## Lifespan ### Lifespan  #### Metadata * Author: [[David A. Sinclair]] * Full Title: Lifespan * Category: #books #### Highlights * She never set foot in Europe again, but she brought every bit of Bohemia with her. She was, I have been told, one of the first women to sport a bikini in Australia and got chased off Bondi Beach because of it. She spent years living in New Guinea—which even today is one of the most intensely rugged places on our planet—all by herself. (Location 108) * 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 (Location 141) ^71d8ae * It was the comedian and actor Robin Williams who first demanded this courage from me through his portrayal of John Keating, the teacher and hero in the film Dead Poets Society, who challenges his teenage students to stare into the faces of the long-dead boys in a fading photo.4 "They are not that different from you, are they?" Keating says. "Invincible, just like you feel. . . . Their eyes are full of hope . . . But you see, gentlemen, these boys are now fertilizing daffodils." (Location 165) * Keating encourages the boys to lean in closer to listen for a message from the grave. Standing behind them, in a quiet, ghostly voice, he whispers, "Carpe. Carpe diem. Seize the day, boys. Make your lives extraordinary." (Location 170) * I am also a cofounder of a journal, Aging, that provides space to other scientists to publish their research on one of the most challenging and exciting questions of our time, and a cofounder of the Academy for Health and Lifespan Research, a group of the top twenty researchers in aging worldwide. (Location 198) * That includes being a stickybeak, the Australian term for someone who is overly inquisitive, perhaps derived from the currawong crows that used to punch through the foil lids of the milk bottles delivered to our homes and drink the milk out of them. My old high school friends still like to tease me about how, whenever they came over to my parents' house, they would find me pulling something apart: a pet moth's cocoon, a spider's curled-up leaf shelter, an old computer, my father's tools, a car. I became quite good at it. I just wasn't very good at putting these things back together. (Location 210) * Ever since I can remember, I have wanted to understand why we grow old. But finding the source of a complex biological process is like searching (Location 232) * This makes sense, because while DNA is broken, sex and reproduction are the last things an organism should be doing. (Location 328) * 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. (Location 345) * If you are taken aback by the notion that there is a singular cause of aging, you are not alone. If you haven't given any thought at all as to why we age, that's perfectly normal, too. A lot of biologists haven't given it much thought, either. Even gerontologists, doctors who specialize in aging, often don't ask why we age—they simply seek to treat the consequences. (Location 366) * Then, in the 1970s, genes that cause cancer when mutated were discovered by the molecular biologists Peter Vogt and Peter Duesberg. 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. By inventing chemicals that specifically block the tumor-promoting proteins, we could finally begin to move away from using radiation and toxic chemotherapeutic agents to attack cancers at their genetic source, while leaving normal cells untouched. (Location 372) * Up until the second half of the twentieth century, it was generally accepted that organisms grow old and die "for the good of the species"—an idea that dates back to Aristotle, if not further. This idea feels quite intuitive. It is the explanation proffered by most people at parties.4 But it is dead wrong. (Location 399) * Kirkwood's hypothesis explains why a mouse lives 3 years while some birds can live to 100.5 It also quite elegantly explains why the American chameleon lizard, Anolis carolinensis, is evolving a longer lifespan as we speak, having found itself a few decades ago on remote Japanese islands without predators. (Location 424) * Individuals don't live forever because natural selection doesn't select for immortality in a world where an existing body plan works perfectly well to pass along a body's selfish genes. And because all species are resource limited, they have evolved to allocate the available energy either to reproduction or to longevity, but not to both. (Location 428) * One hypothesis, proposed independently by Peter Medawar and Leo Szilard, was that aging is caused by DNA damage and a resulting loss of genetic information. Unlike Medawar, who was always a biologist, who built a Nobel Prize–winning career in immunology, Szilard had come to study biology in a roundabout way. The Budapest-born polymath and inventor lived a nomadic life with no permanent job or address, preferring to spend his time staying with colleagues who satisfied his mental curiosities about the big questions facing humanity. Early in his career, he was a pioneering nuclear physicist and a founding