June 10

Rapamycin: A Lifespan Drug for Humans?

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Rapamycin has a good chance to become a lifespan drug for humans, but it needs first to be rigorously tested in people. It has not so far. Anecdotal evidence is compelling that rapamycin does improve the health and healthspan of people, but take a deep breath and wait till it’s tested.

Maoi statue on Rapa Nui, the birthplace of rapamycin.

Rapamycin was isolated in 1972 from a bacterium found on Easter Island, aka Rapa Nui – hence the name. For many years it was mainly a transplant drug used to prevent the rejection of organ transplants by the immune system, but in the early 2000s, rapamycin (also known by its generic name, Sirolimus) was found to significantly extend the lifespan of worms, yeast, flies and mice.

And, of course, what’s good for worms, yeast, flies and mice must be good for humans, right? Of course not right, but you wouldn’t know it given how many people are experimenting with rapamycin for lifespan purposes — from scientists themselves to the guy down the street who rather inject himself with a dose of rapa than improve his nutrition and exercise.

Again, this salutary belief in rapamycin has been instigated by studies with various animals. 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 age-related diseases in them. Several animal studies have shown that even a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.

For these reasons, there will soon be human trials of rapamycin, and anyone interested in extending healthspan/lifespan should know about it.

 

How Rapamycin Works

Rapamycin works by inhibiting the mechanistic target of rapamycin (mTOR) pathway, which is a key regulator of aging. When we’re young, we need it to be activates, but when we get older, we need mTOR to be suppressed to some degree.

During an organism’s growth period, us included, mTOR activation is needed because it regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription (the process by which the information in a strand of DNA is copied into a new molecule of messenger RNA (mRNA). mTOR integrates the input from upstream pathways, including insulin, growth factors, and amino acids, and senses cellular nutrient, oxygen and energy levels [1] [2] [3].

However, as an organism reaches maturity, excessive or prolonged activation of the mTOR pathway can have negative consequences. The continuous stimulation of mTOR leads to an imbalance between cellular growth and maintenance processes, which can contribute to the aging process and age-related diseases [3] [4].

mTOR is activated when nutrients are sufficient, which promotes anabolism and energy storage and utilization. When nutrients are relatively scarce, the body must inhibit the activation of mTOR to keep cell material and energy stable [5]. As mentioned, inhibition of mTOR has been shown to increase lifespan in various organisms, including mice, worms, and flies. Inhibition of mTOR has also been shown to improve healthspan by reducing the incidence of age-related diseases, such as cancer, neurodegeneration and cardiovascular disease [3].

Therefore, during an organism’s later life stages, mTOR deactivation helps with healthspan and lifespan.

Here’s why deactivating mTOR can be beneficial for healthspan and lifespan:

Cellular Senescence and Aging: Persistent mTOR activation can lead to the accumulation of senescent cells, which are cells that have lost their ability to divide and function properly. Senescent cells secrete harmful molecules that contribute to tissue dysfunction, chronic inflammation, and the development of age-related diseases. Deactivating mTOR helps reduce the burden of senescent cells and promotes cellular homeostasis, which can slow down the aging process.

Autophagy and Cellular Quality Control: mTOR activation inhibits autophagy, a cellular process responsible for the removal of damaged cellular components, protein aggregates, and dysfunctional organelles. Autophagy plays a crucial role in maintaining cellular quality control and preventing the accumulation of cellular debris. By inhibiting mTOR, autophagy is stimulated, promoting cellular rejuvenation, and reducing the risk of age-related diseases.

Metabolic Health: Persistent mTOR activation is associated with metabolic dysregulation, such as insulin resistance and impaired glucose metabolism. Deactivating mTOR can improve metabolic health by enhancing insulin sensitivity, reducing inflammation, and promoting efficient energy utilization. Improved metabolic health has been linked to a lower risk of age-related diseases, including diabetes, cardiovascular conditions, and neurodegenerative disorders.

Stress Resistance and Longevity: mTOR deactivation has been shown to increase stress resistance and promote longevity in various model organisms. By inhibiting mTOR, cells activate stress response pathways, such as the AMP-activated protein kinase (AMPK) pathway, which enhances cellular and organismal resilience to various stressors. Improved stress resistance contributes to healthier aging and increased lifespan.

