Lifespan: Why We Age and Why We Don’t Have To by David Sinclair

Advances in our understanding of organismal senescence are all leading to a momentous singular conclusion: that aging is not an inevitable part of life but rather a “disease process with a broad spectrum of pathological consequences.”

Summary & Practical Steps to Slow Aging

The dream of extending human lives did not begin in the early twenty-first century any more than the dream of human flight began in the early twentieth. Nothing begins with science; it all begins with stories.

David Sinclair, a geneticist at Harvard Medical School, explores aging as a ‘disease’. David unpacks the main biological and genetic mechanisms by which we age - mainly the loss of epigenetic information - what he calls ‘epigenetic noise’. This ‘epigenetic noise’ leads to negative modifications of gene expression rather than alteration of the genetic code itself.

An over simplification of his unified theory on aging:

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

Or said another way:

  • 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

By understanding these processes he outlines various approaches we can take to slow or reverse these processes. His conclusion is that aging is not an inevitable part of life but rather a “disease process with a broad spectrum of pathological consequences.”

Spoiler alert: If you want the distilled practical conclusion of what to do with this information and how to slow the aging process, as I did, here is what David Sinclair personally does:

  • 1 gram (1,000 mg) of NMN every morning, along with 1 gram of resveratrol (shaken into homemade yogurt) and 1 gram of metformin.
  • A daily dose of vitamin D, vitamin K2, and 83 mg of aspirin.
  • Strives to keep sugar, bread, and pasta intake as low as possible.
  • Try to skip one meal a day or at least make it really small.
  • Every few months, is analyzed for dozens of biomarkers. When levels of various markers are not optimal, moderates them with food or exercise.
  • Tries to take a lot of steps each day and walk upstairs, he goes to the gym most weekends to lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool.
  • Eat a lot of plants and trys to avoid eating other mammals, even though they do taste good. If he does work out, he will eat meat.
  • Doesn’t smoke, tries to avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans.
  • Trys to stay on the cool side during the day and when sleeping at night.
  • Aims to keep my body weight or BMI in the optimal range for healthspan, which for him is 23 to 25.

If you’re looking for the science behind the practical implications you can take to slow aging listed above - read on.

Epigenetics

When a theory succeeds at explaining previously unexplainable observations about the world, it becomes a tool that scientists can use to discover even more.

  • The term epigenetics was first coined in 1942 by Conrad H. Waddington, a British developmental biologist, while working at Cambridge University. In the past decade, the meaning of the word epigenetics has expanded into other areas of biology that have less to do with heredity—including embryonic development, gene switch networks, and chemical modifications of DNA-packaging proteins.

  • Epigenetics, the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself. Epigenetic information is what orchestrates the assembly of a human newborn made up of 26 billion cells from a single fertilized egg and what allows the genetically identical cells in our bodies to assume thousands of different modalities.

  • 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.

  • If the genome were a computer, the epigenome would be the software. It instructs the newly divided cells on what type of cells they should be and what they should remain, sometimes for decades, as in the case of individual brain neurons and certain immune cells.

  • 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. 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.

  • Because of the fact that nuclear transfer works in cloning, we can say with a high degree of confidence that aging isn’t caused by mutations in nuclear DNA.

  • Sure, it’s possible that some cells in the body don’t mutate and those are the ones that end up making successful clones, but that seems highly unlikely. The simplest explanation is that old animals retain all the requisite genetic information to generate an entirely new, healthy animal and that mutations are not the primary cause of aging.

  • 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

  • A singular reason why we age. Aging, quite simply, is a loss of information. Today, analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren’t transmitted by genetic means.

Longevity Genes

If you’ve had your genome analyzed, you can check if you have any of the known variations of FOXO3 that are associated with a long life. For example, having a C instead of a T variant at position rs2764264 is associated with longer life.

  • Longevity genes 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.

  • It’s worth pausing to consider that we find essentially the same longevity genes in every organism on the planet: trees, yeast, worms, whales, and humans.

  • 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.

  • Sirtuins instruct the histone spooling proteins to bind up DNA tightly, while they leave other regions to flail around. In this way, some genes stay silent, while others can be accessed by DNA-binding transcription factors that turn genes on. Accessible genes are said to be in “euchromatin,” while silent genes are in “heterochromatin.” By removing chemical tags on histones, sirtuins help prevent transcription factors from binding to genes, converting euchromatin into heterochromatin.

  • They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD. 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.

  • 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.

  • In 2006, Frederick Alt, Katrin Chua, and Raul Mostovslavsky at Harvard showed that mice engineered to lack SIRT6 underwent the typical signs of aging faster along with shortened lifespans. When the scientists knocked out a cell’s ability to create this vital protein, the cell lost its ability to repair double-strand DNA breaks, just as we had showed in yeast back in 1999.

  • A 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.

  • 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.

  • 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.

  • 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. 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.

Why Study Yeast?

  • Tiny yeast cells are not so different from ourselves. For their size, their genetic and biochemical makeup is extraordinarily complex, making them an exceptionally good model for understanding the biological processes that sustain life and control lifespans in large complex organisms such as ourselves. If you are skeptical that a yeast cell can tell us anything about cancer, Alzheimer’s disease, rare diseases, or aging, consider that there have been five Nobel Prizes in Physiology or Medicine awarded for genetic studies in yeast, including the 2009 prize for discovering how cells counteract telomere shortening, one of the hallmarks of aging.5

  • Humans are separated from yeast by a billion years of evolution, but we still have a lot in common. S. cerevisiae shares some 70 percent of our genes. And what it does with those genes isn’t so different from what we do with them.

