Successful Aging: A Neuroscientist Explores the Power and Potential of Our Lives

by Daniel J. Levitin

Given the time-dependent nature of hormonal release schedules that are governed by the circadian clock, what is the most important thing about sleep? To go to bed at the same time every night and wake up at the same time every morning. Even on weekends. This may mean forgoing late parties if you’re an early bird, or missing early-morning events if you’re a night owl. Although few of us lived this way in our twenties and thirties, by the time you reach sixty-five or so, you may begin to notice that inconsistency has become even more punishing. Even a slight change to the schedule—staying up an hour later than usual, for instance—can affect your memory, alertness, and immune system for days.

Follow these steps. They apply to people of any age, but as we get older it can become increasingly necessary to be strict about them.

Start getting ready for bed about two hours before sleep time. Stop watching TV, using a computer, tablet, or smartphone, or other sources of blue light (daylight wavelengths) that could act as a zeitgeber for the pineal gland and cause your brain to produce wake-up hormones. Do something that helps you relax—a warm bath, reading, music listening, whatever works for you. Ensure that the room you sleep in is completely dark. If you have a clock, charger, or other device that emits blue light, cover it up. Make sure that your curtains block out both daylight and any artificial light that may come into the bedroom. Sleep in a cool room if possible. Help to keep your sleep and wake cycle synchronized properly by getting sunlight in the morning—even on a cloudy day, the wavelengths you need can activate the pineal gland. A simulated dawn (blue-light) lamp for fifteen to thirty minutes in the morning can help. Write in a journal before bedtime. Recent research shows that it helps you to relax and can improve memory. It’s especially effective if you write a quick to-do list for tomorrow. Worrying about incomplete future tasks is a significant contributor to difficulty falling asleep. Don’t rely on sleeping pills for more than one or two nights. The sleep they induce is less productive and less restorative than natural sleep. Go to bed at the same time every night. Wake up at the same time every morning. If you have to stay up late one night, you should still get up at your fixed ...

LIVING LONGER

The longest life ever authenticated was Jeanne Calment of France, who lived to be more than 122 and died in 1997. There doesn’t appear to be anything remarkable in her diet, exercise routine, or other lifestyle details, at least nothing that would suggest a life span longer than anyone else’s. Jeanne enjoyed desserts. She smoked two cigarettes a day from the age of 21 to 117. (Why she quit at 117 is not clear. Of course, quitting can be difficult—maybe it just took her that long.)

When scientists talk about aging we’re not talking about chronological age, because there is a wide variety of ways that people age. What we’re really interested in is the accumulated effect of things that happen to our bodies that cause difficulties. Neuroscientists use the word senescence—just a fancy Latin-rooted word that means to grow old or to age. You can’t do anything to turn back your chronological age, but you can decrease the likelihood of senescence by adopting simple practices. It has been accepted wisdom for decades that the life span of humans is limited to around 115 years, with only a few exceptions popping up every now and then.

Among modern humans, 90 percent of deaths overall are from cancer and cardiovascular disease. If you could remove injury and disease from the equation, might we live forever?

Biologists have identified several species that can theoretically live forever, if only they can avoid predators, accidents, and nosy scientists; they just don’t seem to age or to die of old age. One is a species of jellyfish (Turritopsis dohrnii). When it encounters a life-threatening stressor, it can revert to what is essentially a younger stage of its life and start over.

an Italian statistician at the University of Rome, Elisabetta Barbi, conducted a thorough analysis of thousands of elderly Italians who had lived to 105 or longer. Normally, the risk of dying increases with age—an 80-year-old is significantly more likely to die within the next five years than a 40-year-old. But Barbi’s team found that after 105, the risk of dying flattens out to a plateau, so after that age, your risk of dying in the upcoming year holds at fifty-fifty. Hekimi, who was not involved in the study, praised it. It suggests that there may not be a limit, especially if we can figure out how to control diseases that typically afflict people between the ages of 80 and 104. Statistically speaking, if you can make it to 104, it’s smooth sailing from there on.

“Current understanding of the biology of aging points firmly away from any idea that the end of life is itself genetically programmed.”

That little drop in risk of death that is visible at the one-hundred-year mark would seem to indicate that people who get close to the age of one hundred want to stay alive to see their one hundredth birthday. I know I would.