collaborator on the Manhattan Project, which ushered in the age of atomic warfare. Horrified by the countless lives his work had helped end, he turned his tortured mind toward making life maximally long. (Location 449) * But although we know with great certainty that radiation can cause all sorts of problems in our cells, it causes only a subset of the signs and symptoms we observe during aging,10 so it cannot serve as a universal theory. (Location 457) * If old habits die hard, the free-radical idea is heroin. The theory was overturned by scientists within the cloisters of my field more than a decade ago, yet it is still widely perpetuated by purveyors of pills and drinks, who fuel a $3 billion global industry.13 With all that advertising, it is not surprising that more than 60 percent of US consumers still look for foods and beverages that are good sources of antioxidants. (Location 476) * Although the discussion about the role of nuclear DNA mutations in aging continues, there is one fact that contradicts all these theories, one that is difficult to refute. Ironically, it was Szilard, in 1960, who initiated the demise of his own theory by figuring out to how to clone a human cell.18 Cloning gives us the answer as to whether or not mutations cause aging. If old cells had indeed lost crucial genetic information and this was the cause of aging, we shouldn't be able to clone new animals from older individuals. Clones would be born old. It's a misconception that cloned animals age prematurely. It has been widely perpetuated in the media and even the National Institutes of Health website says so.19 Yes, it's true that Dolly, the first cloned sheep, created by Keith Campbell and Ian Wilmut at the Roslin Institute at the University of Edinburgh, lived only half a normal lifespan and died of a progressive lung disease. (Location 488) * Meanwhile, the list of animal species that have been cloned and proven to live a normal, healthy lifespan now includes goats, sheep, mice, and cows. (Location 497) * It's certainly no dishonor to those brilliant researchers that their theories haven't withstood the test of time. That's what happens to most science, and perhaps all of it eventually. In The Structure of Scientific Revolutions, Thomas Kuhn noted that scientific discovery is never complete; it goes through predictable stages of evolution. When a theory succeeds at explaining previously unexplainable observations about the world, it becomes a tool that scientists can use to discover even more. (Location 503) * 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 (Location 513) * Researchers began to cautiously agree: address these hallmarks, and you can slow down aging. Slow down aging, and you can forestall disease. Forestall disease, and you can push back death. (Location 523) * 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. (Location 527) * Aging, quite simply, is a loss of information. (Location 553) * But there are two types of information in biology, and they are encoded entirely differently. The first type of information—the type my esteemed predecessors understood—is digital. Digital information, as you likely know, is based on a finite set of possible values—in this instance, not in base 2 or binary, coded as 0s and 1s, but the sort that is quaternary or base 4, coded as adenine, thymine, cytosine, and guanine, the nucleotides A, T, C, G of DNA. (Location 555) * 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.23 The advantages of digital storage explain why chains of nucleic acids have remained the go-to biological storage molecule for the past 4 billion years. (Location 561) * Today, analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren't transmitted by genetic means. (Location 567) * Worse still, information is lost as it's copied. No one was more acutely disturbed by the problem of information loss than Claude Shannon, an electrical engineer from the Massachusetts Institute of Technology (MIT) in Boston. Having lived through World War II, Shannon knew firsthand how the introduction of "noise" into analog radio transmissions could cost lives. After the war, he wrote a short but profound scientific paper called "The Mathematical Theory of Communication" on how to preserve information, which many consider the foundation of Information Theory. If there is one paper that propelled us into the digital, wireless world in which we now live, that would be it. (Location 594) * But we can usually recover information from a scratched DVD. And if I am right, the same kind of process is what it will take to reverse aging. (Location 605) * 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. (Location 620) * 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. (Location 655) * 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). (Location 661) * Up close, the epigenome is more complex and wonderful than anything we humans have invented. It consists of strands of DNA wrapped around spooling proteins called histones, which are bound up