The Body, page 41
In 1961, Leonard Hayflick, then a young researcher at the Wistar Institute in Philadelphia, made a discovery that nearly everyone in his field found impossible to accept. He discovered that cultured human stem cells—that is, cells grown in a lab, as opposed to in a living body—can divide only about fifty times before they mysteriously lose their power to go on. In essence, they appear to be programmed to die of old age. The phenomenon became known as the Hayflick limit. It was a milestone moment for biology because it was the first time anyone had shown that aging was a process happening within cells. Hayflick also found that the cells he cultured could be frozen and kept in storage for any length of time and when thawed would resume their decline from precisely where they had left off. Clearly something within them was serving as a kind of tallying device to keep track of how many times they had divided. The idea that cells possess some form of memory and can count down toward their own extermination was so wildly radical that it was almost universally rejected.
For about a decade, Hayflick’s findings languished. But then a team of researchers at the University of California at San Francisco discovered that stretches of specialized DNA at the end of each chromosome called telomeres fulfill the role of tallying device. With each cell division, telomeres shorten until eventually they reach a predetermined length (which varies markedly from one cell type to another) and the cell dies or becomes inactive. With this finding, the Hayflick limit suddenly became credible. It was hailed as the secret of aging. Arrest the shortening of telomeres and you could stop cell aging in its tracks. Gerontologists everywhere became very excited.
Alas, years of subsequent research have shown that telomere shortening can account for only a small part of the process. After the age of sixty, the risk of death doubles every eight years. A study by geneticists at the University of Utah found that telomere length may account for as little as 4 percent of that additional risk. As the gerontologist Judith Campisi told Stat in 2017, “If all aging was due to telomeres, we would have solved the aging problem a long time ago.”
Aging, it turns out, not only involves much more than telomeres, but telomeres are involved in much more than aging. Telomere chemistry is regulated by an enzyme called telomerase, which switches off the cell when it has reached its preset quota of divisions. In cancerous cells, however, telomerase doesn’t instruct the cells to stop dividing, but rather lets them go on proliferating endlessly. This has raised the possibility that a way to fight cancer would be to target telomerase in the cells. In sum, it’s clear that telomeres are important not just for understanding aging but also for understanding cancer, but unfortunately we are still a long way from fully understanding either.
Two other terms encountered commonly, if no more productively, in discussions of aging are “free radicals” and “antioxidants.” Free radicals are wisps of cellular waste that build up in the body in the process of metabolism. They are a by-product of our breathing oxygen. As one toxicologist has put it, “The biochemical price of breathing is aging.” Antioxidants are molecules that neutralize free radicals, so the thinking is that if you take a lot of them in the form of supplements, you can counter the effects of aging. Unfortunately, there is no scientific evidence to support that.
Most of us would almost certainly never have heard of either free radicals or antioxidants if a research chemist in California named Denham Harman had not, in 1945, read an article about aging in his wife’s Ladies’ Home Journal and developed a theory that free radicals and antioxidants are at the heart of human aging. Harman’s idea was never anything more than a hunch, and subsequent research proved it to be wrong, but nonetheless the idea has taken hold and will not go away. The sale of antioxidant supplements alone is now worth well over $2 billion a year.
“It is a massive racket,” David Gems of University College London told Nature in 2015. “The reason the notion of oxidation and ageing hangs around is because it is perpetuated by people making money out of it.”
“Some studies have even suggested that antioxidant supplements can be harmful,” The New York Times has noted. The principal learned journal of the field, Antioxidants and Redox Signaling, noted in 2013 that “antioxidant supplementation did not lower the incidence of many age-associated diseases but, in some cases, increased the risk of death.”
In the United States, there is the additional, rather extraordinary consideration that the Food and Drug Administration exercises practically no oversight on supplements. As long as supplements don’t contain any prescription medications and don’t obviously kill or seriously harm anybody, manufacturers can sell pretty much whatever they want, with “no guarantees of purity or potency, no established guidelines on dosage, and often no warnings about side effects that may result when the products are taken along with approved medications,” as an article in Scientific American noted. The products might be beneficial; it’s just that no one has to prove it.
Although Dr. Harman didn’t have anything to do with the supplements industry and was not a spokesman for antioxidant theories, he did follow a lifelong regime of taking high doses of the antioxidant vitamins C and E, and eating large quantities of antioxidant-rich fruits and vegetables, and it must be said it didn’t do him any harm at all. He lived to be ninety-eight.
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Even if you enjoy robust health, aging has inescapable consequences for us all. As we age, the bladder becomes less elastic and cannot hold as much, which is why one of the curses of aging is being forever on the lookout for a restroom. Skin loses elasticity, too, and becomes drier and more leathery. The blood vessels break more readily and create bruises. The immune system fails to detect intruders as reliably as it once did. The number of pigment cells usually decreases, but those that remain sometimes enlarge, producing age spots, or liver spots, which of course have nothing to do with the liver. The layer of fat directly associated with skin also thins, making it harder for elderly people to stay warm.
