# Lifespan (David Andrew Sinclair)
* 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. That was as true for M. superstes as it was and still is for all species that have ever lived on this planet. All, that is, except one: Homo sapiens. (p. 12)
* 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. (p. 15)
* Mutations are not the primary cause of aging. (p. 16)
* 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. (p. 24)
* 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. (p. 24)
* Sirtuins aren’t the only longevity genes. Two other very well studied sets of genes perform similar roles, which also have been proven to be manipulable in ways that can offer longer and healthier lives. One of these is called target of rapamycin, or TOR, a complex of proteins that regulates growth and metabolism. (p. 25)
* 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. (p. 25)
* The other pathway is a metabolic control enzyme known as AMPK, which evolved to respond to low energy levels. (p. 26)
* 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. (p. 26)
* Unlike the oncogenes that were discovered in the 1970s and that have given us a good target for going to battle against cancer, we haven’t identified a singular gene that causes aging. And we won’t. Because our genes did not evolve to cause aging. (p. 28)
* Over the past billion years, presumably millions of yeast cells have spontaneously mutated to make more Sir2, but they died out because they had no advantage over other yeast cells. Living for 28 divisions was no advantage over those that lived for 24 and, because Sir2 uses up energy, having more of the protein may have even been a disadvantage. (p. 48)
* We hadn’t given the mice all of those ailments. We had given them aging. And if you can give something, you can take it away. (p. 52)
* For example, having a C instead of a T variant at position rs2764264 is associated with longer life. (p. 75)
* In this way of thinking, cancer, heart disease, Alzheimer’s, and other conditions we commonly associate with getting old are not necessarily diseases themselves but symptoms of something greater. Or, put more simply and perhaps even more seditiously: aging itself is a disease. (p. 86)
* So even though most people who live in developed nations can now feel confident that they will make it to 80, these days the chances that any of us will reach a century is just 3 in 100. Getting to 115 is a 1-in-100-million proposition. And reaching 130 is a mathematical improbability of the highest order. At least it is right now. (p. 88)
* When I was a young boy, I used to steal her cigarettes and hide them. It infuriated her. The fact that she didn’t respond to my pleas to stop smoking infuriated me, too. (p. 89)
* There are some simple tests to determine how biologically old you probably are. The number of push-ups you can do is a good indicator. If you are over 45 and can do more than twenty, you are doing well. The other test of age is the sitting-rising test (SRT). Sit on the floor, barefooted, with legs crossed. Lean forward quickly and see if you can get up in one move. A young person can. A middle-aged person typically needs to push off with one of their hands. An elderly person often needs to get onto one knee. A study of people 51 to 80 years found that 157 out of 159 people who passed away in 75 months had received less than perfect SRT scores. (p. 91)
* Thanks to statins, triple-bypass surgeries, defibrillators, transplants, and other medical interventions, our hearts are staying alive longer than ever. But we haven’t been nearly so attentive to our other organs, including the most important one of all: our brains. The result is that more of us are spending more years suffering from brain-related maladies, such as dementia. (p. 96)
* I believe that aging is a disease. I believe it is treatable. I believe we can treat it within our lifetimes. And in doing so, I believe, everything we know about human health will be fundamentally changed. (p. 99)
* When we stay healthy and vibrant, as long as we feel young physically and mentally, our age doesn’t matter. That’s true whether you are 32, 52, or 92. Most middle-aged and older adults in the United States report feeling ten to twenty years younger than their age, because they still feel healthy. And feeling younger than your age predicts lower mortality and better cognitive abilities later in life.22 It’s a virtuous cycle, as long as you keep pedaling. (p. 101)
* 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. (p. 106)
* As far back as the 1970s, though, there have been observational studies that strongly suggested long-term calorie restriction could help humans live longer and healthier lives, too. (p. 108)
* But with so little fat on their bodies, they needed the extra warmth. (p. 110)
* He didn’t look much younger than his age, though; in large part, I suspect this was because a lack of fat exposes wrinkles, but his blood biochemistry suggested otherwise. (p. 110)
