A scientist at the forefront of ageing research explains what we are learning, what can be done now, and what may be possible in the near future, to help us all live longer.
25 February 2021
I had never heard of David Sinclair until 22 April 2020 when he was a guest on the podcast “Exponential View with Azeem Azhar.”
You can listen to that 48-minute podcast on any of the main podcast providers. I have provided a link to the recording on Google podcasts.
After listening to the podcast, I immediately bought this book. My approach with books costing £20, or less, is to regard buying the book as equivalent to “buying the option to read it.” I know that if I do not buy the book immediately, I will forget about it.
Much more significant is that within a few weeks of the book arriving, I read it.
Because I buy far more books than I can read, I often allow decades to elapse between buying a book and reading it. However, given the subject matter and my age, it seemed ludicrous to buy a book about slowing or reversing ageing, and then delaying reading it for many years!
After I had read the book, I gave it to my wife to read. She also read it promptly.
The book's message is very simple. Scientific knowledge has advanced to the stage where we are starting to understand the process of ageing itself, and how ageing might be slowed down or reversed.
Even if ageing can be eliminated, humans will not live forever. What "no ageing" would mean is that our chance of dying from all causes (accident, murder, infectious diseases etc.) would be constant in each year of our lives.
At present, ageing means that your chance of dying next year is much higher if you are aged 80 than if you are aged 20.
There are many frauds who claim they can stop ageing, peddling all kinds of magic cures, especially with the assistance of the internet.
The author is the exact opposite. David Sinclair, PhD, AO is a Professor in the Department of Genetics at Harvard Medical School. That is all you need to know to appreciate that he is a top-level scientist.
The AO after his name tells you that he has received the Order of Australia, an order of chivalry established on 14 February 1975 by Elizabeth II, Queen of Australia, on the recommendation of the Australian government, to recognise Australian citizens and other persons for achievement or meritorious service.
Matthew D. LaPlante is an associate professor of journalistic writing at Utah State University. A selection of his work as a journalist, radio host, author, and co-writer can be found at www.mdlaplante.com
The book comprises 310 pages + 94 pages of notes, index etc. It has 9 chapters plus a conclusion.
As the chapter headings are not particularly informative without the book, I have not listed them, except where I quote from the book to illustrate its style, communication quality, and scientific depth.
In this chapter, the author explains the essence of his information theory of ageing.
He takes us back to the beginnings of life on Earth.
“Day in and day out, the microscopic, fragile life-forms begin to involve into more advanced forms, spreading into rivers and lakes.
Along comes a new threat: a prolonged dry season. The level of the scum-covered lakes has dropped by a few feet during the dry season, but the lakes have always filled up again as the rains returned. But this year, thanks to unusually intense volcanic activity on the other side of the planet, the annual rains don’t fall as they usually do and the clouds pass on by. The lakes dry up completely.
What remains is a thick, yellow crust covering the lake beds. It is an ecosystem defined not by the annual waxing and waning of the waters but by a brutal struggle for survival. And more than that: it is a fight for the future – because the organisms that survive will be the progenitors of every living thing to come: archaea, bacteria, fungi, plants, and animals.
Within this dying mass of cells, each scrapping for and scraping by on the merest minimums of nutrients and moisture, each one doing whatever it can to answer the primal call to reproduce, there is a unique species. Let’s call it Magna superstes. That’s Latin for “great survivor.”
It does not look very different from the other organisms of the day, but M. superstes has a distinct advantage: it has evolved a genetic survival mechanism.
There will be far more complicated evolutionary steps in the eons to come, changes so extreme that entire branches of life will emerge. These changes – the products of mutations, insertions, gene rearrangements, and the horizontal transfer of genes from one species to another – will create organisms with bilateral symmetry, stereoscopic vision, and even consciousness.
By comparison, this early evolutionary step looks, at first, to be rather simple. It is a circuit. A gene circuit.