  • Like a whole lot of humans, yeast cells are almost always trying to do one of two things: either they’re trying to eat, or they’re trying to reproduce. They’re hungry or they’re horny. As they age, much like humans, they slow down and grow larger, rounder, and less fertile. Sir2 has an important job: it is an epigenetic factor, an enzyme that sits on genes, bundles up the DNA, and keeps them silent. At the molecular level, Sir2 achieves this via its enzymatic activity, making sure that chemicals called acetyls don’t accumulate on the histones and loosen the DNA packaging.

How Things Go Awry

  • Our DNA is constantly under attack. On average, each of our forty-six chromosomes is broken in some way every time a cell copies its DNA, amounting to more than 2 trillion breaks in our bodies per day. And that’s just the breaks that occur during replication. Others are caused by natural radiation, chemicals in our environment, and the X-rays and CT scans that we’re subjected to.

  • Adding in more copies of the sirtuin genes SIRT1 and SIRT6 does just the opposite: it increases the health and extends the lifespan of mice, just as adding extra copies of the yeast SIR2 gene does in yeast.

  • In mammals, the sirtuins have since taken on a variety of new roles, not just as controllers of fertility (which they still are). They remove acetyls from hundreds of proteins in the cell: histones, yes, but also proteins that control cell division, cell survival, DNA repair, inflammation, glucose metabolism, mitochondria, and many other functions. 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.

  • When sirtuins shift from their typical priorities to engage in DNA repair, their epigenetic function at home ends for a bit. Then, when the damage is fixed and they head back to home base, they get back to doing what they usually do: controlling genes and making sure the cell retains its identity and optimal function.

  • Wherever epigenetic factors leave the genome to address damage, genes that should be off, switch on and vice versa. Wherever they stop on the genome, they do the same, altering the epigenome in ways that were never intended when we were born.

  • Cells lose their identity and malfunction. Chaos ensues. The chaos materializes as aging. This is the epigenetic noise that is at the heart of our unified theory. How does the SIR2 gene actually turn off genes? SIR2 codes for a specialized protein called a histone deacetylase, or HDAC, that enzymatically cleaves the acetyl chemical tags from histones, which, as you’ll recall, causes the DNA to bundle up, preventing it from being transcribed into RNA.

  • When the Sir2 enzyme is sitting on the mating-type genes, they remain silent and the cell continues to mate and reproduce. But when a DNA break occurs, Sir2 is recruited to the break to remove the acetyl tags from the histones at the DNA break. This bundles up the histones to prevent the frayed DNA from being chewed back and to help recruit other repair proteins. Once the DNA repair is complete, most of the Sir2 protein goes back to the mating-type genes to silence them and restore fertility. That is, unless there is another emergency, such as the massive genome instability that occurs when ERCs accumulate in the nucleoli of old yeast cells.

  • For the survival circuit to work and for it to cause aging, Sir2 and other epigenetic regulators must occur in “limiting amounts.” In other words, the cell doesn’t make enough Sir2 protein to simultaneously silence the mating-type genes and repair broken DNA; it has to shuttle Sir2 between the various places on an “as-needed” basis. This is why adding an extra copy of the SIR2 gene extends lifespan and delays infertility: cells have enough Sir2 to repair DNA breaks and enough Sir2 to silence the mating-type genes.

  • 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.

  • The repeated shuffling of sirtuins and other epigenetic factors away from genes to sites of broken DNA, then back again, while helpful in the short term, is ultimately what causes us to age. Over time, the wrong genes come on at the wrong time and in the wrong place.

  • Similarly, among monozygotic human twins, epigenetic forces can drive two people with the same genome in vastly different directions.

  • 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.

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

  • We all share the survival circuit, a protective cellular network that helps us when times are tough. This same network is our downfall. Severe types of damage, such as broken strands of DNA, cannot be avoided. They overwork the survival circuit and change cellular identity. We’re all subject to epigenetic noise that should, under the Information Theory of Aging, cause aging.

  • Horvath Clock—an accurate way of estimating someone’s biological age by measuring thousands of epigenetic marks on the DNA, called methylation. We tend to think of aging as something that begins happening to us at midlife, because that’s when we start to see significant changes to our bodies. But Horvath’s clock begins ticking the moment we are born.

  • All of the symptoms of aging—the conditions that push mice, like humans, farther toward the precipice of death—were being caused not by mutation but by the epigenetic changes that come as a result of DNA damage signals.

  • Certain variants called FOXO3 have been found in human communities in which people are known to enjoy both longer lifespans and healthspans, such as the people of China’s Red River Basin. These FOXO3 variants likely turn on the body’s defenses against diseases and aging, not just when times are tough but throughout life.

Embryonic Stem Cells

  • An embryonic stem cell is represented by a marble at the top of a mountain peak. During embryonic development, the marble rolls down the hill and comes to rest in one of hundreds of different valleys, each representing a different possible cell type in the body. This is called “differentiation.” The epigenome guides the marbles, but it also acts as gravity after the cells come to rest, ensuring that they don’t move back up the slope or hop over into another valley. The final resting place is known as the cell’s “fate.” We used to think this was a one-way street, an irreversible path. But in biology there is no such thing as fate. In the last decade, we’ve learned that the marbles in the Waddington landscape aren’t fixed; they have a terrible tendency to move around over time. At the molecular level, what’s really going on as the marble rolls down the slope is that different genes are being switched on and off, guided by transcription factors, sirtuins and other enzymes such as DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), which mark the DNA and its packing proteins with chemical tags that instruct the cell and its descendants to behave in a certain way.

