Rapamycin and the Fountain of Youth Series: The Anti-Aging Drug

Should there be a single drug that can miraculously extend human life span given the diverse effects aging has across organs and biological systems?

The answer is yes but if you ask me, way too few people are excited about it.

Let us recap: aging effects everyone but some people live longer than others. When looking at centenarians, the question arises as to the reason for how they die in the end. The answer is that they die of the same stuff that everybody else dies of (cardio-vascular disease, cancer and a diminished immune system unable to fight infections like pneumonia) but centenarians only get those diseases twenty years later.

If we could just push out these diseases for twenty years, we would solve a lot of the problems in our health care system – but how likely is it that we would find a single intervention that does it?

Actually, one such intervention has been with us for centuries and – very topical given that today is Ash Wednesday, the beginning of Lent – is fasting (or caloric restriction).

The Fight Between Carnival and Lent Der Kampf zwischen Karneval und Fasten

Religion (especially when it includes adherence to ritual) has gone out of favor and instead, we have replaced true fasting (i.e., not eating) with very modest, metaphorical abstinence during Lent such as this year’s fasting slogan in the German Lutheran Church of „climate fasting“ (supposedly doing good stuff for the climate which can include vacation fasting).

Can a pill provide the same benefit without actually having to do a real fast? Actually, it can and you will not be surprised that the best candidate for such a drug is rapamycin.

Here is the data:

• It dramatically extends longevity in flies, worms and mice (which are very close to us biochemically but live much shorter lives so that you can study longevity in a controlled manner much more easily) and there are some great studies in dogs on its way
• Especially, the mouse data is very convincing given that the data came from genetically heterogeneous mice (i.e., not some breeding artifact) at various laboratories coming to the same conclusion in multiple sites and for multiple study protocols
• It is very likely to have the same life-extending effect in humans and we already know that rapamycin (and its analogues) ameliorate many of the symptoms of aging such as improving immune-system function in humans
• Best of all it is safe, approved for human use (if not for the specific use as an anti-aging drug) by the FDA and EMA and available as a generic (i.e., potentially cheap) since last year

So why do only fitness/life-hack nerds and a few aging researchers talk about rapamycin as a solution to slowing the aging process? Here is a list from Robin Hogarth, a decision scientist, on why people resist „simple“ solutions to complex problems

1. People generally believe that complex systems/problems require complex solutions
2. New ideas are hard to accept
3. It can be difficult to know if simple solutions work

While I believe that the first two are real obstacles (and the additional complicating fact that there is no money in it for the pharmaceutical industry under the current model), I am optimistic regarding the third point.

While it is exceedingly difficult (and expensive) to do randomized-controlled trials with the measured endpoint of lifespan given human longevity, we might not even need it in the current environment.

For me, a relevant case study is the example of the high-fat/low-carbohydrate diet for weight control and reversal of insulin-resistance. While its proponents were clearly seen as cranks just a few years ago, the individual data from people trying it for themselves is so convincing that there is no going back. As a kid growing up in the 80s on a diet of toast and orange juice for breakfast, lots of pasta, very little salt and definitely no eggs and cream I had problems maintaining my weight as an adult despite being an avid runner. Since changing the way I eat about 10 years ago, I have not spent a minute worrying about maintaining my weight and simply eat to satiety twice a day. Do I need a randomized-clinical trial as validation?

After we have all given rapamycin a try to see if the effects are indeed as great as claimed, the pharmaceutical industry might well get back to us due to popular demand as they have recently done in the pharmacological treatment of depression with ketamine. Ketamine, a general anesthetic and popular recreational street drug, was long known for its anti-depressant properties and prescribed on an off-label basis (i.e., not for the indication for which it was originally approved) but is now hailed as the greatest breakthrough in anti-depression therapy in the last 50 years after the regulatory approval of patent-protected nasal spray of a simple enantiomer of ketamine specifically for the treatment of depression – so that there is real money it it again.

