Lifespan. Dr David A. Sinclair

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. Functionality of proteins, such as the ones coded for by the Werner gene, is therefore vital, since more than half of our genome is, in fact, repetitive.

      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.

      After the swap, the yeast cells’ lifespan was cut in half. Ordinarily, this would not have been news. Many events unrelated to aging—such as being eaten by a mite, drying out on a grape, or being placed in an oven—can and do shorten the lifespan of yeast cells. And here we’d messed with their DNA, which could have short-circuited the cells in a thousand different ways to cause early death.

      But those cells weren’t just dying. They were dying after a precipitous decline in health and function. As the SGS1 mutants became older, they slowed down in their cell cycle. They grew larger. Both male and female “mating-type” genes (descendants of gene A) were switched on at the same time, so they were sterile and couldn’t mate. These were all known hallmarks of aging in yeast. And it was happening more quickly in the mutants we’d made. It certainly looked like a yeast version of Werner’s.

      Using specialized stains, we colored the DNA blue and used red for the nucleolus, which sits inside the nucleus of all eukaryotic cells. That made it easier to see under the microscope what was happening at a cellular level.

      And what was happening was fascinating.

      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.

      In the aged SGS1 cells, the nucleolus looked as if it had exploded. Instead of a single red crescent swimming in a blue ocean, the nucleolus was scattered into half a dozen small islands. It was tragic and beautiful. The picture, which would later appear in the August 1997 issue of the prestigious journal Science, still hangs in my office.

      What happened next was both enchanting and illuminating. In response to the damage, like rats to the call of the Pied Piper, the protein called 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.

      That was a beautiful sight to me, but it was a problem for the yeast. 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.

      When sirtuins left the mating genes—the ones descended from gene A that controlled fertility and reproduction—the mutant cells turned on both male and female genes, causing them to lose their sexual identity, just as in normal old cells, but much earlier.

      I didn’t understand at first why the nucleolus was exploding, let alone why the sirtuins were moving toward it as the cells grew older. I agonized over the question for weeks.

      And then one night, after a long day in the lab, I woke up with an idea.

      It came in the space between sleep-deprived delirium and deep dreaming. The wisps of a concept. A few words jumbled together. A muddled picture of something. That was enough, though, to jolt me awake and pull me from my bed.

      I grabbed my notebook and went to the kitchen. There, hunched over the table in the early morning hours of October 28, 1996, I began to write.

      I wrote for about an hour, jotting down ideas, drawing pictures, sketching out graphs, formulating new equations.¹¹ Scientific observations that had previously made no sense to me were falling perfectly into a larger picture. 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.

      There was, I imagined, a singular process that controlled them all. Not a countless number of separate cellular changes or diseases. Not even a set of hallmarks that could be addressed one at a time. There was something bigger—and more singular—than any of that.

      This was the foundation for understanding the survival circuit and its role in aging.

      The next day I showed Guarente my notes. I was excited; it felt like the biggest idea I’d ever had. But I was nervous, too; afraid he would find a hole in my logic and tear it apart. Instead, he looked over my notebook quietly, asked a few questions, and sent me on my way with six words.

      “I like it,” he said. “Go prove it.”

      THE RECITAL

      To understand the Information Theory of Aging, we need to pay another visit to the epigenome, the part of the cell that the sirtuins help control.

      Up close, the epigenome is more complex and wonderful than anything we humans have 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 skin cell is the epigenome, the collective term for the control systems and cellular structures that tell the cell which genes should be turned on and which should remain off. And this, far more than our genes, is what actually controls much of our lives.

      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) or allegretto (played quickly). For master pianists, there are hundreds of ways to play each individual key and endless ways to play the keys together, in chords and combinations that create music we know as jazz, ragtime, rock, reggae, waltzes, whatever.

      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.

      Yes, sometimes the size, shape, and condition of a piano dictate what a pianist can do with it. It’s tough to play a concerto on an eighteen-key toy piano, and it’s mighty hard to make beautiful music on an instrument that hasn’t been tuned in fifty years. Likewise, the genome certainly dictates what the epigenome can do. 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. Similarly, the child of two parents from a long line of people with black hair and brown eyes isn’t likely to develop blond hair and blue eyes, but twin agouti mice in the lab can turn out brown or golden, depending on how much the