So-called blue zones made headlines in 2008 when demographers discovered the four places in the world that had the highest number of people over age one hundred: Nicoya, Costa Rica; Sardinia, Italy; Ikaria, Greece; and Okinawa, Japan

Most people living in the blue zones have the following in common: They are physically active, not through weight and endurance training, but through chores, gardening, and walking as an integrated part of their lives—they move a lot. Their lives have a sense of purpose by doing things they find meaningful. They have lower levels of stress and a slower pace. They have strong family and community ties. They follow a varied diet with a moderate caloric intake, but mostly based on plant sources and high-quality food.

a concept called assortative mating. When selecting a mate, most of us tend to be most comfortable with someone who is somewhat like us in terms of physical attractiveness, intellect, sociability, and other traits. That means that we’re choosing people who possess some genes similar to ours, even though we are not closely related. What this all means is that culture and environment—the healthy lifestyle changes you make—are more important than genes for predicting how long you’ll live.

In 1961, anatomist Leonard Hayflick at the Wistar Institute in Philadelphia was having trouble getting his experiments to work. For decades, it was accepted wisdom that human cells would continue to duplicate indefinitely. But Hayflick could not get his to.

To rule out the possibility of contamination, he put old cells and younger ones in the same glass bottle—it was only the old ones that stopped dividing. He subsequently documented that the limit to human cell division was between forty and sixty cell divisions, or replications (the Hayflick limit is usually cited as fifty).

One of the startling discoveries was that Hayflick could freeze the samples for up to five years, and, when thawed, they’d begin replicating as before and still stop at the forty-to-sixty limit.

when the telomeres get too short, cell division—and thus cellular repair and renewal—stops. When DNA cells stop dividing, you don’t die immediately—the human body has around 10 trillion cells, each carrying DNA—although it’s well-established that people with short telomeres die younger than people with long telomeres. One leading hypothesis is that when telomeres shorten, and cells stop replicating, they enter a state of senescence and begin to gum up the works. But it is still not certain that the telomere shortening is the cause as opposed to simply a marker of trouble.

Telomere length is mediated by a number of factors. Remember Conscientiousness—the propensity to be planful, reliable, and industrious and to adhere to social norms and tolerate delayed gratification? It turns out that childhood Conscientiousness predicts telomere length forty years later, as shown by Sarah Hampson and her colleagues. Exercise is associated with increased telomere length and remediating the negative effects of stress. A diet of whole foods is associated with increased telomere length,

Neighborhoods with low social cohesion, where people don’t know one another or trust one another, are bad for telomeres, and this is true at all income levels. It doesn’t matter to the telomeres whether you’re living in a sketchy part of a major city or you’re in a mansion on a suburban hill—if you do not have friendly relationships with your neighbors, if you don’t actually enjoy talking to them, chances are your telomeres are getting shorter by the day.

Not all kinds of stress shorten telomeres. Short-term, manageable stressors are actually good for you because they keep you challenged and give you a repertoire of coping skills, strengthening cells through a process called hormesis—this describes anything that in a low dose is helpful but in a high dose is toxic.

The kind of stress that shortens telomeres is long-term, chronic stress. In particular, long-term caregiving for a family member, job burnout, and serious traumas such as rape, abuse, domestic violence, and bullying are damaging to telomeres. And in general, it takes a long period of stress before your telomeres are damaged—a monthlong crisis at work probably isn’t enough. But when stress is an enduring, defining feature of your life, that’s when your telomeres will get shorter.

an important moderating factor in the relationship between stress and telomere length is your response to stress. If you’ve developed good methods of coping and you can stay calm, and find reasons to be happy, your telomeres may not take a hit at all. Some people approach difficult events with a “can-do” attitude, a “bring it on” mentality, seeing these events as a challenge and an opportunity to learn; other people cave in to despair. The physiological response to a sudden stressor is that your adrenal gland releases cortisol. In short bursts that is a good thing, a hormetic response that increases your energy. Athletes who have this kind of healthful challenge response during competitions win more often; Olympic athletes and successful people in many domains tend to see life’s problems as challenges to be overcome.

Mindfulness meditation (the kind favored by the Dalai Lama) increases the activity of telomer...

Chronic pain is a stressor, and stress decreases telomere length.

I’ve heard a lot of patients say that they “can live with” the pain they are in, and I wonder if this is some effort to display toughness and hardiness. If they knew that living in pain could shorten their lives, would they still eschew the physical therapy and medications that might relieve their pain?