  • 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 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.

  • Embryonic cells, often depicted as marbles, roll downhill and land in the right valley that dictates their identity. As we age, threats to survival, such as broken DNA, activate the survival circuit and rejigger the epigenome in small ways. Over time, cells progressively move towards adjacent valleys and lose their original identity, eventually transforming into zombielike senescent cells in old tissues. That’s aging. This loss of information is what leads each of us into a world of heart disease, cancer, pain, frailty, and death. If the loss of analog information is the singular reason why we age, is there anything we can do about it? Can we stabilize the marbles, keeping the valley walls high and the gravity strong? Yes. I can say with confidence that there is.

  • Advances in our understanding of organismal senescence are all leading to a momentous singular conclusion: that aging is not an inevitable part of life but rather a “disease process with a broad spectrum of pathological consequences.”

Food & Fasting on Aging

  • The most critical daily decisions that affect how long we live are centered around the foods we eat.

  • After twenty-five years of researching aging and having read thousands of scientific papers, if there is one piece of advice I can offer, one surefire way to stay healthy longer, one thing you can do to maximize your lifespan right now, it’s this: eat less often.

  • 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.

  • 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.

  • In one such study, participants ate a normal diet most of the time but turned to a significantly restricted diet consisting primarily of vegetable soup, energy bars, and supplements for five days each month. Over the course of just three months, those who maintained the “fasting mimicking” diet lost weight, reduced their body fat, and lowered their blood pressure, too. Perhaps most important, though, the participants had lower levels of a hormone made primarily in the liver called insulin-like growth factor 1, or IGF-1. Mutations in IGF-1 and the IGF-1 receptor gene are associated with lower rates of death and disease and found in abundance in females whose families tend to live past 100.15 Levels of IGF-1 have been closely linked to longevity. The impact is so strong, in fact, that in some cases it can be used to predict—with great accuracy—how long someone will live, according Some people are simply winners in the genetic lottery. The rest of us have some extra work to do. But the good news is that the epigenome is malleable. Since it’s not digital, it’s easier to impact. We can control the behavior of this analog element of our biology by how we live our lives.

  • We find that there are scores of ways to calorie restrict that are sustainable, and many take the form of what has come to be known as periodic fasting—not being hungry all the time but using hunger some of the time to engage our survival circuit.

  • We’d die quite quickly without amino acids, the organic compounds that serve as the building blocks for every protein in the human body. Without them—and in particular the nine essential amino acids that our bodies cannot make on their own—our cells can’t assemble the life-giving enzymes needed for life.

  • There isn’t much debate on the downsides of consumption of animal protein. Study after study has demonstrated that heavily animal-based diets are associated with high cardiovascular mortality and cancer risk. Processed red meats are especially bad. Hot dogs, sausage, ham, and bacon might be gloriously delicious, but they’re ingloriously carcinogenic, according to hundreds of studies that have demonstrated a link between these foods and colorectal, pancreatic, and prostate cancer.20 Red meat also contains carnitine, which gut bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is suspected of causing heart disease.

  • When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly. From an energy perspective, the good news is that there isn’t a single amino acid that can’t be obtained by consuming plant-based protein sources. The bad news is that, unlike most meats, weight for weight, any given plant usually delivers limited amounts of amino acids.

  • From a vitality perspective, though, that’s great news. Because a body that is in short supply of amino acids overall, or any single amino acid for a spell, is a body under the very sort of stress that engages our survival circuits. You’ll recall that when the enzyme known as mTOR is inhibited, it forces cells to spend less energy dividing and more energy in the process of autophagy, which recycles damaged and misfolded proteins. That act of hunkering down ends up being good for prolonged vitality in every organism we’ve studied. What we’re coming to learn is that mTOR isn’t impacted only by caloric restriction.23 If you want to keep mTOR from being activated too much or too often, limiting your intake of amino acids is a good way to start, so inhibiting this particular longevity gene is really as simple as limiting your intake of meat and dairy.

  • Jay Mitchell at Harvard Medical School have found over the years that feeding mice a diet with low levels of the amino acid methionine works particularly well to turn on their bodily defenses, to protect organs from hypoxia during surgery, and to increase healthy lifespan by 20 percent.24

  • We can’t live without methionine. But we can do a better job of restricting the amount of it we put into our bodies. There’s a lot of methionine in beef, lamb, poultry, pork, and eggs, whereas plant proteins, in general, tend to contain low levels of that amino acid—enough to keep the light on, as it were, but not enough to let biological complacency set in. The same is true for arginine and the three branched-chain amino acids, leucine, isoleucine, and valine, all of which can activate mTOR. Low levels of these amino acids correlate with increased lifespan26 and in human studies, a decreased consumption of branched-chain amino Even if we eat a low-protein, vegetable-rich diet, we may live longer, but we won’t maximize our lifespans—because putting our bodies into nutritional adversity isn’t going to maximally trigger our longevity genes. We need to induce some physical adversity, too. If that doesn’t happen, we miss a key opportunity to trigger our survival circuits further. Like a beautiful sports car driven only a block and back on Sunday mornings, our longevity genes will go tragically underutilized. With so much horsepower under the hood, we just have to fire up the engine and take it out for a spin.