Rapamycin and the Fountain of Youth Series: The Biology of mTOR

In biology, drugs often give us insights into the underlying function of cells that these drugs hijack. In general, drugs can only work because they latch onto some natural function of the cell and either mimic it or block it. There are specific molecules, called receptors, that drugs bind to in order to have their effects. The drug/receptor interaction can be compared to the interaction between a lock and a key with the receptor being the lock and the drug being the key which opens or closes the door to some function of the cell. 

Rapamycin works just the same. It binds to and inhibits a molecule called mTOR (mechanistic Target of Rapamycin). This molecule is present in all organisms from plants, yeast, fruit flies, worms all the way up to mammals. Usually, if something is conserved this well across species, it points to a very basic and central function of the cell.

David Sabatini (now at MIT) purified the mTOR protein as a postgraduate student and contributed greatly to our understanding of how it works (and has a beautiful three-part video series on youtube).

Here are the three things you need to know:

1. mTOR is part of a protein complex (called mTOR complex 1 or mTOR C1) and detects two things at the same time: the local availability of nutrients and the growth factors/hormones (like insulin-growth factor) that travel to it mainly via the blood to inform it about the availability of nutrients in other places/organs
2. mTOR C1 is the integrator (or in Sabatini’s words, the general contractor) to make a key decision for the cell about growth: are you fasting (low availability of nutrients) or feeding to go either catabolic (recycle and repair) or anabolic (grow and divide)
3. Rapamycin blocks the function of mTOR C1 and thus acts like fasting (or vice versa) – it therefore sends the organism towards the „recycling and repair“ branch

Source: David Sabatini YouTube

This of course explains the diverse and seemingly contradictory effects of rapamycin when blocking mTOR from immunosuppression (“antibodies: stop dividing like crazy and attacking the transplant”) to tumor suppression (“cancer cell: stop dividing and attacking other tissues”) and its anti-aging effect – but more on that next time.

Rapamycin and the Fountain of Youth Series: The Discovery of Rapamycin

To discover new drugs, pharmaceutical researchers go around the world collecting biological samples in their quest to find plants, fungi or bacteria that contain substances that have properties that make them candidates for drug development but rarely as far as Rapa Nui.

And oftentimes (as in this case), serendipity not a directed search strategy plays an essential role.

It starts with another modern Easter Island expedition under the leadership of Georges Nógrády, a bacteriologist from the University of Montreal with a ship from the Canadian Navy and a crew of 40 scientists and doctors that took off from Halifax, Nova Scotia in 1964. Georges Nógrády and his team were looking for something entirely different when they collected soil samples from all across the island looking for tetanus spores (which they did find very few of). 

Suren Seghal, Transplantation76(3):623-624, August 15th, 2003.

The samples were given to the research laboratories of Ayerst in Montreal (which has since through a set of mergers become part of Pfizer, one of the largest pharmaceutical companies in the world). Pharmaceutical companies love biological samples as they always look for new molecules that can be isolated and have medicinal properties that make them candidates for developing them into commercial drugs and Nógrády brought back 5,000 carefully frozen samples.

In 1972, Suren Seghal, a researcher with an almost stubborn determination to stick with his discoveries, was able to grow bacteria from the Easter Island soil samples and isolate a novel bacterial product originally called Rapamycin – Rapa because it is the indigenous name of the island and mycin because it showed properties against fungi.

He was happy because the novel molecule Rapamycin had anti-fungal properties but he was surprised that it also suppressed the growth of cancer (Seghal sent a sample to the National Cancer Institute but they were not interested at that time) and immune cells.

In 1983, Ayerst closed down the facility in Montreal, laying off 95% of the staff and moving with a small group that included Seghal to Princeton. Knowing that he would not have access to the large fermentors to grow the bacteria in Princeton, Seghal synthesized a large batch of Rapamycin in Montreal to take with him to Princeton and thus saved it for the world and the research to come.

With the growing interest in transplant medicine (and new management at his company), Seghal helped to develop Rapamycin for this purpose and it was approved in 1999 by the FDA as an immunosuppressant for organ transplantation.

Rapamycin (and its analogues) have since used to treat various cancers, rare lung diseases (LAM), venous malformations and even used to coat stents for heart surgery to prevent re-clogging.

