Deep Dive: Longevity’s Moon Landing

 

 

Just for a moment – let’s rewind time: It’s the year 1900 and no motor-operated sustained flight has ever been achieved. As Homo Sapiens we have simply accepted that we are destined for the ground. You would be called a mad-man for suggesting humans could ever take to the skies.

A mere three years later, in 1903, the Wright brothers achieved the first piloted controlled flight. It was a remarkable achievement – times changed rapidly. Even after that first flight, those that had not witnessed it refused to believe it. Absolute madness they would say, albeit only referring to a flight of 12 seconds over a distance of 120 feet. To put that in perspective – that ground-breaking flight was a shorter distance than the wingspan of a Boeing 747 today.

Even as the number of successful flights increased, many people remained in disbelief until flight became a part of our everyday lives. What once seemed impossible, suddenly became obvious quickly after it had been achieved. Oh, the benefit of hindsight.

When something has not been done before, humans simply fail to acknowledge its possibility. In 1900, you would have been shunned for even dreaming that 69 years later, humans would set foot on the moon over 200 000 miles away.

The strides that are being made in the longevity space today are comparable to that of the Wright brothers in the first decade of the 20th century. Despite truly remarkable discoveries and breakthroughs, there remains a lack of excitement. Those that do not understand the science belittle its potential, not wanting to get their hopes up. Just as they once said “Humans don’t fly, accept it”, today it has become “Humans die, accept it”.

Someday, albeit in the distant future, we will reach what I call Longevity’s Moon Landing: non-trivial increases in life expectancy or, more simply, humans living for hundreds of years.

Why do I call that day ‘Longevity’s Moon Landing’? Well, the discourse today surrounding significant life extension parallels what was seen around the turn of the 20th century on the potential for flight and space travel. The idea of human flight was by many seen as absolutely ludicrous. However, as with the actual moon landing, when Longevity’s Moon Landing is achieved, the benefit of hindsight will let us say that it was inevitable.

The best part about it? Even if Longevity’s Moon Landing happens in the distant future, it might just be possible to buy your ticket and hop on board today, so that you will still be around hundreds or even thousands of years from now. But more on that later. For now, let’s go on a journey together.

First, we need to build some background and zoom in on the details of the hottest longevity research of the last few years, and then with that knowledge, we can zoom all the way out with a new perspective on Longevity’s Moon Landing. One day, humans will live for hundreds of years.

 

Here is the route for our journey:

Part 1: Understanding Longevity

Part 2: What the hell is an epigenome?

Part 3: The demise of our epigenome

Part 4: Unsuccessfully fighting our epigenetic demise

Part 5: The trick to slowing the demise

Part 6: Reversing the damage

Part 7: Longevity’s Moon Landing

Part 8: Getting to the moon will be complicated

Part 9: What if we miss the moon? 

 

Hope you’re buckled up – because once this journey is complete, I hope you see your life in an entirely new way.

 

 

Part 1: Understanding longevity

 

Let’s take our magnifying glass, and zoom right in on the details.

 

 

Let’s start with you. And when I say you, I mean us – Homo Sapiens.

 

 

As we age, our bodies become frail, our mental capability deteriorates and eventually we die. It has become an accepted part of life. It sucks, but we acknowledge that life is good while it lasts.

But what exactly stops us from living? The answer is aging – or the process of deterioration of the body and mind over time. Today there are eight (or nine) “hallmarks” of aging that are generally accepted. Now to be clear, these are not necessarily causes of aging, but rather, they are strongly associated with aging – meaning they are likely either the reason we age, or that these are things that happen as we age. The last hallmark will be essential to our exploration today, but first, let’s briefly explore each one in layman’s terms:

Genomic instability caused by DNA damage: DNA is the code for life and resides in each of our cells.

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Our DNA contains the information that programs proteins that ultimately result in the formation of our tissues. By existing in this world, we are exposed to harmful chemicals that may result in our DNA becoming damaged. When our code of life is damaged, our body struggles to function as it should.

Attrition of telomeres: when our DNA is neatly packed for storage and replication it is in chromosomal form. At the end of these chromosomes are our telomeres which protect our chromosomes from fraying, much like an aglet to a shoelace (the plastic tips at the end).  However, each time a cell divides, we lose some aglet. After enough divisions (known as the Hayflick Limit), our chromosome is no longer protected by its aglet and begins to fray. It makes sense that this can be devastating.

Loss of healthy protein maintenance (proteostasis): proteostasis is the complex set of processes that regulate the proteins within our cells. These processes are vital to maintaining the health of our cells and hence our health too. Proteostasis stops happening when we age, and so we stop happening too.

Deregulated nutrient-sensing: nutrient-sensing is all about our cells recognizing and responding to fuel such as glucose. As we age, our cells are no longer able to recognize different nutrients and hence are not able to respond to them. The result is that cells are not able to carry out their functions. Imagine not being able to recognize the difference between broccoli and a tide pod.

Mitochondrial dysfunction: one of the first things high school biology students are taught is that the mitochondria are the powerhouse of the cell. When the mitochondria malfunction, our cells do not have the energy to function properly, hence our body cannot function as it should. Rotten mitochondria, rotten us.

