Women May Have an Alternative to Freezing Their Eggs

Here’s how it could go: Some day in the future, it’s routine for every young woman of a certain age—for argument’s sake, let’s say 21—to undergo a procedure to snip off a piece of tissue from one of her ovaries. Her doctor slices up the tissue into a half-dozen or so microthin sections; these are frozen, to be used whenever she’s ready for a baby. Her ovaries function normally, and she keeps menstruating and ovulating just as she has since puberty. But she doesn’t worry about rushing into baby-making. The timetable of how her life unfolds need not adhere to a pesky biological clock.

Later, maybe much later, maybe not for another 20 years, this woman wants to start a family. She remembers those strips of ovarian tissue in deep freeze. Each strip contains thousands of follicles, the proto-eggs of the ovary, preserved at their peak. The follicles in her body have been getting progressively less robust, but in the lab freezer her proto-­eggs have been in suspended animation, protected from the degradation of age.

So she goes back to the doctor, who defrosts one of the strips and implants it in her ovary. It becomes established there, starts pumping out hormones at the level of a younger woman, and transforms one follicle each month into a mature egg. Each menstrual cycle, the hardy egg of a 21-year-old is deposited into the fallopian tube, where it can be fertilized. Ideally, one of those youthful eggs turns into an embryo that embeds itself in the uterus and grows into a healthy baby. Ideally, that one strip of ovarian tissue keeps producing hormones and releasing eggs for years, long enough for the woman—who might be 45 or even older by the time it’s all done—to have a couple of children.

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Nik Mirus

If the first implant doesn’t work, or if it stops working before the woman’s family is complete, doctors can defrost and implant another strip. And if she doesn’t need the strips for childbearing—maybe she decides not to have children at all, or she gets pregnant naturally without needing to take any strips out of deep freeze—she can use them for a different purpose: postponing menopause. As she enters her fifties, this woman thaws a strip and has it implanted in her forearm, where it releases estrogen and other sex hormones in a way that mimics the feedback loop of a younger woman, in theory with fewer side effects than with artificial hormones. She still menstruates, which is the downside, but she also remains at lower risk of chronic conditions, like heart disease and osteoporosis, that usually get worse after menopause, at least in part because of the drop in estrogen. In this future, the one-two punch of nature’s timetable—first making it harder to have healthy babies after about age 35, then making it harder to stay healthy yourself after about age 50—is something women have finally transcended.

Here’s the reality of where things stand: At the Center for Human Reproduction in New York, there’s a room with a boxy machine that slow-freezes slices of ovarian tissue before they are transferred to a stubby deep-freeze tank that bears an uncanny resemblance to R2-D2. But of the 14 tanks in the room, most contain frozen embryos or frozen eggs or sperm, not ovarian tissue. That’s because right now, removing ovarian tissue involves an expensive surgery requiring a hospital stay. (Infertile men can have a bit of testicular tissue removed via a comparatively simple probe-and-snip procedure; the hope is that a similar procedure can be developed for women.) Transplanting the tissue later requires another operation.

Which is all to say, we already do live in a world where bits of ovarian tissue can be harvested, frozen, and then reimplanted later to make a woman fertile, but it’s harrowing. The process was developed for young women or girls with cancer, who face oncological treatments that are certain to make them sterile; since 2004, about 100 babies have been born to these women using the technique. In the view of most researchers and the American Society of Reproductive Medicine, ovarian tissue extraction is still too experimental to recommend for healthy women.

As she enters her fifties, the woman thaws a strip and has it implanted in her forearm, where it releases estrogen and other sex hormones in a way that mimics the feedback loop of a younger woman.

But soon, say experts like Sherman Silber, director of the Infertility Center of St. Louis, freezing ovarian tissue could become the next big form of what’s known as “social freezing” (or, as it’s called in some waggish circles, “AGE freezing,” short for “anticipated gamete exhaustion”)—whereby women try to prolong their fertility not for a medical reason but just to give themselves the option of delayed childbearing. For now, the only way to pause the biological clock this way is to freeze one’s eggs, a route taken by some 6,200 women in the US in 2015. But egg freezing is expensive (up to $18,000 per cycle) and uncertain. Experts calculate that each egg frozen before age 38 has just a 2 to 12 percent chance of turning into a baby one day. Egg freezing also requires women to inject themselves with hormones powerful enough to produce more than 10 times the normal number of mature eggs at a time. These hormones can lead to mood swings, nausea, and abdominal pain; a slight chance of the serious condition known as ovarian hyperstimulation syndrome; and an unknown risk of ovarian or breast cancer down the road.