More seriously, the amount of blood pushed out with each heartbeat falls gradually as we age. If nothing else gets you first, your heart will eventually give out. That is a certainty. And because the amount of blood being moved around by the heart falls, your organs get less blood, too. After the age of forty, the volume of blood going to the kidneys decreases by an average of 1 percent a year.
Women are vividly reminded of the aging process when they reach menopause. Most animals die soon after they cease to be reproductive, but not (and thank goodness, of course) human females, who spend roughly a third of their lives in a postmenopausal state. We are the only primates that undergo menopause, and one of only a very few animals. The Florey Institute in Melbourne, for instance, studies menopause using sheep for the simple reason that sheep are almost the only land-based creatures known to experience menopause, too. At least two species of whales also go through it. Why any animals get it is a question yet to be answered.
The bad news is that menopause can be a terrible ordeal. Hot flashes are experienced by about three-quarters of women during menopause. (It is a feeling of sudden warmth, generally in the chest or above, induced by hormonal changes for unknown reasons.) Menopause is related to a fall in production of estrogen, but even now there isn’t any test that can definitively confirm the condition. The best indicators for a woman that she is entering menopause (a stage known as perimenopause) are that her periods become irregular and she is likely to find herself experiencing a “sense that things aren’t quite right,” as Rose George wrote for the Wellcome Trust publication Mosaic.
Menopause is as much a mystery as aging itself. Two principal theories have been advanced, known rather neatly as the mother hypothesis and the grandmother hypothesis. The mother hypothesis is that childbearing is dangerous and exhausting, and it becomes more of both as women age. So menopause may simply be a kind of protection strategy. By no longer having the wear and distraction of further childbirth, a woman can better focus on maintaining her own health while completing the rearing of her children just as they are entering their most productive years. This leads naturally to the grandmother hypothesis, which is that women stop breeding in middle age so that they can help their offspring raise their children.
It is a myth, incidentally, that menopause is triggered by women exhausting their supply of eggs. They still have eggs. Not many, to be sure, but more than enough to remain fertile. So it isn’t the literal running out of eggs that triggers the process (as even many doctors appear to believe). No one knows exactly what is the trigger.
II
A STUDY BY the Albert Einstein College of Medicine in New York in 2016 concluded that however much medical care may advance, it is unlikely that many people will ever live past about 115 years. On the other hand, Matt Kaeberlein, a University of Washington biogerontologist, thinks that young people alive today may routinely live up to 50 percent longer than people do now, and Dr. Aubrey de Grey, chief science officer of the SENS Research Foundation of Mountain View, California, believes that some people alive right now will live to be one thousand. Richard Cawthon, a geneticist at the University of Utah, has suggested that such a span is at least theoretically possible.
We’ll have to wait and see. What can be said is that at present only about one person in ten thousand lives to be even a hundred. We don’t know much at all about people who live beyond that, partly because there aren’t many of them. The Gerontology Research Group in Los Angeles keeps track, as well as it can, of all the world’s supercentenarians—that is, people who have reached their 110th birthday. But because records in much of the world are poor and because a lot of people for various reasons would like the world to think they are older than they really are, the GRG researchers tend to be cautious in admitting candidates to this most exclusive of clubs. Usually about seventy confirmed supercentenarians are on the group’s books, but that is probably only about half the actual number in the world.
The chances of reaching your 110th birthday are about one in seven million. It helps a lot to be a woman; they are ten times more likely to reach 110 than a man. It is an interesting fact that women have always outlived men. This is a little counterintuitive when you consider that no man has ever died in childbirth. Nor, through much of history, have men been as closely exposed to contagions through nursing the sick. Yet in every period in history, in every society examined, women have always lived several years longer on average than men. And they still do now, even though men and women are subjected to more or less identical health care.
The longest-lived person that we know of was Jeanne Louise Calment of Arles, in Provence, who died at the decidedly ripe age of 122 years and 164 days in 1997. She was the first person to reach not only 122 but also 116, 117, 118, 119, 120, and 121. Calment had a leisurely life: her father was a rich shipbuilder and her husband a prosperous businessman. She never worked. She outlived her husband by more than half a century and her only child, a daughter, by sixty-three years. Calment smoked all her life—at the age of 117, when she finally gave up, she was still smoking two cigarettes a day—and ate two pounds of chocolate every week but was active up to the very end and enjoyed robust health. Her proud and charming boast in old age was, “I’ve never had but one wrinkle, and I’m sitting on it.”
Calment was also a beneficiary of one of the most delightfully misjudged deals ever made. In 1965, when she ran into financial difficulties, she agreed to leave her apartment to a lawyer in return for a payment of 2,500 francs a months until she died. Because Calment was then ninety, it seemed a pretty good deal for the lawyer. In fact, it was the lawyer who died first, thirty years after signing the deal, having paid Calment more than 900,000 francs for an apartment he was never able to occupy.
