Growing Young Page 3
It may seem unbelievable that Jeanne Calment enjoyed relatively good health until the very end. In reality, though, that was to be expected. Here is some surprising biology: studies show that the longer you live, the higher the likelihood of staying in close-to-perfect shape until the day you drop dead while gardening or rollerblading across the globe. We tend to be amazed by media stories of centenarians jumping with parachutes or participating in marathons. We shouldn’t be. In a way, it’s less remarkable that a centenarian can run long-distance than an eighty-year-old. While a regular Joe or Sue will spend almost 18 percent of their time on earth overtaken by disease—admittedly not a happy prospect—for an average supercentenarian that number is just 5 percent. Typically, they stay in good health until the age of 109, and one in ten manages to escape disease till the very last three months of their lives.
When I read these numbers, my first thought was that such people must have some remarkable genes (something I probably don’t possess). Research indicates that there may be some truth to this. Calment’s personality alone likely wouldn’t have been enough to push her over the 115-birthday threshold. She probably had the genes for it, too. Robine and his colleagues managed to find the length-of-life data for fifty-five direct ancestors of Calment, spanning five generations all the way back to the seventeenth century. They also created a control “family” by including individuals of the same sex married in the same municipality as Calment’s ancestors and who appeared on the register of marriages just before or just after them. This way they discovered an unprecedented number of long-lived people in Calment’s family: as many as thirteen out of the fifty-five lived to be over eighty years old, an achievement in the seventeenth and eighteenth centuries. In the control “family” only one person lived that long. That’s 24 percent versus 2 percent.
Robine now believes that Calment did indeed have an unusual accumulation of good genes. Still, she was an outlier. For most of us, how long we live is only about 20 to 25 percent heritable. What’s more, although scientists have been on the lookout for specific longevity genes for quite some time now, the results are less than impressive. There appear to be plenty of different genes associated with lifespan—we have discovered over a hundred of them in mice alone. It’s impossible to tell at this point which particular genes might have helped Calment live as long as she did. Hopefully we will know more in the future, since a vial of Calment’s blood, with all the precious information in it, is still held in one lab in Paris.
Although Calment’s case certainly stretched our knowledge about how long humans can live, it did little to answer another question that keeps bugging researchers: whether aging itself is unavoidable. Until very recently, it seemed that it was. And then came the hydra.
A typical freshwater hydra is usually under 0.39 inches (1 cm) long, so to see it well you have to put it under a microscope. It has a head with long tentacles and a tube-like body, reminding me of Sideshow Bob from The Simpsons. And just like Sideshow Bob, hydras are immortal—at least as long as they are kept in the relative safety of a lab, since in the wild they tend to succumb to various accidents in a matter of weeks. If kept in petri dishes, away from predators and other environmental dangers, these animals have such amazingly low mortality rates that many would be still alive after three thousand years (even in labs accidental deaths happen, like when a researcher forgets to close a hydra-containing dish properly and the hydras dry out—true story).
From the fact that hydras can live forever, we now know that aging can be side-stepped. Why does it exist at all in the first place, then? Is it part of nature’s programmed plan? Or is it just an unpleasant side effect of living? These, too, are questions that tend to put many scientists on edge, with some voting for the aging-is-programmed theory and others—admittedly, the majority—favouring the view that we get old simply because the universe doesn’t care much about what happens to you once you’ve passed on your genes.
The thing is that some of the genes that are very beneficial when your goal is to make tons of babies have detrimental side effects down the road, once you’ve stopped reproducing. Take the genes encoding the growth hormone that on the one hand boosts fertility, but on the other hand accelerates aging and promotes cancer. Natural selection doesn’t really act once your gene-passing—that is, baby-making—times are over, so there is no selection pressure to wipe out genes that have harmful effects later in life. In case you are into names, this theory has a complicated one: “antagonistic pleiotropy”—basically meaning “opposing effects” (good when young, bad when old). Antagonistic pleiotropy is likely one reason mice have shorter lives than elephants. If you are a tiny vermin, you have to reproduce fast before you get snatched by a cat or a snake. You breed, you deteriorate, you die. But massive elephants, with low risk of accidental death, can take their time awaiting offspring—and as a result can reach the age of sixty years or more.