Surprisingly, it turns out that excessively long telomeres are also bad for you. In one large study of more than twenty-six thousand people, overall cancer risk increased by 37 percent with doubled telomere length. And some cancers were more impacted than others. For people with the longest telomeres, lung cancer risk increased by 90 percent, breast cancer by 48 percent, prostate cancer by 32 percent, and colorectal cancer by 35 percent. The most troubling effect was a more than doubling of the risk for pancreatic cancer. But just to show how complicated the relationship is between telomere length and cancer, those who had the shortest telomeres also had increased risk for certain cancers: 63 percent greater for stomach cancer and 41 percent greater for liver cancer. In a study of 9,127 patients and thirty-one cancer types, telomeres were found to be shorter in tumors and longer in sarcomas and gliomas. (Sarcomas are cancers of connective tissues such as bones, tendons, cartilage, muscle, and fat; gliomas are tumors that start in glial cells of the brain or spine.) The relationship between telomere length and telomerase activity in this study remains unclear.

Disturbingly large numbers of entrepreneurs are luring gullible and frequently desperate customers of all ages to “longevity” clinics, claiming a scientific basis for the antiaging products they recommend and, often, sell. At the same time, the Internet has enabled those who seek lucre from supposed antiaging products to reach new consumers with ease. Alarmed by these trends, scientists who study aging, including the three of us, have issued a position statement containing this warning: No currently marketed intervention—none—has yet been proved to slow, stop or reverse human aging, and some can be downright dangerous.

People are living longer and longer on average, and this is owing to a number of positive environmental factors such as medical advances, access to clean water, and so on—not to longevity products.

That doesn’t stop a lot of people from trying, nor does it look like it will slow the multibillion-dollar antiaging industry. I remember reading about the death of Robert Atkins, the physician who popularized the low-carb, high-fat, and high-protein diet bearing his name. He did not live particularly long, dying at age seventy-two after slipping on some ice in New York City and hitting his head. A running, dark joke in my lab was that while the Atkins diet did great things for your heart, it caused people to slip on ice. In fact, at least in Atkins’ own case, it wasn’t so great for his heart, either, as medical records released posthumously revealed that he had hypertension, a heart attack, and congestive heart failure—all the reasons we were told not to eat diets high in animal fat. (If you’ve got to choose, it looks like you’re better off getting your calories from fat than from sugar.)

Shortened telomeres cause otherwise healthy cells to go senescent. Senescent cells are a double-edged sword. On the one hand, they can’t divide, meaning they don’t go cancerous; cellular senescence is a way to prevent tumors from forming. On the other hand they produce SASP (senescence-associated secretory phenotype)—toxins and inflammatory mediators that do most of the damage that we associate with aging and mortality.

Normally, when cells die, they are cleaned out by cellular housekeeping processes. But these cells, like zombies in a horror movie, won’t die. So basically, unless the uncontrolled cellular reproduction of cancer gets us, we die in a pile of senescent cellular garbage of our own making.

Biochemist Jan van Deursen and his colleagues found a chemical marker that distinguishes certain senescent cells from healthy ones and then administered a drug called AP20187 that causes those cells to die. Drugs like this are called senolytics (combining the first part of the word senescence with lytic, which means destroying) and the proposed treatment is called senotherapy. Van Deursen found that clearance of these zombie cells in young mice delayed aging. In already aged mice, it slowed the progression of age-related disorders. Removing the senescent cells appears to jump-start some of the tissues’ natural repair mechanisms. Subsequent work in mice has shown that removing the zombie cells in this way can repair damage from lung disease and damaged cartilage, and it can extend life span by 25 percent. It can also prevent memory loss.

Now, the complicated part of all this is that cellular senescence is a good thing—if a cell becomes damaged it could start to divide uncontrollably and cause cancer. One of the risks of using senolytics is that they could interfere with the processes that normally inhibit cancer growth if they target presenescent cells that could go either way—toward zombies or cancer. There are other problems. In rats, senolytics slow down the wound-healing process. None of the known senolytics are yet safe in humans. As one researcher says, “Everything looks good in mice and when you get to people that is where things go wrong.” But if they prove otherwise safe in humans, we still run the risk that senolytics could promote cancer. If only there was a way to somehow check the progression of cancer before it takes over.

Two immunologists, Jim Allison and Tasuku Honjo, received the 2018 Nobel Prize for their work on immunotherapy cures for cancer. (Again, cancer is uncontrolled cell division.) Allison has been working on what he calls immune checkpoint blockades.

The goal was to use your own body’s immune system to attack cancers as they form, something our immune system does al...