  • In the 1920s, doctors began to prescribe guanidine as a way to lower blood glucose levels in patients with diabetes.Type 1 diabetes, which occurs when the pancreas doesn’t produce enough of the hormones needed to alert the body to sugar, is now widely treated by supplemental insulin. But the fight was not over.

  • The type 2 version of the disease, so-called age-associated diabetes, occurs when the pancreas is able to make enough insulin but the body is deaf to it. The 9 percent of all adults globally with this disease need a drug that restores their body’s sensitivity to insulin so cells take up and use the sugar that’s coursing through their bloodstreams. That’s important for at least two reasons: it gives the overworked pancreas a rest, and it prevents spikes of freely floating sugar from essentially caramelizing proteins in the body. Recent results indicate high blood sugar can also speed up the epigenetic clock.

Exercise & Temperature on Aging

All it took was an intrepid idea and the courage to buck convention.

  • 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.

  • The longevity regulators AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise, irrespective of caloric intake, building new blood vessels, improving heart and lung health, making people stronger, and, yes, extending 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.36

  • 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.

  • Exposing your body to less-than-comfortable temperatures is another very effective way to turn on your longevity genes.

  • COLD ACTIVATES LONGEVITY GENES Sirtuins are switched on by cold, which in turn activates protective brown fat in our back and shoulders.

  • As a curious aside, the legislation was written by Senator Royal Copeland, a homeopathic physician who, only days before he died, entrenched protections for natural supplements that today fuel a largely unregulated industry with revenues of $122 billion. Another thing you can try is activating the mitochondria in your brown fat by being a bit cold. The best way to do this might be the simplest—a brisk walk in a T-shirt on a winter day in a city such as Boston will do the trick. Exercising in the cold, in particular, appears to turbocharge the creation of brown adipose tissue.52 Leaving a window open overnight or not using a heavy blanket while you sleep could help, too.

  • A more convincing study followed a group of more than 2,300 middle-aged men from eastern Finland for more than twenty years. Those who used a sauna with great frequency—up to seven times a week—enjoyed a twofold drop in heart disease, fatal hearts attacks, and all-cause mortality events over those who heat bathed once per week.

  • A bit of adversity or cellular stress is good for our epigenome because it stimulates our longevity genes. It activates AMPK, turns down mTOR, boosts NAD levels, and activates the sirtuins—the disaster response teams—to keep up with the normal wear and tear that comes from living on planet Earth.

Metformin, Resveratrol, and NAD Boosters

Richard Feynman expressed succinctly: “There is nothing in biology yet found that indicates the inevitability of death. This suggests to me that it is not at all inevitable and that it is only a matter of time before biologists discover what it is that is causing us the trouble.”

METFORMIN: A molecule derived from the French hellebore used to treat type 2 (age-associated) diabetes that may be a longevity medicine.

RESVERATROL: Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sources of resveratrol in food include the skin of grapes, blueberries, raspberries, mulberries, and peanuts.

NAD: Nicotinamide adenine nucleotide, a chemical used for more than five hundred chemical reactions and for sirtuins to remove acetyl groups of other proteins such as histones to turn genes off or give them cell protective functions. A healthy diet and exercise raise NAD levels. The “+” sign you sometimes see, as in NAD+, indicates that it is not carrying a hydrogen atom.

  • In twenty-six studies of rodents treated with metformin, twenty-five showed protection from cancer.

  • Like rapamycin, metformin mimics aspects of calorie restriction. But instead of inhibiting TOR, it limits the metabolic reactions in mitochondria, slowing down the process by which our cellular powerhouses convert macronutrients into energy.20 The result is the activation of AMPK, an enzyme known for its ability to respond to low energy levels and restore the function of mitochondria. It also activates SIRT1, one of my lab’s favorite proteins. Among other beneficial effects, metformin inhibits cancer cell metabolism, increases mitochondrial activity, and removes misfolded proteins.21

  • A study of more than 41,000 metformin users between the ages of 68 and 81 concluded that metformin reduced the likelihood of dementia, cardiovascular disease, cancer, frailty, and depression, and not by a small amount.

  • If all metformin could do was reduce cancer incidence, it would still be worth prescribing widely. In the United States, the lifetime risk of being diagnosed with cancer is greater than 40 percent.

  • The beauty of metformin is that it impacts many diseases. Through the power of AMPK activation, it makes more NAD and turns on sirtuins and other defenses against aging as a whole—engaging the survival circuit upstream of these conditions, ostensibly slowing the loss of epigenetic information and keeping metabolism in check, so all organs stay younger and healthier.

  • THE THREE MAIN LONGEVITY PATHWAYS, mTOR, AMPK, AND SIRTUINS, EVOLVED TO PROTECT THE BODY DURING TIMES OF ADVERSITY BY ACTIVATING SURVIVAL MECHANISMS. When they are activated, either by low-calorie or low-amino-acid diets, or by exercise, organisms become healthier, disease resistant, and longer lived. Molecules that tweak these pathways, such as rapamycin, metformin, resveratrol, and NAD boosters, can mimic the benefits of low-calorie diets and exercise and extend the lifespan of diverse organisms.

  • Resveratrol-fed yeast were slightly smaller and grew slightly more slowly than untreated yeast, getting to an average of thirty-four divisions before dying, as though they were calorie restricted. The human equivalent would be an extra 50 years of life. We saw increases in maximum lifespan, too—on resveratrol, they kept going past 35. We tested resveratrol in yeast cells with no SIR2 gene, and there was no effect. We tested it on calorie-restricted yeast, and saw no further increase in lifespan, suggesting that the same pathway was being activated; this was how calorie restriction was working.

