Lifespan: The Revolutionary Science of Why We Age—and Why We Don't Have To

by David A. Sinclair

There are few people who have studied death as intimately as the Holocaust documentary filmmaker Claude Lanzmann. And his assessment—indeed, his warning—is chilling. “Every death is violent,” he said in 2010. “There is no natural death, unlike the picture we like to paint of the father who dies quietly in his sleep, surrounded by his loved ones. I don’t believe in that.”1

Unique insight

What’s the upward limit? I don’t think there is one. Many of my colleagues agree.14 There is no biological law that says we must age.15 Those who say there is don’t know what they’re talking about. We’re probably still a long way off from a world in which death is a rarity, but we’re not far from pushing it ever farther into the future.

IMAGINE A PLANET ABOUT THE SIZE OF OUR OWN, ABOUT AS FAR FROM ITS STAR, rotating around its axis a bit faster, such that a day lasts about twenty hours. It is covered with a shallow ocean of salty water and has no continents to speak of—just some sporadic chains of basaltic black islands peeking up above the waterline. Its atmosphere does not have the same mix of gases as ours. It is a humid, toxic blanket of nitrogen, methane, and carbon dioxide. There is no oxygen. There is no life. Because this planet, our planet as it was 4 billion years ago, is a ruthlessly unforgiving place. Hot and volcanic. Electric. Tumultuous. But that is about to change. Water is pooling next to warm thermal vents that litter one of the larger islands. Organic molecules cover all surfaces, having ridden in on the backs of meteorites and comets. Sitting on dry, volcanic rock, these molecules will remain just molecules, but when dissolved in pools of warm water, through cycles of wetting and drying at the pools’ edges, a special chemistry takes place.1 As the nucleic acids concentrate, they grow into polymers, the way salt crystals form when a seaside puddle evaporates. These are the world’s first RNA molecules, the predecessors to DNA. When the pond refills, the primitive genetic material becomes encapsulated by fatty acids to form microscopic soap bubbles—the first cell membranes.2 It doesn’t take long, a week perhaps, before the shallow ponds are covered with a yellow froth of trillions of tiny...

A nice description of the early precursive cell at the heart of our lineage. All hail the protocell.

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 lake 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.

Genetic preservation akin to hibernation, though substantially less effective in terms of respiration and anti-oxidation.

myopia

Word

These so-called oncogenes shifted the entire paradigm of cancer research. Pharmaceutical developers now had targets to go after: the tumor-inducing proteins encoded by genes, such as BRAF, HER2, and BCR-ABL.

Cancer genes

When it comes to longevity, they agreed, individuals look out for themselves. Driven by their selfish genes, they press on and try to breed for as long and as fast as they can, so long as it doesn’t kill them. (In some cases, however, they press on too much, as my great-grandfather Miklós Vitéz, a Hungarian screenwriter, proved to his bride forty-five years his junior on their wedding night.) If our genes don’t ever want to die, why don’t we live forever?

Having capitalized on its relatively large brain and a thriving civilization to overcome the unfortunate hand that evolution dealt it—weak limbs, sensitivity to cold, poor sense of smell, and eyes that see well only in daylight and in the visible spectrum—this highly unusual species continues to innovate. It has already provided itself with an abundance of food, nutrients, and water while reducing deaths from predation, exposure, infectious diseases, and warfare. These were all once limits to its evolving a longer lifespan. With them removed, a few million years of evolution might double its lifespan, bringing it closer to the lifespans of some other species at the top of their game. But it won’t have to wait that long, nowhere near that. Because this species is diligently working to invent medicines and technologies to give it the robustness of a much longer lived one, literally overcoming what evolution failed to provide.

Why lifespan could increase (with the exemption oc extinction events). Refer to negligible senescence in turtles for example

metallurgy,

Word

I had the pleasure of meeting the Harman family in 2013. His wife told me that Professor Harman had been taking high doses

Dosing ALA against aging

Science has since demonstrated that the positive health effects attainable from an antioxidant-rich diet are more likely caused by stimulating the body’s natural defenses against aging, including boosting the production of the body’s enzymes that eliminate free radicals, not as a result of the antioxidant activity itself.

Antioxidants and their role in aging

In The Structure of Scientific Revolutions, Thomas Kuhn noted that scientific discovery is never complete; it goes through predictable stages of evolution.

