansion of morbidity.)

    The problem is that CR may be too difficult to implement in humans, and as Keys et al had noted, hunger does not seem to dissipate with CR, and humans complain of being lethargic, tired, and cold. (Speakman and Hambly, Journal of Nutrition, 2007) The goal may be, say Balasubramanian et al, (Ebiomedicine, 2017) to understand its mechanism, rather than "promote it as a lifestyle." For example, there have been two human studies—the randomized controlled trials, CALERIE 1 and 2 (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), to assess the physiological and psychological effects of CR on healthy, non-obese subjects. The researchers describe it as not exactly a clinical trial but rather "a model of a controlled experiment in free-living humans." (Stewart et al, Contemporary Clinical Trials, 2013) Initially the researchers had aimed for a 30 percent reduction in calories, but then realized that was not feasible and settled for 25 percent. By the end of the two years, though, CR was achieved at only 12 percent. (Das et al, Molecular and Cellular Endocrinology, 2017)

    Bottom Line: There are several theories about the mechanisms involved in caloric restriction with adequate nutrition, but there remain many unanswered questions, such as how much CR is beneficial when should it first be implemented, including ethical issues of starting when someone is too young (where CR may affect growth, development, and even reproduction when CR may lead to amenorrhea in women) (Speakman and Hambly, 2007) and what are the most advantageous macronutrient percentages of fat, protein, and carbohydrate, i.e, the varying "dietary landscape." (Simpson et al, Ageing Research Reviews, 2017). Studies seem to demonstrate CR's efficacy in reducing age-related morbidities but for most, CR may not be feasible for the long term. Investigators are now studying compounds (e.g. resveratrol, rapamycin, metformin) to mimic the effects of CR. (Balasubramanian et al, 2017)

    Note: In recent years, Ancel Keys has been unfairly maligned for his work on the connection between heart disease and fat intake in his major Seven Countries Study. For a comprehensive discussion, see the White Paper available online by researchers Pett, Kahn, Willett, and Katz, Ancel Keys and the Seven Countries Study: An Evidenced-based Response to Revisionist Histories. (2017)