Immunotherapeutic approaches to cancer are getting a lot of laboratory attention. As the techniques become more refined over the coming five to ten years, I predict that they will become increasingly important for longevity, wiping out one of the biggest killers that prevent us from living longer. As the curves above show, conventional therapies have a survival rate of close to zero. Immunotherapy allows for the curve to level off. All of this is great news, but it’s not the end-all answer to longevity; it’s been calculated that even if cancer were eradicated, it would only extend average life span by seven years—that’s because if you survive cancer, you’ll die of other things, like cardiovascular disease or neurodegeneration.

If we could remove all disease, might we live forever? Maybe, but that’s a long way off. Most diseases are caused by the basic biological process of aging. Removing diseases present today would permit a new set of diseases to get you—like a game of Whac-A-Mole. And we probably wouldn’t like those diseases very much either.

Felipe Sierra of the US National Institute on Aging (NIA), and who of course wants to live a long and healthy life, says: None of this is ready for prime time. The bottom line is I don’t try any of these things. Why don’t I? Because I’m not a mouse.

My advice, based on what I’ve learned from the literature and from Sinclair himself, is to wait for the dust to settle on this whole NAD+ thing. If it becomes approved by the FDA as a drug, rather than a supplement, the purity will be tightly regulated, which it is not now—and it will have been shown to work in humans, not just mice.

Another idea being studied is the possibility of harnessing the power of regeneration that some amphibians possess. The Mexican axolotl, a type of salamander, is about nine inches long and has astonishing abilities to regenerate severed limbs, damaged brain tissue, and even a crushed spinal cord. Its genome was just recently sequenced, and you can be sure that researchers on aging will be looking for clues about how genetic therapies might help to regenerate aging human tissue. Interestingly, axolotls do not live particularly long, unlike, say, hydras, but their ability to avoid dying after accidents that would be fatal for most species is a promising direction for future research.

An octogenarian today can count on living another eight years, four years longer than eighty-year-olds had in 1990. Centenarians live longer than ever before after they have reached one hundred. And the number of people over eighty who are making meaningful contributions, to their families, to their communities, and to the world, is increasing as we find health spans increasing dramatically. We are living in a time during which being old means more health and more opportunities than at any point in recorded history. Sixty-year-olds are doing the things that forty-year-olds used to do. It is no longer surprising to hear about people in their eighties who still work.

Jane Fonda, eighty-one, is starring in the hit TV show I mentioned earlier, Grace and Frankie, Jiro Ono,

We really don’t know how to extend health span or life span with any certainty. You could avoid smoking, and war, and getting repeatedly hit in the head. You can be conscientious about vaccination, hygiene, exercise, not working too hard, being warm in the winter and cool in the summer, and eating noncontaminated fresh produce all year long . . . Or you could be like Jeanne Calment and smoke until you’re 117. Or like Richard Overton, the oldest surviving World War II veteran (at the time of his death), who lived to be 112 and whose secret to a long life was cigars (twelve a day), whiskey, and coffee (with three teaspoons of sugar). Fate is capricious.

LIVING SMARTER

We found little compelling evidence that practicing cognitive tasks in brain-training products produces lasting cognitive benefits for real-world cognition. . . . If your hope is to stave off the cognitive losses that sometimes accompany aging or to enhance your performance at school or in your profession, you should be skeptical. Consumers should also consider the comparative costs and benefits of engaging in a brain-training regimen. Time spent using brain-training software could be allocated to other activities or even other forms of “brain training” (e.g., physical exercise) that might have broader benefits for health and well-being.

I do crosswords and KenKen every day, but they don’t make me better at writing books or calculating a tip on a restaurant check—they are their own world, a world I enjoy and consider to be among my rewarding hobbies. I do them because they give me pleasure and challenge me mentally, not because I think they’ll make me better at other things.

You may be better off engaging in things that more closely resemble the kind of mental activities you enjoy or want to improve. Do you want to learn more from reading? Join a book club and discuss your thoughts with others. Do you want to be more attentive in daily activities? Practice the specific kinds of activities that demand such mental processes. Do you want to be creative? Learn a new musical piece, dance step, or dinner recipe. Explore new locations around your neighborhood.

Stimulants—Adderall, Modafinil, Pitolisant, Ritalin, Nicotine

Members of the US Bioethics Commission write: Adderall and other stimulants are used off-label by individuals who desire to increase their competitive advantage by working longer hours with greater attentiveness while sleeping less. At every turn, we see headlines announcing “epidemic” amphetamine use by high-achieving students seeking top grades and standardized test scores.