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

by David A. Sinclair

By studying resveratrol, we also learned that it is possible to activate sirtuins with a chemical. This prompted a flood of research into other sirtuin-activating compounds, called STACs, that are many times more potent than resveratrol at stimulating the survival circuit and extending healthy lifespans in animals. They go by names such as SRT1720 and SRT2104, both of which extend the healthy lifespan of mice when given to them late in life.

SRT1720 & 2104 STACs

Another STAC is NAD, sometimes written as NAD+.39 NAD has an advantage over other STACs because it boosts the activity of all seven sirtuins.

NAD+

NAD is a product of the vitamin niacin, a severe lack of which causes inflamed skin, diarrhea, dementia, skin sores, and ultimately death. And because NAD is used by over five hundred different enzymes, without any NAD, we’d be dead in thirty seconds.

NAD

We first discovered a gene called PNC1, which turns vitamin B3 into NAD. That led us to try boosting PNC1 by introducing four extra copies of it into the yeast cells, giving them five copies in total. Those yeast cells lived 50 percent longer than normal, but not if we removed the SIR2 gene. The cells were making extra NAD, and the sirtuin survival circuit was being engaged!

PNC1

Charles Brenner, who is now the head of biochemistry at the University of Iowa, discovered in 2004 that a form of vitamin B3 called nicotinamide riboside, or NR, is a vital precursor of NAD. He later found that NR, which is found in trace levels in milk, can extend the lifespan of yeast cells by boosting NAD and increasing the activity of Sir2. Once a rare chemical, NR is now sold by the ton each month as a nutraceutical.

NR

researchers, including us, were homing in on a chemical called nicotinamide mononucleotide, or NMN, a compound made by our cells and found in foods such as avocado, broccoli, and cabbage. In the body, NR is converted into NMN, which is then converted into NAD.

NMN

Give an animal a drink with NR or NMN in it,40 and the levels of NAD in its body go up about 25 percent over the next couple of hours, about the same as if it had been fasting or exercising a great deal.

Same result

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.

Comparison

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.

Mechanism

These cases could, perhaps, be the result of a placebo effect. But a trial in 2018 to test whether an NAD booster could restore the fertility of old horses was successful, surprising the skeptical supervising veterinarian. As far as I know, horses don’t experience the placebo effect.

Even menopause. horse without placebo effect

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.

Methods

And it’s very possible that there is an as-yet-undiscovered chemical out there, hiding in a microorganism such as S. hygroscopicus or in a flower such as G. officinalis, that is just waiting to show us another way to help our bodies stay healthier longer. And that’s just the natural chemicals—which are typically many times less effective than the synthetic drugs they inspire. Indeed, the emerging analogs of the molecules I’ve already described are demonstrating tremendous potential in early-stage human clinical trials.

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

Main

Just by washing up before surgery, we have profoundly improved the rates at which patients survive. Once we understood what the problem was, it was an easy problem to solve. For goodness’ sake, we solved it with soap.

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.

Wow. Cancer

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,

Zombie cells

Small numbers of senescent cells can cause widespread havoc. Even though they stop dividing, they continue to release tiny proteins called cytokines that cause inflammation and attract immune cells called macrophages that then attack the tissue. 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.2 Inflammation is also a driving force in heart disease, diabetes, and dementia.

Cytokines. Inflammation. Senescent cells

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.

Cytokines

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.

Senolytics

Cellular senescence is a consequence of our inherited primordial survival circuits, which evolved to stop cell division and reproduction when DNA breaks were detected. 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.

Main

George Williams was already on the case. His work, built upon by Judith Campisi from the Buck Institute for Research on Aging in California, proposes that we evolved senescence as a rather clever trick to prevent cancer when we are in our 30s and 40s. Senescent cells, after all, don’t divide, which means that cells with mutations aren’t able to spread and form tumors.

Senescent cells

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.

Senolytics

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

Quercetin

(Rapamycin, the Easter Island longevity molecule, is what’s known as a “senomorphic” molecule, in that it doesn’t kill senescent cells but does prevent them from releasing inflammatory molecules, which may be almost as good.

Rapamycin

The first human trials of senolytics were started in 2018 to treat osteoarthritis and glaucoma, conditions in which senescent cells can accumulate. It will be a few more years before we know enough about the effects and safety of these drugs to provide them to everyone, but if they work, the potential is vast.

We fight diseases of all kinds that God or Mother Nature gave us. We’ve been doing so for a long time, and we’re going to keep doing so for a long time to come.

There are two ways to play an old, scratched DVD with fidelity. You could buy a better DVD player, one with a more powerful laser that could reveal the data under the scratches. Or you could polish the disc to expose the information again, making the DVD as good as new. I’ve heard that a rag with toothpaste on it works just fine. Restoring youth in an organism is never going to be as simple as polishing a disk with toothpaste, but the first approach, putting a scratched DVD into a new player, was.