Accumulation of senescent cells: senescent cells are often compared to zombies. They are dead, but they don’t lie there keeping to themselves. Instead, they refuse to truly die and send out panic signals that inflame surrounding cells. As we age, these ‘zombie cells’ accumulate. Not exactly what we need for healthy tissues.

Exhaustion of stem cells: Most cells in our body are differentiated. This means they have specialized functions in the body, for example, eye cells, skin cells, and so on. Stem cells are different. They are undifferentiated meaning that they still have the potential to develop into any type of cell. As long as these stem cells are plentiful, we can generate all the different cells needed to heal damaged tissues as we age. Unfortunately, we lose these stem cells over time and hence can no longer replenish damaged tissues.

Altered intercellular communication: our cells stop communicating properly with one another as we age. Luckily, this one seems to be a product of the other hallmarks, so it doesn’t provide a unique set of challenges.

The last one is epigenetic alterations, but trust me, we will have enough time to cover this one. When we look at these “hallmarks of aging”, they seem complex. That’s because they are, and it explains why there are numerous companies all around the world, at times working to tackle just one of the hallmarks. Progress is being made, there is no doubt about that. Be excited.

 

But why do we age?

 

 

Why we age is a complex question that has been pondered deeply for centuries. Many theories have come and gone. In the last decade, a somewhat new theory started gaining traction. The Information Theory of Aging proposed by Harvard professor and geneticist David Sinclair is quite different from theories proposed before. Sinclair is convinced that the last hallmark – epigenetic alterations – is the upstream cause of the other eight. In his world, solve one, solve all. Be very excited.

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Sinclair sees the other eight hallmarks as a consequence of these epigenetic changes. Now, this idea is seriously interesting with huge upside potential. Could this be the key to finding a cure for aging? Could this be the start of Longevity’s Moon Landing? Not so fast – we need some more background first.

 

 

Part 2: What the hell is an epigenome?

 

For far too long, the epigenome was a mysterious concept to me. I just couldn’t grasp it. However, there are a few simple analogies that helped de-mystify the epigenome for me, and today we will walk through them together. Before we get into those analogies, let’s define the epigenome.

All of our cells have the exact same DNA in them (Remember: DNA is the code for life). If that’s the case, then how can your skin cells and brain cells with the exact same DNA turn out so different? The answer to that is epigenetics. At its most fundamental level, our epigenome is a set of chemical modifications to our DNA that regulate which genes are expressed within a given cell. In other words, which aspects of our ‘code for life’ is going to be used to code for proteins.

 

The piano and the pianist

The first analogy comes straight from David Sinclair’s latest New York Times bestseller, Lifespan. Think about a pianist playing the piano at a concert. There are so many keys available on the piano to be played. The piano is our genome (our DNA sequence in the cells). With the piano sitting vacant on the stage, anyone can go up there and smash their hands around to make some noise. But that would be unpleasant. We need a pianist with a plan – the pianist is our epigenome. It chooses the right keys to play at the right time. In the case of the piano, this results in an acoustic masterpiece, and in the case of our cells and our epigenome, it’s the reason we are alive. We need something to make our DNA useful – that’s the epigenome.

 

Waddington’s epigenetic landscape

The second, and more common analogy, comes from British developmental biologist and geneticist, Conrad Waddington. Known as Waddington’s Epigenetic Landscape, the analogy asks us to imagine a handful of marbles dropped from the top of a hill. At the top of the hill, the marbles represent stem cells (we discussed these briefly in Part 1 under the hallmarks of aging). As the marbles roll down and find their resting place, each spot represents a differentiated cell type (for example, eye cell, skin cell, etc.). It is the epigenome that determines the path marbles roll down the hill and where they find their resting place.

 

 

 

Developing a basic molecular understanding

In order to truly understand the beauty of the latest research on epigenetics and aging, it’s going to be helpful to revise some basics of cellular biology. As we have mentioned, inside each of our cells there is a nucleus that contains the exact same DNA sequence. Remember this?
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Across 23 pairs of chromosomes, the DNA sequence is made up of approximately 3 billion base pairs. Now if our DNA was not folded and wrapped, each cell’s DNA would extend over 2 meters in length. Imagine the tangles!

That’s where histones come in. Histones are basic proteins found in our cells that pack and order our DNA. Our DNA wraps around the histones tightly in some parts and loosely in others. This is all driven by charges between our DNA and the histones. We will cover this in more detail shortly.

For now, the key is that there are some parts of our DNA that are exposed (not wrapped up) and other parts that are not. This pattern differs in each cell type, and in fact, largely is what determines the cell type. This pattern, how tightly or loosely our DNA wraps around histones at different parts of the DNA sequence is our epigenome. This pattern determines which proteins are encoded from that cell’s DNA.

 

 

When the DNA is exposed, it allows the DNA to be transcribed into RNA and then translated into proteins by ribosomes. These proteins determine the cell’s function and characteristics. It now becomes clear that the pattern of ‘exposed’ and ‘unexposed’ parts of the DNA determine cell types and is essential for life. That’s the epigenome!