As we get older, our bodies slowly fall apart due to simple wear and tear, which, from an evolutionary perspective, is not worth cleaning up. We accumulate mutations and damage to our DNA, mitochondria, and proteins. And if you want to see how this damage works in practice, there is hardly a better creature to observe than the tiny worm Caenorhabditis elegans, or C. elegans for short.
Old Mitochondria, Telomeres, and Longevity Genes
“Is it dead?” I asked as I stared down the microscope at a minuscule creature that resembles an earthworm. The animal hadn’t moved in what felt like forever.
“Nah, just old,” Lynne Cox replied as she took a look through the eyepiece herself. “It must be on its last legs, though. Can you see how the insides are all shrivelled up? Although it’s not as wrinkly as they can get,” Cox said, then chuckled. “It aged well—maybe this one here is an optimistic worm?” I watched as she changed the dish under the microscope for a different one, glass scraping against the plastic. In a white-walled lab cluttered with black-and-white equipment, the purple gloves on Cox’s hands stood out in a splash of colour. The air smelled of latex and disinfectant. Done with the dish swap, the biochemist encouraged me to check out the contents of the new one. I looked down. Now there was plenty of movement on the little glass. Dozens of C. elegans were squirming in a snake-like fashion, wriggling around. These guys were barely five days old—the equivalent of humans in their twenties. “Can you see how they are moving happily?” Cox asked me. She sighed. “They are cool, aren’t they? You tend to fall in love with these worms when you work with them.”
Longevity researchers do indeed have plenty of reasons to fall in love with C. elegans. The worms are ultra-easy to breed, they share a large amount of their genome with humans, most of them are hermaphrodites—so each can reproduce on its own, making tons of genetically identical copies—and, on top of everything, they are see-through. With just a glimpse through a microscope you can observe all the changes happening in the worms’ bodies without the need to cut them open. “As they age you can see the whole structure of the tissues break down,” Cox told me. What’s more, if you want to change their gene expression, all you have to do is feed them specially prepared bacteria. It’s no wonder then that Cox and her colleagues chose C. elegans to study the changes that aging inflicts on a molecular level, including damage to the DNA.
Just like in C. elegans, almost all of your cells contain DNA—long, two-stranded molecules, most of it inside the nucleus, and a tiny bit in the mitochondria, the cells’ powerhouses. But your DNA doesn’t stay unchanged throughout your life. Much the same as your favourite shoes or the book you’ve read many times, DNA gets worn out with use. Sometimes it’s outside factors, such as radiation or chemicals, that can cause mutations. Or it can be due to simple mistakes during cell replication. And sometimes the damage is done by free radicals, by-products of energy production inside the cell. As a result, the DNA strands can get small lesions or even break completely. Most of the time, the cell’s cleaning and repair services will march in and fix the pr
oblem. But like any mechanic, these processes are not perfect, and will overlook some of the damage or make additional mistakes. Year after year, the flaws in your DNA will accumulate. This, in turn, can lead to such health problems as cancer, cardiovascular issues, and Alzheimer’s disease.
The DNA in your cells’ mitochondria, the free radical–producing powerhouse, can get damaged even more than that in the nucleus (imagine keeping your favourite book beside an open fire). Other stuff in the mitochondria suffers, too: the membranes, the proteins, the lipids. With time, the mitochondria decline in function—they simply stop producing enough energy to power the cell. That’s one of the main reasons why the old, wrinkly C. elegans I observed under Cox’s microscope barely moved. That may also be part of the reason why by 5 p.m. I’m usually ready to plop down tiredly on the couch while my six-year-old daughter keeps jumping around like a bouncy rabbit, as if showing off the power of her young, undamaged mitochondria.
