by Jamie Metzl
If we consider possibilities for changing a human attribute affirmatively selected over hundreds of millions of years—breathing is a good example—we push hard against the weight of evolution itself. But trying to tweak an attribute that evolution has somewhat ignored should, theoretically at least, give us some preliminary cause for hope.
But while we haven’t necessarily been selected for longevity, we certainly have been selected for our ability to survive hard times. Many times over the billions of years of our evolution, our ancestors have teetered on the brink of starvation. Genetic analysis suggests that about 1.2 million years ago our prehuman ancestors dwindled to a mere twenty-six thousand people. Then, about 150 thousand years ago, our ancestor population may have shrunk to as little as 600 people barely hanging on to life in the southern tip of Africa. After the ash spewing from a massive Sumatran volcano 70,000 years ago dimmed the sun for six years, the number of total humans may have again shrunk to as little as a few thousand souls.
With each of these accordion-like swings, only those of our ancestors with the greatest ability to do without nourishment survived. Everyone else withered away. These extreme survivors were then able to pass on their genetic predisposition for surviving tough times through the generations to us. This has left us, like many other species who have faced these same types of challenges, with a built-in heartiness that turns out to be quite useful in our quest for longevity.
Scores of studies have shown repeatedly and for decades that calorie restriction, or CR, extends the life of yeast, flies, worms, mice, rats, and other organisms. Studying whether CR extends the life of longer living mammals like us is more difficult because our longevity makes human studies too darn long and our naturally erratic behavior makes it all but impossible to force human subjects to meticulously avoid eating Ding Dongs for their entire lives. Starting in the 1980s, however, scientists set up a couple of studies seeking to measure the impact of CR on macaque (also known as rhesus) monkeys, which share 93 percent of their DNA with us. The CR monkeys in both studies lived an average of three years longer and remained on average healthier than their peers living in the same conditions but consuming more calories. At least four of the monkeys in one of the studies exceeded all previous records for the longest-lived macaques in captivity.11 Promising.
A U.S. National Institutes of Health–funded study called the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy, or CALERIE, convinced thirty-four people to reduce their overall calorie intake by 15 percent for two years. These people agreed to submit to weekly blood, bone, urine, internal body temperature, and other tests, and even spend twenty-four-hour periods in sealed metabolic chambers so that their breath could be measured for its ratio of oxygen to carbon dioxide. Based on all of this input, the researchers concluded that the 15 percent decrease in calorie intake translated into 10 percent lower metabolism. Although the study could not determine whether the still-living subjects would live longer than they would otherwise have, they concluded that lower metabolism led to a “decreased rate of living,” or less wear and tear on the cells, and the possibility of longer and healthier lives for the human equivalent to the macaque monkeys.12
Another place to look to understand how long we might have the potential to live is at the oldest Homo sapiens around us. Gilgamesh and Methuselah notwithstanding, the oldest person reliably recorded was a remarkable French woman named Jean Calment.
Born in the French town of Arles in 1875, young Jean encountered Vincent Van Gogh when she was twelve and married her cousin in 1896, who died in 1942 when Jean was sixty-seven. She was just getting started.
When Jean was ninety, a young lawyer named Francois Raffray convinced her to sell her apartment to him on a contingency contract. Jean would still live in the apartment, and Raffray, according to the contract, would pay her 2,500 francs a month, the equivalent of $500 dollars today, until she died, when he would take possession of the home. Little did he know…
Eating two pounds of chocolate a day, Jean rode her bike around the city until she was 100, remained extremely active past 110, and only began to slow down after a fall at 115. By then, she had become a local celebrity whose fame was growing with the passing years.
Raffray, meanwhile, was contractually bound to keep sending the monthly checks, whose value now far exceeded that of the apartment. After he died at age seventy-seven, his family was still legally required to keep paying for an additional year until Jean Calment died in 1997 at the age of 122, two years beyond Yahweh’s declared upper limit from Genesis 6:3 (but then again Yahweh doesn’t appear in the Bible to have known about chocolate).
Books have been written about why Jean lived so long. Famously unflappable, she attributed her longevity to her low levels of stress and positive attitude, but genetics also played a key role. “I’ve only had one wrinkle in my life,” Jean once famously said, “and I’m sitting on it.”
Jean Calment’s colorful story tells us what might be the upper limit of possibility, based on today’s biology and intervention options. To be more systematic, we can also try to understand large groups of super-agers like Jean to see what allows them to live that long. That’s exactly what Nir Barzilai is doing.
Director of the Institute for Aging Research at the Albert Einstein College of Medicine and one of the world’s great experts on aging, Nir has been recruiting and studying a large and growing number of Ashkenazi Jewish centenarians* in the greater New York area for years. There are many words that could be used to describe Nir—spritely, cherubic, infectiously positive—but none fully captures his essence. Although described by some as an elfin Austin Powers lookalike, Nir is a giant in the field of aging.
He’s encountered some truly remarkable people along the way, like Irving Kahn, a passionate learner who worked as an investment banker until his death at 109. Irving’s siblings, collectively the longest living siblings in recorded history, lived to be 109, 103, and 101. Irma Daniel, another of Nir’s centenarians, was a sharp-witted survivor of Nazi Europe who held court in Hoboken, New Jersey, until the age of 106. For each of these people, Nir and his colleagues are taking full life and health histories, sequencing their genomes, and conducting a battery of tests to determine what might be the “special sauce” for living so long. Although the research is ongoing, it has already made clear that while healthy habits can help people live somewhat longer lives, the best way to today live past one hundred is to have the right genetics.