This could be an interesting book to pick up

In this more nuanced view, aging and the diseases that come with it are the result of multiple “hallmarks” of aging: Genomic instability caused by DNA damage Attrition of the protective chromosomal endcaps, the telomeres Alterations to the epigenome that controls which genes are turned on and off Loss of healthy protein maintenance, known as proteostasis Deregulated nutrient sensing caused by metabolic changes Mitochondrial dysfunction Accumulation of senescent zombielike cells that inflame healthy cells Exhaustion of stem cells Altered intercellular communication and the production of inflammatory molecules

Current model of aging

Take stem cells, which have the potential to develop into many other kinds of cells: if we can keep these undifferentiated cells from tiring out, they can continue to generate all the differentiated cells necessary to heal damaged tissues and battle all kinds of diseases. Meanwhile, we’re improving the rates of acceptance of bone marrow transplants, which are the most common form of stem cell therapy, and using stem cells for the treatment of arthritic joints, type 1 diabetes, loss of vision, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. These stem cell–based interventions are adding years to people’s lives. Or take senescent cells, which have reached the end of their ability to divide but refuse to die, continuing to spit out panic signals that inflame surrounding cells: if we can kill off senescent cells or keep them from accumulating in the first place, we can keep our tissues much healthier for longer. The same can be said for combating telomere loss, the decline in proteostasis, and all of the other hallmarks. Each can be addressed one by one, a little at a time, in ways that can help us extend human healthspans.

Explanations of these aging processes

Diagram of aging processes

Because DNA is digital, it is a reliable way to store and copy information. Indeed, it can be copied again and again with tremendous accuracy, no different in principle from digital information stored in computer memory or on a DVD. DNA is also robust. When I first worked in a lab, I was shocked by how this “molecule of life” could survive for hours in boiling water and thrilled that it was recoverable from Neanderthal remains at least 40,000 years old.

Interesting validation of why genes aren't as instable as they seem. Although, fossilization is preserved in part due to protective sediment and from a lack of oxidation inflicted in the pre-cursive fossil's pocket of air.

Today, analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren’t transmitted by genetic means.

Analog information

In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin.

DNA in the cell isn’t flailing around disorganized, it is wrapped around tiny balls of protein called histones.

The centre of the DNA helical strand (as visualised)

In simple species, like ancient M. superstes and fungi today, epigenetic information storage and transfer is important for survival. For complex life, it is essential. By complex life,

“The Mathematical Theory of Communication”

I should read this sometime

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.

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 use histones in DNA to reexpress genetic information

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.

Vitamin B3, Related to aging

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.27

Another cofactor of Aging

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 among species and, as with sirtuins and TOR, we have learned a lot about how to control it.

Another cofactor of aging

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).

Activities to reduce aging

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.

Hormesis

hormesis-mimicking molecules.

Mimics exercise

In yeast, the equivalent of the WRN gene is Slow Growth Suppressor 1, or SGS1.

In the aged SGS1 cells, the nucleolus looked as if it had exploded. Instead of a single red crescent swimming in a blue ocean, the nucleolus was scattered into half a dozen small islands. It was tragic and beautiful. The picture, which would later appear in the August 1997 issue of the prestigious journal Science, still hangs in my office.

Likewise, the genome certainly dictates what the epigenome can do. A caterpillar can’t become a human being, but it can become a butterfly by virtue of changes in epigenetic expression that occur during metamorphosis, even though its genome never changes. Similarly, the child of two parents from a long line of people with black hair and brown eyes isn’t likely to develop blond hair and blue eyes, but twin agouti mice in the lab can turn out brown or golden, depending on how much the Agouti gene is turned on during gestation by environmental influences on the epigenome, such as folic acid, vitamin B12, genistein from soy, or the toxin bisphenol A.

Epigenome is malleable to a degree

Youth → broken DNA → genome instability → disruption of DNA packaging and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death.

The sequence of aging

Three of them, SIRT1, SIRT6, and SIRT7, are critical to the control of the epigenome and DNA repair. The others, SIRT3, SIRT4, and SIRT5, reside in mitochondria, where they control energy metabolism, while SIRT2 buzzes around the cytoplasm, where it controls cell division and healthy egg production.

SIR2-7 excluding 1

We found that SIRT1 in mammals moves from silent genes to help repair broken DNA in mouse and human cells.22

Sirt-1

But the true extent to which the survival circuit is conserved between yeast and humans wasn’t fully known until 2017, when Eva Bober’s team at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, reported that sirtuins stabilize human rDNA.23 Then, in 2018, Katrin Chua at Stanford University found that, by stabilizing human rDNA, sirtuins prevent cellular senescence—essentially the same antiaging function as we had found for sirtuins in yeast twenty years earlier.24

Evidence for preventing cellular senescence

I had noticed that yeast cells fed with lower amounts of sugar were not just living longer, but their rDNA was exceptionally compact—significantly delaying the inevitable ERC accumulation, catastrophic numbers of DNA breaks, nucleolar explosion, sterility, and death.

The proto cell shows sugars toxicity

I’ve come to think of sirtuins as the directors of a multifaceted disaster response corps, sending out a variety of specialized emergency teams to address DNA stability, DNA repair, cell survivability, metabolism, and cell-to-cell communication.

