field, I dreamt of publishing just one study in a top-tier journal. During those years, our group was publishing one every few months.
We demonstrated that the redistribution of Sir2 to the nucleolus is a response to numerous DNA breakages, which happen as a result of ERCs multiplying and inserting back into the genome or joining together to form superlarge ERCs. When Sir2 moves to combat DNA instability, it causes sterility in old, bloated yeast cells. That was the first step of the survival circuit, though at the time we had no idea that it was as ancient and as essential to our very existence as it turned out to be.
We told the world that we could give yeast a Werner-like syndrome, causing exploded nucleoli.18 We described the ways in which mutants of SGS1, those we’d plagued with the yeast equivalent to the Werner syndrome mutation, accumulated ERCs more rapidly, leading to premature aging and a shortened lifespan.19 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. And by artificially breaking the DNA in the cell and watching the cellular response, we showed why sirtuins move—to help with DNA repair.20 That turned out to be the second step of the survival circuit.21 The DNA damage that gave rise to the ERCs was distracting Sir2 from the mating-type genes, causing them to become sterile, a hallmark of yeast aging.
It was epigenomic noise in its purest form.
It took another twenty years to learn if those findings in yeast were relevant to organisms more complex than yeast. We mammals have seven sirtuin genes that have evolved a variety of functions beyond what simple SIR2 can do. Three of them, SIRT1, SIRT6, and SIRT7, are critical to the control of the epigenome and DNA repair. 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.
There had been many clues along the way. Brown University’s Stephen Helfand showed that adding extra copies of the dSir2 gene to fruit flies suppresses epigenetic noise and extends their lifespan. We found that SIRT1 in mammals moves from silent genes to help repair broken DNA in mouse and human cells.22 But the true extent to which the survival circuit is conserved between yeast and humans wasn’t fully known until 2017, when Eva Bober’s team at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, reported that sirtuins stabilize human rDNA.23 Then, in 2018, Katrin Chua at Stanford University found that, by stabilizing human rDNA, sirtuins prevent cellular senescence—essentially the same antiaging function as we had found for sirtuins in yeast twenty years earlier.24
That was an astonishing revelation: over a billion years of separation between yeast and us, and, in essence, the circuit hadn’t changed.
By the time those findings appeared, though, it was clear to me that epigenomic noise was a likely catalyst of human aging. Two decades of research had already been leading us in that direction.25
In 1999, I moved from MIT across the river to Harvard Medical School, where I set up a new lab on aging. There I was hoping to answer a new question that had increasingly been occupying my thoughts.
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.
Why was that happening?
THE SURVIVAL CIRCUIT COMES OF AGE
Our DNA is constantly under attack. On average, each of our forty-six chromosomes is broken in some way every time a cell copies its DNA, amounting to more than 2 trillion breaks in our bodies per day. And that’s just the breaks that occur during replication. Others are caused by natural radiation, chemicals in our environment, and the X-rays and CT scans that we’re subjected to.
If we didn’t have a way to repair our DNA, we wouldn’t last long. That’s why, way back in primordium, the ancestors of every living thing on this planet today evolved to sense DNA damage, slow cellular growth, and divert energy to DNA repair until it was fixed—what I call the survival circuit.
Since the yeast work, evidence that yeast aren’t so different from us has continued to accumulate. In 2003, Michael McBurney from the University of Ottawa in Canada discovered that mouse embryos manipulated to be unable to produce one of the seven sirtuin enzymes, SIRT1, couldn’t last past the fourteenth day of development—about two-thirds of the way into a mouse’s gestation period.26 Among the reasons, the team reported in the journal Cancer Cell, was an impaired ability to respond to and repair DNA damage.27 In 2006, Frederick Alt, Katrin Chua, and Raul Mostovslavsky at Harvard showed that mice engineered to lack SIRT6 underwent the typical signs of aging faster along with shortened lifespans.28 When the scientists knocked out a cell’s ability to create this vital protein, the cell lost its ability to repair double-strand DNA breaks, just as we had showed in yeast back in 1999.
If you are skeptical, and you should be, you might assume these SIRT mutant mice could just be sick and, therefore, short lived. But adding in more copies of the sirtuin genes SIRT1 and SIRT6 does just the opposite: it increases the health and extends the lifespan of mice, just as adding extra copies of the yeast SIR2 gene does in yeast.29 Credit for these discoveries goes to two of my previous colleagues, Shin-ichiro Imai, my former drinking buddy at the Guarente lab, and Haim Cohen, my first postdoc at Harvard.
In yeast, we had shown that DNA breaks cause sirtuins to relocalize away from silent mating-type genes, causing old cells to become sterile. That was a simple system, and we’d figured it out in a few years.
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.
In mammals, the sirtuins have since taken on a variety of new roles, not just as controllers of fertility (which they still are). They remove acetyls from hundreds of proteins in the cell: histones, yes, but also proteins that control cell division, cell survival, DNA repair, inflammation, glucose metabolism, mitochondria, and many other functions.
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. Some were working in the storm-ravaged communities for a few days and others for a few weeks before returning to their normal lives. And for most, it wasn’t the first or last time they had done something like that; anytime there’s a mass disaster that impacts utilities, they swoop in to help.
When they’re home, those folks take care of the typical business of being at home: paying bills, mowing lawns, coaching baseball, whatever. But when they’re away, helping keep places like the Gulf Coast from descending into anarchy—a condition that would have had disastrous results for the rest of the nation—a lot of those things have to be put on hold.
When sirtuins shift from their typical priorities