 

 

Part 3: The demise of our epigenome

 

Unfortunately, as time goes by, our epigenome loses its mind a tad. Think about that DNA pattern – a certain pattern will code for the proteins of a skin cell but what if instead a skin cell’s epigenome starts coding for liver proteins instead? Not the end of the world. But what if a brain cell’s epigenome starts coding for a skin cell’s proteins? That’s when we land in trouble.

 

The demented pianist

Think back to the piano and the pianist. For the duration of the performance, the piano remains in top shape. There is no damage to the DNA itself (the piano). No genetic information is lost. That’s why we are able to clone a healthy organism from an old one. We are using the DNA not the epigenome.

Now as the performance begins, the pianist hits every note perfectly. A few minutes into the performance, the pianist plays an off note here and there. No big deal. Just a few cells not doing what they should be. That’s fine. This is what happens from before we are born – most of the time this is not a problem.

However, as the song progresses, more and more off-notes are played. Instead of a crescendo, the pianist plays a decrescendo. In the frontal cortex, a brain cell may start coding for skin cell proteins. The crowd notices something is off. Not long after, the pianist becomes demented. The performance is chaos. Your epigenome goes crazy and you are toast. Yup, that’s what happens to our epigenome as we age.

 

Life’s an earthquake

In Waddington’s Epigenetic Landscape, as we move along in our lives we experience earthquakes resulting in the marbles hopping out of their correct valleys. This is the equivalent of our cells losing function and identity. These earthquakes are epigenetic noise. Epigenetic noise changes the configuration of our DNA – it changes that pattern that is so important for coding the correct proteins. As the marbles start bouncing around – our cells stop performing the functions they need to and we start to age.

 

 

 

Inside our cells

What do these changes look like inside the nucleus of our cells? The pattern of DNA and histones in our nuclei start changing so that the wrong DNA sequences are read, and wrong proteins produced.

But why does this happen? As we live life we accumulate tags on our histones and DNA that alter how tightly or loosely the DNA wraps around the histones. The accumulation of these tags is influenced by a variety of different factors such as nutrition, stress, physical activity, working habits, smoking, alcohol consumption, and exposure to environmental pollutants.

The most common epigenetic alterations are acetyl and methyl groups. The acetyl tags, which are negatively charged, are slightly more straightforward to understand, so let’s focus on them. Let’s unwind some basic biochemistry. We know that opposite charges attract. The phosphate backbone of our DNA provides the DNA with a negative charge. Histones have a positive charge, which explains why the DNA so naturally wraps around the histones. Now when a negatively charged acetyl tag attaches to a histone tail, it reduces the charge of the histone (making it less positively charged), reducing the attraction between the histone and the DNA.

 

 

When this attraction is reduced, the DNA loosens – and if it loosens enough, the part of the DNA that should be wrapped up (and not read) is now vacant for RNA to read and transcribe. These exposed genes are now translated into proteins that should never have been produced in this particular cell. Our brain cell becomes somewhat of a skin cell if skin cell proteins are produced. Not good.

 

 

Part 4: Unsuccessfully fighting our epigenetic demise

 

So now we know that as we age, we accumulate acetyl tags on our histones which cause our epigenome to lose its mind. Luckily, our body has developed a mechanism to get rid of these tags in order to keep our epigenome sane and to keep us healthier for longer. This is where longevity genes come into play.

 

Longevity Genes

Longevity genes are known as genes that code for enzymes that slow down the aging process in one way or another. It is generally accepted that there are three sets of longevity genes – mTOR, AMPK, and Sirtuins. It is in our best interest to have less mTOR and more AMPK and sirtuin activity. For our purposes here, we are going to focus on the sirtuins, as the pathways in which they operate are directly linked to the epigenetic alterations and the Information Theory of Aging we have discussed.

We have 7 sirtuin genes, SIR1 to SIR7, which code for proteins Sir1 to Sir7. Sirtuins play an absolutely vital role (particularly Sir1, Sir6, and Sir 7) in controlling the epigenome. They do this by removing the acetyl tags that accumulate on our histones. The removal of acetyl tags ensures that genes that should be all wrapped up, do in fact remain silent. It should then come as no surprise that SIR stands for Silent Information Regulator. These sirtuins are all about keeping genes quiet when they are not needed. Essentially, sirtuins are like a security guard in a movie theater – silencing the audience when they need to be silenced.

 

 

Essentially, we can imagine that these sirtuins keep the marbles in their valleys, they ensure our pianist does not miss a note and ensure that our histone pattern remains constant so that our cells can continue doing their thing.

 

Sirtuins have a side-gig

The job of the mighty sirtuins doesn’t end here. They do even more. As we live life and are exposed to harmful things such as the sun’s UV rays, our body suffers more than the sunburn our eyes perceive. Chromosomes, and the DNA they contain, can often become brittle and break. Now, this is not good news for the cell. In fact, it’s one of the worst things that can happen. If the DNA break is not repaired, the cell will either mutate into a tumor or die. Luckily most of the time, this doesn’t have to happen. Fixing these breaks is the side-gig for the sirtuins.

 

 

Now, as time passes we suffer more and more DNA breaks, meaning that more and more of the sirtuins’ time and energy are dedicated to the side-gig, and not to the main affair of epigenetic regulation. What if on the way home from repairing a DNA break, the sirtuin gets lost or runs out of fuel? What if the sirtuin becomes so busy with the side job it doesn’t have time for its main call of duty?

