lab’s animals while I was on a trip to my lab in Australia.
“One of the mice is really sick,” she said. “I think we need to put it down.”
I asked her to text me a photo of the mouse she was talking about. When the photo came over my phone, I couldn’t help but laugh.
“That’s not a sick mouse,” I replied. “That’s an old mouse.”
“David,” she said, “I think you’re mistaken. It says here that it’s the sister of these other mice in the cage, and they’re perfectly normal.”
Her confusion was understandable. At 16 months old, a regular lab mouse still has a thick coat of fur, a sturdy tail, a muscular figure, perky ears, and clear eyes. A tamoxifen-triggered ICE mouse at the same age has thinning, graying hair, a bent spine, paper-thin ears, and cloudy eyes.
Remember, we’d done nothing to change the genome. We’d simply broken the mice’s DNA in places where there aren’t any genes and forced the cell to paste, or “ligate,” them back together. Just to make sure, later we broke the DNA in other places, too, with the same results. Those breaks had induced a sirtuin response. When those fixers went to work, their absence from their normal duties and presence on other parts of the genome altered the ways in which lots of genes were being expressed at the wrong time.
THE MAKING OF THE ICE MOUSE TO TEST IF THE CAUSE OF AGING MIGHT BE INFORMATION LOSS. A gene from a slime mold that encodes an enzyme that cuts DNA at a specific place was inserted into a stem cell and injected into an embryo to generate the ICE mouse. Turning on the slime mold gene cut the DNA and distracted the sirtuins, causing the mouse to undergo aging.
Those findings were aligned to discoveries being made by Trey Ideker and Kang Zhang, at UC San Diego, and Steve Horvath, at UCLA. Steve’s name stuck, and today he’s the namesake of the Horvath Clock—an accurate way of estimating someone’s biological age by measuring thousands of epigenetic marks on the DNA, called methylation. We tend to think of aging as something that begins happening to us at midlife, because that’s when we start to see significant changes to our bodies. But Horvath’s clock begins ticking the moment we are born. Mice have an epigenetic clock, too. Were the ICE mice older than their siblings? Yes, they were—about 50 percent older.
We’d found life’s master clock winder.
In another manner of thinking, we’d scratched up the DVD of life about 50 percent faster than it normally gets scratched. The digital code that is, and was, the basic blueprint for our mice was the same as it had always been. But the analog machine built to read that code was able to pick up only bits and pieces of the data.
Here’s the vital takeaway: we could age mice without affecting any of the most commonly assumed causes of aging. We hadn’t made their cells mutate. We hadn’t touched their telomeres. We hadn’t messed with their mitochondria. We hadn’t directly exhausted their stem cells. Yet the ICE mice were suffering from a loss of body mass, mitochondria, and muscle strength and an increase in cataracts, arthritis, dementia, bone loss, and frailty.
All of the symptoms of aging—the conditions that push mice, like humans, farther toward the precipice of death—were being caused not by mutation but by the epigenetic changes that come as a result of DNA damage signals.
We hadn’t given the mice all of those ailments. We had given them aging.
And if you can give something, you can take it away.
FRUIT OF THE SAME TREE
Like the gnarled hands of giant zombies breaking free of the rocky soil, the ancient bristlecone pine trees of California’s White Mountains strike haunting silhouettes against the dewy morning sun.
The oldest of these trees have been here since before the pyramids of Egypt were built, before the construction of Stonehenge, and before the last of the woolly mammoths left our world. They have shared this planet with Moses, Jesus, Muhammad, and the first Buddha. Standing some two miles above sea level, adding fractions of a millimeter of growth to their twisted trunks each year, defying lightning 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.32
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.33
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.34 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
