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

by David A. Sinclair

We’ve found longevity genes that control the body’s defenses against aging and thus offer a path to slowing aging through natural, pharmaceutical, and technological interventions. But unlike the oncogenes that were discovered in the 1970s and that have given us a good target for going to battle agains...

Because our genes did not evolve to...

The work Mortimer and Johnston did—and, in particular, a seminal paper in 1959 that demonstrated that mother and daughter yeast cells can have vastly different lifespans—would set the stage for a world-shattering change in the way we view the limits of life.

and I agreed on one thing: if we couldn’t solve the problem of aging in yeast, we had no chance in humans.

Afterward, two things became clear. One, don’t bring wine to an interview because it can be seen as a bribe.

Now that the Werner gene, known as WRN, had been identified in humans, the next step was to test if the similar gene in yeast had the same function.

If so, we could use yeast to more rapidly determine the cause of Werner syndrome and perhaps help us better understand aging in general.

In yeast, the equivalent of the WRN gene is Slow Growth Suppressor 1, or SGS1.

The gene was already suspected to code for a type of enzyme called a DNA helicase that untangles tangled strands of DNA before they break. Helicases are especially important in repetitive DNA sequences that are inherently prone to tangling and breaking.

Through a gene-swapping process in which cells are tricked into picking up extra pieces of DNA, we swapped out the functional SGS1 gene with a mutant version. In effect, we were testing to see if it was possible to give the yeast Werner syndrome.

The nucleolus is a part of the nucleus in which ribosomal DNA, or rDNA, resides. rDNA is copied into ribosomal RNA, which is used by ribosome enzymes to stitch amino acids together to make every new protein.

Sir2—the first known sirtuin, which is encoded by the gene SIR210 and descended from gene B—had moved away from the mating genes that control fertility and into the nucleolus.

Sir2 has an important job: it is an epigenetic factor, an enzyme that sits on genes, bundles up the DNA, and keeps them silent.

At the molecular level, Sir2 achieves this via its enzymatic activity, making sure that chemicals called acetyls don’t accumulate on the histones and loosen the DNA packaging.

Broken DNA causes genome instability, I wrote, which distracts the Sir2 protein, which changes the epigenome, causing the cells to lose their identity and become sterile while they fixed the damage. Those were the analog scratches on the digital DVDs. Epigenetic changes cause aging.

“I like it,” he said. “Go prove it.”

invented. It consists of strands of DNA wrapped around spooling proteins called histones, which are bound up into bigger loops called chromatin, which are bound up into even bigger loops called chromosomes.

Sirtuins instruct the histone spooling proteins to bind up DNA tightly, while they leave other regions to flail around. In this way, some genes stay silent, while others can be accessed by DNA-binding transcription factors that turn genes on.12 Accessible genes are said to be in “euchromatin,” while silent genes are in “heterochromatin.” By removing chemical tags on histones, sirtuins help prevent transcription factors from binding to genes, converting euchromatin into heterochromatin.

Every one of our cells has the same DNA, of course, so what differentiates a nerve cell from a...

which genes should be turned on and which sho...

One of the best ways to visualize this is to think of our genome as a grand piano.13 Each gene is a key. Each key produces a note.

And from instrument to instrument, depending on the maker, the materials, and the circumstances of manufacturing, each will sound a bit different, even if played the exact same way. These are our genes. We have about 20,000 of them, give or take a few thousand.14

Each key can also be played pianissimo (soft) or forte (with force). The notes can be tenuto (held) o...

The pianist that makes this happen is the epigenome.

Through a process of revealing our DNA or bundling it up in tight protein packages, and by marking genes with chemical tags called methyls and acetyls composed of carbon, oxygen, and hydrogen, the epigenome uses our genome to make the music of our lives.

A caterpillar can’t become a human being, but it can become a butterfly by virtue of changes in epigenetic expression that occur during metamorphosis, even though its genome never changes.