  • xenohormesis—the idea that stressed plants produce chemicals for themselves that tell their cells to hunker down and survive.

  • Other researchers went on to show in hundreds of published studies that resveratrol protects mice against dozens of diseases, including a variety of cancers, heart disease, stroke and heart attacks, neurodegeneration, inflammatory diseases, and wound healing, and generally makes mice healthier and more resilient.

  • Without sufficient NAD, the sirtuins don’t work efficiently: they can’t remove the acetyl groups from histones, they can’t silence genes, and they can’t extend lifespan. “Which is the superior molecule: NR or NMN?” We find NMN to be more stable than NR and see some health benefits in mouse experiments that aren’t seen when NR is used. But it’s NR that has been proven to extend the lifespan of mice. NMN is still being tested. So there’s no definitive answer, at least not yet.

  • We know that NAD boosters are an effective treatment for a wide variety of ailments in mice and that they extend their lifespan even when given late in life.

  • We also know that the way it does this, in terms of the epigenetic landscape, is by creating the right level of stress—just enough to push our longevity genes into action to suppress epigenetic changes to maintain the youthful program. In doing so, NMN and other vitality molecules, including metformin and rapamycin, reduce the buildup of informational noise that causes aging, thus restoring the program.

  • In 2004, Jonathan Tilly—a highly controversial figure in the reproductive biology community—claimed that human stem cells that can give rise to new eggs, late in life, exist in the ovaries. Controversial though this theory is, it would explain how it is possible to restore fertility even in mice that are old or have undergone chemotherapy.41,42 we need to remember what an ovary is. It’s not just, as so many of us were taught in school, a slow-release mechanism for human eggs. It’s an organ—just like our hearts, kidneys, or lungs—that has a day-to-day function, both holding on to eggs that were created during embryonic development and potentially being a repository for additional eggs derived from precursor cells later in life.

  • Once you recognize that there are universal regulators of aging in everything from yeast to roundworms to mice to humans . . . . . . and once you understand that those regulators can be changed with a molecule such as NMN or a few hours of vigorous exercise or a few less meals . . . . . . and once you realize that it’s all just one disease . . . . . . it all becomes clear:

Senescent Cells & Chronic Inflammation

“A new scientific truth does not triumph by convincing its opponents and making them see the light,” Planck wrote shortly before his death in 1947, “but rather because its opponents eventually die, and a new generation grows up that is familiar with it.”

  • Senescent cells are often referred to as “zombie cells,” because even though they should be dead, they refuse to die. In the petri dish and in frozen, thinly sliced tissue sections, we can stain zombie cells blue because they make a rare enzyme called beta-galactosidase, and when we do that, they light up clearly.

  • Being chronically inflamed is unhealthy: just ask someone with multiple sclerosis, inflammatory bowel disease, or psoriasis. All these diseases are associated with excess cytokine proteins. Inflammation is also a driving force in heart disease, diabetes, and dementia.

  • One of the key hallmarks of aging is the accumulation of senescent cells. These are cells that have permanently ceased reproduction. Young human cells taken out of the body and grown in a petri dish divide about forty to sixty times until their telomeres become critically short, a point discovered by the anatomist Leonard Hayflick that we now call the Hayflick limit. Although the enzyme known as telomerase can extend telomeres—the discovery of which afforded Elizabeth Blackburn, Carol Greider, and Jack Szostak a Nobel Prize in 2009—it is switched off to protect us from cancer, except in stem cells.

  • Why short telomeres cause senescence has been mostly worked out. A very short telomere will lose its histone packaging, and, like a shoelace that’s lost an aglet, the DNA at the end of the chromosome becomes exposed. The cell detects the DNA end and thinks it’s a DNA break. It goes to work to try to repair the DNA end, sometimes fusing two ends of different chromosomes together, which leads to hypergenome instability as chromosomes are shredded during cell division and fused again, over and over, potentially becoming a cancer.

  • The other, safer solution to a short telomere is to shut the cell down. This happens, it’s believed, by permanently engaging the survival circuit. The exposed telomere, seen as a DNA break, causes epigenetic factors such as the sirtuins to leave their posts permanently in an attempt to repair the damage, but there is no other DNA end to ligate it to. This shuts cell replication down, similar to the way that broken DNA in old yeast distracts Sir2 from the mating genes and shuts down fertility.

  • And cytokines don’t just cause inflammation; they also cause other cells to become zombies, like a biological apocalypse. When this happens, they can even stimulate surrounding cells to become a tumor and spread.

  • Senescent cells are hard to reverse aging in, so the best thing to do is to kill them off. Drugs called senolytics are in development to do just that, and they could rapidly rejuvenate us.

  • Just as in old yeast cells, if DNA breaks happen too frequently or they overwhelm the circuit, human cells will stop dividing, then sit there in a panic, trying to repair the damage, messing up their epigenome, and secreting cytokines. This is the final stage of cellular aging—and it’s not pretty.

  • So we live longer—and evolution hasn’t had a chance to catch up. We’re plagued by senescent cells, which might as well be radioactive waste. If you put a tiny dab of these cells under a young mouse’s skin, it won’t be long before inflammation spreads and the entire mouse is filled with zombie cells that cause premature signs of aging.

  • A class of pharmaceuticals called senolytics may be the zombie killers we need to fight the battle against aging on this front. These small-molecule drugs are designed to specifically kill senescent cells by inducing the death program that should have happened in the first place.

