Lifespan: Why We Age—and Why We Don't Have To

by David A. Sinclair

It takes courage to consciously think about your loved ones’ mortality before it actually happens. It takes even more courage to deeply ponder your own.

By and large, these increases in life expectancy came as more of us gained access to stable food sources and clean water. And largely the average was pushed upward from the bottom; deaths during infancy and childhood fell, and life expectancy rose.

Our planet has been home to more than 100 billion humans so far. We know of just one, Jeanne Calment of France, who ostensibly lived past the age of 120. Most scientists believe she died in 1997 at the age of 122, although it’s also possible that her daughter replaced her to avoid paying taxes.13 Whether or not she actually made it to that age really doesn’t matter; others have come within a few years of that age but most of us, 95 percent to be precise, are dead before 100.

Thanks to a combination of a BRAF inhibitor and immunotherapy, survival of melanoma brain metastases, one of the deadliest types of cancer, has increased by 91 percent since 2011. Between 1991 and 2016, overall deaths from cancer in the United States declined by 27 percent and continue to fall.

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.

about a decade at the University of Texas at San Antonio testing if increasing free-radical damage or mutations in mice led to aging; it didn’t.16 In my lab and others, it has proven surprisingly simple to restore the function of mitochondria in old mice, indicating that a large part of aging is not due to mutations in mitochondrial DNA, either, at least not until late in life.17

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.

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

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

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.

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

Though it’s not immortal, the Greenland shark Somniosus microcephalus is still an impressive animal and far more closely related to us. About the size of a great white, it does not even reach sexual maturity until it is 150 years old.

Radiocarbon dating estimated that one very large individual may have lived more than 510 years, at least up until it was caught by scientists so they could measure its age.

That discovery sparked a new scientific interest in Balaena mysticetus, and later research, employing an age-determining method that measures the levels of aspartic acid in the lens of a whale’s eye, estimated that one bowhead was 211 years old when it was killed by native whalers.

We discovered that when calories are restricted MSN2 extends yeast lifespan by turning up genes that recycle NAD, thereby giving the sirtuins a boost.

In the United States alone, each year, 82,000 elderly people have a limb amputated. That’s ten every hour. All this pain, all this cost, comes from relatively minor initial injuries: foot wounds.

The average age of death can vary rather significantly over time, and is affected by many factors, including the prevalence of obesity, sedentary lifestyles, and drug overdoses.

I recognized that smoking would increase my mother’s chances of getting lung cancer. I also knew why: cigarette smoke contains a chemical called benzo(a)pyrene, which binds to guanine in DNA, induces double-strand breaks, and causes mutations. The repair process also causes epigenetic drift and metabolic changes that cancer cells thrive on, in a process we’ve called geroncogenesis.19

But consider this: though smoking increases the risk of getting cancer fivefold, being 50 years old increases your cancer risk a hundredfold. By the age of 70, it is a thousandfold.21

“longevity diets” that are based on the commonalities in the foods eaten in places where there are lots of centenarians. And overwhelmingly that advice comes down to eating more vegetables, legumes, and whole grains, while consuming less meat, dairy products, and sugar.

There is widespread disagreement, even among the best nutritionists in the world, as to what constitutes the “best” diet for H. sapiens. That’s likely because there is no best diet; we’re all different enough that our diets need to be subtly and sometimes substantially different, too. But we’re also all similar enough that there are some very broad commonalities: more veggies and less meat; fresh food versus processed food.

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.

Not malnutrition. Not starvation. These are not pathways to more years, let alone better years. But fasting—allowing our bodies to exist in a state of want, more often than most of us allow in our privileged world of plenty—is unquestionably good for our health and longevity.

Luigi Cornaro, a fifteenth-century Venetian nobleman who could, and probably should, be considered the father of the self-help book.

Before the study, the maximum known lifespan for any rhesus monkey was 40 years. But of twenty monkeys in the study that lived on calorie-restricted diets, six reached that age, which is roughly equivalent to their reaching 120 in human terms.

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.

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.

A popular method is to skip breakfast and have a late lunch (the 16:8 diet). Another is to eat 75 percent fewer calories for two days a week (the 5:2 diet). If you’re a bit more adventurous, you can try skipping food a couple of days a week (Eat Stop Eat), or as the health pundit Peter Attia does, go hungry for an entire week every quarter.

Meat contains all nine of the essential amino acids.

Red meat also contains carnitine, which gut bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is suspected of causing heart disease.

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.

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.

Low levels of these amino acids correlate with increased lifespan26 and in human studies, a decreased consumption of branched-chain amino acids has been shown to improve markers of metabolic health significantly.

according to one study funded by the Centers for Disease Control and Prevention and published in 2017, individuals who exercise more—the equivalent of at least a half hour of jogging five days a week—have telomeres that appear to be nearly a decade younger than those who live a more sedentary life.

One recent study found that those who ran four to five miles a week—for most people, that’s an amount of exercise that can be done in less than 15 minutes per day—reduce their chance of death from a heart attack by 40 percent and all-cause mortality by 45 percent.

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.

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.2

actinobacterium secreted an antifungal compound. Sehgal named that compound rapamycin,

We’ve known for a long time that greater parental age is a risk factor for disease in the next generation. That’s the power of epigenetics.

Thanks to an increasingly sedentary lifestyle and the abundance of sugars and carbohydrates on every supermarket shelf around the globe, high blood sugar is causing the premature deaths of 3.8 million people a year.

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.

If Barzilai and his colleagues can show metformin has measurable benefits in the ongoing Targeting Aging with Metformin (TAME) study, the US Food and Drug Administration has agreed to consider aging as a treatable condition.

rapamycin, metformin, resveratrol, and NAD boosters, can mimic the benefits of low-calorie diets and exercise and extend the lifespan of diverse organisms.

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. Plants have survival circuits, too, and we think we might have evolved to sense the chemicals they produce in times of stress as an early-warning system, of sorts, to alert our bodies to hunker down as well.

for hundreds of years to come, doctors rebelled against the idea that they needed to wash their hands before surgery. Now infections, one of the chief reasons patients used to die after surgery, have become the very thing hospital personnel are most fastidiously attentive to preventing in the operating room. Just by washing up before surgery, we have profoundly improved the rates at which patients survive.

We now know that vaccines are the single most effective medical intervention in human history in terms of saving and extending lifespans.

By injecting the mice with stem cells inactivated by radiation and later adding a booster shot like those humans use for tetanus, hepatitis B, and whooping cough, the stem cells primed the immune system to attack cancers that normally would be invisible to the immune system.

The DNA in our cells holds about the same amount of data as a DVD, but in six feet of DNA that’s packed into a cell a tenth the size of a speck of dust. Together, all the DNA in our body, if laid end to end, would stretch twice the diameter of the solar system. Unlike a simple DVD, though, the DNA in our cells is wet and vibrating in three dimensions. And there aren’t 50 songs, there are more than 20,000.

• 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.

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.