Lifespan. David Sinclair
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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.70 Among the reasons, the team reported in the journal Cancer Cell, was an impaired ability to respond to and repair DNA damage.71 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.72 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.73 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.74 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 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.
But what happens when there’s one emergency after another to tend to? Hurricane after hurricane? Earthquake after earthquake? The repair crews are away from home a lot. The work they normally do piles up. The bills come due, then overdue, and then the folks from collections start calling. The grass grows too long, and soon the president of the neighborhood association is sending nastygrams. The baseball team goes coachless, and the team devolves into the Bad News Bears. And most of all, one of the most important things they do while at home—reproducing—doesn’t get done. This form of hormesis, the original survival circuit, works fine to keep organisms alive in the short term. But unlike longevity molecules that simply mimic hormesis by tweaking sirtuins, mTOR, or AMPK, sending out the troops on fake emergencies, these real emergencies create life-threatening damage.
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, but there is a subtle but vital shift we have to make in that manner of thinking. 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.
Wherever epigenetic factors leave the genome to address damage, genes that should be off, switch on and vice versa. Wherever they stop on the genome, they do the same, altering the epigenome in ways that were never intended when we were born.
Cells lose their identity and malfunction. Chaos ensues. The chaos materializes as aging. This is the epigenetic noise that is at the heart of our unified theory.
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 recruit other repair proteins. 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 occurs when ERCs accumulate in the nucleoli of old yeast cells.
For the survival circuit to work and for it to cause aging, Sir2 and other epigenetic regulators must occur in “limiting amounts.” In other words, the cell doesn’t make enough Sir2 protein to simultaneously silence the mating-type genes and repair broken DNA; it has to shuttle Sir2 between the various places on an “as-needed” basis. 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.75
Over the past billion years, presumably millions of yeast cells have spontaneously mutated to make more Sir2, but they died out because they had no advantage over other yeast cells. 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.
M. W. McBurney, X. Yang, K. Jardine, et al., “The Mammalian SIR2alpha Protein Has a Role in Embryogenesis and Gametogenesis,”
R.-H. Wang, K. Sengupta, L. Cuiling, et al., “Impaired DNA Damage Response, Genome Instability, and Tumorigenesis in SIRT1 Mutant Mice,”
R. Mostoslavsky, K. F. Chua, D. B. Lombard, et al., “Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6,”
The treatments work better in male mice, for reasons that are not yet known, but my former postdoc Haim Cohen at Bar-Ilan University in Israel wins the award for the best-ever name given to a transgenic mouse strain: MOSES. A. Satoh, C. S. Brace, N. Rensing, et al., “Sirt1 Extends Life Span and Delays Aging in Mice Through the Regulation of Nk2 Homeobox 1 in the DMH and LH,”
When we write
It’s possible that by not allowing mating-type genes to turn on, yeast with additional copies of