In 1888 Charles-Édouard Brown-Séquard, a famed French physician, claimed to have rejuvenated his septuagenarian self with injection of extracts of animal testes. Around the same time, Élie Metchnikoff, a Nobel Prize–winning Russian father of modern immunology, believed hormone injections were among the essentials for the prolongation of life. In 1907 his book The Prolongation of Life made hormone injections popular10 in many countries, most prominently Germany and the United States. Serge Voronoff, while disdained by his French medical colleagues in the first half of the twentieth century, achieved great public popularity for his work on glandular grafts and injections of monkey hormones for rejuvenation of older people.
In the twenty-first century, it’s the specific techniques we plan to use to achieve longevity that have changed, not the goal itself or even many of the scientific strategies.
In organisms from yeast and roundworms to mice and nonhuman primates, caloric restriction11 has markedly improved health and extended the life span. It lowers body fat, delays immune system changes, improves DNA repair capacity, and much more. In one article, in addition to the usual graphs, there are photographs of two sets of monkeys, both twenty-seven years old. The monkeys fed a usual diet look old, with wrinkles, sunken faces, and lost muscle mass and hair, while their calorie-restricted peers appear young and healthy. The restricted ones also had better blood sugar and cholesterol levels, and lived longer. At age thirty, fewer than a quarter of the control monkeys were alive, compared with 70 percent of the calorie-restricted ones. The long-lived (human) Okinawans, with their twelve-hundred-calorie-a-day diet, suggest something similar happens in humans. Some people are giving it a try. An international calorie restriction society claims thousands of members, although its physician founder died at age seventy-nine. Preliminary human studies haven’t lasted long enough to affect longevity but show positive hormonal changes,12 such as lower insulin levels and higher maintenance levels of the steroid hormone DHEA, similar to those seen in the calorie-restricted monkeys.
That’s great news, except most of us have trouble restricting ourselves to so-called normal amounts of food. Most Americans are overweight, and many in normal weight ranges still regularly eat more calories than they need, just for the fun of it—I do, and I love it, even though I know I shouldn’t and even as I live to regret it. Most scientists also like to eat, so they began looking for the biological mechanisms of calorie restriction. Maybe, they hypothesized, it worked via a molecule that they could copy, manipulate, or manufacture so people could get the benefits of calorie restriction without having to deprive themselves so drastically.
Enter resveratrol, a plant-derived compound that activates sirtuins,13 a class of intracellular proteins that regulate important biological pathways related to aging and other processes that influence aging, including inflammation, energy efficiency, and stress resistance. Resveratrol induces cellular changes associated with longer life spans, extends the life span of multiple lower species, including fruit flies and fish, and improves both health and survival in mice on a high-calorie diet. It can also be credited with the increased popularity of red wine. People are most likely to adopt dietary changes they enjoy.
Scientists are also investigating other molecules that the body makes in response to caloric restriction, such as the ketone body beta-hydroxybutyric acid (BHB) created when people eat a “ketogenic diet” high in fat and low in protein and carbohydrates. A recent study in aging mammals demonstrated positive effects of BHB on memory and life span. The results suggested that BHB affected gene expression. As the senior scientist involved in the project stated, “We’re looking for drug targets.14 The ultimate goal is to find a way for humans to benefit from BHBs without having to go on a restrictive diet.” Those who want the benefits now can exercise, a natural way to create ketone bodies. In fact, ketogenesis may be why exercise improves brain function, health span, and life span.
There are many different paths through which scientists believe they can affect aging, health, and possibly longevity. Cell-based strategies include therapies such as “senolytics,”15 clearing senescent cells with certain aging-associated markers.16 Other therapies under investigation to slow or stop aging include antioxidant supplementation and a compound called rapamycin, which was first discovered oozing from bacteria on Easter Island. Rapamycin influences the immune system (it’s already used in transplant medicine) and has been shown to prolong life in flies,17 worms, and rodents. Last but not least, and putting a modern twist on the humoral approach, several start-ups now replace the blood of older people with blood from young volunteers, hoping to transfer a variety of youth-related compounds all at once.
Some therapies, however widely touted and seemingly sound, aren’t remotely ready for human trials. Stem cells,18 for example: although they have proven uses in regeneration, in 2018 there is no evidence they work at achieving longevity.
The language and arguments of “anti-aging” have evolved, but the underlying message isn’t new. Nor is the participation of physicians in the anti-aging business. Throughout history, some have entered that arena with the intent of improving human lives, while others have exploited people’s endless appetite for self-deception and false hopes. Market-driven manipulators have invoked the same militaristic terms used by medicine in reference to cancer, drug abuse, and AIDS, simultaneously suggesting that not to “fight,” “battle,” or “defy” aging is foolhardy, and that to do so is to avail oneself of the full armamentarium of modern medical science. Never mind that only a tiny minority of these products and procedures are considered medical enough to warrant the investigation, impartial review, and safety and efficacy oversight we accord actual medical products and devices. And the field is made confusing by the overlap between real and pseudoscience in the use of hormones,19 blood, and other bodily substances that were no less popular in the 1880s than they are today. It’s also gendered. Men aim for ongoing sexual vigor and, among the supremely wealthy and powerful, more time in which to enjoy their money and power. Women strive for beauty and all that feminine beauty carries with it in our society—namely, visibility, relevance, allure, and worth.