into bigger loops called chromatin, which are bound up into even bigger loops called chromosomes. (Location 812) * Every one of our cells has the same DNA, of course, so what differentiates a nerve cell from a skin cell is the epigenome, the collective term for the control systems and cellular structures that tell the cell which genes should be turned on and which should remain off. And this, far more than our genes, is what actually controls much of our lives. One of the best ways to visualize this is to think of our genome as a grand piano.13 Each gene is a key. Each key produces a note. And from instrument to instrument, depending on the maker, the materials, and the circumstances of manufacturing, each will sound a bit different, even if played the exact same way. These are our genes. We have about 20,000 of them, give or take a few thousand.14 Each key can also be played pianissimo (soft) or forte (with force). The notes can be tenuto (held) or allegretto (played quickly). For master pianists, there are hundreds of ways to play each individual key and endless ways to play the keys together, in chords and combinations that create music we know as jazz, ragtime, rock, reggae, waltzes, whatever. The pianist that makes this happen is the epigenome. Through a process of revealing our DNA or bundling it up in tight protein packages, and by marking genes with chemical tags called methyls and acetyls composed of carbon, oxygen, and hydrogen, the epigenome uses our genome to make the music of our lives. Yes, sometimes the size, shape, and condition of a piano dictate what a pianist can do with it. (Location 818) * It's tough to play a concerto on an eighteen-key toy piano, and it's mighty hard to make beautiful music on an instrument that hasn't been tuned in fifty years. 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. (Location 831) * Epigenetic noise causes the same kind of chaos. It is driven in large part by highly disruptive insults to the cell, such as broken DNA, as it was in the original survival circuit of M. superstes and in the old yeast cells that lost their fertility. And this, according to the Information Theory of Aging, is why we age. It's why our hair grays. It's why our skin wrinkles. It's why our joints begin to ache. Moreover, it's why each one of the hallmarks of aging occurs, from stem cell exhaustion and cellular senescence to mitochondrial dysfunction and rapid telomere shortening. (Location 851) * 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. (Location 968) # Lifespan  ## Metadata - Author: [[David A. Sinclair]] - Full Title: Lifespan - Category: #books ## Highlights - She never set foot in Europe again, but she brought every bit of Bohemia with her. She was, I have been told, one of the first women to sport a bikini in Australia and got chased off Bondi Beach because of it. She spent years living in New Guinea—which even today is one of the most intensely rugged places on our planet—all by herself. (Location 108) - 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 (Location 141) - It was the comedian and actor Robin Williams who first demanded this courage from me through his portrayal of John Keating, the teacher and hero in the film Dead Poets Society, who challenges his teenage students to stare into the faces of the long-dead boys in a fading photo.4 “They are not that different from you, are they?” Keating says. “Invincible, just like you feel. . . . Their eyes are full of hope . . . But you see, gentlemen, these boys are now fertilizing daffodils.” (Location 165) - Keating encourages the boys to lean in closer to listen for a message from the grave. Standing behind them, in a quiet, ghostly voice, he whispers, “Carpe. Carpe diem. Seize the day, boys. Make your lives extraordinary.” (Location 170) - I am also a cofounder of a journal, Aging, that provides space to other scientists to publish their research on one of the most challenging and exciting questions of our time, and a cofounder of the Academy for Health and Lifespan Research, a group of the top twenty researchers in aging worldwide. (Location 198) - That includes being a stickybeak, the Australian term for someone who is overly inquisitive, perhaps derived from the currawong crows that used to punch through the foil lids of the milk bottles delivered to our homes and drink the milk out of them. My old high school friends still like to tease me about how, whenever they came over to my parents’ house, they would find me pulling something apart: a pet moth’s cocoon, a spider’s curled-up leaf shelter, an old computer, my father’s tools, a car. I became quite good at it. I just wasn’t very good at putting these things back together. (Location 210) - Ever since I can remember, I have wanted to understand why we grow old. But finding the source of a complex biological process is like searching (Location 232) - This makes sense, because while DNA is broken, sex and reproduction are the last things an organism should be doing. (Location 328) - 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. (Location 345) - If you are taken aback by the notion that there is a singular cause of aging, you are not alone. If you haven’t given any thought at all as to why we age, that’s perfectly normal, too. A lot of biologists haven’t given it much thought, either. Even gerontologists, doctors who specialize in aging, often don’t ask why we age—they simply seek to treat the consequences. (Location 366) - Then, in the 1970s, genes that cause cancer when mutated were discovered by the molecular biologists Peter Vogt and Peter Duesberg. 