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

by David A. Sinclair

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.

Wow

“I accustomed myself to the habit of never fully satisfying my appetite, either with eating or drinking,” Cornaro wrote in his First Discourse on the Temperate Life, “always leaving the table well able to take more.”

Reducing calories works even in yeast. I first noticed this in the late 1990s. Cells fed with lower doses of glucose were living longer, and their DNA was exceptionally compact—significantly delaying the inevitable ERC accumulation, nucleolar explosion, and sterility.

It engages the survival circuit, telling longevity genes to do what they have been doing since primordial times: boost cellular defenses, keep organisms alive during times of adversity, ward off disease and deterioration, minimize epigenetic change, and slow down aging.

Malnutrition?

the earlier the mice start on CR, the greater the lifespan extension.

Intermittent fasting, or IF—eating normal portions of food but with periodic episodes without meals—is often portrayed as a new innovation in health.

IF.periodic table

In 1946, University of Chicago researchers Anton Carlson and Frederick Hoelzel subjected rats to periodic food restriction and found, when they did, that those that went hungry every third day lived 15 to 20 percent longer than their cousins on a regular diet.

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.

5 days a month

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

IGF-1. insulin-like growth factor 1

Many of the centenarians in this region have spent their lives eschewing a morning meal. They generally eat their first small meal of the day around noon, then share a larger meal with their families at twilight. In this way, they typically spend sixteen hours or more of each day without eating.

Interesting.small brunch. Normal dinner

Over time, some of these ways of limiting food will prove to be more effective than others. 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.

Different ways

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.

Red meat

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.

Good and bad. Amino acid

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.

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.

Limit dairy and animal protein

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.

Methionine

The same is true for arginine and the three branched-chain amino acids, leucine, isoleucine, and valine, all of which can activate mTOR.

putting our bodies into nutritional adversity isn’t going to maximally trigger our longevity genes. We need to induce some physical adversity, too.

Exercise

And 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.

Wow.running

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.

Raise NAD level

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.

exercises

Because it’s not the absence of food or any particular nutrient that puts these genes into action; instead it is the hormesis program governed by the survival circuit, the mild kind of adversity that wakes up and mobilizes cellular defenses without causing too much havoc.

Hormesis. Mild Adversity

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.33 That’s a massive effect.

Facts

The big shock was that the health benefits were remarkably similar no matter how much running the people had done. Even about ten minutes of moderate exercise a day added years to their lives.35

Facts

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

Facts

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. This is the hypoxic response, and it’s great for inducing just enough stress to activate your body’s defenses against aging without doing permanent harm.

Wow.facts

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. We’ve known for a long time that these bodily activities fall as we age. What we also know now is that the genes most impacted by exercise-induced stress can bring them back to the levels associated with youth.

Facts

In other words: exercise turns on the genes to make us young again at a cellular level.

Main

Often I’m asked, “Can I just eat what I want and run off the extra calories?” My answer is “Unlikely.” When you give rats a high-calorie diet and allow them to burn ...

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.

Cold

Cryotherapy—a few minutes in a box superchilled to −110°C or −166°F—is an increasingly popular method of inducing a helping of this sort of stress to our bodies, although the research is still a ways away from being conclusive as to how, why, and even whether it truly works.

Cyrotherapy

Hypothermia is not good for our health. Neither is frostbite. But goose bumps, chattering teeth, and shivering arms aren’t dangerous conditions—they’re simply signs that you’re not in Sydney. And when we experience these conditions often enough, our longevity genes get the stress they need to order up some additional healthy fat.

Hypothermia

We know from work in my lab that raising the temperature of yeast—from 30°C to 37°C, just below the limits of what those single-celled organisms can sustain—turns on the PNC1 gene and boosts their NAD production, so their Sir2 proteins can work that much harder.

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.

Main

You can’t avoid radon particles or cosmic rays unless you live in a lead box at the bottom of the ocean. And even if you were to move to a desert island, the fish you’d have to eat would likely contain mercury, PCBs, PBDEs, dioxins, and chlorinated pesticides, all of which can damage your DNA.64 In our modern world, even with the most “natural” lifestyle you can follow, this sort of DNA damage is inevitable.

Inevitable

there are no biological, chemical, or physical laws that say life must end. Yes, aging is an increase in entropy, a loss of information leading to disorder. But living things are not closed systems. Life can potentially last forever, as long as it can preserve critical biological information and absorb energy from somewhere in the universe.

It it a step by step process

Because in recent years it has become clear that rapamycin isn’t just an antifungal compound and it isn’t just an immune system suppressor; it’s also one of the most consistently successful compounds for extending life.

Rapamycin

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

Metformin

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.

Metformin

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.

Metformin

we’d reported that the cause of yeast aging was the movement of Sir2 away from the mating-type genes to deal with DNA breaks and a whole lot of ensuing genome instability.27 We’d shown that extra copies of the SIR2 gene could stabilize the rDNA and extend lifespan.

Sir2

we’d reported that the cause of yeast aging was the movement of Sir2 away from the mating-type genes to deal with DNA breaks and a whole lot of ensuing genome instability.27 We’d shown that extra copies of the SIR2 gene could stabilize the rDNA and extend lifespan.

Sir2 away

The first SIRT1-activating compound, or STAC, was a polyphenol called fisetin, which helps gives plants such as strawberries and persimmons their color and is now known to also kill senescent cells.

SIR1. STAC.fisetin. strawberries

The second was a molecule called butein, which can be found in numerous flowering plants as well as a toxic plant known as the Chinese lacquer tree.

Butein

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.

Main!

It seemed like a joke’s punch line—not only had we found a calorie-restriction mimetic, something that could extend longevity without hunger, but we’d found it in a bottle of red wine.

Red wine

we get resveratrol from grapes, aspirin from willow bark, metformin from lilacs, epigallocatechin gallate from green tea, quercetin from fruits, and allicin from garlic.

Food

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.29

Xanohormesis. Plant survival circuit

Look for the most highly colored ones because xenohormetic molecules are often yellow, red, orange, or blue. One added benefit: they tend to taste better.

The best wines in the world are produced in dry, sun-exposed soil or from stress-sensitive varietals such as Pinot Noir; as you might guess, they also contain the most resveratrol.

Pinot Noir