  • Vaccines against senescent cells, CR mimetics, and retrotransposon suppressors are possible pathways to prolonged vitality, and work is under way already in labs and clinics around the world.

The Future

Aging is going to be remarkably easy to tackle. Easier than cancer. I know how that sounds. It sounds crazy.

  • WE ARE ANALOG, THEREFORE WE AGE. According to the Information Theory of Aging, we become old and susceptible to diseases because our cells lose youthful information. DNA stores information digitally, a robust format, whereas the epigenome stores it in analog format, and is therefore prone to the introduction of epigenetic “noise.” An apt metaphor is a DVD player from the 1990s. The information is digital; the reader that moves around is analog. Aging is similar to the accumulation of scratches on the disc so the information can no longer be read correctly. Where’s the polish?

  • There are three different components that have analogs in biology: • The “source” of the information is the egg and sperm, from your parents. • The “transmitter” is the epigenome, transmitting analog information through space and time. • The “receiver” is your body in the future.

  • When an egg is fertilized, epigenetic information—biological “radio signals”—is sent out. It travels between dividing cells and across time. If all goes well, the egg develops into a healthy baby and eventually a healthy teenager. But with successive cell divisions and the overreaction of the survival circuit to DNA damage, the signal becomes increasingly noisy. Eventually, the receiver, your body when it is 80, has lost a lot of the original information.

  • In the 1990s, there were major concerns about the safety of delivering genes to humans. But there are a rapidly increasing number of approved gene therapy products and hundreds of clinical trials under way. Patients with an RPE65 mutation that causes blindness, for example, can now be cured with a simple injection of a safe virus that infects the retina and delivers, forever, the functional RPE65 gene.

  • EPIGENETIC REPROGRAMMING REGROWS OPTIC NERVES AND RESTORES EYESIGHT IN OLD MICE. The Information Theory of Aging predicts that it is a loss of epigenetic rather than genetic information in the form of mutations. By infecting mice with reprogramming genes called Oct4, Sox2, and Klf4, the age of cells is reversed by the TET enzymes, which remove just the right methyl tags on DNA, reversing the clock of aging and allowing the cells to survive and grow like a newborn’s. How the enzymes know which tags are the youthful ones is a mystery. Solving that mystery would be the equivalent of finding Claude Shannon’s “observer,” the person who holds the the original data.

  • From the time he began studying computational biology in the early 1980s, Boguski has been driven by the idea of making medical care more exacting. He is a luminary in the field of genomics—and one of the first scientists engaged in the Human Genome Project.

  • There are 3.234 billion base pairs, or letters, in the human genome. In 1990, when the Human Genome Project was launched, it cost about $10 to read just one letter in the genome, an A, G, C, or T. The entire project took ten years, thousands of scientists, and cost a few billion dollars. And that was for one genome. Today, I can read an entire human genome of 25,000 genes in a few days for less than a hundred dollars on a candy bar–sized DNA sequencer called a MinION that I plug into my laptop. And that’s for a fairly complete readout of a human genome, plus the DNA methyl marks that tell you your biological age.2 Targeted sequencing aimed at answering a specific question—such as “What kind of cancer is this?” or “What infection do I have?”—can now be done in less than twenty-four hours. Within ten years, it will be done in a few minutes, and the most expensive part will be the lancet that pricks your finger.3 But

  • If females and males are in the same environment, in general, females will live longer. It’s a common theme throughout the animal kingdom. Scientists have tested whether it is the X chromosome or the ovary that is important. Using a genetic trick, they created mice with one or two Xs, with either ovaries or testes.9 Those

  • I am a scientific adviser to a local company, spun out of MIT, called InsideTracker.

  • Will people trade a little more privacy to stop a global disease pandemic? Sadly, probably not. The tragedy of the commons is that humans are not very good at taking personal action to solve collective problems. The trick to revolutionary change is finding ways to make self-interest align with the common good.

  • The Great Ocean Road, which runs along the Australian coast west of Melbourne, is among the most beautiful stretches of highway in the world.

  • When technologies go exponential, even experts can be blindsided. The American physicist Albert Michelson, who won a Nobel Prize for measuring the speed of light, gave a speech at the University of Chicago in 1894, declaring that there was probably little else to discover in physics besides additional decimal places. He died in 1931, as quantum mechanics was in full swing. And in his 1995 book, The Road Ahead, Bill Gates made no mention of the internet, though he substantially revised it about a year later, humbly admitting that he had “vastly underestimated how important and how quickly” the internet would come to prominence. Kevin Kelly, the founding editor of Wired magazine, who has a better track record than most at predicting the future, has a golden rule: “Embrace things rather than try and fight them. Work with things rather than try and run from them or prohibit them.”

  • We often fail to acknowledge that knowledge is multiplicative and technologies are synergistic. Humankind is far more innovative than we give it credit for. Over the past two centuries, generation after generation has witnessed the sudden appearance of new and strange technologies: steam engines, metal ships, horseless carriages, skyscrapers, planes, personal computers, the internet, flat-screen TVs, mobile devices, and gene-edited babies. At first we are shocked; then we barely notice. When the human brain was evolving, the only things to change in a lifetime were the seasons. It should come as no surprise that we find it hard to predict what will happen when millions of people work on complex technologies that suddenly merge.

  • Americans consume more than three times the amount of food they need to survive and about 250 times as much water. In return, they produce 4.4 pounds of trash each day, recycling or composting only about of a third of it.

