Rapamycin may be the first “youth pill” in the History of Medecine

Rapamycin is an immunosupressant drug, mainly used today after organ transplants. However, recently, scientists have discovered that it may have “gero-protective” properties, arguably offering between 9% and 14% of additional lifespan in humans.

The story of Rapamycin

Rapamycin is a molecule produced by a bacteria called “Streptomyces hygroscopicus”, and was first discovered in 1964, by a Canadian scientist in the Easter Island (do the mysterious staring eyes statues ring a bell?). This molecule was firsthand intriguing by its unusually strong antifungal properties.

A couple of years later, the pharmaceutical company which was financing the research, called Ayerst, closed their canadian lab, and formally requested all rapamycin cultures and extracts to be destroyed. However, one of the researchers, called Suren Sehgal, did not obey orders, and hid the samples from Easter Island in his personal fridge.

A few years later, the Sehgal’s new management team agreed to resume the research on Rapamycin. It proved useful in healing all sorts of fungal conditions (athlete’s foot, body rash, etc.), but also in partially suppressing immune reactions to organ transplant rejection (mainly kidneys and liver), for which it has been approved by the FDA (Food and Drug Administration) in 1999.

However, this is where things get really interesting: back in 2006, Rapamycin has been shown to lengthen the lifespan of eukaryotic cells, that is, cells from multi-cellular organisms such as humans (experts out there please pardon me for the extreme approximation of this definition).

Why this time it may be different

Discovering the “youth pill” has been a human obsession since the most ancient times. It has inspired myths, writers, poets, explorers, and charlatans throughout the ages. It is said that selling so-called magical “eternal youth potions” has been the 2nd oldest profession on Earth 🙂 Juan Ponce de Leon (1474 – 1521), was such an utopian explorer, who is said to have devoted his life to searching the “fountain of youth“. Of course, none of them came anywhere close to it.

Well, today, scientists have valid reasons to consider that the time has finally come for such a groundbreaking discovery. Before explaining how this molecule works in complex multi-cellular organisms, let me tell you why this time it’s different:

– Rapamycin has been tested in various animal models (yeast, worms, flies, mice) and worked in all of them, which is extremely rare for any drug. Is now being tested on primates (a short-lived monkey called “marmoset“), dogs, and even elder humans with yet to be formally confirmed but promising and encouraging results so far.

– Rapamycin “makes sense” as a gero-protective molecule, by inhibiting a specific pathway in the eukaryotic cells. This cellular mechanism appeared so early in the evolution of life on Earth, that it is common to a big proportion of life forms as of today. More on the scientific explanation below in this article.

– This is by no way a scientific proof of anything , but many world renown scientists and doctors who study the aging processes take Rapamycin and publicly admit it, even disclosing how much and frequently they take it. They’ve made their choice, decided not to wait until FDA approves it, they have “skin in the game”, they eat their own dog food 🙂

How and why Rapamycin works

Mammals have a mechanism called mTor (mammalian target of rapamycin), which works like an “organism growth manager”: when nutrients are proficient, the mTor pathway is activated, and the organism goes into “growth mode”, cells divide, the cell metabolism increases. When nutrients are scarce, mTor is inhibited, and the organisms tends to go in “survival mode”, and each cell tends to “recycle” its waste, save energy, instead of spoiling resources.

Well, what Rapamycin does, and this is why it seems to work as an anti-aging drug, is that it inhibits mTor, forcing the organism and each and every cell within it, to go into “survival” mode: less nutrients waste, more recycling, less cell division, more cell repair.


While there are very strong reasons to consider that Ramaycin may be the first gero-protector in the History of Mankind, we need to take into account that as of today, the scientific community has not finished the work on this very promising molecule:

– studies on humans are still incomplete

– optimal posology is still unclear (how much, how frequently should one take it?)

– the FDA has not yet approved this drug as an anti-aging treatment

– this drug has some minor side-effects (called mouth ulcers, which may be easily treated however and are insignificant given the advantages)

– even if unlikely, this drug may have yet unknown adverse effects

– you cannot buy this drug without prescription, and you won’t get a prescription as an anti-agind drug in many countries (France being one of them). It seems you can buy it in Spain without prescription, but I haven’t yet investigated enough to be sure of it.

– remember that the stakes here is “only” 9% – 14% of additional lifespan, which is at the same time a lot and very little. It doesn’t prevent us all from all the other longevity measures (healthy diet, physical activity, etc …). Also, it doesn’t prevent us from pressing the pedal to the metal and discover more efficient gero-protectors, pushing the human healthspan even further.