The oldest man, meanwhile, was Jiroemon Kimura of Japan, who died aged 116 years and 54 days in 2013, after a quiet life as a government communications worker followed by a very long retirement in a village near Kyoto. Kimura lived a healthy lifestyle, but then millions of Japanese do. What enabled him to live so much longer than the rest of us is a question to which there is no answer, but family genes seem to play a significant role. As Daniel Lieberman told me, reaching 80 is largely a consequence of following a healthy lifestyle, but after that it is almost entirely a matter of genes. Or as Bernard Starr, a professor emeritus at City University of New York, put it, “The best way to assure longevity is to pick your parents.”
At the time of writing, there were three people on Earth with a confirmed age of 115 (two in Japan, one in Italy) and three aged 114 (two in France, one in Japan).
Some people live longer than they ought to by any known measures. As Jo Marchant notes in her book Cure, Costa Ricans have only about one-fifth the personal wealth of Americans, and have poorer health care, but live longer. Moreover, people in one of the poorest regions of Costa Rica, the Nicoya Peninsula, live longest of all, even though they have much higher rates of obesity and hypertension. They also have longer telomeres. The theory is that they benefit from closer social bonds and family relationships. Curiously, it was found that if they live alone or don’t see a child at least once a week, the telomere length advantage vanishes. It is an extraordinary fact that having good and loving relationships physically alters your DNA. Conversely, a 2010 U.S. study found, not having such relationships doubles your risk of dying from any cause.
III
IN NOVEMBER 1901, at a psychiatric hospital in Frankfurt am Main, Germany, a woman named Auguste Deter presented herself to the pathologist and psychiatrist Alois Alzheimer (1864–1915) complaining of persistent and worsening forgetfulness. She could feel her personality draining away, like sand from an hourglass. “I have lost myself,” she explained sadly.
Alzheimer, a gruff but kindly Bavarian with pince-nez spectacles and a cigar perpetually plugged into the side of his mouth, was fascinated and frustrated by his inability to do anything to slow the unfortunate woman’s deterioration. This was a sad time for Alzheimer himself. His wife of just seven years, Cäcilia, had died earlier in the year, leaving him with three children to raise, so when Frau Deter came into his life, he had to deal with his profoundest grief and greatest clinical impotence at the same time. Over the following weeks, the woman became increasingly confused and agitated, and nothing Alzheimer tried provided even slight relief.
Alzheimer moved to Munich the following year to take up a new post but continued to follow Frau Deter’s decline from a distance, and when at last she died in 1906, he had her brain sent to him for autopsy. Alzheimer found that the poor woman’s brain was riddled with clumps of destroyed cells. He reported these findings in a lecture and a paper, and in so doing became permanently associated with the disease, though in fact it was a colleague who first called it Alzheimer’s disease in 1910. Remarkably, the tissue samples Alzheimer took from Frau Deter survived and have been restudied using modern techniques, and it turns out that she was suffering from a genetic mutation unlike any ever seen in another Alzheimer’s patient. It appears that she might have been suffering not from Alzheimer’s at all but rather from another genetic condition known as metachromatic leukodystrophy. Alzheimer didn’t live long enough to fully understand the importance of his findings. He died from complications of a severe cold in 1915 aged just fifty-one.
We now know that Alzheimer’s begins with an accumulation of a protein fragment called beta-amyloid in the sufferer’s brain. Nobody is quite sure what amyloids do for us when they are working properly, but it is thought they may have a role in forming memories. In any case, they are normally cleared away after they have been used and are no longer needed. In Alzheimer’s victims, however, they aren’t flushed away but accumulate in clusters known as plaques and stop the brain from functioning as it should.
Later in the disease, victims also accumulate tangled fibrils of tau proteins, which are invariably referred to as tau tangles. How tau proteins relate to amyloids and how both relate to Alzheimer’s are also uncertain, but the bottom line is that sufferers experience steady, irreversible memory loss. In its normal progression, Alzheimer’s first demolishes short-term memories, then moves on to all or most memories, leading to confusion, shortness of temper, loss of inhibition, and eventually loss of all bodily functions, including how to breathe and swallow. As one observer has put it, in the end “one forgets, on a muscular level, how to exhale.” People with Alzheimer’s, it could be said, die twice—first in the mind, then in the body.
This much has been known for a century, but beyond that nearly all is confusion. The bewildering fact is that it is possible to have dementia without having buildups of amyloid and tau, and it is equally possible to have amyloid and tau buildups without having dementia. One study found that about 30 percent of elderly people have substantial beta-amyloid accumulations but no hint of cognitive decline.
It may be that plaques and tangles aren’t the cause of the disease but simply its “signature”—the detritus left behind by the disease itself. In short, nobody knows if amyloid and tau are there because the victim is making too much of them or is simply failing to clear them adequately. The absence of consensus means that researchers fall into two camps: those who principally blame beta-amyloid proteins (and who are wryly known as baptists) and those who blame tau (known as tauists).
One thing that is known is that plaques and tangles accumulate slowly and begin their buildup long before signs of dementia become evident, so clearly the key to treating Alzheimer’s will be to get to accumulations early, before they start doing real damage. So far we lack the technology to do so. We can’t even definitively diagnose Alzheimer’s. The only certain way to identify the condition is postmortem—after the patient dies.
