Lifespan. David Sinclair
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storms and periodic droughts, they are the epitome of perseverance.
It’s easy to stand in wonder of these great and ancient things. It’s easy to be swept away by their might and majesty. It’s easy to simply stare at them in awe. But there’s another way to view these antediluvian patriarchs—a harder way, but a way in which we should seek to view every living thing on this planet: as our teachers.
Bristlecones are, after all, our eukaryotic cousins. About half of their genes are close relatives of ours.
Yet they do not age.
Oh, they add years to their lives—thousands upon thousands of them, marked by the nearly microscopic rings hidden in their dense heartwood, which also record in their size, shape, and chemical composition climate events long past, as when the eruption of Krakatoa sent a cloud of ash around the globe in 1883, leaving a fuzzy ring of growth in 1884 and 1885, barely a centimeter from the outer ring of bark that marks our current time.76
Yet even over the course of many thousands of years, their cells do not appear to have undergone any decline in function. Scientists call this “negligible senescence.” Indeed, when a team from the Institute of Forest Genetics went looking for signs of cellular aging—studying bristlecones from 23 to 4,713 years old—they came up empty-handed. Between young and old trees, their 2001 study found, there were no meaningful differences in the chemical transportation systems, in the rate of shoot growth, in the quality of the pollen they produced, in the size of their seeds, or in the way those seeds germinated.77
The researchers also looked for deleterious mutations—the sorts of which many scientists at the time expected to be a primary cause of aging. They found none.78 I expect that if they were to look for epigenetic changes, they would similarly come up empty-handed.
Bristlecones are outliers in the biological world, but they are not unique in their defiance of aging. The freshwater polyp known as Hydra vulgaris has also evolved to defy senescence. Under the right conditions, these tiny cnidarians have demonstrated a remarkable refusal to age. In the wild they might live for only a few months, subject to the powers of predation, disease, and desiccation. But in labs around the world they have been kept alive for upward of 40 years—with no signs that they’ll stop there—and indicators of health don’t differ significantly between the very young and the very old.
A couple of species of jellyfish can completely regenerate from adult body parts, earning them the nickname “immortal jellies.” Only the elegant moon jelly Aurelia aurita from the US West Coast and the centimeter-long Turritopsis dohrnii from the Mediterranean are currently known to regenerate, but I’m guessing the majority of jellies do. We just need to look. If you separate one of these amazing animals into single cells, the cells jostle around until they form clumps that then assemble back into a complete organism, like the T-1000 cyborg in Terminator 2, most likely resetting their aging clock.
Of course, we humans don’t want to be mashed into single cells to be immortal. What use is reassembling or spawning if you have no recollection of your present life? We may as well be reincarnated.
What matters is what these biological equivalents of F. Scott Fitzgerald’s backward-aging 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.
Though it’s not immortal, the Greenland shark Somniosus microcephalus is still an impressive animal and far more closely related to us. About the size of a great white, it does not even reach sexual maturity until it is 150 years old. Researchers believe the Arctic Ocean could be home to Greenland sharks that were born before Columbus got lost in the New World. Radiocarbon dating estimated that one very large individual may have lived more than 510 years, at least up until it was caught by scientists so they could measure its age. Whether this shark’s cells undergo aging is an open scientific question; very few biologists had so much as looked at S. microcephalus until the past few years. At the very least, this longest-living vertebrate undergoes the process of aging very, very slowly.
Evolutionarily speaking, all of these life-forms are closer to us than yeast, and just think of what we’ve learned about human aging from that tiny fungus. But it is certainly forgivable to consider the distances between pine trees, hydrozoans, cartilaginous fish, and mammals like ourselves on the enormous tree of life and say, “No, these things are just too different.”
What, then, of another mammal? A warm-blooded, milk-producing, live-birth-giving cousin?
Back in 2007, aboriginal hunters in Alaska caught a bowhead whale that, when butchered, was found to have the head of an old harpoon embedded in its blubber. The weapon, historians would later determine, had been manufactured in the late 1800s, and they estimated the whale’s age at about 130. That discovery sparked a new scientific interest in Balaena mysticetus, and later research, employing an age-determining method that measures the levels of aspartic acid in the lens of a whale’s eye, estimated that one bowhead was 211 years old when it was killed by native whalers.