In scientific circles, anti-aging usually refers to efforts to delay or “cure” old age, not to the multitude of discriminatory beliefs and policies related to aging. In coining that term, proponents hoped to align it with words like antibiotics, one of the most significant medical advances in human history. But this anti- is primarily used in relation to aging as it is used in the words antiestablishment or anti-immigration, meaning opposed to or against part of the natural life cycle. Worse still, it’s a tiny leap from that usage of anti-aging to being against aging people and traits.
The American Academy of Anti-Aging Medicine, unlike most medical organizations, has a.com and not a.org address—the difference being a profit goal versus a mission goal. In 2002 fifty-two of aging’s most prominent scientists—including Leonard Hayflick, who showed the finitude of cell divisions,20 “the Hayflick limit,” and Jay Olshansky, who has worked on discovering the upper limits of longevity—issued a statement that “the business of what has become known as anti-aging medicine has grown in recent years in the United States and abroad into a multimillion-dollar industry. The products being sold have no scientifically demonstrated efficacy, in some cases, they may be harmful,21 and those selling them often misrepresent the science upon which they are based.”
For at least the last century and a half, humans have had great faith in our ability to affect aging in ways superior to those of our predecessors. In 1905 the immunologist Arthur E. McFarlane wrote in “Prolonging the Prime of Life” that science will bring fitness and health to old age. Over a hundred years later, science has yet to deliver on that prediction. The leading researchers say the prospects are promising, although that has been said by leading researchers for centuries. That they haven’t succeeded yet doesn’t necessarily mean the concept is flawed; perhaps the failures come from the methods rather than the goal. (Neve
r mind the various nondisease issues, including overpopulation, climate change, pseudo foods, social policies, and tech use that have negative impacts on human health and longevity.) For many, science and technology have become the only hope, the only way. As a result, clear and present suffering gets ignored, as do the many noncurative strategies that might diminish or alleviate it.
Also largely ignored are the late effects of cures. Fixing one problem often creates new ones that might be avoided or mitigated if only all people and problems counted and we were willing to invest in the full range of tools and skills at our disposal. For instance, survive your cancer and you’re liable to develop delayed side effects ranging from other cancers to diseases of any organ in the body. Survive your heart attack or infection and you’re likely to become old. That will mostly be a good thing, except that the longer we keep you alive, the more likely you are to reach the phase of old age when most of modern society and medicine have nothing for you, not even dignity or compassion.
Innovation comes with trade-offs. Our ingenuity and technical skills have nearly doubled the human life span, but now people who previously would have died shortly after birth, or after devastating war injuries, or in extreme old age, remain alive. Draw the line too close, and lives are unnecessarily sacrificed; draw it too far, and we cause systematic suffering. To further complicate matters, looking at the same set of circumstances, people draw the line in different places. Generally, we tend to err toward life. Some of this is likely instinct, but part may be learned, a sociocultural habit adopted in the early years of modern medicine when antibiotics and surgeries offered what would have seemed like miracles in earlier eras. Our current advances have very different consequences than the ones of earlier generations—consequences that millions must live with but that are barely recognized or addressed by the medical institutions that produce them, especially if the current best approaches to improving human health and lives don’t require science or technology so much as shifts in attitudes, priorities, and values.
Someday, iterations of one or more of the “anti-aging” approaches are likely to succeed, maybe not in reversing aging altogether but in eliminating some of its downsides. Meanwhile, there are two paths we can take that would be transformative in the near future: justice in policy and kindness of attitude.
GAPS
Before clinic one day, our administrator informed me that my new patient was ninety-eight years old and went by the name of Kid. I began reviewing his old records with a smile on my face and high expectations for our first meeting.
Seconds later, I stared at my computer in disbelief. Although by and large American health care puts its money and efforts into treatment, prevention is unequivocally the better approach economically, medically, and morally, since it keeps people from getting sick and needing medical care in the first place. Usually, I am all for prevention. But the most recent entry into Kid’s electronic medical record was a note from a neurologist prescribing daily aspirin for stroke prevention, and I was not at all sure about aspirin for Kid.
Aspirin has risks that increase considerably with age and include internal bleeding, hospitalization, and death. A 2011 study found it was one of the top four drugs22 associated with emergency hospital visits in people over age sixty-five.
Kid had been older than sixty-five for over thirty years. What does prevention mean, I wondered, when a person has already outlived 99.99 percent of his fellow humans?