 

 

Unfortunately, that’s exactly what happens as we live life. It is when these sirtuins no longer perform their silencing role that we see what is known as epigenetic noise. Acetyl tags accumulate – rearranging the epigenetic patterns in our cells. This means we lose cell function and identity – our marbles jump around and our pianist becomes demented. In other words, we age.

 

Running out of fuel

Our sirtuins are driven by a molecule that activates them. This molecule is one of the most important for our survival. Without it, we would probably die within a minute. Nicotinamide adenine dinucleotide (NAD) increases our sirtuin activity. It does a lot more than just fuel the sirtuins, but the fueling is the part that is valuable for our discussion today. NAD essentially serves as a fuel that our sirtuins require to successfully silence genes, contribute to DNA repair, and perform their other necessary functions. Think of it as being a motivator for the sirtuins to get everything done. The more motivation, the better.

 

 

This is all great, except for the fact that NAD levels decline over time. NAD is destroyed by an enzyme called CD38.  Whether there is potential to limit CD38 and stop the decline of NAD is being thoroughly researched for its potential to extend lifespans.

By now we should understand that the decline in NAD levels over time means that sirtuins can no longer work two jobs successfully. We suffer from epigenetic alterations – our marbles go crazy, our pianist becomes demented and our cells start doing all sorts of things. This, according to David Sinclair and his Information Theory of Aging, is why we age.

 

 

Part 5: The trick to slowing the demise

 

Although it is not yet clear if we can stop the natural decline in NAD, there may be another option. There is a large and rapidly growing body of literature on how to minimize the decrease in NAD levels by boosting them either naturally or artificially. The key is maintaining our NAD levels as time passes so that we don’t actually biologically age. How on earth is this possible?

 

What doesn’t kill you makes you live longer

We need to take a slight detour here. It will all make sense soon, I promise (I hope). Imagine, an incredibly primitive organism, one with only two types of genes. Gene A stops cells from reproducing when times are tough. Gene B codes for a silencing protein that shuts Gene A off when times are good so that the organism can reproduce. However, Gene B also has a second function, it also helps repair DNA. What is beautiful about this basic organism is that when times are tough it can hunker down, stop replicating, and repair broken DNA. This is a process so vital for survival that we find a form of “Gene B” in our cells today. It’s simple, in tough times, our cells focus on maintaining and repairing, not growing.

In short, when our bodies think we are in stressful situations (biological stress, not mental or emotional stress), our cells stop thinking about replicating but instead they focus on DNA repair. This is the central reason why we live longer if we put our bodies under an optimal level of stress during our lifetime.

How do we exert this stress? Exercise, calorie restriction, intermittent fasting, and even extreme temperatures modulate our three longevity regulators (mTOR, AMPK, and sirtuins) in the right directions. Some of these stressors increase our levels of NAD in our cells which is exactly what we need to do to ensure epigenetic regulation and hence healthy cells.

It’s all about the concept of hormesis – applying enough stress so that we reap benefits but not so much stress that we do damage to ourselves. Making yourself a little uncomfortable throughout your life may make you live longer.

 

 

But yes, we are not going to live miserable lives just to live longer. People won’t live their entire lives on only 70% of the recommended calories, or fasting for 16 hours a day, or even fasting one week per month. That’s just crazy and we will be miserable. Luckily for us, we may be able to trick our bodies into producing more NAD without these stressful endeavors.

 

The trickery

There is growing research on how to trick our bodies into thinking we are facing biological stress to activate these longevity pathways, when in fact we may just be hanging around with buddies. There is a range of molecules available today that may play a role in either directly boosting NAD, or otherwise stimulating our longevity pathways in other ways. These molecules include nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), resveratrol, pterostilbene, rapamycin, and metformin. Each of these molecules has varying ranges of evidence supporting their potential ability to activate our longevity genes and in mice, research has shown these molecules extend lifespans.

It may surprise many that these molecules, with the exception of metformin and rapamycin, are available over the counter. I would estimate that hundreds of thousands, if not millions, around the world already include some combination of these molecules into their daily lives. We will not dig into each of these molecules separately, but instead, only focus on those molecules that are known to directly boost our NAD levels, and hence fuel our sirtuins.

 

NAD boosters – what’s the deal?

NR and NMN are particularly interesting as they are what are known as NAD boosters. These molecules are the direct precursors to NAD in our cells. NR is transformed into NMN which is transformed into NAD. Although the jury is still out on which of these two molecules are superior in boosting NAD levels, it is certain that these two molecules have immense potential.

 

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The research on these NAD boosters started in 2004 and focused on yeast. Charles Brenner discovered that NR extends the lifespan of yeast cells by boosting NAD and increasing the activity of Sir2. The key is that when the sirtuins are genetically removed from an organism, there is no lifespan extension, providing support for the theory that sirtuins are the vehicle through which NAD extends lifespan. 

Since then, several studies in mice have yielded lifespans of up to 30% longer when NAD levels were increased through these NAD boosters. It’s not just about longer but better too. In studies, cognitive and sensory functions improved even in older mice.