That bowheads have been selected for exceptional longevity among mammals should perhaps not be surprising. They have few predators and can afford to build a long-lived body and breed slowly. Most likely they maintain their survival program on high alert, repairing cells while maintaining a stable epigenome, thereby making sure the symphony of the cells plays on for centuries.
Can these long-lived species teach us how to live healthier and for longer?
In terms of their looks and habitats, pine trees, jellyfish, and whales are certainly very different from humans. But in other ways, we’re very similar. Consider the bowheads. Like us, they are complex, social, communicative, and conscious mammals. We share 12,787 known genes, including some interesting variants in a gene known as FOXO3. Also known as DAF-16, this gene was first identified as a longevity gene in roundworms by University of California at San Francisco researcher Cynthia Kenyon. She found it to be essential for defects in the insulin hormone pathway to double worm lifespan. Playing an integral role in the survival circuit, DAF-16 encodes a small transcription factor protein that latches onto the DNA sequence TTGTTTAC and works with sirtuins to increase cellular survival when times are tough.79
In mammals, there are four DAF-16 genes, called FOXO1, FOXO3, FOXO4, and FOXO6. If you suspect that we scientists sometimes intentionally complicate matters, you’d be right, but not in this case. Genes in the same “gene family” have ended up with different names because they were named before DNA sequences were easily deciphered. It’s similar to the not uncommon situation in which people have their genome analyzed and learn they have a sibling on the other side of town.80 DAF-16 is an acronym for dauer larvae formation. In German, “dauer” means “long lasting,” and this is actually relevant to this story. Turns out, worms become dauer when they are starved or crowded, hunkering down until times improve. Mutations that activate DAF-16 extend lifespan by turning on the worm defense program even when times are good.
I first encountered FOXO/DAF-16 in yeast, where it is known as MSN2, which stands for “multicopy suppressor of SNF1 (AMPK) epigenetic regulator.” Like DAF-16, MSN2’s job in yeast is to turn on genes that push cells away from cell death and toward stress resistance.81 We discovered that when calories are restricted MSN2 extends yeast lifespan by turning up genes that recycle NAD, thereby giving the sirtuins a boost.82
Hidden within the sometimes byzantine way scientists talk about science are several repeating themes: low energy sensors (SNF1/AMPK), transcription factors (MSN2/DAF-16/FOXO), NAD and sirtuins, stress resistance, and longevity. This is no coincidence—these are all key parts of the ancient survival circuit.
But what about FOXO genes in humans? Certain variants called FOXO3 have been found in human communities in which people are known to enjoy
M. G. L. Baillie,
Along with bristlecones, Matthew LaPlante, my coauthor on
When researchers compared trees of a variety of ages to look for a steady incremental decline in annual shoot growth, they found “no statistically significant age-related differences.” R. M. Lanner, and K. F. Connor, “Does Bristlecone Pine Senesce?,”
Investigating mutations in the gene Daf-2, researchers made a remarkable find: the largest reported lifespan extension of any living thing, namely twice as long. This relied on the involvement of two genes, Daf-2 and Daf-16, opening the door to new horizons of ways to understand how to prolong life. C. Kenyon, J. Chang, E. Gensch, et al., “A
Why do genes often have a variety of names? The language of genetics is just like any other language; its words contain the echoes of history. Knowing the entire genome of a yeast cell, a nematode worm, or a human was the stuff of dreams less than a quarter century ago. Now, of course, I can sequence my own genome in a day on a USB drive–sized sequencer. When I was a student, genes would be given a name based on the characteristics of mutants we would generate with mutagenic chemicals. Typically, all we knew about a gene when we named it was its rough location on a particular chromosome. Only later were its distant cousins identified.
A. Brunet, L. B. Sweeney, J. F. Sturgill, et al., “Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase,”
O. Medvedik, D. W. Lamming, K. D. Kim, and D. A. Sinclair, “