A nice analogy

from histones, which, as you’ll recall, causes the DNA to bundle up, preventing it from being transcribed into RNA.

Over the past billion years, presumably millions of yeast cells have spontaneously mutated to make more Sir2, but they died out because they had no advantage over other yeast cells. Living for 28 divisions was no advantage over those that lived for 24 and, because Sir2 uses up energy, having more of the protein may have even been a disadvantage. In the lab, however, we don’t notice any disadvantage because the yeast are given more sugar than they could possibly ever eat. By adding extra copies of the SIR2 gene, we gave the yeast cells what evolution failed to provide. If the information theory is correct—that aging is caused by overworked epigenetic signalers responding to cellular insult and damage—it doesn’t so much matter where the damage occurs. What matters is that it is being damaged and that sirtuins are rushing all over the place to address that damage, leaving their typical responsibilities and sometimes returning to other places along the genome where they are silencing genes that aren’t supposed to be silenced. This is the cellular equivalent of distracting the cellular pianist.

Sirt 2 function

To do that, we got our hands on a gene similar to Cas9, the CRISPR gene-editing tool from bacteria that cuts DNA at precise places.

Those findings were aligned to discoveries being made by Trey Ideker and Kang Zhang, at UC San Diego, and Steve Horvath, at UCLA. Steve’s name stuck, and today he’s the namesake of the Horvath Clock—an accurate way of estimating someone’s biological age by measuring thousands of epigenetic marks on the DNA, called methylation.

Horvath Clock

antediluvian

including some interesting variants in a gene known as FOXO3. Also known as DAF-16, this gene was first identified as a longevity gene in roundworms by University of California at San Francisco researcher Cynthia Kenyon. She found it to be essential for defects in the insulin hormone pathway to double worm lifespan. Playing an integral role in the survival circuit, DAF-16 encodes a small transcription factor protein that latches onto the DNA sequence TTGTTTAC and works with sirtuins to increase cellular survival when times are tough.35

Genes related to lifespan extension

In mammals, there are four DAF-16 genes, called FOXO1, FOXO3, FOXO4, and FOXO6. If you suspect that we scientists sometimes intentionally complicate matters, you’d be right, but not in this case. Genes in the same “gene family” have ended up with different names because they were named before DNA sequences were easily deciphered. It’s similar to the not uncommon situation in which people have their genome analyzed and learn they have a sibling on the other side of town.36 DAF-16 is an acronym for dauer larvae formation. In German, “dauer” means “long lasting,” and this is actually relevant to this story. Turns out, worms become dauer when they are starved or crowded, hunkering down until times improve. Mutations that activate DAF-16 extend lifespan by turning on the worm defense program even when times are good. I first encountered FOXO/DAF-16 in yeast, where it is known as MSN2, which stands for “multicopy suppressor of SNF1 (AMPK) epigenetic regulator.” Like DAF-16, MSN2’s job in yeast is to turn on genes that push cells away from cell death and toward stress resistance.37 We discovered that when calories are restricted MSN2 extends yeast lifespan by turning up genes that recycle NAD, thereby giving the sirtuins a boost.38 Hidden within the sometimes byzantine way scientists talk about science are several repeating themes: low energy sensors (SNF1/AMPK), transcription factors (MSN2/DAF-16/FOXO), NAD and sirtuins, stress resistance, and longevity. This is no coincidence—t...

Check for gene

Every time there’s a radical adjustment to the epigenome, say, after DNA damage from the sun or an X-ray, the marbles are jostled—envision a small earthquake that ever so slightly changes the map. Over time, with repeated earthquakes and erosion of the mountains, the marbles are moved up the sides of the slope, toward a new valley. A cell’s identity changes. A skin cell starts behaving differently, turning on genes that were shut off in the womb and were meant to stay off. Now it is 90 percent a skin cell and 10 percent other cell types, all mixed up, with properties of neurons and kidney cells. The cell becomes inept at the things skin cells must do, such as making hair, keeping the skin supple, and healing when injured. In my lab we say the cell has ex-differentiated. Each cell is succumbing to epigenetic noise. The tissue made up of thousands of cells is becoming a melange, a medley, a miscellaneous set of cells. As you’ll recall, the epigenome is inherently unstable because it is analog information—based on an infinite number of possible values—and thus it’s difficult to prevent the accumulation of noise and nearly impossible to duplicate without some information loss. The earthquakes are a fact of life. The landscape is always changing.

Information loss

“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.”

They ran over the exceeded limit 3km

Why? One of our key findings, in a study we published in 2018,42 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.

It was an exercise mimetic, the first of its kind, and a sure sign that some aspects of age reversal are possible.

Age reversal is possible

Sir Francis Bacon, the Enlightenment’s promulgator of “the prolongation of life.”