Last but not least, Rapamycin prolongs lifespan in yeast, worms, flies and mice and one of its analogues prevents age-dependent decline in the immune system of humans (very topical: they measured the positive effect by an improved reaction to a flu shot).

How can a single drug have such wonderful but diverse effects? In the next part of this series, we will dive deep into the molecular biology of how cell growth and division is regulated and what role Rapamycin plays in it.

Rapamycin and The Fountain of Youth Series: The Island of Rapa Nui

After reading abut Lucy, fast forward from about 2 million years ago when our ancestors first started running, to around 3,000 years ago. It is the story of one of the most amazing feats that humans could perform with a greatly enlarged brain and a body made for endurance exercise, the colonization of the South Pacific including its most remote islands. 

Human beings had long left East Africa and populated the entire world with few spots still left untouched by human feet. Taking off from what is today Taiwan around 3,000 BC, they used catamaran-like canoes to first reach the Philippines, then the Melanesian Islands to finally reach one of the most remote places on earth, Easter Island (or Rapa Nui as it is know in the local language) at around 900 AD. 

By Ian Sewell – http://www.ianandwendy.com/OtherTrips/SouthPacific/Easter-Island/index.htm, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1195545

Easter Island (famous for its impressive statues and the rapid decline of their civilization described in Jared Diamond’s popular book Collapse) is so remote that the nearest town with a population over 500 is on the Island of Mangareva 2,600km away, the place from which the original colonizers most likely have taken off. 

This task, sailing without any modern navigation tools on small, human powered vessels across 2,600km on the open sea was so heroic that many people in modern days still doubted that it was possible at all. 

All doubts were erased once a group from the Polynesian Voyaging Society (a group of enthusiasts who want to keep the art and science of traditional Polynesian voyaging and the spirit of exploration based out of Hawaii founded in the 1970s) successfully repeated the task using original equipment (double-hulled voyaging canoe) and navigation techniques (basically navigating without instruments following the sun and stars and observing ocean-swells) and completed the journey in 19 days in 1999.

This remote place, Rapa Nui, also is the origin of a story that helps our understanding of a healthy life in general and exercise in particular and has even been likened to the discovery of the mysterious fountain of youth. It is the story of a most essential biological mechanism of cell growth and proliferation which we will come back to in the following installments of this series of articles.

The Masters Athlete Series: Matters of the Heart

If aging is the loss of dynamic homeostatic capacity (i.e., your reduced ability to deal with changes in the environment) can you attach a number to it to know where you stand?

Fortunately, you can and it is called heart rate variability or HRV. Heart rate variability has two great advantages (1) it is a highly integrated and meaningful measure and (2) it is super-easy to measure (at least today).

Before going into why it is meaningful and how to measure it, here is a very brief introduction into what it measures.

What is heart rate variability?

Heart rate variability is a measure of the variation in time between your heartbeats. Your heart is not a drum machine and does not keep a constant timing. Indeed, more differences between heartbeats (i.e., a higher HRV) are in general beneficial and a measure of good health. There are many ways of expressing your HRV but the most common is a statistical measure called the rMSSD (root mean square of the successive differences) which you will most often find displayed on consumer applications. When explaining what it actually measures you most often hear that it reflects the balance between your sympathetic nervous system (speeding up) and your parasympathetic nervous system (slowing down). While its sound attractively ying-yangy and is kind of true, I advise to either (1) ignore trying to understand it physiologically and instead focus on what it means below or (2) actually go a bit deeper and discover that it actually is a bit more complicated and of a higher order of integration that goes beyond heartbeats alone.

Why is HRV meaningful?

Clinically, HRV scores are used in cardiology and other medical disciplines as a risk stratification tool. Poor HRV score is an early predictor of poor outcome in coronary artery disease, cardiomyopathy, arterial hypertension, sudden death, chronic obstructive pulmonary disease, renal failure, heart failure, diabetes, stroke, Alzheimer’s disease, leukemia, obstructive sleep apnea, epilepsy, headache and others. This is consistent with the view that HRV measures how well you deal with disruptions and your ability to return to homeostasis.