Some ancient philosophers used to believe that we die because each person is born with a limited number of breaths or heartbeats that we can have in life. When you use them up, you kick the bucket. Modern science shows that there may be something to this way of thinking, although it’s not breaths or heartbeats that are finite (of course). What we run out of are pairs of telomeres—parts of the DNA that function as protective caps at the ends of chromosomes, and which are often compared to aglets—those plastic thingies on shoelaces that prevent fraying.
When you are born you have about ten thousand base pairs of DNA making up the telomeres on each of your chromosomes. But every time a cell in your body divides, you lose anywhere from fifty to two hundred of those pairs. What’s more, just like any part of the DNA, telomeres can get damaged by free radicals. And once they get too short, the cell may stop dividing and even die. That, in turn, has been linked to aging.
If you are into books and articles on longevity, and have read a few in the recent past, you probably have already come across telomeres—they feature quite prominently in many such publications, often paired with expressions such as “miracle,” “immortality,” or “key to longevity.” Just eat this and that, the thinking goes, exercise X minutes a day, and your telomeres will stay long, which in turn will make you stay young.
The first time I read about telomeres I was quite excited: here was an easy way to measure aging and anti-aging therapies. But as I dug deeper into new research, my hopes dispersed. It seems that the role of telomeres in aging has been quite overhyped. Cox goes as far as to say that the telomere field “worries her a bit.” The early thinking was that telomeres could act as a kind of a biological clock: since we lose about twenty-five base pairs per year, you could assume that someone who had shorter telomeres was biologically older than someone with long telomeres, irrespective of what their birth certificate said. Thanks to recent studies, however, we now know that the biggest difference in telomere length between any two people is already apparent at birth. Some of us are simply born with hundreds of extra pairs. Part of the reason is genetics. Another is your mom (yes, you can blame her now). “Suboptimal intrauterine conditions,” as scientists call it, basically refers to things such as maternal stress, smoking, bad diet, and exposure to air pollution, all of which have been shown to considerably shorten the telomeres of babies.
Yet having shorter telomeres is not always that bad. In fact, in line with the antagonistic pleiotropy theory, short telomeres can protect animals from developing cancer, especially in youth. Considering their size, elephants should have about a million-fold higher risk of cancer than your average mouse (the more cells you have, the greater the chances that some of them will go rogue). And yet, elephants don’t get much cancer. Most likely, they are protected by their short telomeres and a subdued activity of an enzyme called telomerase that can extend the telomeres.
The telomerase-cancer link, which has also been shown in humans, is among the reasons Cox is so weary of the media hype surrounding telomeres. On the internet you can now purchase supplements claimed to activate telomerase, promising “anti-aging from the inside out” or reduction in “cellular aging.” If you take telomerase pills you could, maybe, roll back the speed of your aging—although even that is speculative—but the side effect might be cancer. As it often is in biology, telomeres are about balance, keeping in check cancer versus degenerative diseases, and oversimplifications may be dangerous.
A better biological aging clock, many scientists now argue, is based on DNA methylation, also known as the “epigenetic clock.” As we get older, our cells collect more and more epigenetic changes—changes that turn genes on or off without affecting the DNA sequence itself. Your diet, stress levels, whether you meditate—all this can speed up or slow down your epigenetic clock, leaving visible marks in the appearance of your DNA for scientists to analyze. Unsurprisingly, some commercial labs are already offering to measure your epigenetic clock. Pay a few hundred dollars, send in a blood sample, and you will receive an estimation of your DNA methylation age. Studies show that for about half of people, their epigenetic age differs only by less than 3.6 years from their chronological age, but for some others the difference is astounding: some forty-year-olds have a DNA methylation age as low as twenty, while others have one as high as fifty. That’s a three-decade spread!