It’s important to note that mTOR plays complex and context-dependent roles in cellular processes, and complete inhibition of mTOR throughout an organism’s lifespan may not be desirable or feasible. Fine-tuning mTOR activity and achieving a balanced regulation of its pathway is crucial for achieving the optimal benefits for healthspan and lifespan.

The question is:

What’s the right balance of mTOR regulation for humans?

The answer:

We don’t know yet.

Nonetheless, I admit that despite my misgivings that there’s not enough evidence to indicate it’s safe and effective for humans, I’m intrigued by rapamycin. True, there have been no published human trials testing rapamycin, but the anecdotal “evidence” of its effectiveness — at least related to various biomarkers related to aging — is mounting and becoming too significant to ignore.

But is it too risky?  That’s up to you.

 

Cost-Benefit Review of Rapamycin for Healthspan/Lifespan Enhancement

Let’s examine the benefits of rapamycin versus the drawbacks and safety concerns.

Benefits of Rapamycin

I see three primary benefits from taking rapamycin:

  1. Potential extended healthspan and lifespan,
  2. Delayed onset of age-related diseases, and
  3. Lower healthcare costs.

1. Extended Healthspan and Lifespan:

Numerous studies in model organisms have shown that rapamycin extends lifespan and delays age-related diseases such as cancer, neurodegeneration, and cardiovascular conditions.

For example, a study conducted on mice by Harrison et al. (2009) demonstrated a 28% increase in lifespan in rapamycin-treated mice compared to control groups [6]. These findings suggest that rapamycin has the potential to enhance both healthspan and lifespan in humans, which, as mentioned, is why many people are experimenting with it.

Here are some of the potential aging and lifespan extension benefits derived by rapamycin in animal studies:

  • Increases longevity and lifespan: Rapamycin can improve autophagy in the body when it inhibits mTOR. It simultaneously boosts the process and disrupts unhealthy cell growth. As a result, the body can delay the onset of the aging process and age-related diseases, giving people a longer and healthier life [7].
  • Delays age-related dysfunction: The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. A short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome [7].
  • Increases lifespan: Rapamycin can extend lifespan if given in adulthood or later in life in various mouse strains, including genetically diverse [8].
  • Prolongs lifespan of many species: Rapamycin has been shown to prolong the lifespan of many species of mice, yeast, and fruit flies (Drosophila melanogaster) [9].
  • Increases lifespan by 9-14%: When taken late in life, rapamycin increases lifespan by 9-14%, despite the dosage being suboptimal [10].

2. Delayed Onset of Age-Related Diseases:

Rapamycin’s ability to modulate the mTOR pathway has been linked to delaying the onset of various age-related diseases. By inhibiting mTOR, rapamycin promotes cellular and metabolic processes that contribute to improved health.

For instance, it reduces the accumulation of senescent cells, which are associated with aging and age-related diseases. Studies in mice have shown a reduction in cancer incidence and improved cognitive function with rapamycin treatment.

3. Lower Healthcare Costs:

If rapamycin proves effective in extending healthspan and lifespan in humans, it has the potential to reduce healthcare costs associated with age-related diseases.

By delaying or preventing the onset of conditions such as cancer, cardiovascular diseases, and neurodegeneration, rapamycin could alleviate the burden on healthcare systems, leading to substantial cost savings.

Consider these costs of various types of health care administered in the United States:

  • The average medical spending from all payers during the last 12 months of life for an individual was $80,000 (in 2011, measured in 2014 dollars) and spending during the last three calendar years of life was $155,000 [11].
  • In 2019, the national patient economic burden associated with cancer care was $21.09 billion, made up of patient out-of-pocket costs of $16.22 billion and patient time costs of $4.87 billion [12].
  • Heart disease costs the United States about $219 billion each year. This total includes the cost of healthcare services, medications, and premature death [13].
  • Neurodegenerative diseases costs in the U.S.was $655 billion in 2020, including direct medical and non-medical costs and indirect costs from lost productivity and uncompensated care-giving hours [14].

Obviously, if rapamycin could help alleviate the burden of chronic disease while also extending healthy lifespan, it would be a wonder drug.