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. By inventing chemicals that specifically block the tumor-promoting proteins, we could finally begin to move away from using radiation and toxic chemotherapeutic agents to attack cancers at their genetic source, while leaving normal cells untouched. (Location 372) - Up until the second half of the twentieth century, it was generally accepted that organisms grow old and die “for the good of the species”—an idea that dates back to Aristotle, if not further. This idea feels quite intuitive. It is the explanation proffered by most people at parties.4 But it is dead wrong. (Location 399) - Kirkwood’s hypothesis explains why a mouse lives 3 years while some birds can live to 100.5 It also quite elegantly explains why the American chameleon lizard, Anolis carolinensis, is evolving a longer lifespan as we speak, having found itself a few decades ago on remote Japanese islands without predators. (Location 424) - Individuals don’t live forever because natural selection doesn’t select for immortality in a world where an existing body plan works perfectly well to pass along a body’s selfish genes. And because all species are resource limited, they have evolved to allocate the available energy either to reproduction or to longevity, but not to both. (Location 428) - One hypothesis, proposed independently by Peter Medawar and Leo Szilard, was that aging is caused by DNA damage and a resulting loss of genetic information. Unlike Medawar, who was always a biologist, who built a Nobel Prize–winning career in immunology, Szilard had come to study biology in a roundabout way. The Budapest-born polymath and inventor lived a nomadic life with no permanent job or address, preferring to spend his time staying with colleagues who satisfied his mental curiosities about the big questions facing humanity. Early in his career, he was a pioneering nuclear physicist and a founding collaborator on the Manhattan Project, which ushered in the age of atomic warfare. Horrified by the countless lives his work had helped end, he turned his tortured mind toward making life maximally long. (Location 449) - But although we know with great certainty that radiation can cause all sorts of problems in our cells, it causes only a subset of the signs and symptoms we observe during aging,10 so it cannot serve as a universal theory. (Location 457) - If old habits die hard, the free-radical idea is heroin. The theory was overturned by scientists within the cloisters of my field more than a decade ago, yet it is still widely perpetuated by purveyors of pills and drinks, who fuel a $3 billion global industry.13 With all that advertising, it is not surprising that more than 60 percent of US consumers still look for foods and beverages that are good sources of antioxidants. (Location 476) - Although the discussion about the role of nuclear DNA mutations in aging continues, there is one fact that contradicts all these theories, one that is difficult to refute. Ironically, it was Szilard, in 1960, who initiated the demise of his own theory by figuring out to how to clone a human cell.18 Cloning gives us the answer as to whether or not mutations cause aging. If old cells had indeed lost crucial genetic information and this was the cause of aging, we shouldn’t be able to clone new animals from older individuals. Clones would be born old. It’s a misconception that cloned animals age prematurely. It has been widely perpetuated in the media and even the National Institutes of Health website says so.19 Yes, it’s true that Dolly, the first cloned sheep, created by Keith Campbell and Ian Wilmut at the Roslin Institute at the University of Edinburgh, lived only half a normal lifespan and died of a progressive lung disease. (Location 488) - Meanwhile, the list of animal species that have been cloned and proven to live a normal, healthy lifespan now includes goats, sheep, mice, and cows. (Location 497) - It’s certainly no dishonor to those brilliant researchers that their theories haven’t withstood the test of time. That’s what happens to most science, and perhaps all of it eventually. In The Structure of Scientific Revolutions, Thomas Kuhn noted that scientific discovery is never complete; it goes through predictable stages of evolution. When a theory succeeds at explaining previously unexplainable observations about the world, it becomes a tool that scientists can use to discover even more. (Location 