So as women wait longer and longer to have kids—more than 26,000 women 40 or older became first-time mothers in 2016, an increase of nearly 30 percent over 2001—there’s plenty of incentive for the fertility industry to figure out how to make ovarian tissue extraction a better bet than egg freezing. For one thing, it would do away with the need for multiple rounds of in vitro fertilization. If all goes well, Silber says, the thawed and transplanted tissue will latch on to the rest of the ovary, become functional within about four-and-a-half months, and lead to pregnancy the old-fashioned way.

Roger Gosden, who helped develop the ovarian tissue-freezing procedure in sheep in the 1990s, worries that the social freezing of ovarian tissue will be fraught with the same hazards and anxieties as egg freezing: “A lot of commercial pressure and social pressure” will promote a procedure that most women end up not even needing—all “at great cost, great inconvenience, and a little bit of risk.” It’s also possible that the whole cold-storage approach to infertility could eventually be replaced by a better one: turning stem cells into egg cells, say, whenever a woman is ready to conceive.

But the biggest benefits of socking away young ovarian tissue may come at the other end of a woman’s reproductive life cycle. “One of the really big health challenges of the future is that we’re getting too old,” says Claus Yding Andersen, a professor at the Laboratory of Reproductive Biology at the University Hospital of Copenhagen. “The longer you’re in menopause, the greater your risk of osteoporosis and cardiovascular disease. The very best thing you can do to reduce those risks is to have your own menstrual cycles.” However they go about managing their fertility, women of the future who wait until their forties to start having children will probably want to put off the indignities of an aging body as long as possible. They will know they’ll need a spring in their step—not to mention sturdy hearts and flexible knees—if they’re going to keep up with those long-awaited kids.

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Robin Marantz Henig (@robinhenig) is a science writer and the author of nine books, including Pandora’s Baby.

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Telomeres Are the New Cholesterol. Now What?

“I am a bit concerned about your telomeres,” the doctor told me, evenly. Telomeres are the caplike segments at the ends of the strands of DNA that make up your chromosomes—think of the plastic aglets at the ends of a shoelace—and some of mine, he could see, were not as long as he would have liked them to be.

Fifteen years ago, geneticists at the University of Utah published the results of a small test with the following finding: People older than 60 with short telomeres were three times more likely to die from heart disease and eight times more likely to die from infectious disease. It’s complicated, but essentially shorter telomeres make it more difficult for your cells to split and replicate, which can lead to diseased tissue, which, in turn, can lead to all manner of health problems. Other researchers have cautioned that larger, longitudinal studies are necessary before telomere length can be firmly established as a key indicator of aging. Still, at the edge of modern medicine, where the doctor I was seeing, Joseph Raffaele, practices, the length of your telomeres has become a key indicator, or what he calls a biomarker, of how well you’re aging. Raffaele talks of telomeres as a sort of “biological 401(k)”—molecular-­level security with which to fend off the health challenges of getting old.

Raffaele hadn’t literally seen those telomeres of mine. What he’d seen were the results of blood work carried out by a lab called Repeat Diagnostics, in Vancouver, British Columbia, which has become a leader in the burgeoning field of telomere diagnostics. Burgeoning because, as Raffaele posits, “telomeres are the new cholesterol”—by which he means they are (A) something measurable and understood to have explanatory powers and (B) something Big Pharma can aim at in the hope of finding the equivalent of a statin to make them more robust.

Everyone’s telomeres shorten over time, and a lot of mine were fine enough, but the ones found in a type of cell called granulocytes were really short: bottom 10 percent for my age. Not good, should some serious disease come calling.

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I was, chronologically, about to turn 65, as the day’s mail—Medicare enrollment forms, Social Security statements, brochures for cemetery plots—regularly reminded me. But Raffaele has staked his practice and his reputation on the belief that an individual’s muscles, organs, and bodily systems tend to age physiologically at different rates. You might have been born in 1958, and your cardio­vascular system might be that of a 60-year-old, but your lungs could be more like those of a 50-year-old and your immune system that of someone in their early seventies. Raffaele is a practitioner of age-management medicine, and he assesses several dozen biomarkers—things like telomeres and arterial stiffness—in order to assess patients and assign them a different so-called Immuno­Age, CardioAge, TelomerAge, NeuroAge, CutoAge, and PulmoAge.