The circuit begins with gene A, a caretaker that stops cells from reproducing when times are tough. This is key, because on early planet Earth, most times are tough. The circuit also has a gene B, which encodes for a “silencing” protein. This silencing protein shuts gene A off when times are good, so the cell can make copies of itself when, and only when, it and its offspring will likely survive.
The genes themselves aren’t novel. All life in the lakes has these two genes. But what makes M. superstes unique is that the gene B silencer has mutated to give it a second function: it helps repair DNA. When the cell’s DNA breaks, the silencing protein encoded by gene B moves from gene A to help with DNA repair, which turns on gene A. This temporarily stops all sex and reproduction until the DNA repair is complete.
This makes sense, because while DNA is broken, sex and reproduction are the last things an organism should be doing. In future multicellular organisms, for instance, cells that fail to pause while fixing a DNA break will almost certainly lose genetic material. This is because DNA is pulled apart prior to cell division from only one attachment site on the DNA, dragging the rest of the DNA with it. If DNA is broken, part of a chromosome will be lost or duplicated. The cells will likely die or multiply uncontrollably into a tumor.
With a new type of gene silencer that repairs DNA, too, M. superstes has an edge. It hunkers down when its DNA is damaged, then revives. It is superprimed for survival.
And that’s good, because now comes yet another assault on life. Powerful cosmic rays from a distant solar eruption are bathing the Earth, shredding the DNA of all the microbes in the dying lakes. The vast majority of them carry on dividing as if nothing has happened, unaware that their genomes have been broken and that reproducing will kill them. Unequal amounts of DNA are shared between mother and daughter cells, causing both to malfunction. Ultimately, the endeavor is hopeless. The cells all die, and nothing is left.
Nothing, that is, but M. superstes. For as the rays wreak their havoc, M. superstes does something unusual: thanks to the movement of protein B away from gene A to help repair the DNA breaks, gene A switches on and the cells stop almost everything else they are doing, turning their limited energy toward fixing the DNA that has been broken. By virtue of its defiance of the ancient imperative to reproduce, M. superstes has survived.
When the latest dry period ends and the lakes refill, M. superstes wakes up. Now it can reproduce. Again and again it does so. Multiplying. Moving into new biomes. Evolving. Creating generations upon generations of new descendants.
They are our Adam and Eve.
Like Adam and Eve, we don’t know if M. superstes ever existed. But my research over the past twenty-five years suggests that every living thing we see around us today is a product of this great survivor, or at least a primitive organism very much like it. The fossil record in our genes goes a long way to proving that every living thing that shares this planet with us still carries this ancient genetic survival circuit, in more or less the same basic form. It is there in every plant. It is there in every fungus. It is there in every animal.
It is there in us.
I propose the reason this gene circuit is conserved is that it is a rather simple and elegant solution to the challenges of a sometimes brutish and sometimes bounteous world that better ensures the survival of the organisms that carry it. It is, in essence, a primordial survival kit that diverts energy to the area of greatest need, fixing what exists in times when the stresses of the world are conspiring to wreak havoc on the genome, while permitting reproduction only when more favorable times prevail.
And it is so simple and so robust that not only did it ensure life’s continued existence on the planet, it ensured that Earth’s chemical survival circuit was passed on from parent to offspring, mutating and steadily improving, helping life continue for billions of years, no matter what the cosmos brought, and in many cases allowing individuals’ lives to continue for far longer than they actually needed to.
The human body, though far from perfect and still evolving, carries an advanced version of the survival circuit that allows it to last for decades past the age of reproduction. While it is interesting to speculate why our long lifespans first evolved – the need for grandparents to educate the tribe is one appealing theory – given the chaos that exists at the molecular scale, it’s a wonder we survive thirty seconds, let alone make it to our reproductive years, let alone reach 80 more often than not.
But we do. Marvelously we do. Miraculously we do. For we are the progeny of a very long lineage of great survivors. Ergo, we are great survivors.
But there is a trade-off. For this circuit within us, the descendant of a series of mutations in our most distant ancestors, is also the reason we age.
And yes, that definite singular article is correct: it is the reason.”
In the concluding part of this chapter, the author further explains his theory of ageing.