Equally important, HRV scores decline with age also consistent with our definition of aging as reduced dynamic, homeostatic capacity.

Also, HRV scores have been used as proxies for positive training adaptations and most prominently as tools for load and recovery management. Simply spoken, you are ready to hit it hard again once your HRV has returned to your base level and better athletes recover faster.

So how do you measure HRV?

It is as simple as downloading an application on your phone and holding your finger on top of the camera for a short period of time (some apps are free, some are not).

What you will discover when starting to measure HRV is that it varies quite a bit an so it should. Therefore, it is important to establish a baseline by measuring under similar conditions (e.g., sitting or lying down) at the same time of the day (e.g., right after getting up and before reading your email) as both stress and circadian rhythm affect HRV scores.

How do you improve your HRV score?

And now the fun starts as you can experiment with all the things effecting both your base score as well as your HRV recovery after exercise. If you have been reading any of the other articles in this series, you will not be surprised that you should optimize successful aging (which will then improve HRV) and we already know how to do this in general: exercise, keeping insulin low (fasting/reducing carbohydrates/increasing muscle mass) and sleeping properly/reducing chronic stress. Please remember to only compare yourself to yourself over time and not to others. You do not win a prize for having the highest HRV in the universe but for keeping or even better improving yours over time.

So let’s play with individual interventions (here are some that I have tested):

• How honest am I with my easy sessions? Are they really easy enough so that I recover my HRV base within 30-60 minutes?
• How come walking is so effective in improving base HRV even if it is below even Zone 1 levels of exertion?
• How honest am I about acute and chronic stressors such as alcohol – does dry January help in improving base HRV?

Fun Bonus Episode

Flying into space improves your HRV and the effect is likely to be anti-aging for humans and proven to be life-extending for worms (C. elegans).

Surprise again (not): when they analyzed the genes down-regulated in space that are likely to be responsible for the anti-aging effect, they found the insulin equivalent in worms as well as others involved in dietary-restriction signalling.

The Masters Athlete Series: What is Aging?

There are basically three views on aging relevant to an athlete thinking about mitigating its deleterious effects:

• The Statistical View
• The Cell & Molecular Biology View
• The Systems View

Ghirlandaio, Domenico – An Old Man and His Grandson

The Statistical View

The statistical view on aging is based on a definition that – simple as it sounds – actually helps in making sense of many of the things we experience everyday. In its essence, aging is viewed as an increasing probability of dying with time passing. That’s trivial you might shout but then again it is not well understood by the general public. Most of us in January 2021 are still subject to some form of Coronavirus-related lock downs and you will have heard the rationale for it over and over again. COVID-19 is particularly dangerous to the old whom we must protect as the fatality rate increases exponentially with age. Well, indeed it does as does the fatality rate of everything else that you can possibly die off from other respiratory viruses such an influenza to all of the diseases of civilization 2.0 from diabetes to cancer. If your overall risk of dying increases exponentially so should the reasons for dying (at least on average).

Of course this definition does not help us in understanding why this curious statistical pattern should be true.

The Biological View

And in comes biology. Current biological thinking on aging is best summarized with two seemingly contradictory points that you have to contemporaneously hold in your head

• Aging is an expression of a pretty complicated interplay of many components
• It is pretty simple (at least in animal models) to find single interventions to make you live longer

The Hallmarks of Aging

Let’s start with the complicated: inspired from ideas in cancer biology, Guido Kroemer and colleagues have published a very influential review in 2013 that defines the biological hallmarks of aging of which there are nine in total:

• The first type are those are called primary hallmarks and are thought to be the underlying causes of something going wrong. These are (1) genomic instability (i.e., your DNA getting damaged by the environment but also by the byproducts of your own metabolism), (2) telomere attrition (i.e., the protective ends of your chromosome getting shorter with every cell division), (3) epigenetic alterations (i.e., damage to all the stuff that makes sure your DNA can properly replicate) and (4) loss of proteostasis (i.e. the inability to keep your proteins that do the work properly folded)
• As a result of the first type, the organism reacts with a second type called antagonistic hallmarks which first try to defeat the damage. The first and very important one is (5) altered nutrient sensing. In its very simplest form, the cell has a nutrient sensing system that is very similar for all animals and even yeast across evolution. It sees if there is enough food out there. If there is, it can afford to divide and grow and if there is not it rather protects what it has and waits for better times but both need to cycle and be in balance. The same is true for (6) altered mitochondrial function. Mitochondria produce reactive oxygen species as a result of stress which are a signal to up the cell’s defense but again too much is bad as it overwhelms the defense capabilities. And last but not least you have (7) cellular senescence or programmed cell death. If cells go bad and are beyond repair, they are made to die but too many dying cells of course are a problem all by itself.
• The third category finally are called integrative hallmarks because they lead to what you see (the phenotype) as a result of all that happened previously. They are (8) stem cell exhaustion and (9) altered cellular communication. Stem cell loss leads to trivial results such as hair loss but also more serious results such as reduced repair of muscle and bone while altered cellular communication is most prominently on display in the gradual loss of the competence of the immune system to accurately detect and destroy foreign invaders.

The Interventions – How to live longer

You might agree with me that that was rather complicated and often a bit hand-wavy especially when it comes to the „proper balance“ of the mechanisms of defense or antagonistic hallmarks. Why then do we think it is simple overall? Well, it is quite easy to make animals live longer – and while experiments in humans are a bit more ethically challenging, observational results point in the same direction as the results from animal studies.

Here is what you can do to make an animal/human live longer:

• Give them anti-aging drugs that primarily affect the nutrient-sensing pathways (metformin and rapamycin)
• Restrict their calorie intake (fasting for humans)
• Mutate single genes that are (mostly) involved in the same pathways of nutrient sensing – easier for worms that humans
• Make them exercise – easier for humans than worms

In my view, exercise is special as it speaks directly to maintaining the cycling and balance between competing systems that only appear to be antagonistic but really are synergistic in nature. Yes, a long run activates many of the same pathways that signal nutrient scarcity but then again, a strength-session activates the competing and insulin-dependent growth pathway for hypertrophy and many sessions will do both at the same time (if in different places).

The Systems View

So how do we have to think about what aging actually does from a system performance point of view.

Humans are complex systems. Complex systems are characterized by many individual components that are connected with each other and give rise to patterns to which they themselves react. An example is cars and traffic. Cars generate traffic but also react to it individually.

Humans are a complex system that maintains homeostasis or a relatively stable internal state (e.g., body temperature) despite changes in the environment (e.g., the weather). Aging can then be defined as a decrease in the dynamic capacity to return the body to its homeostatic state. If you are a masters athlete reading this, you can probably remember your younger self and how much easier it was back then to get away with a lack of sleep or a likely much junkier diet that you adhere to today. Equally, one of the differences between training masters athletes and younger athletes is that masters need a lot more recovery time (or time to return to homeostasis).

There are two important implications to this view of aging:

• First, you need to keep challenging the system to keep its own defense mechanisms up. In my view, this is why it is so important to include strength training and high intensity units (with adequate recovery) into your routine. The system is only as good as the ability to deal with external challenges to homeostasis so challenge it. Almost any acute challenge is good the same way that all danger comes from chronic exposure to disruptions of homeostasis (stress, inflammation, lack of exercise, nutrient abundance, …)
• Secondly, a complex system can break down at a thousand points and often in surprising ways which are caused by small changes to initial conditions. Here is a example from 2006 and the electrical power grid:

„Germany’s biggest power supplier said on Nov. 15 that human error was to blame for the electricity cut that plunged parts of Western Europe into darkness on November 4. E.ON said the switching-off of an electricity line over the Ems River in western Germany to allow a cruise ship to pass through, coupled with the outage of a second transmission line, „set off the domino effect which led to the temporary disconnection of the European inter-connected power grid.“

Industry News, Nov 15, 2006

If you know your weak spots, do not ignore them but pay particular attention to safeguarding the function of the entire system. If we are honest, we can probably identify some of our potential break-points simply by looking at family history.

In one of my next posts, I will discuss how to read-out the state of your system (other than getting to know and listening to your body) and its dynamic homeostatic capacity.