In truth, medicine has not yet reached a consensus on how aging comes about, much less Pulmo­Aging. Growing old is one of the most complex biological processes. The mystery of how it works has, if anything, only grown more elusive as our sense of the physical self extends to include our genes, our microbiomes, our stresses. Moreover, Raffaele’s embrace of biomarkers for aging is not universally accepted. The National Institute on Aging concluded, after 10 years of trying to establish a set of such biomarkers, that none of them could be scientifically validated.

Nonetheless, there are thousands of age-­management practitioners worldwide. Raffaele’s own practice licenses its PhysioAge technology and protocols to scores of physicians. He and other age-­management physicians are experimenters, and their patients—who tend to be affluent, as out-of-pocket costs can run to more than $5,000 a year—are willing to experiment along with them. Raffaele doesn’t promise that his patients will live longer, necessarily—that’s a big ask—but he suggests they could live out their last years better, spending less time immobile, pained, and befogged.

I wanted this, for sure, but I was also seeking something else: to better understand my aging identity, not only in terms of my mind’s involutions and attachments but no less crucially through the corporeal expressions of my organs, muscles, systems, and cells. This side of age-management medicine draws on the tools of molecular diagnostics, imaging, and data analytics. What has been my embodied life arc? Who am I, deep inside? And why?

The length of certain telomeres, Raffaele explained, not only tends to correlate with the healthiness of various organ systems; it “gives a history of all the assaults a person has been subject to over the course of her lifetime.” Hearing this, my mind drifted to the blockage from my stomach to my intestines that nearly killed me as a 6-week-old, as my mother regularly reminded me until her death two years ago; and then moved on to scarlet fever, which, when I contracted it as a 7-year-old, kept me quarantined for nearly two months and thus, in its way, determined what I would devote my life to: reading. Such are my memories. Were those short telomeres molecular memories?

It turns out that biological self-­knowledge is not easy even with a trail of biomarkers. Telomere shortening is often a result of chronic or acute inflammation, research suggests, but my inflammation was lower than average, according to another test Raffaele had analyzed. Stress? Not a problem—at least now, in semiretirement. My cortisol level (another lab test) was “optimal.” Still, when my data was analyzed in Raffaele’s system, I had the ImmunoAge of a 71-year-old. “I’m going to say it’s genetic,” Raffaele told me. Despite the efforts I made to eat right and exercise, my disease-fending self was old before its time.

Raffaele, 58, was trained as an internist. He was practicing in New Hampshire in the 1990s when his parents began showing signs of Alzheimer’s, and he was struck by how little he could do for them. Could there be preventive care with regard to aging?

Since then Raffaele has become one of the more outspoken proponents of evaluating biomarkers for physiological age. He was spurred, he said, by a remark from Robert Butler, the founding director of the National Institute on Aging and, until his death in 2010, arguably the country’s most prominent aging expert. Butler pointed out to Raffaele that conventional medicine had established multiple ways of measuring vital signs, like blood pressure, and setting them against baselines of a broader public. What, Butler wanted to know, was Raffaele using to determine a valid baseline? How did he know his therapies were working? “I went searching for the biomarkers of aging,” Raffaele says.

Biomarkers themselves are nothing new in medicine. When a series of tests over time reveals a rapidly rising presence of prostate-specific antigen in a man’s blood, it’s a valid indicator that he may be developing prostate cancer. But aging is far less specific than prostate cancer. And the search for its biomarkers is in its infancy, with no generally agreed upon number of biomarkers or standards for measurement among the practitioners of age-­management medicine. Raffaele’s system is proprietary and thus can’t be scrutinized, but he will say that he draws on large databases of patients who have taken his baseline exam, along with larger databases provided by the companies that do the blood testing and whose machines he uses for scanning. He also monitors the change over time in biomarkers he assesses. If my telomeres were to be no shorter 10 years from now, for instance, then they’d no longer be much of a concern.