So a powerful laser

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.

Main

CLAUDE SHANNON’S 1948 SOLUTION TO RECOVERING LOST INFORMATION DURING DATA TRANSMISSIONS LED TO CELL PHONES AND THE INTERNET.

An “observer” who records the original data The original “correction data” And a “correcting device” to restore the original signal

In 2006, the Japanese stem cell researcher Shinya Yamanaka announced to the world that after testing dozens of combinations of genes, he had discovered that a set of four—Oct4, Klf4, Sox2, and c-Myc—could induce adult cells to become pluripotent stem cells, or iPSCs, which are immature cells that can be coaxed into becoming any other cell type.

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.

at the Salk Institute for Biological Studies in San Diego, have already engineered mice that have all of the Yamanaka factors from birth; these can be turned on by injecting the mice with doxycycline. In a now-famous study from 2016, when Belmonte triggered the Yamanaka factors for just two days a week throughout the lifespan of a prematurely aging mouse breed called LMNA, the mice remained young compared to their untreated siblings and lived 40 percent longer.

Yamanaka factor. Doxycycline.

The intricate network of cells and fibers that transmit nervous signals across our bodies is divided into two parts: the peripheral system and the central system. We’ve known for a long time that peripheral nerves, like those in our arms and legs, can grow back, albeit very, very slowly. The nerves of the central system, though—optic nerves and the nerves of the spinal cord—never grow back.

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.

Main

We know from our experiments that the biological information correcting device requires enzymes called ten-eleven translocation enzymes, or TETs, which clip off methyl tags from DNA, the same chemical tags that mark the passage of the Horvath aging clock.

TETs

How the TETs know to remove only the more recent methyls while preserving the original ones is a complete mystery.

Thanks to the plummeting prices of DNA sequencing, wearable devices, massive computing power, and artificial intelligence, we’re moving into a world in which treatment decisions no longer have to be based on what is best for most people most of the time. These technologies are available to some patients now and will be available to most people on the planet in the next couple of decades. That’s going to save millions of lives—and it’s going to extend average healthy lifespans irrespective of whether we extend maximum lifespans.

It won’t be long before prescribing a drug without first knowing a patient’s genome will seem medieval.

When I asked her what food had been the most surprising, she didn’t hesitate. “Grapes!” she exclaimed. “Avoid grapes.”

Avoid grapes

As I write this, I am wearing a regular-sized ring that is monitoring my heart rate, body temperature, and movements. It tells me each morning if I slept well, how much I dreamed, and how alert I will be during the day.

Interesting. health monitor

In 2018, a peer-reviewed study published by the team at InsideTracker and me, showed that biotracking and computer-generated food recommendations reduce blood sugar levels as efficiently as the leading diabetes drug, while optimizing other health biomarkers,

(If you don’t get flu vaccines or vaccinate your kids, please do. We are privileged to live in an age in which we can protect ourselves and our children from potentially deadly diseases.)

Vaccine

One report, which examined sixty-five different scientific projections, concluded that the most common estimated “carrying capacity” of our planet is 8 billion.

capacity

If there has been a consistent driving force that has made our world a kinder, more tolerant, more inclusive, and more just place, it is that humans don’t last long.

Interesting. what if people are less in a rush

“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.”26

Wow. win when you outlive?

nationalism has moved from being the purview of angry fringe groups to being the force behind powerful political movements around the world. There is no one single factor that can explain all of these movements, but the economist Harun Onder is among those who have made a demographic observation: nationalist arguments tend to resonate with older people.27 Therefore, it is likely that the antiglobalist wave will be with us for some time to come.

older people and nationalism

Older constituencies support older politicians. As it is now, politicians seem steadfastly opposed to stepping down in their 70s and 80s. More than half of the US senators running for reelection in 2018 were 65 or older.

Older politician

Riches are not just invested into companies; they provide rich people with access to the world’s leading doctors (there are about five in the United States that they all seem to use), nutritionists, personal trainers, yoga instructors, and the latest medical therapies—stem cell injections, hormones, longevity drugs—which mean they stay healthier and live longer, which allows them to accumulate even more wealth during their lifetimes.

Money spent

Well, as it turned out, the disease was the cure. The Cannon Street Bridge, completed the same year that cursed London with the Final Catastrophe and blessed the world with the genius of H. G. Wells, stands as a testament to the ways in which the London of yesterday came to be the London of today, of how population and progress are intrinsically connected, and, indeed, of utopian dreams realized. For London’s nineteenth-century population boom forced the city to confront its most horrific challenges. There was simply no other option. The choice was clear: adapt or perish.

The cannon street railway