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

by David A. Sinclair

This is the cellular equivalent of distracting the cellular pianist.

Cas9, the CRISPR gene-editing tool from bacteria that cuts DNA at precise places.

DNA-editing genes such as Cas9 and I-PpoI are nature’s gifts to science.

To create a mouse to test the information theory, we inserted I-PpoI into a circular DNA molecule called a plasmid, along with all the regulatory DNA elements needed to control the gene, and then inserted that DNA into the genome of a mouse embryonic stem cell line we were culturing in plastic dishes in the lab. We then injected the genetically modified stem cells into a 90-cell mouse embryo called a blastocyst, implanted it into a female mouse’s uterus, and waited about twenty days for a baby mouse to show up.

This all sounds complicated, but it’s not. After some training, a college student can do it. It’s such a commodity these days, you can even order a mouse out of a catalog or pay ...

vital—because there’s nothing different about these mice until we feed them a low dose of tamoxifen.

tamoxifen would turn on the I-PpoI gene.

The enzyme would go to work, cutting the genome and slightly overwhelming the survival circuit,

And since tamoxifen has a half-life of only a couple of days, removing it from the mice’s food...

Her confusion was understandable. At 16 months old, a regular lab mouse still has a thick coat of fur, a sturdy tail, a muscular figure, perky ears, and clear eyes. A tamoxifen-triggered ICE mouse at the same age has thinning, graying hair, a bent spine, paper-thin ears, and cloudy eyes.

Remember, we’d done nothing to change the genome. We’d simply broken the mice’s DNA in places where there aren’t any genes and forced the cell to paste, or “ligate,” them back together. Just to make sure, later we broke the DNA in other places, too, with the same results. Those breaks had induced a sirtuin response. When those fixers went to work, their absence from their normal duties and presence on other parts of the genome altered the ways in which lots of genes were being expressed at the wrong time.

THE MAKING OF THE ICE MOUSE TO TEST IF THE CAUSE OF AGING MIGHT BE INFORMATION LOSS. A gene from a slime mold that encodes an enzyme that cuts DNA at a specific place was inserted into a stem cell and injected into an embryo to generate the ICE mouse. Turning on the slime mold gene cut the DNA and distracted the sirtuins, causing the mouse to undergo aging.

Here’s the vital takeaway: we could age mice without affecting any of the most commonly assumed causes of aging. We hadn’t made their cells mutate. We hadn’t touched their telomeres. We hadn’t messed with their mitochondria. We hadn’t directly exhausted their stem cells. Yet the ICE mice were suffering from a loss of body mass, mitochondria, and muscle strength and an increase in cataracts, arthritis, dementia, bone loss, and frailty.

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.

Bristlecones are, after all, our eukaryotic cousins. About half of their genes are close relatives of ours. Yet they do not age. Oh, they add years to their lives—thousands upon thousands of them, marked by the nearly microscopic rings hidden in their dense heartwood, which also record in their size, shape, and chemical composition climate events long past, as when the eruption of Krakatoa sent a cloud of ash around the globe in 1883, leaving a fuzzy ring of growth in 1884 and 1885, barely a centimeter from the outer ring of bark that marks our current time.

Yet even over the course of many thousands of years, their cells do not appear to have undergone any decline in function. Scientists call this “negligible senescence.”

It’s worth pausing to consider how remarkable it is that we find essentially the same longevity genes in every organism on the planet: trees, yeast, worms, whales, and humans. All living creatures come from the same place in primordium that we do. When we look through a microscope, we’re all made of the same stuff. 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.

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.

I believe the blame lies with M. superstes and the survival circuit.

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 ...

That’s aging. This loss of information is what leads each of us into a world of heart disease, cancer, pain, frailty, and death.

Yes. I can say with confidence that there is.

Why? One of our key findings, in a study we published in 2018,42 was that when treated with an NAD-boosting molecule that activated the SIRT1 enzyme, the elderly mice’s endothelial cells, which line the blood vessels, were pushing their way into areas of the muscle that weren’t getting very much blood flow. New tiny blood vessels, capillaries, were formed, supplying badly needed oxygen, removing lactic acid and toxic metabolites from muscles, and reversing one of the most significant causes of frailty in mice and in humans. That was how these old mice suddenly became such mighty marathoners.

Or, put more simply and perhaps even more seditiously: aging itself is a disease.

The way doctors treat illness today “is simple,” wrote S. Jay Olshansky, a demographer at the University of Illinois. “As soon as a disease appears, attack that disease as if nothing else is present; beat the disease down, and once you succeed, push the patient out the door until he or she faces the next challenge; then beat that one down. Repeat until failure.”14

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

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.

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.

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.

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.

The longevity regulators AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise, irrespective of caloric intake,

There’s really no way around this. We all need to be pushing ourselves, especially as we get older, yet only 10 percent of people over the age of 65 do.32 The good news is that we don’t have to exercise for hours on end. 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.

(Avoid microwaving these; it releases even more PCBs.)

the movement of Sir2 away from the mating-type genes to deal with DNA breaks and a whole lot of ensuing genome instability.

We’d shown that extra copies of the SIR2 gene could stabilize the rDNA and extend lifespan. We’d linked genetic instability to epigenetic instability and found one of the world’s first true longevity genes—and the yeast hadn’t had to go hungry to receive its benefits.

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

resveratrol, a natural molecule that is found in red wine and that many plants produce in times of stress.

There, I saw something incredible: the 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 ...

chemicals they produce in times of stress as an early-warning system, of sorts, to alert our bodies to hunker down as well.

And in collaboration with de Cabo, we discovered that when resveratrol is combined with intermittent fasting, it can greatly extend both average and maximum lifespan even beyond what fasting alone accomplishes.

“The study said that to get the same dose as they gave the mice you’d have to drink between 750 and 1,000 glasses of red wine every day,” the wife says. “The news just keeps getting better and better,” the husband replies.

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.

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.

Somehow they can cope with it. Perhaps they are just superefficient at repairing DNA breaks and head home before they get lost, or if half the sirtuins head off, the remaining enzymes can hold down the fort.

Waddington’s marbles from escaping their valleys. And even if they have started to head out of the valley, molecules such as NMN may push them back down, like extra gravity.