“The Information Theory of Ageing starts with the primordial survival circuit we inherited from our distant ancestors.
Over time, as you might expect, the circuit has evolved. Mammals, for instance, don’t have just a couple of genes that create a survival circuit, such as those that first appeared in M. superstes. Scientists have found more than two dozen of them within our genome. Most of my colleagues call these “longevity genes” because they have demonstrated the ability to extend both average and maximum lifespans in many organisms. But these genes don’t just make life longer, they make it healthier, which is why they can also be thought of as “vitality genes.”
Together, these genes form a surveillance network within our bodies, communicating with one another between cells and between organs by releasing proteins and chemicals into the bloodstream, monitoring and responding to what we eat, how much we exercise, and what time of day it is. They tell us to hunker down when the going gets tough, and they tell us to grow fast and reproduce fast when the going gets easier.
And now that we know these genes are there and what many of them do, scientific discovery has given us an opportunity to explore and exploit them; to imagine their potential; to push them to work for us in different ways. Using molecules both natural and novel, using technology both simple and complex, using wisdom both old and new, we can read them, turn them up and down, and even change them altogether.
The longevity genes I work on are called “sirtuins,” named after the yeast SIR2 gene, the first one to be discovered. There are seven sirtuins in mammals, SIRT1 to SIRT7, and they are made by almost every cell in the body. When I started my research, sirtuins were barely on the scientific radar. Now this family of genes is at the forefront of medical research and drug development.
Descended from gene B in M. superstes, sirtuins are enzymes that remove acetyl tags from histones and other proteins and, by doing so, change the packaging of the DNA, turning genes off and on when needed. These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair. After a few billion years of advancement since the days of yeast, they have evolved to control our health, our fitness, and our very survival. They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD. As we will see later, the loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.
Trading reproduction for repair, the sirtuins order our bodies to “buckle down” in times of stress and protect us against the major diseases of ageing: diabetes and heart disease, Alzheimer’s disease and osteoporosis, even cancer. They mute the chronic, overactive inflammation that drives diseases such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis, and asthma. They prevent cell death and boost mitochondria, the power packs of the cell. They go to battle with muscle wasting, osteoporosis, and macular degeneration. In studies on mice, activating the sirtuins can improve DNA repair, boost memory, increase exercise endurance, and help the mice stay thin, regardless of what they eat. These are not wild guesses as to their power; scientists have established all of this in peer-reviewed studies published in journals such as Nature, Cell, and Science.
And in no small measure, because sirtuins do all of this based on a rather simple program – the wondrous gene B in the survival circuit – they’re turning out to be more amenable to manipulation than many other longevity genes. They are, it would appear, one of the first dominoes in the magnificent Rube Goldberg machine of life, the key to understanding how our genetic material protects itself during times of adversity, allowing life to persist and thrive for billions of years.
Sirtuins aren’t the only longevity genes. Two other very well studied sets of genes perform similar roles, which also have been proven to be manipulable in ways that can offer longer and healthier lives.
One of these is called target of rapamycin, or TOR, a complex of proteins that regulates growth and metabolism. Like sirtuins, scientists have found TOR – called mTOR in mammals – in every organism in which they've looked for it. Like that of sirtuins, mTOR activity is exquisitely regulated by nutrients. And like the sirtuins, mTOR can signal cells in stress to hunker down and improve survival by boosting such activities as DNA repair, reducing inflammation caused by senescent cells, and perhaps its most important function, digesting old proteins.
When all is well and fine, TOR is a master driver of cell growth. It senses the amount of amino acids that is available and dictates how much protein is created in response. When it is inhibited, though, it forces cells to hunker down, dividing less and reusing old cellular components to maintain energy and extend survival – sort of like going to the junkyard to find parts with which to fix up an old car rather than buying a new one, a process called autophagy. When our ancestors were unsuccessful in bringing down a woolly mammoth and had to survive on meager rations of protein, it was the shutting down of mTOR that permitted them to survive.
