Will you live to 120? · The Reset

Resetting the clock

In 2006, Shinya Yamanaka pushed the ball back up the hill — and won a Nobel Prize for proving the one-way trip was nothing of the kind. He took a fully specialized adult cell — an ordinary skin cell, sitting deep in its valley — and forced it to switch on just four genes (master regulators now called the Yamanaka factors). And the skin cell climbed back out of its valley, all the way to the top of the landscape, becoming a pluripotent cell again — able, once more, to become any cell type in the body. These reprogrammed cells are called induced pluripotent stem cells. Cell identity, it turned out, was not a permanent destination but a reversible state, held in place by the epigenome and capable of being reset. The landscape was not a one-way slope; with the right push, the ball could roll back up. (Yamanaka’s leap built on a stranger, earlier one: decades before, John Gurdon had shown by transplanting the nucleus of an adult cell into an egg that an adult cell still contains all the instructions to build a whole organism — the same insight that, years later, produced Dolly the cloned sheep. The information for youth was never lost. It was only switched off.)

Resetting the clock

Now connect that to aging, and the radical promise comes into focus.

When you reprogram an old cell back toward pluripotency, you do not only reset its identity. You reset its age. The epigenetic clock from Chapter 2 — the methylation pattern that tracks biological age — runs almost all the way back to zero. Telomeres, the counters from Chapter 1, can lengthen again. The accumulated epigenetic damage of decades is wiped, and the cell becomes, by the molecular measures we have, young again. This is rejuvenation of a wholly different kind from anything in the previous six chapters. Every intervention we have examined so far tried to slow the damage (the nutrient dial, Chapter 4) or clear it (senolytics, autophagy, Chapters 3 and 6) — to help the cell’s failing maintenance keep up. Reprogramming proposes something far more audacious: not to slow or clear the damage but to erase it, resetting the cell’s age the way every one of us was reset at conception, when two aged parental cells gave rise to a brand-new, age-zero embryo. The reset button, it turns out, exists. The cell has always known how to become young, because it does it every generation.

Deeper Water — what reprogramming actually does, and the two things it resets at once. The Yamanaka factors are transcription factors — proteins that bind DNA and switch genes on and off — and what they do, mechanistically, is drive a wholesale remodeling of the epigenome. They recruit the machinery that erases and rewrites methylation marks and reorganizes chromatin, dismantling the epigenetic pattern that defined the old, specialized cell and re-establishing the pattern of a pluripotent one. Crucially, this remodeling erases two distinct things that happen to be written in the same ink: the marks that specify the cell’s identity (skin cell, neuron) and the marks that have accumulated with age (the epigenetic drift of Chapter 2). The central scientific bet of this entire field is that these two can be decoupled — that you can erase the age marks while leaving the identity marks intact, rolling the ball partway up the hill to shed its years without rolling it so far that it forgets what kind of cell it is. Whether age and identity are cleanly separable, or whether they are too entangled in the same epigenetic ink to pull apart safely, is one of the deepest open questions in the field. This is also, you’ll notice, the most literal possible version of the “information theory of aging” from Chapter 2: if aging is the corruption of epigenetic information, then reprogramming is restoring the information from the cell’s own developmental backup — and the question of whether the backup is clean enough to restore from is exactly the question of whether the age marks and identity marks can be told apart.*

The catch: youth and cancer, one last time

By now you can feel the shape of what’s coming, because it is the shape this book keeps returning to. The reset button comes with a price, and the price is the same one we have paid in chapter after chapter.

The problem with full reprogramming is that erasing a cell’s age all the way to zero also erases its identity all the way to zero. A skin cell reprogrammed to pluripotency is no longer a skin cell; it doesn’t do the skin’s job. And pluripotent cells loose in a living body do something terrible: they form teratomas — grotesque tumors containing a chaotic jumble of tissues, teeth and hair and gut lining all tangled together, the unmistakable signature of cells with unlimited developmental potential and no instructions. So you cannot simply switch the four factors on throughout an old person’s body. You would not rejuvenate their organs; you would dissolve them into tumors.

This is the youth-and-cancer entanglement from Chapter 1 and Chapter 3, arriving now in its deepest and most fundamental form. In Chapter 1, the enzyme that keeps cells young (telomerase) was the one cancers switch on to become immortal. In Chapter 3, the cells that protect us from cancer when young (senescent cells) poison us when old. Here, at the bottom of the whole stack, the principle reaches bedrock: the very plasticity that lets a cell become young again — the loosening of its fixed identity, the reawakening of developmental potential — is exactly the plasticity that cancer exploits. Cancer, too, is in large part a loss of stable cell identity and a return to a more primitive, unlimited state. Reprogramming and cancer are not neighbors; they are drawing on the same well. The most powerful rejuvenation we know is dangerous for precisely the same reason it is powerful. The brake-and-price theme that opened this book — that in aging biology, the obvious intervention is never free, because the thing that makes a cell young is bound up with the thing that makes it cancerous — is not a coincidence repeated across seven chapters. It is, it turns out, a single deep fact about life, seen from seven angles.

Partial reprogramming: threading the needle

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