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

by David A. Sinclair

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.

You might recall that one of the key hallmarks of aging is the accumulation of senescent cells. These are cells that have permanently ceased reproduction. Young human cells taken out of the body and grown in a petri dish divide about forty to sixty times until their telomeres become critically short, a point discovered by the anatomist Leonard Hayflick that we now call the Hayflick limit.

telomerase can extend telomeres—the discovery of which afforded Elizabeth Blackburn, Carol Greider, and Jack Szostak a Nobel Prize in 2009—it is switched off to protect us from cancer, except in stem cells.

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.

The other, safer solution to a short telomere is to shut the cell down. This happens, I believe, by permanently engaging the survival circuit. The exposed telomere, seen as a DNA break, causes epigenetic factors such as the sirtuins to leave their posts permanently in an attempt to repair the damage, but there is no other DNA end to ligate it to.

Triggering of the DNA damage response and major alterations to the epigenome are well known to occur in human senescent cells—and when we introduce epigenetic noise into the ICE cells they go on to senesce earlier than untreated cells, so maybe this idea has merit. I suspect that senescence in nerve and muscle cells, which don’t divide much or at all, is the result of epigenetic noise that causes cells to lose their identity and shut down. This once-beneficial response, which evolved to help cells survive DNA damage, has a dark side: the permanently panicked cell sends out signals to surrounding cells, causing them to panic, too.

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, and when we do that, they light up clearly. The older the cells, the more blue we see. For example, a sample of white fat looks white when we are in our 20s, pale blue in middle age, and dark royal blue in old age. And that’s scary, because when we have lots of these senescent cells in our bodies, it’s a clear sign that aging is getting a strong grip on us.

And cytokines don’t just cause inflammation; they also cause other cells to become zombies, like a biological apocalypse.

We already know that destroying senescent cells in mice can give them substantially healthier and significantly longer lives. It keeps their kidneys functioning better for longer. It makes their hearts more resistant to stress. Their lifespans, as a result, are 20 to 30 percent longer,

But if senescence evolved to prevent cancer, why would it eventually promote cancer in adjacent tissue, not to mention a host of other aging-related symptoms?

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. Yes, natural selection is callous, but it works.

If you put a tiny dab of these cells under a young mouse’s skin, it won’t be long before inflammation spreads and the entire mouse is filled with zombie cells that cause premature signs of aging.

(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.

retrotransposons, are prevented by chromatin from jumping out of the genome, then breaking DNA to reinsert themselves elsewhere. We and others have shown that LINE-1 genes are bundled up and rendered silent by sirtuins.6 But as mice age, and possibly as we do as well, these sirtuins become scattered all over the genome, having been recruited away to repair DNA breaks elsewhere, and many of them never find their way home.

Without sirtuins to spool the chromatin and silence the transposon DNA, cells start to transcribe these endogenous viruses.

Over time, as mice age, the once silent LINE-1 prisoners are turned into RNA and the RNA is turned into DNA, which is reinserted into the genome at a different place. Besides creating genome instability and epigenomic noise that causes inflammation, LINE-1 DNA leaks from the nucleus into the cytoplasm, where it is recognized as a foreign invader. In response, the cells release even more immunostimulatory cytokines that cause inflammation throughout the body.

senescent cells, like cancers, remain invisible to the immune system by waving little protein signs that say, “No zombie cells here.”

Yes, the solution to aging could be cellular reprogramming, a resetting of the landscape—the way, for instance, that jellyfish have been shown to do by using small body fragments to regenerate polyps that spawn a dozen new jellies.

The DNA blueprint to be young, after all, is always there, even when we are old. So how can we make the cell reread the blueprint?

Dolly, whose birth was met with a heated public debate about the purported dangers of cloning. The debate overshadowed the most important point: that old DNA retains the information needed to be young again.

DNA stores information digitally, a robust format, whereas the epigenome stores it in analog format, and is therefore prone to the introduction of epigenetic “noise.”

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.

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

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.

four genes Yamanaka factors.

I predict that cellular reprogramming in the body will first be used to treat age-related diseases in the eye, such as glaucoma and macular degeneration (the eye is the organ of choice to trial gene therapies because it is immunologically isolated).

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

about 5 percent of cancer patients, or 86,500 people, are misdiagnosed every year.

That’s the idea behind one of the cancer-fighting innovations we discussed earlier, CAR T-cell therapy, in which doctors remove immune system cells from a patient’s blood and add a gene that allows the cells to bind to proteins on the patient’s tumor. Grown en masse in a lab and then reinfused into the patient’s body, the CAR T-cells go to work, hunting down cancer cells and killing them by using the body’s own defenses.

In this approach, drugs are used to block the ability of cancer cells to present themselves as regular cells, essentially confiscating their fake passports and thus making it easier for T-cells to discriminate between friend and foe. This is the approach that was used, along with radiation therapy, by former president Jimmy Carter’s doctors to help his immune system fight off the melanoma in his brain and liver. Prior to this innovation, a diagnosis like his was, without exception, fatal.

There are 3.234 billion base pairs, or letters, in the human genome. In 1990, when the Human Genome Project was launched, it cost about $10 to read just one letter in the genome, an A, G, C, or T. The entire project took ten years, thousands of scientists, and cost a few billion dollars. And that was for one genome.

Today, I can read an entire human genome of 25,000 genes in a few days for less than a hundred dollars on a candy bar–sized DNA sequencer called a MinION that I plug into my laptop. And that’s for a fairly complete readout of a human genome, plus the DNA methyl marks that tell you your biological age.

But those aren’t the only questions that our DNA can answer. Increasingly, it can also tell you what foods to eat, what microbiomes to cultivate in your gut and on your skin, and what therapies will work best to ensure that you reach your maximum potential lifespan. And it can give you guidance for how to treat your body as the unique machine it is.

large gender differences in the effects of longevity genes and molecules have been seen.

insulin or mTOR signaling typically favor females, whereas chemical therapies typically favor males, and no one really knows why.

pharmacoepigenetics.

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

All of this means we’re on the way to a fundamental shift in the way we search for, diagnose, and treat disease. Our flawed, symptom-first approach to medicine is about to change.

Changes in how you move your hands while speaking, and even the manner in which your strike the keys on your computer,25 will be used to diagnose neurodegenerative diseases years before symptoms would be noticed by you or your doctor.

Antibiotic-resistant strains of bacteria continue to spread, and new studies implicate bacteria as causal agents in cancer, heart disease, and Alzheimer’s disease.

“high-throughput sequencing.”

We often fail to acknowledge that knowledge is multiplicative and technologies are synergistic.

We’ll never destroy the global patriarchy if our children don’t first practice on their fathers.