In 2017, in a study at Harvard, giving NMN to old mice resulted in what the research team called the Great Mouse Treadmill Failure. They had to reset their entire tracking program after a treadmill broke because no one expected any mouse, let alone an elderly mouse, to run anywhere near three kilometers. This was the impact of NAD boosters.

These are, however, only studies in mice. We have not seen any proven longevity increases in humans for obvious reasons – we would all likely die before seeing any convincing results on that front. However, it has certainly been proven in several studies that these molecules are safe for humans to consume and that they boost our NAD levels.

A 2017 randomized double-blind placebo-controlled study on the effects of NR and pterostilbene showed substantial increases (40% – 90% depending on dose) in NAD levels. There is no evidence that heightened levels of NAD, one of the most important molecules for life, could be a bad thing. This may be about as good as the evidence is going to get for some time. The best thing we can hope for is more and more studies replicating these findings.

The potential of these NAD boosters is so great that there are even two companies, Chromodex and Elysium, battling out lawsuits to reign supreme in the NAD booster world. While they battle it out, there are other companies silently working on super-NAD-boosting molecules that are likely only a couple of years away. What exactly these super-boosters will entail, and how they will prove themselves as being more effective remains to be seen. However, what is clear, is that progress is rapidly being made, and we should all hope this research develops quickly.

 

Leap of faith?

Ultimately, one day you may decide to take a leap of faith without having conclusive evidence on these boosters. David Sinclair, the chief architect of all of this epigenetics and aging stuff, admits that no one really knows the truth, and anyone who claims to know the truth is either lying or is wrong. We can only go to where the best available evidence is pointing us. Many people justify their use of these molecules by citing very convincing anecdotal evidence for longevity. But that’s where it ends, anecdotal. In the words of Robert Plomin, arguably the world’s leading behavioral geneticist, “anecdotes are not data”.

However, even with the limited clinical evidence, the markets for these molecules are growing rapidly. Many people take a mixture of these supplements daily. Sinclair is no different. He and his family have a complex combination of these molecules that they take on a daily basis. Why does he take these molecules even when the evidence is not conclusive? Well, we know what happens if we don’t: we get old and frail and we die. It may just be worth it to experiment a little.

All of this may seem crazy, but it’s absolutely nothing in comparison to what may come. These molecules and research we have explored are only about slowing aging – keeping our marbles in their valleys and keeping the pianist sane. What about reversing aging? Surely that’s sci-fi? Nope, the science is around the corner.

Side note:  Epigenetic alterations occur both via histone acetylation and DNA methylation. DNA methylation is more complex than the acetyl tags we have explored, as the link between the methylation and gene activity is dependent on the context of where the methyl tag is placed. The bottom line remains the same – as we live life, we accumulate these tags on our epigenome. These tags impact gene expression, which in turn impacts cell function, and according to David Sinclair’s Information Theory of Aging, is the reason why we age.

 

 

Part 6: Reversing the damage

 

What’s about to come next in the world of longevity will sound like sci-fi. Could we really convince an already demented pianist to become sane again? Could we possibly return those marbles to the correct valleys after they have bobbled out? Could we really reverse aging? We are steadily making incredible progress in this space. In relative terms, it’s around the corner. It’s the biggest leap yet to Longevity’s Moon Landing.

It all starts with the Japanese stem cell researcher Shinya Yamanaka who won the Nobel prize in 2012 for the discovery that mature cells can be converted into stem cells. That means a cell can be ex-differentiated. In other words, a skin cell can be converted back to a stem cell which can be used to create almost any other cell type. These cells are called induced pluripotent stem cells (iPSCs) and are the equivalent of taking a marble from a valley of our landscape all the way back to the top of the hill. It now has the potential of a brand new undifferentiated cell. The genes involved with creating iPSCs (Oct 3/4, Sox2, Klf4, and c-Myc) have rightly been dubbed the Yamanaka Factors after the Nobel Laureate.

However, it is not as simple as inserting these 4 factors and reversing aging. We need differentiated cells! Without cell differentiation, we would become a pile of stem cells. This is not what we want. We only want to remove the epigenetic noise and take the cells back to their youth, because we know the underlying DNA is still in pristine condition.

Through testing of different combinations of the Yamanaka factors, and being able to turn the factors on and off, scientists have found a way to do just that. This is what scientists refer to as cellular reprogramming – taking a cell back to its younger, but still differentiated, state.

 

How do we know the Yamanaka Factors reprogram cells? 

In a 2019 paper, Yuancheng Lu, a student of David Sinclair’s at Harvard, demonstrated that the expression of three of the four Yamanaka Factors was able to reset youthful gene expression patterns in mice. Essentially these Yamanaka factors allowed for the cell to go back in time – back to its differentiated state but without the epigenetic noise. The outcome? The Yamanaka Factors allowed vision to be restored to previously blind mice. In our analogies, the controlled treatment by a specific set of the Yamanaka factors ensured the marbles returned to their correct valleys and ensured the demented pianist became sane again.