Studies of identical twins place the genetic influences on longevity at between 10 and 25 percent which, by any estimation, is surprisingly low.16

It’s important to remember that there is nothing wrong with the piano. And the pianist is playing most of the notes prescribed by the composer. She’s just also playing some extra notes. Initially, this is just annoying. Over time it becomes unsettling. Eventually it ruins the concerto. Indeed, we’d assume that there was something wrong with the pianist. Someone might even rush onto the stage to make sure she is all right.

chaos. It is driven in large part by highly disruptive insults to the cell, such as broken DNA, as it was in the original survival circuit of M. superstes and in the old yeast cells that lost their fertility. And this, according to the Information Theory of Aging, is why we age. It’s why our hair grays. It’s why our skin wrinkles. It’s why our joints begin to ache.

lot. As good scientists, what we had left to do was to try our best to disprove it and see how long it survived.

extrachromosomal ribosomal DNA circles,

Just like the mutants, the normal old yeast cells were packed with ERCs. That was a “Eureka!” moment. Not proof—a good scientist never has proof of anything—but the first substantial confirmation of a theory, the foundation upon which I and others would build more discoveries in the years to come.

When the extra SIR2 was added, ERCs were prevented, and he saw a 30 percent increase in the yeast cells’ lifespan,

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

The implications were profound: if we could intervene in any of these steps, we might help people live longer.

SIRT1, SIRT6, and SIRT7,

The others, SIRT3, SIRT4, and SIRT5, reside in mitochondria, where they control energy metabolism, while SIRT2 buzzes around the cytoplasm, where it controls cell division and healthy egg production.

I had noticed that yeast cells fed with lower amounts of sugar were not just living longer, but their rDNA was exceptionally compact—significantly delaying the inevitable ERC accumulation, catastrophic numbers of DNA breaks, nucleolar explosion, sterility, and death.

But is the survival circuit causing aging in mammals? What parts of the system survived the billion years, and which are yeast specific? Those questions are on the cutting edge of human knowledge right now, but the answers are beginning to reveal themselves.

What I’m suggesting is that the SIR2 gene in yeast and the SIRT genes in mammals are all descendants of gene B, the original gene silencer in M. superstes.30 Its original job was to silence a gene that controlled reproduction.

I’ve come to think of sirtuins as the directors of a multifaceted disaster response corps, sending out a variety of specialized emergency teams to address DNA stability, DNA repair, cell survivability, metabolism, and cell-to-cell communication. In a way, this is like the command center for the thousands of utility workers who descended upon Louisiana and Mississippi in the wake of Hurricane Katrina in 2005. Most of the workers weren’t from the Gulf Coast, but they came, did their level best to fix what was broken, and then went home.

When sirtuins shift from their typical priorities to engage in DNA repair, their epigenetic function at home ends for a bit. Then, when the damage is fixed and they head back to home base, they get back to doing what they usually do: controlling genes and making sure the cell retains its identity and optimal function.

What could cause so many emergencies? DNA damage. And what causes that? Well, over time, life does. Malign chemicals. Radiation. Even normal DNA copying. These are the things that we’ve come to believe are the causes of aging,

It’s not so much that the sirtuins are overwhelmed, though they probably are when you are sunburned or get an X-ray; what’s happening every day is that the sirtuins and their coworkers that control the epigenome don’t always find their way back to their original gene stations after they are called away. It’s as if a few emergency workers who came to address the damage done in the Gulf Coast by Katrina had lost their home address. Then disaster strikes again and again, and they must redeploy.

How does the SIR2 gene actually turn off genes? SIR2 codes for a specialized protein called a histone deacetylase, or HDAC, that enzymatically cleaves the acetyl chemical tags from histones, which, as you’ll recall, causes the DNA to bundle up, preventing it from being transcribed into RNA.

When the Sir2 enzyme is sitting on the mating-type genes, they remain silent and the cell continues to mate and reproduce. But when a DNA break occurs, Sir2 is recruited to the break to remove the acetyl tags from the histones at the DNA break.

This bundles up the histones to prevent the frayed DNA from being chewed back and to help rec...

Once the DNA repair is complete, most of the Sir2 protein goes back to the mating-type genes to silence them and restore fertility. That is, unless there is another emergency, such as the massive genome instability that occ...

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.31

Living for 28 divisions was no advantage over those that lived for 24 and, because Sir2 uses up energy, having more of the protein may have even been a disadvantage. In the lab, however, we don’t notice any disadvantage because the yeast are given more sugar than they could possibly ever eat. By adding extra copies of the SIR2 gene, we gave the yeast cells what evolution failed to provide.