503) - 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 (Location 513) - Researchers began to cautiously agree: address these hallmarks, and you can slow down aging. Slow down aging, and you can forestall disease. Forestall disease, and you can push back death. (Location 523) - 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. (Location 527) - Aging, quite simply, is a loss of information. (Location 553) - But there are two types of information in biology, and they are encoded entirely differently. The first type of information—the type my esteemed predecessors understood—is digital. Digital information, as you likely know, is based on a finite set of possible values—in this instance, not in base 2 or binary, coded as 0s and 1s, but the sort that is quaternary or base 4, coded as adenine, thymine, cytosine, and guanine, the nucleotides A, T, C, G of DNA. (Location 555) - 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.23 The advantages of digital storage explain why chains of nucleic acids have remained the go-to biological storage molecule for the past 4 billion years. (Location 561) - Today, analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren’t transmitted by genetic means. (Location 567) - Worse still, information is lost as it’s copied. No one was more acutely disturbed by the problem of information loss than Claude Shannon, an electrical engineer from the Massachusetts Institute of Technology (MIT) in Boston. Having lived through World War II, Shannon knew firsthand how the introduction of “noise” into analog radio transmissions could cost lives. After the war, he wrote a short but profound scientific paper called “The Mathematical Theory of Communication” on how to preserve information, which many consider the foundation of Information Theory. If there is one paper that propelled us into the digital, wireless world in which we now live, that would be it. (Location 594) - But we can usually recover information from a scratched DVD. And if I am right, the same kind of process is what it will take to reverse aging. (Location 605) - 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. (Location 620) - 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. (Location 655) - 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). (Location 661) - Up close, the epigenome is more complex and wonderful than anything we humans have invented. It consists of strands of DNA wrapped around spooling proteins called histones, which are bound up into bigger loops called chromatin, which are bound up into even bigger loops called chromosomes. (Location 812) - Every one of our cells has the same DNA, of course, so what differentiates a nerve cell from a skin cell is the epigenome, the collective term for the control systems and cellular structures that tell the cell which genes should be turned on and which should remain off. And this, far more than our genes, is what actually controls much of our lives. One of the best ways to visualize this is to think of our genome as a grand piano.13 Each gene is a key. Each key produces a note. And from instrument to instrument, depending on the maker, the materials, and the circumstances of manufacturing, each will sound a bit different, even if played the exact same way. These are our genes. We have about 20,000 of them, give or take a few thousand.14 Each key can also be played pianissimo (soft) or forte (with force). The notes can be tenuto (held) or allegretto (played quickly). For master pianists, there are hundreds of ways to play each individual key and endless ways to play the keys together, in chords and combinations that create music we know as jazz, ragtime, rock, reggae, waltzes, whatever. The pianist that makes this happen is the epigenome. Through a process of revealing our DNA or bundling it up in tight protein packages, and by marking genes with chemical tags called methyls and acetyls composed of carbon, oxygen, and hydrogen, the epigenome uses our genome to make the music of our lives. Yes, sometimes the size, shape, and condition of a piano dictate what a pianist can do with it. (Location 818) - It’s tough to play a concerto on an eighteen-key toy piano, and it’s mighty hard to make beautiful music on an instrument that hasn’t been tuned in fifty years. 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. (Location 831) - Epigenetic noise causes the same kind of chaos. It is driven in large part by highly disruptive insults to the cell, such as broken DNA, as it was in the original survival circuit of M. superstes and in the old yeast cells that lost their fertility. And this, according to the Information Theory of Aging, is why we age. It’s why our hair grays. It’s why our skin wrinkles. It’s why our joints begin to ache. Moreover, it’s why each one of the hallmarks of aging occurs, from stem cell exhaustion and cellular senescence to mitochondrial dysfunction and rapid telomere shortening. (Location 851) - 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. (Location 968)