A similar process was implemented at the Salk Institute for Biological Studies, one of the world’s best biomedical research centers. The only difference was that at the Salk Institute the Yamanaka Factors were used in entire mice. The results? The researchers witnessed mice living 40% longer. The fascinating part was not merely the increase in lifespan but rather that the tissues of the animals were healthier and did not accumulate the aging hallmarks. Here’s a snippet of the work by the Salk Institute.

Although still in early stages, Sinclair notes that they are making progress every week in restoring the youthful epigenome of mice by delivering reprogramming factors. However, epigenetic reprogramming has shown potential beyond the mouse world. In 2020, a paper by Stanford University researchers concluded that after exposure to the Yamanaka Factors, old human cells could rejuvenate and become almost indistinguishable from younger cells.

Treatment with the Yamanaka factors may take some time to become abundantly available and is likely to start with a focus on treating age-related diseases when it makes its way to humans. However, if it was safe to deliver this therapy to the whole body – which long term mice studies have already shown they are – the future looks pretty brilliant.

 

The wild future

Imagine this – in our 20s, before we start declining from our peak and aging starts to play with our minds, we pop to a special doctor’s office for a week’s course of three injections that come with a specially engineered virus. This virus treatment will be incredibly similar to the ‘Yamanaka treatment’ already being used at the Salk Institute today.

This virus, which would cause a mild immune response, would carry a combination of the Yamanaka Factors and a switch. A switch is necessary to turn the factors on and off. We do not want the Yamanaka factors to permanently be on. As mentioned earlier we would become a pile of stem cells – this is no good. We simply want our epigenome to reset to its youthful state, which requires only temporary activity of the Yamanaka Factors.

At this stage after receiving the virus which contains the Yamanaka Factors, nothing changes. Ten years later, when the signs of aging begin to show, we opt to flip the switch. The switch can be flipped via a common antibiotic such as doxycycline – used to treat acne in teenagers or infections caused by mites, ticks, or lice. During the month-long course of antibiotics, our body undergoes a rejuvenation process – our demented pianist becomes sane, our marbles return to their valleys.

After a month, the antibiotic course is complete and we are essentially biologically 10 years younger. Our cells and tissues are younger and healthier. This is truly remarkable – grey hair disappearing, wrinkles fading, mental clarity returning and mobility increasing. Just imagine!

During this month in which the Yamanaka factors are being activated, we know that a backup of our epigenetic information is being restored. The patterns of our histones and DNA being wrapped and unwrapped, are being returned to their original state. In our epigenetic landscape, our marbles rewind back on their trajectory by returning to their valleys but do not ascend all the way back to the top of the hill. Our demented pianist becomes sane again but doesn’t forget how to play the piano.

We know that the age of the cells is reversed by a set of enzymes removing just the correct tags from our DNA. How these enzymes know which tags to remove remains an absolute mystery to us. This is likely to be an important next step in truly understanding our potential to reverse the aging process.

One huge question remains – how many times would the Yamanaka factors be able to reprogram our cells? Once is cool. Ten times would be the equivalent of another life. If it one day could be done again and again without failure, it would play a large part in humans living for hundreds of years – that would be Longevity’s Moon Landing.

 

 

Part 7: Longevity’s moon landing

 

Alright, we have done a lot of digging in the details, now let’s zoom all the way out and consider the big picture again – Longevity’s Moon Landing, or the potential for humans to live for hundreds of years.

 

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Something does not make sense. There is a huge gap. The first set of longevity pathways we have explored would at best increase lifespan by 30% – that’s less than 30 years! Further, the epigenetic reprogramming in mice yielded at most a 40% increase in lifespan. Albeit exciting, sirtuins and Yamanaka Factors are not getting us anywhere near Longevity’s Moon Landing. So what’s up?

 

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Longevity Escape Velocity

It all comes down to the concept of ‘Longevity Escape Velocity’. Adapted from the physics concept, Longevity Escape Velocity refers to incremental discoveries keeping us one step ahead of death. It means adding more than a year to our lifespan for every year that passes. In other words, there will come a moment at which progress in health care, biotech, and longevity research improve so radically, that each new development extends lifespan by longer than what it takes to make the next big discovery – that’s Longevity Escape Velocity.

 

 

It is due to Longevity Escape Velocity that Aubrey de Grey, a world-famous biological gerontologist, is convinced that the first person to live to 1000 is already alive. Those who dismiss him as mad, often miss his point, so I want to emphasize it again. Absolutely no one, not even the most optimistic of futurists, claims that our biological understanding today is adequate to see a human living to the age of even 200, nevermind 1000. We all agree that is bizarre. However, it is about incremental innovations keeping us one step ahead of death – and that is the key to Longevity’s Moon Landing.

If it’s not yet clear, that massive gap from earlier will be filled by Longevity Escape Velocity. It looks like this:

 

 

 

Innovating along the way

As mentioned earlier, where we are today, is comparable to pre-flight Wright brothers. The inventors at the frontier knew they were onto something special but those that didn’t understand it were dismissive. We are at the same point today, with one massive difference. We can launch to the moon, and innovate on the way there. There is no need to wait for our entire spaceship to be ready and then start the ascent. In simpler terms, there is no expectation of a silver bullet solution that will allow us to live for hundreds of years. Instead, it is all about incremental discoveries and innovations. And more importantly, it’s about staying alive until the next discovery exactly as Longevity Escape Velocity suggests.