The other pathway is a metabolic control enzyme known as AMPK, which evolved to respond to low energy levels. It has also been highly conserved amongst species and, as with sirtuins and TOR, we have learned a lot about how to control it.
These defense systems are all activated in response to biological stress. Clearly, some stresses are simply too great to overcome – step on a snail, and its days are over. Acute trauma and uncontrollable infections will kill an organism without aging that organism. Sometimes the stress inside a cell, such as a multitude of DNA breaks, is too much to handle. Even if the cell is able to repair the breaks in the short term without leaving mutations, there is information loss at the epigenetic level.
Here’s the important point: there are plenty of stressors that will activate longevity genes without damaging the cell, including certain types of exercise, intermittent fasting, low-protein diets, and exposure to hot and cold temperatures (I discuss this in chapter 4). That’s called hormesis. Hormesis is generally good for organisms, especially when it can be induced without causing any lasting damage. When hormesis happens, all is well. And, in fact, all is better than well, because the little bit of stress that occurs when the genes are activated prompts the rest of the system to hunker down, to conserve, to survive a little longer. That’s the start of longevity.
Complementing these approaches are hormesis-mimicking molecules. Drugs in development and at least two drugs on the market can turn on the body’s defenses without creating any damage. It’s like making a prank call to the Pentagon. The troops and the Army Corps of Engineers are sent out, but there’s no war. In this way, we can mimic the benefits of exercise and intermittent fasting with a single pill (I discuss this in chapter 5).
Our ability to control all of these genetic pathways will fundamentally transform medicine and the shape of our everyday lives. Indeed, it will change the way we define our species.
And yes, I realize how that sounds. So let me explain why.”
The book as a whole has made a great impact on me. However, this chapter contains the story that hit me more strongly than anything else.
“Regular exercise “is a commitment,” says Benjamin Levine, a professor at the University of Texas. “But I tell people to think of exercise as part of personal hygiene, like brushing their teeth. It should be something we do as a matter of course to keep ourselves healthy.”
I’m sure he’s right. Most people would exercise a lot more if going to the gym were as easy as brushing their teeth.
Perhaps one day it will be. Experiments in my lab indicates it is possible.
“David, we’ve got a problem,” a postdoctoral researcher named Michael Bonkowski told me one morning in the fall of 2017 when I arrived at the lab.
That’s seldom a good way to start the day.
“Okay,” I said, taking a deep breath and preparing for the worst. “What is it?”
“The mice,” Bonkowski said. “They won’t stop running.”
The mice he was talking about were 20 months old. That’s roughly the equivalent of a 65-year-old human. We had been feeding them a molecule intended to boost the levels of NAD, which we believed would increase the activity of sirtuins. If the mice were developing a running addiction, that would be a very good sign.
“But how can that be a problem?” I said. “That’s great news!”
“Well,” he said, “it would be if not for the fact that they’ve broken our treadmill.”
As it turned out, the treadmill tracking program had been set up to record a mouse running for only up to 3 kilometers. Once the old mice got to that point, the treadmill shutdown. “We’re going to have to start the experiment again,” Bonkowski said.
It took a few moments for that to sink in.
A thousand meters is a good, long run for a mouse. Two thousand meters – five times round a standard running track – would be a substantial run for a young mouse.
But there’s a reason why the program was set to three kilometers. Mice simply don’t run that far. Yet these elderly mice were running ultra-marathons.
Why? One of our key findings, in a study we published in 2018, was that when treated with an NAD-boosting molecule that activated the SIRT1 enzyme, the elderly mice’s endothelial cells, which line the blood vessels, were pushing their way into areas of the muscle that weren’t getting very much blood flow. New tiny blood vessels, capillaries, were formed, supplying badly needed oxygen, removing lactic acid and toxic metabolites from muscles, and reversing one of the most significant causes of frailty in mice and in humans. That was how these old mice suddenly became such mighty marathoners.