Trying to take good care of Kid, my neurologist colleague had applied the only evidence she had—evidence from younger patients—in deciding on a plan of care. That calculation had two important flaws. First, we do not know whether aspirin prevents stroke in ninety-eight-year-olds, as that has never been studied. Second, we do know from outcomes data, common sense, and scientific studies that the body’s response to drugs changes and the risk of drug side effects increases in old age. Basically, we could not know that aspirin would benefit Kid, but could be confident that the medication put him at significant risk for internal bleeding, kidney failure, and other adverse effects.
The routine prescription of medications with proven benefits in younger adults and only proven harms in old people happens with all kinds of drugs. Old people, excluded from the trials that show benefit, are prescribed the drug, and sooner or later the reports of adverse events start coming in—except, of course, when patients, families, nurses, and doctors attribute the symptoms to disease, age, or the relentless decline they expect in a sick old person.
On call one sunny, spring weekend, I received a message from the caregiver grandson of a patient in her nineties with atrial fibrillation. Her cardiologist had started her on a newly approved blood thinner that had been shown to be safer and easier to manage than the one she was on. The potential benefits to this mostly homebound nonagenarian were huge. She wouldn’t need to have her blood drawn to check drug levels. Getting this very old woman into the lab for blood tests was an ordeal, and finding veins was hard, causing bruising. Equally important, since what and how much she ate varied widely and certain foods interfered with her past blood thinner, she had been at risk for having blood that was either too thin, which could lead to dangerous bleeding, or not thin enough, increasing her chances of stroke. That risk would be eliminated on the new drug.
On the phone, her grandson said that she was confused. She didn’t seem sick or different in any other way. While there might have been an illness brewing, medications commonly cause confusion in old people, and the timing was just right for a reaction to the new pill. I stopped it, and she got better. On Monday, the cardiologist said the medication didn’t cause delirium and restarted it. On Tuesday evening, she was confused again. We again stopped it, and she got better. Here’s the worst part of this story: it’s mostly older people who have atrial fibrillation, yet there were no requirements to include them23 in trials of the drugs to treat that or other age-related conditions. (The Inclusion Across the Lifespan Policy starts in 2019.) Even when not excluded based on their age, old people are frequently rejected from studies because of their lab results, organ function, or chronic diseases. Once the studies are published, other older patients with the same conditions are prescribed the “trial proven” medications and told they are safe and helpful.
In clinical medicine, we are supposed look for “Occam’s razor,” or a single unifying diagnosis that explains all a patient’s symptoms, physical exam features, and test results. This strategy often works well in young or mostly healthy people. In older age groups, it’s more often the exception than the rule—as it is for younger and middle-aged people with multiple chronic diseases. And still most guidelines, “standards of care,” and quality metrics are developed one disease at a time. Relatively few guidelines address what happens in the real world24: people who have two, three, or multiple conditions. For them, guidelines can offer contradictory advice or lead to so many recommendations that an inordinate amount of a person’s time, efforts, and money are going to their medications and health behaviors. In that situation, their risk of adverse consequences is high. Medications interact with one another, leading to numerous or synergistic side effects, or the regimen becomes impossible, undesirable, or unaffordable. Maybe the person stops the most expensive drug or the one that makes them feel bad, not knowing until it’s too late whether it was a minor one or a critical one.
Age changes the organs that clear medications (mostly the kidney and liver), and old people are particularly susceptible to adverse reactions that can affect anyone. Older bodies also have reactions that younger bodies generally don’t. An old person taking more than four medications has a significantly increased fall risk, one factor that puts falls in the top tier of problems that cause illness, disability, and death in old age.
In real life, what’s going on with a person’s heart or lungs or mood never occurs in isolation. In science, you need to isolate what you want to study to ensure your results are relevant to your topic. Because medicine leads with science, we have
organ and disease specialists, and they form professional groups and societies that produce guidelines about the care of their organ or disease. In an article for the Journal of the American Medical Association, doctors illustrated what a guideline-adherent hypothetical seventy-nine-year-old patient would have to do if she had diabetes, hypertension, arthritis, osteoporosis, and chronic obstructive pulmonary disease, conditions that commonly coexist.25 Following guidelines, this person would take twelve medications in nineteen doses at five different times of day on average. She also would receive fourteen to twenty-four daily (depending on how you count) recommendations for diet and exercise. Her grand total of twenty-six to thirty-six health activities per day would constitute a near full-time job and put her at jeopardy for many interactions and adverse events. If she failed to do those activities, she would run the risk of being labeled “a non-compliant patient.”
The exclusion of old people from studies26 is ridiculous. Osteoporosis—and the sometimes treatable, sometimes debilitating fractures it causes—is largely a disease of old people,27 with the majority of cases in both men and women occurring in people in their late seventies or eighties. Yet a study looking at all the randomized control trials on the management of osteoporosis entered in the rigorous Cochrane Library Database28 found that the mean age of participants was sixty-four. For this condition with a mean age near eighty-five, a quarter of all trials excluded patients on the basis of age. This is like studying menopause in thirty-year-old women.
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