  • Most countries tax people when they die as a way to limit wealth accumulation over generations, but it’s a little-known fact that, in the United States, estate taxes weren’t initially designed to limit multigenerational wealth; they were imposed to finance wars.41 In 1797, a federal tax was imposed to build a navy to fend off a possible French invasion; in 1862, an inheritance tax was instituted to finance the Civil War. The 1916 estate tax, which was similar to present-day estate taxes, helped pay for World War I.

  • It is easier not to see things coming than to see them, so we tend to extrapolate into the future directly from the way things are now. That’s unfortunate and, in my view, scientifically wrong, for it eliminates an important factor from the equation.

  • The question, then, is not whether the natural and unnatural bounties of our Earth can sustain 8 billion, 16 billion, or 20 billion people. That’s a moot point. The question is whether humans can continue to develop the technologies that will permit us to stay ahead of the curve in the face of population growth, and indeed make the planet a better place for all creatures. So can we? Absolutely. And the past century is proof.

  • Two percent might not seem like a lot, but it added up fast. It took more than 120 years for our population to move from 1 billion to 2 billion, but after reaching that mark in 1927, it took just thirty-three more years to add another billion and then fourteen years to add another. This is how, at the end of the second decade of the twenty-first century, we came to have more than 7.7 billion people on our planet, and every year one additional person per square kilometer.54 Stepping back, if you graph human population size over the last 10,000 years, the transition from humans being very rare creatures to being the dominant species on Earth looks like a vertical step up. That baby inside the bomb would, on the face of it, seem justified.

  • The annual population growth rate has plummeted, from 2 percent around 1970 to about 1 percent today. By 2100, some researchers believe, the growth rate could fall as low as one-tenth of 1 percent. As this happens, United Nations demographers anticipate that our total global population will plateau, reaching about 11 billion people by the year 2100, then stop and drop from there.55

  • THE LAW OF HUMAN MORTALITY. Benjamin Gompertz, a self-taught mathematical genius, was barred from attending university in nineteenth-century London for being a Jew yet was elected to the Royal Society in 1819. His brother-in-law, Sir Moses Montefiore, in partnership with Nathan Rothschild, founded Alliance Assurance Company in 1824, and Gompertz was appointed actuary. His tidy equation, which replaced mortality tables, tracks the exponential increase in the chance of death with age. As important as this “law” is to insurance companies, it does not mean that aging is a fact of life.

  • Pessimism, it turns out, is often indicative of exceptional privilege. When viewed globally, however, it gets a lot harder to make the case that the world is an increasingly miserable place. It’s simply not.

  • Starting in 2017, for the first time since World War II, the US federal government was no longer the majority source of funding for basic scientific research in the United States. It’s worth drilling down into the NIH budget to see which of the 285 diseases that are being researched get the most attention.8 • Heart disease gets $1.7 billion for a disease that affects 11.7 percent of the population. • Cancer gets $6.3 billion to impact 8.7 percent. • Alzheimer’s disease gets $3 billion for a disease that impacts 3 percent—at most.9 How In 2005, a study by Dana Goldman and his colleagues at RAND in Santa Monica put some numbers on this. They estimated the value that new discoveries would add to society and the cost to society to extend a human life by one year.15 The cost of an innovative medicine to prevent diabetes: $147,199. Of a cancer treatment: $498,809. Of a pacemaker: $1,403,740. Of an “antiaging compound” that would extend healthy years by a decade: a mere $8,790. Goldman’s numbers support an idea that should be common sense: that there is no cheaper way to address the health care crisis than to address aging at its core.

  • And although it can be hard to track the origin of every drug in this increasingly interconnected world, by one estimate 57 percent of all medications are developed in the United States.

  • As it stands, the United Nations has warned, we are polluting water far faster than nature can recycle and purify it. We literally throw away half of the world’s edible food each year, more than a billion tons of it, even as millions of people are left hungry or malnourished.32 At the current pace of population growth and economic mobility, the United Nations estimates, by 2050 it will take the equivalent of nearly three of our planet’s resources to sustain our lifestyles for one year.

  • There’s no question that one of the greatest technological advances in this century has been the discovery of precise, programmable “genome editing.” As with most other breakthroughs, there were dozens of brilliant people involved in the lead-up to it,37 but Emmanuelle Charpentier, then at the Laboratory for Molecular Infection Medicine in Sweden, and Jennifer Doudna at UC Berkeley have garnered the most fame for their remarkable discovery that the bacterial Cas9 protein is a DNA-cutting enzyme with an RNA-based “GPS” or “guide.”38 The next year, Feng Zhang at MIT and George Church at Harvard proved that the system could be used to edit human cells. They, too, garnered fame—and some very valuable patents.39 News of the discovery spread quickly down the hall to my lab. It seemed too good to be true—except it was. The technology is colloquially known as CRISPR, for “clustered regularly interspaced short palindromic repeats,” which are the natural DNA targets of Cas9 cutting in bacteria. Cas9, and now dozens of other DNA-editing enzymes from other bacteria, can alter plant genes with accuracy, without using any foreign DNA. They can create exactly the same kind of alterations that occur naturally. Using CRISPR is far more “natural” than bombarding seeds with radiation, a treatment that is not banned.

  • The older we get, the less it takes for an injury or illness to drive us to our deaths. We are pushed closer and closer to the precipice until it takes nothing more than a gentle wind to send us over. This is the very definition of frailty.