* It’s true that what we know about the impact of lifelong calorie restriction in humans comes down to short-term studies and anecdotal experiences. (p. 110)
* CR works to extend the lifespan of mice, even when initiated at 19 months of age, the equivalent of a 60- to 65-year-old human, but the earlier the mice start on CR, the greater the lifespan extension. What these and other animal studies tell us is that it’s hard to “age out” of the longevity benefits of calorie restriction, but it’s probably better to start earlier than later, perhaps after age 40, when things really start to go downhill, molecularly speaking. (p. 111)
* A popular method is to skip breakfast and have a late lunch (the 16:8 diet). (p. 114)
* The short-term studies are promising. I suspect the long-term research will be, too. In the meantime, however, almost any periodic fasting diet that does not result in malnutrition is likely to put your longevity genes to work in ways that will result in a longer, healthier life. (p. 114)
* 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. (p. 116)
* 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. (p. 116)
* Leucine, for instance, is well known to boost muscle, which is why it’s found in large quantities in the protein drinks that bodybuilders often chug before, during, and after workouts. But that muscle building is coming in part because leucine is activating mTOR, which essentially calls out to your body, “Times are good right now, let’s disengage the survival circuit.” In the long run, however, protein drinks may be preventing the mTOR pathway from providing its longevity benefits. (p. 117)
* All of these findings may explain why vegetarians suffer significantly lower rates of cardiovascular disease and cancer than meat eaters. (p. 117)
* Limiting food intake and reducing the heavy load of amino acids in most diets aren’t the only ways to activate longevity genes that order our cells to shift into survival mode. Exercise, by definition, is the application of stress to our bodies. It raises NAD levels, which in turn activates the survival network, which turns up energy production and forces muscles to grow extra oxygen-carrying capillaries. 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. (p. 118)
* Even about ten minutes of moderate exercise a day added years to their lives. (p. 119)
* Your breathing should be deep and rapid at 70 to 85 percent of your maximum heart rate. You should sweat and be unable to say more than a few words without pausing for breath. (p. 120)
* You’ll know you are doing vigorous activity when it feels challenging. Your breathing should be deep and rapid at 70 to 85 percent of your maximum heart rate. You should sweat and be unable to say more than a few words without pausing for breath. (p. 120)
* Being hungry is necessary for CR to work because hunger helps turn on genes in the brain that release longevity hormones. (p. 120)
* Exposing your body to less-than-comfortable temperatures is another very effective way to turn on your longevity genes. (p. 121)
* If you choose to expose yourself to the cold, moderation will be key. Similar to fasting, the greatest benefits are likely to come for those who get close to, but not beyond, the edge. Hypothermia is not good for our health. Neither is frostbite. But goose bumps, chattering teeth, and shivering arms aren’t dangerous conditions. (p. 126)
* None of the sauna studies dug deep enough to tell us why temporary heat exposure may be so good for us. If yeast is any guide, NAMPT, the gene in our bodies that recycles NAD, may be in on the act. NAMPT is turned on by a variety of adversity triggers, including fasting and exercise, which makes more NAD so the sirtuins can work hard at making us healthier. (p. 127)
* But it would also be wise to be wary of the PCBs and other chemicals found in plastics, including many plastic bottles and take-out containers. (p. 129)
* Rapamycin isn’t a panacea. Longer-lived animals might not fare as well on it as shorter-lived ones do; it’s been shown to be toxic to kidneys at high doses over extended periods of time; and it might suppress the immune system over time. That doesn’t mean TOR inhibition is a dead end, though. It might be safe in small or intermittent doses—that worked in mice to extend lifespan. (p. 136)
* A few years ago, researchers noticed a curious phenomenon: people taking metformin were living notably healthier lives—independent, it seemed, of its effect on diabetes. (p. 138)
* 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. In one group of already frail subjects, metformin use over the course of nine years reduced dementia by 4 percent, depression by 16 percent, cardiovascular disease by 19 percent, frailty by 24 percent, and cancer by 4 percent. (p. 139)
* We also knew that many other health-promoting molecules, and chemical derivatives of them, are produced in abundance by stressed plants; we get resveratrol from grapes, aspirin from willow bark, metformin from lilacs, epigallocatechin gallate from green tea, quercetin from fruits, and allicin from garlic. This, we believe, is evidence of xenohormesis—the idea that stressed plants produce chemicals for themselves that tell their cells to hunker down and survive. (p. 145)