Because the sirtuins had been activated, the mice’s epigenomes were becoming more stable. The valley walls were growing higher. Gravity was growing stronger. And Waddington’s marbles were being pushed back to where they belonged. The lining of the capillaries was responding as if the mice were exercised. It was an exercise mimetic, the first of its kind, and a sure sign that some aspects of age reversal are possible.
We still don’t know everything about why this happens. We don’t know what sorts of molecules will work best for activating sirtuins or in what doses. Hundreds of different NAD precursors have been synthesized, and there are clinical trials in progress to answer that question and more.
But that doesn’t mean we need to wait to take advantage of all that we’ve learned about engaging the epigenetic survival circuit and living longer and healthier lives. We don’t need to wait to take advantage of the Information Theory of Ageing.”
I will never forget the mice who would not stop running!
There is a section in this book which transformed my understanding of the benefits of exercise. Obviously, most of us know of the benefits of exercise for heart and lungs. However, exercise is far more important than that.
What I had not known before is that exercise's benefits are felt at the cellular level, indeed at the chromosomal level with its effect on your telomeres.
“Yes, exercise improves blood flow. Yes, it improves lung and heart health. Yes, it gives us bigger, stronger muscles. But more than any of that – and indeed, what is responsible for much of that – is a simple thing that happens at a much smaller scale: the cellular scale.
When researchers studied the telomeres in the blood cells of thousands of adults with all sorts of different exercise habits, they saw a striking correlation: those who exercised more had longer telomeres. And according to one study funded by the Centers for Disease Control and Prevention and published in 2017, individuals who exercise more – the equivalent of at least a half hour of jogging five days a week – have telomeres that appear to be nearly a decade younger than those who live a more sedentary life. But why would exercising delay the erosion of telomeres?
There is a difference between a leisurely walk and a brisk run, however. To engage our longevity genes fully, intensity does matter. Mayo Clinic researchers studying the effects of different types of exercise on different age groups found that although many forms of exercise have positive health effects, it’s high-intensity interval training (HIIT) – the sort that significantly raises your heart and respiration rates – that engages the greatest number of health-promoting genes, and more of them in older exercisers.
You’ll know you are doing vigorous activity when it feels challenging. Your breathing should be deep and rapid at 70 to 85 percent of your maximum heart rate. You should sweat and be unable to say more than a few words without pausing for breath. This is the hypoxic response, and it’s great for inducing just enough stress to activate your body’s defenses against ageing without doing permanent harm.
We’re still working to understand what all of the longevity genes do, but one thing is already clear: many of the longevity genes that are turned on by exercise are responsible for the health benefits of exercise, such as extending telomeres, growing new microvessels that deliver oxygen to cells, and boosting the activity of mitochondria, which burn oxygen to make chemical energy. We’ve known for a long time that these bodily activities fall as we age. What we also know now is that the genes most impacted by exercise-induced stress can bring them back to the levels associated with youth. In other words: exercise turns on the genes to make us young again at a cellular level.”
The author is quite clear that increased human longevity is coming, regardless of how sceptical some people may be. Being directly involved with developing the science, he knows what is happening and what is achievable.
In this chapter he discusses the many social and political implications. His overall message is positive and encouraging, which is also how I see it.
If most people can live longer and healthier lives, they can achieve so much more, and work so much longer. Longevity is something to welcome rather than to fear.
The author is quite open about sharing with the reader what he does personally, while making it clear that he is not being prescriptive.
That text is worth repeating here.
“Save for “Eat fewer calories,” “Don’t sweat the small stuff,” and “Exercise,” I don’t give medical advice. I’m a researcher, not a medical doctor; it’s not my place to tell anyone what to do, and I don’t endorse supplements or other products.
I don’t mind sharing what I do, though, albeit with some caveats:
- This isn’t necessarily, or even likely, what you should do.
- I have no idea if this is even the right thing for me to be doing.
- While human trials are underway, there are no treatments or therapies for aging that have been through the sort of rigorous long-term clinical testing that would be needed to have a more complete understanding of the wide range of potential outcomes.