But I caution you to not go rushing to buy it yet, even if you could get a prescription.

Before we get into the drawbacks and safety concerns of the drug, watch Professor Kaeberlein talk about rapamycin, what are the benefits that it has shown, some of the side effects and myths around them and what doses he is using in the Dog Aging Project:

[responsive_video type=’youtube’ hide_related=’1′ hide_logo=’1′ hide_controls=’0′ hide_title=’0′ hide_fullscreen=’0′ autoplay=’0′]https://www.youtube.com/watch?v=6Zj3l-5lTVo[/responsive_video]

Drawbacks and Safety Concerns

The potential downside from taking rapamycin include various harmful side effects.

Side Effects:

Rapamycin, when used at higher doses, has been associated with side effects such as immunosuppression, impaired wound healing, and metabolic disturbances. These side effects can limit its potential use as an anti-aging intervention. That said, lower doses and intermittent dosing regimens have shown promise in minimizing side effects while retaining efficacy.

Long-Term Effects:

The long-term effects of rapamycin on human health are not yet fully understood. Since rapamycin is an immunosuppressant, there are concerns that chronic use could increase the risk of infections and other immune-related complications. More research is needed to assess the safety and long-term effects of rapamycin in humans.

Until a few human studies show that rapamycin is safe and reveal the ideal dosage protocol, you might consider safer rapamycin alternatives.

 

Safer Rapamycin Alternatives

Two drugs (everolimus and RAD001) might be safer than rapamycin, but still need a prescription. You could also consider fasting, exercise and maybe even metformin.

Everolimus, the rapamycin analog

In this context, an analog drug one that’s chemically similar to another, but not identical, to another drug.

Rapamycin and its analogs (rapalogs) are the first generation of mTOR inhibitors, which have the same molecular scaffold, but different physiochemical properties. Rapalogs are being tested in a wide spectrum of human tumors as both monotherapy and a component of combination therapy [15].

Everolimus is an analog of rapamycin that is already approved for clinical use in certain conditions, such as organ transplantation and some cancers. It has a similar mechanism of action as rapamycin but with a better safety profile. Everolimus has been shown to extend lifespan in model organisms, including yeast, worms, flies, and mice. Clinical trials are currently underway to investigate its potential for age-related diseases.

RAD001

The everolimus derivative RAD001, also known as ridaforolimus, is another rapamycin analog being explored for its anti-aging properties. Like rapamycin and everolimus, RAD001 inhibits mTOR, leading to similar benefits in lifespan extension and healthspan improvement. Studies in mice have shown promising results, indicating increased longevity and enhanced immune function [16].

Caloric restriction and fasting

Caloric restriction (CR) and intermittent fasting (or time restricted eating) have been shown to have overlapping effects with rapamycin, including the activation of autophagy and modulation of the mTOR pathway.

CR and fasting regimes have demonstrated positive outcomes in model organisms, such as increased lifespan and improved metabolic health. Although the translation of these benefits to humans is still under investigation, adopting a healthy dietary pattern that includes intermittent fasting or calorie restriction may provide some of the benefits associated with rapamycin [17][18].

There’s lots of different ways to do the CR-thing. Check out my post about time restricted eating.. ……… In particular, these may be of interest:

Metformin

Metformin is a widely used drug for the treatment of type 2 diabetes that has the  potential to be an intervention to promote healthy aging. A clinical trial dubbed TAME (Targeting Aging with Metformin) was approved by the FDA last year (2022).

Researchers will be tracking the incidence and progression of age-related conditions including heart disease, cancer and dementia.  TAME will engage more than 3,000 individuals between the ages of 65 to 79 in a series of six-year trials at 14 leading research institutions across the country. If successful, TAME will provide proof-of-concept that aging can be treated in the same way we currently treat diseases. [19].

One reason metformin is being studied as an anti-aging drug is because it activates the AMP-activated protein kinase (AMPK) pathway, which intersects with the mTOR pathway.

AMPK is an enzyme that plays a substantial role in maintaining cellular energy homeostasis. When ATP levels fall, AMPK is activated and influences the uptake of fatty acids and glucose. Metformin is thought to activate AMPK by acting as a mild inhibitor of Complex I of the mitochondrial respiratory chain, which leads to an increase in the AMP/ATP ratio [20].