My exam at Raffaele’s office began with a pretty typical form on which I filled in my medical history and recorded my diet and exercise habits. Next, I sat one morning for an hour at home, taking a series of neurological tests on my laptop: the CNS Vital Signs tests, which evaluate the main areas of cognitive function by taxing them relentlessly for 20 minutes; the Stroop test, which measures reaction time; and the Symbol Digit Coding test, to test the aging of the frontal lobes of the brain.

A week or so later, I showed up at the offices on Central Park South in New York: small but elegant, with walls of pale bamboo and a certain hush. I was the only patient there. Raffaele was off at a conference. I was led to a small room, where I was seated in a recliner and a technician drew eight full vials and a half-dozen half-vials of blood. It took a while. Then, after measuring my height and weight and taking my blood pressure, the technician walked me from one machine to the next, scanning, among other things, my carotid and other arteries (with an ultrasound imaging gadget) and obtaining a snapshot of my body fat and muscle distribution with an InBody body-composition-analysis device. It was painless and done in 20 minutes. It was, too, all but completely lacking in those small but psychically significant reassurances we expect from a physical examination. If this is the physical of the future, we are going to have to accustom ourselves to the indifferent graze of whirring, chirping machines.

Raffaele shook my hand when we met, a month after the office visit. Then he settled behind his desk and powered up a touchscreen computer. No lab coat, no stethoscope dangling from his neck: He wore a trim suit with a lavender tie and looked a good deal younger than 58.

There was good news as he walked me through his analysis. I’d entered my sixties training to become a serious senior tennis player, so it didn’t surprise me that my resting heart rate was “athletic,” my arteries were clear of plaque, and my resulting CardioAge was 43. My NeuroAge (processing speed) was “younger” than my chronological age, too.

But the short telomeres in my granulocytes cast a shadow. And then my PulmoAge turned out to be … 81! Really? I ran around a tennis court and regularly did interval sprints. Spirometry, which measures how much and how quickly you exhale, told a different story, however. Raffaele didn’t seem too worried. I had a small rib cage, which meant smaller lungs, he said. “Keep up the interval training.”

My overall PhysioAge, as he computed it, was 61. “You’re in good shape,” he said. But there was room for improvement. I needed to keep up the exercise and healthy diet. I should take vitamin D-3, he advised, to bolster my immune system. I might also consider human-growth-hormone therapy. “Hormone optimization,” as Raffaele put it, plays an important role in his practice. Raffaele himself has for 20 years been taking HGH, testosterone, thyroid hormone, and DHEA. There have been warnings about side effects of hormone therapies—from muscle and joint pain to the exacerbation of cardiac problems—but research to gauge the long-term benefits or risks of such therapies has been inconclusive so far.

The short telomeres in my granulocytes cast a shadow. And my PulmoAge turned out to be … 81!

So, being 61 PhysioAge-wise: Was it any different than being 65? It wasn’t. I did start to worry about the telomeres and my immune system. I’ve been surprised at how many of my friends seem to know about telomeres and seem concerned when I mention my shortened ones. Telomeres, in that sense, are the new cholesterol. I worried, too, that all this testing could be seen as a supreme act of vanity: A guy in good shape for his age dropping thousands of dollars on tests out of curiosity while much of his cohort nationwide struggles with hypertension and diseases like diabetes.

But who we are, physically, is a significant measure of our identity. And I suspect that science will reveal this more exactingly and profoundly in the years to come. Cicero thought that the body’s decline over time was a blessing in its way, leaving more time for learning and reflection by those truer aspects of ourselves, the mind and soul. That view is being challenged. The health of the mind (science doesn’t speak to the soul) may well depend to no small extent on genes and molecules in your gut that Cicero could not have imagined the existence of.

As those molecules become more measurable, and as the meaning behind their signals becomes clearer, it’s worth considering just how much self-knowledge we want. Do you want to know about your own shortened telomeres? Or worse, about some gene mutation, say, that suggests you have a better than even chance of developing an untreatable disease?

If you’re like me, you want to know everything: To comprehend is to live. The smalling down on the path to death is a diminishment that’s never been easy to navigate. It could be made less physically challenging by the kind of diagnostics and treatment Raffaele and others like him are working toward. But knowing yourself, never uncomplicated, is likely to get no less fraught. Just deeper.

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Gerald Marzorati is a former editor of The New York Times Magazine and author of Late to the Ball: A Journey into Tennis and Aging.

This article appears in the April issue. Subscribe now.

Read more: https://www.wired.com/story/biomarkers-age-management/