What links epigenetic changes, telomere shortening, DNA damage, and damage to other parts of the cell such as mitochondria, proteins, and lipids, is that these are all involved in something that scientists call “cellular senescence”—or in simpler words, cellular aging, a phenomenon that makes cells fat, useless, and full of junk, just like the one I saw in Cox’s lab. A healthy young cell is a cell that grows and divides. If it’s useless or too damaged, it commits suicide. That’s how your tissues—like your skin, for instance—get renewed. But sometimes a cell that has accumulated a lot of damage stops dividing, but doesn’t kill itself either. It just sits there, getting bigger and bigger, collecting whole piles of waste, such as misfolded proteins and old mitochondria.
“Normally if your mitochondria stop working you digest them down and make new ones. But old cells just keep their damaged mitochondria—they fill up, like garbage cans. That’s one of the reasons the old cells are so huge,” Cox tells me. Such bloated senescent cells are not quite dead. And these zombie cells accumulate as we age, belching out toxins called senescence-associated secretory phenotype, which in true zombie style can turn other cells senescent, too. What makes things even worse is that the secretions from senescent cells promote low-level chronic inflammation that is sometimes called “inflammaging,” and which lies at the basis of most age-related diseases such as Alzheimer’s disease, rheumatoid arthritis, diabetes, cancer, and heart disease.
Can’t we then just go in with some drugs and kill all the zombie cells, I wondered? Go World War Z on them? It could potentially work. In animal studies, destroying senescent cells delays aging and even prolongs lifespans by about 25 percent (imagine living ninety-seven years instead of the current American average of seventy-eight). Senolytics, drugs that kill zombie cells, and which are ready for clinical trials, are touted by some as the potential anti-aging cure. But there are a few problems with them, I soon learned. First of all, there are potential side effects, such as delayed wound healing. Second, what works in rats doesn’t necessarily work in humans. Cox is also cautious. “If you have lots of senescent cells, you can’t kill, say, 75 percent of your body. And if you suddenly find out that the drugs are taking out too many cells in one go, what do you do?” she asks.
If any animals do not need senolytics, it’s certainly the hydras, the immortal Sideshow Bob look-alikes. When scientists tracked generations of offspring of individual cells taken from the gastric region of hydras, they discovered that they simply don’t turn into zombies. It makes sense: most cells of the hydras are stem cells, which never stop proliferating, constantly renewing the bodies of these tiny creatures. The reason for this, and in effect for
the hydras’ immortality, is the way they breed. Instead of having males mate with females, hydras make babies asexually by budding. To reproduce, they need a constant and reliable supply of freshly divided cells.
Although we will likely never achieve hydra-like immortality (our bodies are far more complicated than theirs), we can certainly learn a few things about aging from the workings of hydras’ stem cells. Stem cells—whether hydra or human ones—are quite amazing little things. They are created shortly after fertilization and then go on to make new, specialized cells throughout our lives, helping us grow and renew tissues. Yet stem cells are not immune to damage, either. As years pass, our stem cells work less and less well, go “zombie,” or die, and their numbers diminish, a process which has been implicated as one of the top reasons for aging.
At least for humans. Hydras are particularly good at repair and maintenance of their stem cells. One type of genes, called FOXOs (otherwise known as the forkhead box O; a lot of genes have strange names) may play a role in this and could be quite important for longevity, from hydras and mice to whales and Jeanne Calment. These particular genes work to protect cells from damage and are involved in DNA repair. In hydras, FOXOs keep stem cells going. If you reduce the activity of FOXOs in these tiny creatures, they turn mortal. In humans, a particular sequence variation in one type of FOXO gene, FOXO3a, has been linked to longevity in various populations, from American men of Japanese ancestry to the Chinese and Germans.
But don’t rush to the internet to look for a lab that will check your FOXO3a polymorphisms. We are much more complicated creatures than hydras; most likely, FOXO3a is just one among many genes responsible for why some people live longer than others (and anyway, longevity is just 20 to 25 percent heritable, remember?).