Some people asked me if I was taking Rapamycin. Given my promise of transparency, let me share my conclusions when it comes to this drug:

– I have personally talked to many scientists and doctors from the longevity ecosystem, many of them take Rapamycin. Some of them were very convincing in explaining why. They don’t want to wait 20 years for the FDA to approve this drug, they’ll be dead by then. Surprisingly, even the most cautious of them take it, under the assumption that even if it’s not useful, at least it’s not harmful.

– Almost all the credible trials related to Rapamycin, and scientific papers, show the same positive conclusion, being published on a regular basis. Sometime in the future, the FDA will approve the treatment when it will be 99.99% certain (not sure of the exact percentage, I just want you to get the idea). Well, as more and more papers and clinical trials results get published, the certainty will go from 90% to 95%, then 99%, and so on, the whole process taking decades. As I read those papers, it’s an ongoing process, where at every step, certainty goes up. At some point, I’d take now a drug that is 99% certain, rather than wait 15 years for it to be 99.99% certain. The numbers I’m using to explain my point are imprecise, but the rationale behind it isn’t. It all comes down to a risk management problem.

– I’m not taking this drug as of now, because I want to set up a biomarker “before – after” tracking protocol, I have too much of an engineer mindset to test stuff on myself just on “believing” it might work. Measuring is an absolute necessity for me. I want to identify the right biomarkers to measure before taking Rapamycin, decide how much I’ll take and how frequently, during how much time, and after that time span I’ll measure the same biomarkers again, to see the difference. Another reason why I’m not taking it yet is that I have to find the right way to buy it, no doctor will prescribe that in France 🙂

When I’ll move forward with this drug, I’ll let you know!

The Yamanaka Factors

It looks like science-fiction, but it’s actually fact-based science. Shinya Yamanaka got the Nobel prize in 2012 by turning differentiated cells (also called somatic cells) back into stem cells. This opened a whole new R&D universe to explore, whose practical applications should be starting to appear in the very next years.

Crash course in Cellular Biology

For accessibility purposes, I’ll make some approximations here, because I want the content to be easy to understand, so that everyone gets how disruptive this major scientific breakthrough is. Please don’t kill me if you’re an expert in microbiology 🙂

Stem cells are undifferentiated cells (similar to the ones that grow once a sperm and an ovocyte met). As the foetus grows, the inner structure grows more an more complex, and mechanisms we do not fully understand today contribute to the specialization of stem cells into neurons, muscle, skin, etc… During our lifetime, stem cells continue to exist though, disseminated everywhere in our bodies, ready to take over in case of accidental or systemic cell damage. When this happens, stem cells follow a complex process of migration and differentiation, which ultimately allows them to replace the damaged tissue.

Once a stem cell specializes into a somatic cell, that cell will fulfil its function, live and probably die at some point. It’s a one way ticket decided by Mother Nature for that cell, which will normally never return into a stem cell again.

The DNA of a stem cell differs from the one of a somatic cell by what called the methylation of the DNA, which is a mechanism by which some portions of the DNA become “blocked” or unreadable and only the portions of DNA which are relevant to that specific category of cells will be expressed again. It makes total sense, as you want a neuron to behave like a neuron, and not like a skin cell, or the other way around, etc.

This is a very simplified version of how Mother Nature works.

The Yamanaka Factors

Yamanaka discovered that there are 4 genes, called the Yamanaka Factors (Oct3/4, Sox2, Klf4, c-Myc), which, when over-expressed to different degrees and combinations, result in any differentiated “adult” cell turning back into a stem cell. That stem cell can then be multiplied at will, and then be differentiated again into any other kind of somatic cell. In plain words, this means taking for example a skin cell, turning it back into a stem cell, and then turning it into a neuron – for example. Mind blowing!

Ongoing Research Projects related to the Yamanaka Factors

There are numerous ongoing projects, I’ll just give a couple of examples, just to barely scratch the surface of such an extensive and fascinating field of research:

– stem cells based therapies. The idea is either to inject stem cells in damaged issue, so that it regenerates faster and better. Another idea is to extract somatic cells, turn them into stem cells, then turn them into specialized cells, and then again provide them locally where they’re most needed. Although not yet approved in US & EU, meet 40 world-class athletes who are using or have used stem cells therapies (Rafael Nadal, Cristiano Ronaldo, etc.)

– create and grow organs in a flask, and then transplant them into human bodies. The process begins with your own cells, which are then differentiated into specialized cells, then multiplied, through a complex process as you can imagine, and then ultimately grown into full sized functional working organs. All of this would have never been possible without using the Yamanaka Factors. For example, meet your future heart if at some point you’ll need a new one.