  • Your chance of developing a lethal disease increases by a thousandfold between the ages of 20 and 70, so preventing one disease makes little difference to lifespan.

  • So prevalent is the combined problem of early mortality and morbidity that there is a statistic for it: the disability-adjusted life year, or DALY, which measures the years of life lost from both premature death and poor state of health. The Russian DALY is the highest in Europe, with twenty-five lost years of healthy life per person. In Israel, it is an impressive ten years. In the United States, the number is a dismal twenty-three.

  • Supplements are far, far less regulated than medicines, so if I do take a supplement, look 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 Scale of Things

Once you understand how cells actually work, they are the most amazing things. The problem with conveying this wonder is that cells exist in four dimensions and buzz around with speeds and on scales we humans cannot perceive or even conceive. To us, the second and the millimeter are short divisions of time and space, but to an enzyme about 10 nanometers across and vibrating every quadrillionth of a second, a millimeter is the size of a continent and a second is more than a year.

In each cell are a total of 75,000 enzymes like catalase, all thrown together, jostling around in a slightly salty sea. At the nanoscale, water is gelatinous, and molecular events are more violent than a category 5 hurricane, with molecules thrown together at speeds we would perceive as a thousand miles per hour. Enzymatic reactions are one-in-a-thousand events, but at the nanoscale one-in-a-thousand events can occur thousands of times a second, enough to sustain life.

  • 1 grain of sand = 10 skin cells 0.5 millimeter
  • 1 skin cell = 5 blood cells 50 micrometers
  • 1 blood cell = 2 X chromosomes or ~2 yeast cells
  • 10 micrometers 1 X chromosome = 1 yeast cell = 10 E. coli 5 micrometers
  • 1 E. coli or mitochondrion = 2 M. superstes 0.5 micrometer
  • 1 M. superstes = 4 ribosomes 0.25 micrometer
  • 1 ribosome = 6 catalase enzymes 30 nanometers
  • 1 catalase enzyme = 5 glucose molecules 5 nanometers
  • 1 glucose molecule or amino acid = approximately 4–6 water molecules
  • 1 nanometer water molecule = 275,000 atomic nuclei 0.275 nanometer
  • 1 atomic nucleus 1 picometer    
  • 1 inch = 25.4 millimeters  
  • 1 foot (12 inches) = 0.3048 meter  
  • 1 yard (3 feet) = 0.9144 meter  
  • 1 mile = 1.6093 kilometers      
  • 1 million = 106 (1 with 6 zeros)  
  • 1 billion = 109 (1 with 9 zeros)  
  • 1 trillion = 1012 (1 with 12 zeros)  
  • milli = 10-3 (1 thousandth)  
  • micro = 10-6 (1 millionth)  
  • nano = 10-9 (1 billionth)  
  • pico = 10-12 (1 1,000 billionth, or a trillionth)      
  • 32°F = 0°C
  • 212°F = 100°C

Terms

EPIGENETIC: Refers to changes to a cell’s gene expression that do not involve altering its DNA code. Instead the DNA and the histones that the DNA is wrapped around are “tagged” with removable chemical signals (see Demethylation and deacetylation). Epigenetic marks tell other proteins where and when to read the DNA, comparable to sticking a note that says “Skip” onto a page of a book. A reader will ignore the page, but the book itself has not been changed.

EPIGENETIC DRIFT AND EPIGENETIC NOISE: Alterations to the epigenome that take place with age due to changes in methylation, often related to an individual’s exposure to environmental factors. Epigenomic drift and noise may be a key driver of aging in all species. Damage to DNA, especially DNA breaks, is a driver of this process.

METFORMIN: A molecule derived from the French hellebore used to treat type 2 (age-associated) diabetes that may be a longevity medicine.

NAD: Nicotinamide adenine nucleotide, a chemical used for more than five hundred chemical reactions and for sirtuins to remove acetyl groups of other proteins such as histones to turn genes off or give them cell protective functions. A healthy diet and exercise raise NAD levels. The “+” sign you sometimes see, as in NAD+, indicates that it is not carrying a hydrogen atom.

RAPAMYCIN: Also known as sirolimus, rapamycin is a compound with immunosuppressant functions in humans. It inhibits activation of T cells and B cells by reducing their sensitivity to the signaling molecule interleukin-2. Extends lifespan by inhibiting mTOR.

SENOLYTICS: Pharmaceuticals currently under development that are hoped to kill senescent cells in order to slow down or even reverse aging-related issues.

SIRTUINS: Enzymes that control longevity; they are found in organisms from yeast to humans and need NAD+ to function. They remove acetyl and acyl groups from proteins to instruct them to protect cells from adversity, disease, and death. During fasting or exercise, sirtuin and NAD+ levels increase, which may explain why those activities are healthy. Named after the yeast SIR2 longevity gene, SIRT1–7 (Sir2 homologs 1 to 7) genes in mammals play key roles in protecting against disease and deterioration. SOMATIC CELLS: All the cells in a multicellular organism except for germ cells (eggs or sperm). Mutations or changes to the DNA in the soma will not be inherited by subsequent generations unless cloning takes place.

WADDINGTON’S LANDSCAPE: A biological metaphor for how cells are endowed with an identity during embryonic development in the form of a 3D relief map. Marbles representing stem cells roll down into bifurcating valleys, each of which marks a different developmental pathway for the cells.

XENOHORMESIS HYPOTHESIS: The idea that our bodies evolved to sense the stress cues of other species, such as plants, in order to protect themselves during times of impending adversity. Explains why so many medicines come from plants.