* As it turned out, resveratrol wasn’t very potent and wasn’t very soluble in the human gut, two attributes that most medicines need to be effective at treating diseases. Despite its limitations as a drug, it did serve as an important first proof that a molecule can give the benefits of calorie restriction without the subject having to go hungry. (p. 147)
* There are, today, hundreds of chemicals that have been demonstrated to have an effect on sirtuins that are even more effective than resveratrol’s and some that have already been demonstrated in clinical trials to lower fatty acid and cholesterol levels, and to treat psoriasis in humans. (p. 147)
* 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. (p. 150)
* By engaging our bodies’ survival mechanisms in the absence of real adversity, will we push our lifespans far beyond what we can today? And what will be the best way to do this? Could it be a souped-up AMPK activator? A TOR inhibitor? A STAC or NAD booster? Or a combination of them with intermittent fasting and high-intensity interval training? The potential permutations are virtually endless. (p. 157)
* Aging is going to be remarkably easy to tackle. Easier than cancer. I know how that sounds. It sounds crazy. (p. 160)
* 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. (p. 164)
* This is where “antagonistic pleiotropy” comes into play: the idea that a survival mechanism that is good for us when we are young is kept through evolution because this far outweighs any problems it might cause when we get older. (p. 165)
* He needed only a quick course of two senolytic molecules—quercetin, which is found in capers, kale, and red onions, and a drug called dasatinib, which is a standard chemotherapy treatment for leukemia—to eliminate the senescent cells in lab mice and extend their lifespan by 36 percent. (p. 166)
* For his discovery, essentially showing that complete cellular age reversal was possible in a petri dish, Yamanaka won the Nobel Prize in Physiology or Medicine along with John Gurdon in 2012. We now call these four genes Yamanaka factors. (p. 176)
* There are more than a hundred companies just in the United States pursuing lightning-fast, superfocused DNA testing that can offer us early and accurate diagnoses of a vast range of ailments and even estimate our rate of biological aging. (p. 197)
* Future generations of sensors will measure and track not only a person’s glucose but his or her basic vital signs, the level of oxygen in the blood, vitamin balance, and thousands of chemicals and hormones. (p. 200)
* Imagine, then, what “hands-off” trackers that collect millions of daily data points can offer us. Now imagine coupling that data with what we learn from routine DNA sequencing. (p. 205)
* Yes, it is true that any one technology might lead to a dead end. But there is simply no way that all of them will fail. Taken separately, any of these innovations in pharmaceuticals, precision medicine, emergency care, and public health would save lives, providing extra years that would otherwise have been lost. When we take them together, though, we are staring up the road at decades of longer, healthier life. (p. 218)
* How long will it be before we are able to reset our epigenome, either with molecules we ingest or by genetically modifying our bodies, as my student now does in mice? How long until we can destroy senescent cells, either by drugs or outright vaccination? How long until we can replace parts of organs, grow entire ones in genetically altered farm animals, or create them in a 3D printer? A couple of decades, perhaps. Maybe three. (p. 222)
* Today, many of my colleagues are just as optimistic as I am, even if they don’t admit it publicly. (p. 223)
* But as for the next century? And the next? It is not at all extravagant to expect that someday living to 150 will be standard. And if the Information Theory of Aging is sound, there may be no upward limit; we could potentially reset the epigenome in perpetuity. This is terrifying to a lot of people—and understandably so. We’re on the cusp of upending nearly every idea we’ve ever had about what it means to be human. And that has a lot of people saying not just that it can’t be done but that it shouldn’t be done—for it will surely lead to our doom. (p. 225)
* Death by death, the world sheds ideas that need to be shed. (p. 232)
* There are no easy answers, but if past is prologue—and it so often is with human behavior—politicians will watch this slow-moving disaster until it becomes a fast-moving disaster; then they will sit and watch some more. (p. 236)
* Eventually prices will come down, but unless governments act soon, there will be a period of major disparity between the very rich and the rest of the world. (p. 239)
* Death will remain a part of our lives for a very long time to come, even as the time of it is pushed out in the coming decades. (p. 251)