– last but not least, it seems possible to apply a partial “mild” activation of some of the 4 Yamanaka factors, so instead of totally reverting a somatic cell from its current state all the way back to a stem cell, that cell is just partially rejuvenated. It keeps its specialization, it does not become a stem cell, but instead of being old and damaged, it is just gets youthful again. This is called “epigenetic reprogramming” and is currently the most promising field in aging research. Altos Labs (arguably the best founded longevity company today, sponsored by Jeff Bezos amongst others) is working specifically on this cellular reprogramming technology, and they’re betting big on it.

Caveats and current limitations

The main problem today, when it comes to reverting somatic cells to stem cells, is that during this process, some of the resulting stem cells become cancer cells, quickly multiplying and creating tumors.

One other problem is that while scientists know how to take a single cell and manipulate it “in-vitro” with regard to these Yamanaka Factors, doing the same thing with multiple cells, and making sure that each and everyone of them corresponds to the expected differentiation stage, is a challenge. Doing so “in-vivo” is even more of a challenge.

However, when it comes to practical applications to come, there are so many companies, and so much money has been invested into this technology, that it is one of the most (if not THE most) promising research domains today, the hottest topic in the field.

The Hallmarks of Aging

Intuitively, for each one of us, aging is “when you grow old and ultimately die”. However, aging is an incredibly difficult phenomenon to define precisely, and no general consensus has yet been reached by the scientific community as to what exactly it means. Today, the best framework we have to describe and understand aging is a set of 14 biological mechanisms, called “The Hallmarks of Aging”. Addressing each one of these mechanisms is the best action plan we have today to slow down aging.

Before 2013, there was a permanent fight between scientists, in a “there can be only 1 of us” conflict, each one of them trying to prove that his theory of aging was the right one, at the detriment of the neighbour’s. However, as some theories were able to explain some observations related to aging, none was able to reasonably explain all of them. Eventually, scientists came with this “Hallmarks of Aging” framework, which encompasses the complexity of the phenomenon, and determine everyone to collaborate in good faith again to move the science of aging forward.

This article is going to be a little bit longer, first because as discussed earlier, aging is a complex phenomenon, which even if simplified to the extreme, still needs some focus and time, and secondly because this post is going to put in place the general knowledge and structure of what’s coming in the news weeks or so, as we’ll do deep dives in each one of the topics below, to illustrate the research that’s being made to address each specific hallmark of aging, and the mind-blowing breakthroughs we expect to come in the next years coming from these specific directions.

1. Telomere Attrition

Telomeres are the small bits of DNA at the end of your Chromosomes. Every time one of your cells divide, and your chromosomes within those cells are copied, these bits of non-coding DNA will shorten. After a couple of dozen of divisions, the telomeres are shortened to exhaustion, and any further cell division will end up cropping small bits of your useful DNA information.

2. Genome Instability

There are 2 main reasons why your DNA information is partially lost as you age. The first one is that when your cells divide, the copying of your DNA is indeed incredibly accurate, but not perfect. The second reasons is that throughout your life, your whole body will suffer a certain level of stress, due to internal and external factors: oxydative stress (from so called ROS – Reactive Oxydative Stress), what you eat, sun radiation, even cosmic radiation. Multiple mutations to your DNA generate dysfunctions in your body, as the cells don’t fully fulfil their roles as they should anymore.

3. Proteostasis Perturbation

Your body is a wonderful piece of chemical machinery, with literally thousands of incredibly complex processes at the cellular level, which govern how the whole system works. At the core of these processes are the proteins, which are the basic bricks of human life. How these proteins are produced, maintained in the right balance and the adequate concentrations, is paramount to the vitality and health of your body. As we age, the dynamics and concentrations of these various proteins in our body starts to dysfunction, leading to frailty, diseases and ultimately death.

4. Stem Cell Exhaustion/Degeneration

Stem cells are undifferentiated cells, similar to the ones foetuses are created from. As kids and healthy adults, we all have stem cells spread all across our bodies, which are used by our body to regenerate (as part of systemic physiological processes, as well as in case of accident). However, the proportion and quality of stem cells decreases as we age, resulting in our body being unable to properly regenerate damaged tissue anymore.

5. Epigenetic Deprogramming

It’s common knowledge nowadays, that our DNA dictates how our body works. However, DNA is just half of the story (in fact, some scientists say it’s only around 20% of the story, but more on this later). The rest of the story is that as cells differentiate from stem cells to specialized cells (such as neurons, skin cells, etc.), large portions of our DNA get silenced by a mechanism called “methylation”, and only the pertinent portions of the DNA related to the specialization of each cell are being expressed. This makes total sense, as you don’t want neuron-related portions of DNA being expressed in skin cells, for example. Well, the bad news is that as we age, this “methylation” mechanism gets chaotic. Thus, you end up having cells in certain tissues behaving as cells in other tissues. No surprise that this partial loss of cell identity ends up in a big mess 🙂

6. Altered Energy Sensing

When you’re young and in good health, your cells have a remarquable capacity to adapt to a wide range of energy and resources related situations. It senses how much oxygen you have in your blood, what the demand in terms of energy production is, how urgent and critical it is, how much glucose and insuline is in your blood, etc … As you age, the performance of the whole “energy sensing” system decreases, with cells taking the wrong decisions as to how much energy to produce and what to do with it, which leads to dysfunctional mechanisms (as for example insuline resistance, related to Diabetes).