People often wonder, when I tell them things like this, why on earth I would subject myself to the potential for unexpected and adverse side effects or even the possibility – low though it seems to be – that I could expedite my own demise.
The answer is simple: I know exactly what is going to happen to me if I don’t do anything at all – and it’s not pretty. So what do I have to lose?
And so, with all that on the table, what do I do?
- I take 1 gram (1,000 mg) of NMN every morning, along with 1 gram of resveratrol (shaken into my home-made yogurt) and 1 gram of metformin.
- I take a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin.
- I strive to keep my sugar, bread, and pasta intake as low as possible. I gave up desserts at age 40, though I do steal tastes.
- I try to skip one meal a day or at least make it really small. My busy schedule almost always means that I miss lunch most days of the week.
- Every few months, a phlebotomist comes to my home to draw my blood, which I have analyzed for dozens of biomarkers. When my levels of various markers are not optimal, I moderate them with food or exercise.
- I try to take a lot of steps every day and walk upstairs, and I go to the gym most weekends with my son, Ben; we lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool.
- I eat a lot of plants and try to avoid eating other mammals, even though they do taste good. If I work out, I will eat meat.
- I don’t smoke. I try to avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans.
- I try to stay on the cool side during the day and when I sleep at night.
- I aim to keep my body weight or BMI in the optimal range for healthspan, which for me is 23 to 25.
About fifty times a day I’m asked about supplements. Before I answer, let me say that I never recommend supplements, I don’t test or study products, nor do I endorse them; if you see a product implying that I do, it’s certainly a scam. Supplements are far, far less regulated than medicines, so if I do take a supplement, I looked for a large manufacturer with a good reputation, seek highly pure molecules (more than 98 percent is a good guide), and look for “GMP” on the label, which means the product was made under “good manufacturing practices.” Nicotinamide riboside, or NR, is converted to NMN, so some people take NR instead of NMN because it is cheaper. Cheaper still are niacin and nicotinamide, but they don’t seem to raise NAD levels as NMN and NR do.”
The author also has a website to accompany the book. That contains additional material including answers to some questions that have been asked. It is www.lifespanbook.com
It is very simple.
Reading this book, and then acting upon it by changing your lifestyle, should make you live a longer and healthier life.
With my scientific education, I found the book very straightforward to understand, even though at university I read Mathematics rather than Biochemistry. The book should be readily understood by most educated people, regardless of their existing scientific knowledge.
I already had a relatively healthy lifestyle.
As explained on my page “How to control your weight” I am careful about my diet which is calorie controlled, low in sugars and starches, and almost entirely plants and fish, with only small amounts of meat. (I average one meat meal per week.)
I already took a number of supplements additional to my medical prescription of 40 mg of Atorvastatin and 75 mg of slow-release aspirin daily. In the interests of full disclosure, I have listed them below:
When in London, I normally walk very briskly, and always walk up and down the escalators in the London Underground.
Despite that, I have made the following changes.
For about 20 years I have owned a cross trainer which occupies space in our bedroom but for many years has been used only for hanging clothes! After reading the book, I have made it a discipline to use the cross trainer for 30 minutes every day, and have been slowly increasing the intensity level as my body adjusts to each level.
I have increased my nightly sleep target by 30 minutes.
I have copied the author by taking 1000 mg of resveratrol and 1000 mg of NMN every day.
I phased this in since I wanted to check for possible adverse reactions. Accordingly, I began with just the 1000 mg of resveratrol. A few months later, when I was happy that my body was not objecting to the resveratrol, I added 500 mg of NMN per day, and continued at that level for three months before doubling it to 1000 mg of NMN per day.
Of course, it could just be the placebo effect, but I do feel better for having added these supplements to the ones I was already taking.
I have not done anything yet. However, I intend to test out my ability to do this for one or two days each week.
Obviously during Ramadan one goes for a long period of time every 24 hours without eating.
While tracking down the podcast mentioned above, I came across a talk that David Sinclair gave at Google including answering questions from Google's highly intelligent staff.
You can watch it below, and I recommend it, although obviously it is no substitute for reading the book.