 

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A child born today can expect to live to 2100 if we assume a life expectancy of 80. If she stimulates her longevity pathways as we have discussed, we add on another 20 years – conservative in my view, in the event that results from mice do not replicate as well in humans. This means she may live to 100, reaching the year 2120. Next, let’s say epigenetic reprogramming with the Yamanaka Factors buys her another 20 years, again a conservative estimate in the event that these two treatments may work through the same pathways. That’s an expected lifespan of 120 years, living to the year 2140.

 

 

2140 for the non-mathematicians is 120 years from now. That’s 120 years of discoveries and innovations. If we consider the innovations we have made in the last 120 years, it is truly astonishing. In 1900 we had not yet even invented plastic. Today we have genetically modified children, albeit only two.

 

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120 years is a long time – and a lot will happen. Between now and 2140, the innovations we will see will be exponentially more astonishing because innovation begets exponentially better innovation. The world of even 2100 is truly unthinkable to us today.

 

The key is Collective Magic

Although the Information Theory of Aging and the need for epigenetic regulation that we have explored today is incredibly fascinating and has immense potential, it is only one piece in a complex puzzle.

 

 

It seems a bit more underwhelming now doesn’t it…

As with the moon landing back in 1969, there is not only one group of people working on this goal, nor is there only one way in which it can be achieved. Instead, there are hundreds of thousands of scientists in some form dedicating their lives to different branches of research that all tie into the same goal. This hugely increases our chances of success. Once we make a breakthrough, it is generally shared with the world, so that the wheel does not need to be invented again – one person’s discovery opens up doors for the entire field. So what are some other exciting fields that may play a role in Longevity’s Moon Landing?

 

 

These technologies or sub-fields are only a handful of the total work that is being done. They each have their own story and scientific explanation. Each of these innovations will no doubt play a role in Longevity’s Moon Landing – let’s briefly explore them:

Nanorobotics – An exciting emerging field that involves, as the name would suggest, robots at the scale of a nanometer. A nanometer is one-billionth of a meter – so these robots would be tiny. In fact, so tiny that they would be able to repair damage at the cellular level in our bodies. As cellular damage is one of the greatest causes of aging, the potential for nanobots in delaying and reversing aging is huge.

Genetic Editing – As we discussed a while back, humans have what are known as longevity genes that may help us live longer. However, at the same time, there may be genes with the opposite effect. What if we were to knock-out genes that had the effect of shortening our lifespans? In the case of the roundworm, or C. elegans, knocking out just two specific genes led to a 5-fold increase in lifespan. Although likely to be substantially more complex in humans, the potential for extending lifespans through genetic editing is huge.

Tissue engineering – As we age, our organs slowly start to lose function. Far too often a mere single faulty organ leads to death. With the advancements in tissue engineering, the potential to grow replacement organs in a lab is right around the corner. A replacement organ will not buy you decades in lifespan, but it may just buy you the few additional years you need to benefit from another new advancement.

Precision medicine – The advancement of artificial intelligence and machine learning will drive the rise of precision medicine. Precision medicine as the name describes refers to medications and treatments specifically tailored for your individual needs whether it be based on your medical history, genetic sequence, or other environmental factors. Precision medicine will as far as is possible ensure that when you need a treatment, the correct treatment will be given. Precision medicine is likely to add some years to the human lifespan but could turn out to be more important to our healthspan.

Senolytics – Right in the beginning we discussed that senescent cells are cells that have deteriorated and start to poison other cells around them, hence playing a role in aging. Senolytics is at its core the destruction of these senescent cells. Unity Biotechnology, a NASDAQ listed biotech startup, focuses on drugs that target senescent cells. In mice, such drugs have shown a lifespan and healthspan extension of 35%. The most exciting part? Some of Unity’s first products are already in phase 1 clinical trials.

New drug discovery – As the field of quantum mechanics emerges and gains traction, so will our ability to discover new pharmaceutical drugs. Quantum computing has special properties giving it the potential to simulate molecules and molecular processes in ways that a standard computer cannot. Therefore, as more and more labs get hold of quantum computing power, both the quality and quantity of new drugs in the pipeline should accelerate.

General wellbeing – Although not an innovation, general wellbeing cannot be ignored. General wellbeing includes diet, sleep, exercise, and avoiding carcinogens. In my view, general wellbeing is less about extending lifespan than it is about not actively shortening it. However, in the world of Longevity Escape Velocity, the outcomes are equally important: stay alive and healthy for as long as possible to maximize the chance you have to benefit from biomedical advancements.

I’m hoping that by now you share the excitement of the field of longevity with me. If these exciting bio-technologies only live up to half of their potential, and we make literally not a single new discovery beyond these – we would likely buy another few decades. That’s not bad. Although as we have explored, innovation begets innovation, and it’s unlikely that as Homo Sapiens we would stop at another few decades. Eventually, via incremental innovations, we are going to see humans thriving at hundreds of years of age, and that would be Longevity’s Moon Landing.