* Did these improvements to the human condition occur in spite of our population boom or because of it? I contend it is the latter, but it actually doesn’t matter. They happened simultaneously. As yet, there is really no evidence in modern times that population levels correlate with, let alone cause, increases in human misery. Much to the contrary, in fact, our world is more populated today than it ever has been—and it’s a better place for more people, too. (p. 254)
* Looking through old magazines, it’s easy to see what scared previous generations. It’s always the same; there are too many people and not enough resources: too many people and not enough jobs. (p. 259)
* The first nations to define aging as a disease, both in custom and on paper, will change the course of the future. The first places to provide large amounts of public funding to augment the fast-growing private investments in this field will prosper in kind. It will be their citizens who benefit first. Doctors will feel comfortable prescribing medicines, such as metformin, to their patients before they become irreversibly frail. Jobs will be created. Scientists and drug makers will flock to that country. Industries will thrive. Their national budget will see a significant return on investment. Their leaders’ names will be in the history books. (p. 273)
* Thanks to the burgeoning addiction to calories and opioids, and a health care system that is inadequate, if not completely inaccessible to one-third of its population, the United States recently experienced a decline in life expectancy for the first time since the early 1960s. That decline may soon exceed the decline in life expectancy caused by the Spanish flu epidemic in 1918. This is happening despite the fact that the United States spends 17 percent of its GDP on health care, nearly double that of Australia. (p. 279)
* By the way, if you’re under the misconception that if we screw up this planet we can just travel to a new one, consider that the closest known habitable exoplanet is 4.2 light-years away, as the crow flies. That sounds close, but barring the discovery of a space wormhole or light sailing of tiny cargoes at near light speed, it would take at least 10,000 years to get a few humans there27 (which, I’ve argued, is another good reason to figure out how to extend human lifespan). (p. 282)
* I’ve talked to hundreds of people about this topic. Most people who want immortality are not afraid of death. They just love life. They love their family. They love their careers. They would love to see what the future holds. (p. 284)
* It turns out that most people aren’t afraid of losing their lives; they are afraid of losing their humanity. (p. 285)
* Therefore, we must invest in research that allows us to grow more healthy food and transport it more effectively. And please make no mistake: that includes accepting genetically modified crops, those engineered to include a trait in the plant that doesn’t occur in its wild form, such as resistance to insects, tolerance to drought, greater vitamin A production, or more efficient use of sunlight to convert CO2 to sugar—as an absolutely necessary part of our food future. (p. 287)
* There is nothing wrong with skepticism, but after thousands of studies, the evidence is irrefutable: if you believe climate change is a threat, you can’t say that GMOs are, because the evidence that GMOs are safe is stronger than the evidence that climate change is occurring. (p. 288)
* Longer, healthier lives will do us little good if we consume ourselves into oblivion. The imperative is clear: whether or not we increase human longevity, our survival depends on consuming less, innovating more, and bringing balance to our relationship with the bounty of our natural world. (p. 291)
* And so, with all that on the table, what do I do? • I take 1 gram (1,000 mg) of NMN every morning, along with 1 gram of resveratrol (shaken into my homemade yogurt) and 1 gram of metformin.7 • I take a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin. • I strive to keep my sugar, bread, and pasta intake as low as possible. I gave up desserts at age 40, though I do steal tastes. • I try to skip one meal a day or at least make it really small. My busy schedule almost always means that I miss lunch most days of the week. • Every few months, a phlebotomist comes to my home to draw my blood, which I have analyzed for dozens of biomarkers. When my levels of various markers are not optimal, I moderate them with food or exercise. • I try to take a lot of steps each day and walk upstairs, and I go to the gym most weekends with my son, Ben; we lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool. • I eat a lot of plants and try to avoid eating other mammals, even though they do taste good. If I work out, I will eat meat. • I don’t smoke. I try to avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans. • I try to stay on the cool side during the day and when I sleep at night. • I aim to keep my body weight or BMI in the optimal range for healthspan, which for me is 23 to 25. (p. 306)