Lifespan: Why We Age—and Why We Don't Have To

by David A. Sinclair

Our DNA is not our destiny.

Steinway grand.

senescence

telomere

blot

wispy

Not proof—a good scientist never has proof of anything—but

hoping. Our hypothesis seemed to be standing up to scrutiny: the fundamental, upstream cause of sterility and aging in yeast was the inherent instability of the genome.

Youth → broken DNA → genome instability → disruption of DNA packaging and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death.

But what if we could intervene in all of them? Could we stop aging?

Crucially, by demonstrating that if you add an ERC to young cells they age prematurely, we had crucial evidence that ERCs don’t just happen during aging, they cause it.

That was an astonishing revelation: over a billion years of separation between yeast and us, and, in essence, the circuit hadn’t changed.

30 Its original job was to silence a gene that controlled reproduction.

nastygrams.

Well, over time, life does.

cleaves

This is why adding an extra copy of the SIR2 gene extends lifespan and delays infertility: cells have enough Sir2 to repair DNA breaks and enough Sir2 to silence the mating-type genes.

What matters is that it is being damaged and that sirtuins are rushing all over the place to address that damage, leaving their typical responsibilities and sometimes returning to other places along the genome where they are silencing genes that aren’t supposed to be silenced.

goopy

tamoxifen.

Horvath Clock—an

gnarled

teachers.

Bristlecones

cnidarians

desiccation.

Benjamin Button teach us: that cellular age can be fully reset, something I’m convinced we will be able to do one day without losing our wisdom, our memories, or our souls.

ascertain

jostled—envision

supple,

analog

digital

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

But that doesn’t mean we need to wait to take advantage of all that we’ve learned about engaging the epigenetic survival circuit and living longer and healthier lives. We don’t need to wait to take advantage of the Information Theory of Aging. There are steps we can take right now to live much longer and much healthier lives. There are things we can do to slow, stop, and even reverse aspects of aging.

motley

that aging is not an inevitable part of life but rather a “disease process with a broad spectrum of pathological consequences.”

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

“decrepitude”

“feebleness

fussy

This is why heart disease, type 2 diabetes, and dementia are major focuses of research and interventionary medical care, while aging is not, even though aging is the greatest cause of all those diseases.

ire

“the idea that people die of pure aging, without pathology, is nuts.”

obfuscates

though it’s certainly important to know why someone fell from a cliff, it’s equally important to know what brought that person to the precipice in the first place.

“It is possible that death may be the consequence of two generally co-existing causes; the one, chance, without previous disposition to death or deterioration; the other, a deterioration, or an increased inability to withstand destruction.”

The first part of the law says that there is an internal clock that ticks away at random, like the chance a glass at a restaurant will break; essentially a first-order rate reaction, similar to radioactive decay, with some glasses lasting far longer than most. The second part says that, as time passes, due to an unknown runaway process, humans experience an exponential increase in their probability of death.

For larger organisms, we don’t know exactly what the two clocks are, but we do know in yeast cells: the chance clock is the formation of an rDNA circle, and the exponential clock is the replication and exponential increase in the numbers of rDNA circles, with the resulting movement of Sir2 away from the silent mating-type genes that causes sterility.8

amenable

pleas