 

Societal transformation

How exactly Longevity’s Moon Landing will unfold in society is not predetermined, but instead will be our duty to shape. Firstly, we will need to grapple with questions on accessibility and equity, as is the case with most new discoveries and inventions. Further down the line, we will need to grapple with questions on food, pollution, urban planning, representative democracy, and the reshaping of the conventional career trajectory.

Long before we grapple with these questions, we will need to drive the necessary innovations needed to make Longevity’s Moon Landing a reality. Regardless of how optimistic I am, it’s not inevitable and won’t be straightforward. In fact, it’s going to be darn complicated.

 

 

Part 8: Getting to the moon will be complicated

 

 

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There is a lot to be excited about, but achieving significant life extension will be no walk in the park. The body is incredibly complicated, hence getting the body to live hundreds of years will likely be complicated too. We will consistently be dealing with complex biological systems, where a tweak here, can cause an unintended consequence there. There can be positive, or negative feedback mechanisms making our research and treatments all the more difficult. Even when we think we may have found a silver bullet, there will be more to it.

Let’s go back to Sinclair’s Information Theory of Aging. Even these relatively well understood and described pathways are more complicated than the aspects we have highlighted and explored today. It appears to be pretty clear that epigenetic alterations are an upstream cause of most, if not all, of the hallmarks of aging. However, I would challenge the idea that it is the only upstream cause. What if there were two or more upstream sources of our undoing?

 

 

This would mean that more discoveries would need to be made sooner along the way in order to keep death at bay. With all those other fields swiftly making discoveries and improving their technologies, we should manage.

However, what if there was a feedback loop between these upstream causes and hallmarks? That would make things even more complicated.

 

 

Well unfortunately we live in a complicated world. It appears as if at least one of these feedback loops exist. Right in the beginning, we explored that senescent cells are one of the hallmarks of aging. In part 4, we discussed how a chemical called CD38 destroys NAD hence leading to a decline in sirtuin activity as we age. This decline in sirtuin activity in part leads to epigenetic alterations. It turns out that these senescent cells are one of the biggest producers of CD38. There is some form of a feedback loop.

 

 

Even though such feedback loops make the research far more complicated, this too is land for opportunity, as destroying senescent cells, the producer of CD38, would lead to higher NAD levels and more longevity pathway activation.

This is just one example of how the outcomes even only within the Information Theory of Aging are not as straightforward as we would like them to be. Every one of the innovations we explored earlier will come with its own set of hurdles such as this one. That is why it is so important that there are hundreds of thousands of the world’s greatest minds working on this goal simultaneously.

The beauty of Longevity Escape Velocity’s incremental innovations is that we do not have all of our eggs in one basket – but instead if one technology does not live to its full potential, there are others that will make up for it.

Regardless of my optimism, I do not have a crystal ball to see into the future. Regardless of how likely I believe Longevity’s Moon Landing to be, I do not ignore the possibility that I could be wrong. However, I believe that even if I am wrong, and we never achieve significant life-extension, there is still more than enough to be excited about.

 

 

Part 9: What if we miss the moon? 

 

 

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What if we miss the moon and never achieve non-trivial extensions to human lifespan? What if there is an age beyond which we simply could not reach? Unfortunately, it may be the case. Today there are around 550,000 people older than 100, but only about 500 supercentenarians, individuals older than 110. It is as if there is a steep cliff at 110 and we simply fall off.

 

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Even if this were the case, there is still reason to be optimistic about these latest scientific findings. Longevity research is not only about keeping us alive, but about keeping us healthier so it’s fun to be alive. It’s not only about living longer but also about living better.

What if we were to maintain mobility and mental clarity until our 110th birthday, and simply declined and fell off the cliff within a period of 6 months instead of a slow, painful, humiliating decline over 30 years. We would be able to play sports late into life, spend time with our great-grandchildren, and redefine what old-age meant.

 

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Living in the second of these two worlds where we would continue to truly live life right to the end would be game-changing. It would entirely change the way we plan our lives. A significant increase in our healthspan is certainly not bad for a worst outcome scenario. It’s about our healthspan, not our lifespan after all.

 

Final thoughts

Those that are interested in healthspan or lifespan extensions can start today. Start by doing the obvious: living a healthy lifestyle. Make sure you eat well, exercise, and prioritize sleep. However, that’s only one piece to the puzzle. You can also put your body under stress, or trick it into thinking you are. Your cells will hunker down, repair any damage, silence genes, and science says, you are likely to live longer.

We start aging the day we are born so longevity research is not just relevant for the elderly among us, but rather for everyone. In fact, there is evidence that there is a compounding effect – the earlier we start looking after ourselves and boosting our longevity pathways, the better.

There certainly is a lot for us to be optimistic about if this last decade of research is anything to go by. I guess we could say humans are doing pretty decently. However, as we have seen countless times before – humans don’t settle at decent. As a species, we will continue to strive for more, and as we have also seen countless times before, we generally get more.

In the coming decades, we will see exponential technologies converging on the field of longevity in ways our wildest dreams cannot imagine. As our understanding continues to develop at an exponential pace, we will steadily make our way towards Longevity’s Moon Landing.

Longevity’s Moon Landing will happen – generations of humans will eventually live for hundreds of years. The most important question remains: will it be us?

 


 

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