Once activated, AMPK has several downstream effects, including:

  • Reduction of acetyl-CoA carboxylase (ACC) activity: ACC is an enzyme involved in fatty acid synthesis, and its reduction leads to a decrease in fatty acid synthesis [21].
  • Induction of fatty acid oxidation: AMPK activation leads to an increase in fatty acid oxidation, which helps to reduce the amount of glucose in the blood [21].
  • .Inhibition of mTORC1 signaling: Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC. The mTOR pathway is a key regulator of cell growth and proliferation, and its inhibition can lead to a decrease in cell growth and proliferation [22].
  • Induction of autophagy: Autophagy is a process by which cells break down and recycle damaged or unnecessary components. AMPK activation has been shown to induce autophagy, which can help to remove damaged proteins and organelles from cells [23].
  • Modulation of neuro-inflammation: AMPK activation has been found to be substantially responsible for the neuroprotective effect of metformin. AMPK activation modulates neuro-inflammation and autophagy [24].

The AMPK pathway intersects with the mTOR pathway, which is a key regulator of cell growth and proliferation[4]. The inhibition of mTORC1 signaling by metformin via AMPK activation can lead to a decrease in cell growth and proliferation [22].

Metformin has been associated with improvements in age-related conditions, such as cardiovascular disease and cancer. While metformin does not directly target mTOR like rapamycin, it may provide some overlapping benefits for healthspan enhancement.

Supplements

No supplements that I’m aware of have been tested in humans relative to mTOR suppression, but there are a few that have been tested in worms. Yeah, you’re not a worm, so don’t break a leg hunting these down as rapamycin alternatives, although curcumin, green tea and quercetin are solid health-promoting supplements. (Can’t speak to geldanamycin.)

  • Curcumin: Curcumin is a polyphenol found in turmeric. It has been shown to inhibit mTOR and extend lifespan in worms.
  • Green tea: Green tea contains polyphenols called catechins, which have been shown to inhibit mTOR and extend lifespan in worms.
  • Quercetin: Quercetin is a flavonoid found in many fruits and vegetables. It has been shown to inhibit mTOR and extend lifespan in worms.
  • Geldanamycin: Geldanamycin is a natural compound derived from the bacterium Streptomyces hygroscopicus. It has been shown to suppress mTOR phosphorylation of downstream targets and extend lifespan in worms.

 

My Bottom Line On Rapamycin

Rapamycin clearly extends the health and lifespan in every animal model tested, but humans are one animal that has yet to be tested under controlled circumstances.

Yes, there is much anecdotal evidence that attests to rapamycin’s ability to downregulate mTOR in humans, and some of them have had the common sense and discipline to regularly test themselves for various biomarkers that can track health and aging. For a deep dive into rapamycin self-hackers, check out Rapamycin News.

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Dr. Peter Attia takes it, has prescribed it off-label for his patients and, during one interview, called it “hands down the most important and exciting and promising neuroprotective molecule.” https://honehealth.com/edge/health/rapamycin-anti-aging/

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Matt Kaeberlein takes rapamycin
Dr. Matt Kaeberlein: “I take rapamycin myself, and I think that it’s a very promising intervention for improving healthspan and potentially lifespan in humans”

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The promising results of rapamycin are preliminary, and this means you should not twist your doctor’s arm until (s)he prescribes rapamycin for you, nor should you attempt to buy it on some wheeler-dealer website that doesn’t require a prescription. This is because we don’t know the long-term effects of rapamycin on humans when used for longevity purposes. You could follow what others are doing, but without consistent blood work metrics to monitor potential negative side effects, you could do yourself harm.

So, why do I bother to tell you about rapamycin?

Simply because if you haven’t already, you’re going to hear about it. There’s an ongoing study examining the impact of rapamycin on dogs, scientists are busy raising funds for human trials, and there is a devoted community that is experimenting with it.

Clearly, you’re going to hear more and more about rapamycin.

 

Last Updated on July 7, 2023 by Joe Garma


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  1. From what I understand, there’s currently no active human trials underway or at least publicly. Is that correct?

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