7. Altered Intercellular Communication

Cells communicate with each other, and it has even been recently discovered, as incredible as it may sound, that in extreme situations, “better off” cells will create nano-bridges/nano-tubes to connect with other stressed cells, to send them parts (such as mitochondria) and nutrients, to prevent them from dying. As we age, this communication is more and more disturbed. Not only cells don’t help each other anymore, but stress signals emitted by certain cells end up contaminating the cells around them, in a snowball effect.

8. Cellular Senescence

Cells are meant to fulfil a certain function, and reproduce as part of the natural regeneration tissue flow. However, when the DNA baggage of a certain cell is damaged or the overall disorder in that cell goes beyond a certain threshold, this leads either to cell death (called apoptosis), either to cell senescence, which may also be remembered as “zombie mode”: the cell is not dead, but is not working properly anymore, is not dividing anymore. Therefore, not only does it use resources at the detriment of other healthy cells, but it also sends negative signals to its proximity, contaminating other cells and turning them into zombie cells as well.

9. Mitochondrial Dysfunction

Mitochondria are the energy production factories of our cells. In short, they eat up glucose, and turn it into another product called ATP, which is used as energy currency in the cell. As we age, there are fewer mitochondria, and their quality is also lower, and without proper levels of energy, the maintenance processes of our cells are heavily impacted.

10. Compromised Autophagy

When cells don’t have enough energy, it may actually be a good thing (more on this in future posts). In those situations, cells turn into a particular mode where they’ll recycle and clean up accumulated toxines and unused reserves. This is positive, as these unused waste is at risk to clutter the cells, and increase the disorder in their processes. Well, as we age, autophagy does not work properly anymore, so the damaded parts of the cell don’t get recycled anymore.

11. Microbiome Disturbance

The Microbiome is the whole bacteria and other micro-organism ecosystem, which lives in symbiosis with your body, and is located in your gut. The nature of these micro-organisms, and how they interact with your gut, is closely related to your health: digestive diseases come from microbiome problems, even neuro-degenerative diseases seem to be related to it. Recent studies seem to suggest that as we age, the microbiome changes also, leading to our food being less well decomposed into basic nutrients for our body.

12. Inflammation (also called inflamm-aging – no pun intended)

Inflammation is the way our body reacts to agression. It is a healthy and essential part of how our body protects itself from pathogens. When it’s “business as usual”, you get a wound, a disease, and then that part of your body will swell, 2 hormones proper to inflammation are produced – bradykinin and histamine – and everything is set up for recovery. However, as we age, the inflammation may become permanent (chronic), leading to exhaustion of your immune system. In addition to this, your immune system gets disoriented, and starts attacking healthy cells, further affecting the overall functions of the affected tissues.

13. Altered Mechanical Properties

Our cells do not just plainly “stick” together by themselves. They’re placed in “collagen complexes”, that come in many shape and sizes, which form the basic “scallfolding” structures for our bodies. For example, the degradation of our collagen structure accounts for our skin being less and less flexible as we age, and wrinkles appearing on our faces. Collagen is produced by a specific category of cells called fibroblasts. Well, chaotic collagen creation and preservation generates not only aesthetic discomfort, but also functional damage, in our bones, our muscles, heart, etc.

14. Splicing Dysregulation

Splicing is the process by which the DNA gets transcripted into mRNA. In order to understand it, let’s get back to basics (remember your high school biology classes). Your DNA lies within the nucleus of your cells. When your cell needs to create a protein, the first step is to unfold the DNA from the chromosomes, and to copy the portion of relevant DNA in the form of mRNA, which is then sent outside the nucleus of the cell, to manage the creation of that protein. The process by which DNA is turned into mRNA is called the transcription. However, the mRNA is not an exact replica of the relevant DNA. Before it is sent outside the nucleus of the cell, it suffers a process called “splicing”, which consists of cutting portions of the copied DNA, and linking them back together. Well, this process of “splicing” works less well in old cells.

Tadaaaaaa, this is it! Now you have the big picture of what’s going on in your body as you age, and also what the scientific community is working on as I write this, in their laboratories!