These supercentenarians don’t just live longer, they live healthier longer. Most tend to have most of their faculties late into their lives and only die after relatively quick and compressed periods of illness.13 A Scripps Research Institute study of the sequenced genomes of over fourteen hundred “wellderly” people over the age of eighty similarly found that genetic variants in these people seemed to help maintain their cognitive health and protect them from major chronic diseases.14 Although popular perceptions of people living into their one hundreds imagine them hooked up to ventilators, the cost of health care for the average person dying past one hundred is only 30 percent that of the average person who dies in his or her seventies.
Nir and other researchers found that while many of the centenarians would be expected, based on their age, to pick up diseases like Parkinson’s, Alzheimer’s, and cardiovascular disease at higher percentages, they somehow didn’t.15 His team zeroed in on the gene ADIPOQ, common in most people but absent in many of the super-agers, which seems to protect them against inflammation of the arteries. Other researchers have identified tens of genes that, in one expression or another, seem to protect against brain disorders16 and inflated cholesterol levels,17 provide additional protection against Alzheimer’s,18 and increase life span more generally.19 More genes associated with longevity are being identified at a rapid clip.
They say if you’d like to live to ninety, eat well, relax, sleep, and exercise. If you want to live past one hundred, choose your parents wisely. But this maxim coul
d very well become OBS—overcome by science.
Identifying more of the genes that increase a person’s potential to live longer and healthier will allow us to introduce some of these genes into people via gene therapy or, more likely, figure out what the genes are doing and find a way to mimic that.
We all know that no matter what our genetic predisposition, we can live longer and healthier lives if we make smart lifestyle choices. Although lifestyle choices often feel like a separate category from genetics, they are not. Our lifestyle choices significantly impact the epigenetic instructions orchestrating how our genes work. Understanding which lifestyles facilitate the most optimal expressions of our genes, therefore, tells us not only what we might do to live healthier lives but also, at least for the cheaters among us, how we might trick our genes and our biology more generally to give us credit for the smart choices we have not made.
Trying to crack the code of what types of backgrounds and lifestyles deliver the greatest benefit, National Geographic Fellow Dan Buettner poured over global life-expectancy records, looking for the world’s statistically longest-lived populations. He labeled the places he found—in Icaria (Greece), Loma Linda (California, United States), Nicoya (Costa Rica), Okinawa (Japan), and Sardinia (Italy)—blue zones and set out to uncover their common denominators.
In a 2005 National Geographic cover story and 2008 book titled The Blue Zone: Lessons for Living Longer from the People Who’ve Lived the Longest, Dan described how people in blue zones do the following nine things:
1.They have moderate, regular physical activity woven into their lives that nudge them into moving every twenty minutes or so—not necessarily going to the gym but getting around their towns or villages to take care of necessities;
2.They can articulate their life purpose, or raison d’être—what the Japanese call ikigai;
3.They honor sacred, daily rituals that help them live relatively low-stress lives;
4.They only consume a moderate amount of calories per day;
5.They have plant-based, but not necessarily vegetarian, diets, mostly consisting of whole grains, tubers, nuts, greens, and beans;
6.They consume alcohol only moderately, if at all;
7.They have engaged spiritual or religious lives;
8.They have active and integrated family lives; and
9.They were born into or joined committed circles of devoted friends and are embedded in regular, active, and highly supportive social communities.20
People in blue zones weren’t necessarily becoming centenarians at higher rates than everyone else but they were, on average, living longer and healthier longer. So, living like people in blue zones can help us live longer than some of our neighbors but not longer than Jean Calment (who ate more chocolate than tubers and nuts!). In addition to looking at how and why certain people and communities live longer than others, another way of cracking the genetic code of mortality is to look for clues in the animal world by examining related animal species with significantly different life spans.
The average mouse, for example, can live up to about three years in the wild and four years in captivity, but the remarkable naked mole rat, a close relative, can live up to thirty-one. Less mature writers than I have described the naked mole rat as looking like a penis with two sharp teeth but I, a paragon of restraint, will just let you decide for yourself.
Photo courtesy of University of Rochester.
Native to Ethiopia, Kenya, and Somalia, these underground-dwelling, highly social, nearly hairless mammals live far longer than would be estimated based on their size. On average, larger species tend to live longer than smaller ones even though smaller versions of the same species tend to live longer than larger versions.21 Naked mole rats live more of their lives in good health than most other comparable creatures, repair any genetic damage more steadily, apparently feel little pain, and are immune to cancer. For these reasons, scientists are increasingly deploying genome sequencing, big-data analytics, and other advanced tools to try to understand the secret of the naked mole rats’ success.
Calico, for example, Google’s San Francisco–based life-extension company, maintains one of the world’s largest captive colonies of naked mole rats to see if it can uncover biomarkers of aging and unlock the secrets of naked mole rat longevity.22 Other studies are already beginning to generate hypotheses for what’s helping these creatures live so long and healthily, with an eye toward ultimately expanding human longevity, cancer resistance, and health span.
One study hypothesized that naked mole rat genetics make their cells produce high levels of a protein called HSP25 that serves almost as an automatic spell-check function, eliminating other faulty proteins in cells before they can cause a problem.23 Another found that naked mole rats have four pieces of ribosomal RNA—the tiny structures that translate DNA code into instructions for the cell to manufacture proteins—instead of the usual three for most other multicellular life forms like us. For a reason that scientists don’t fully understand, the four-part naked mole rat RNA structures makes significantly fewer translation errors than the three-part structures in other mammals.24
Researcher Vera Gorbunova explains one logical theory for why naked mole rats live longer and healthier than we might expect, compared to the biology of mice: living underground protects the naked mole rats from predators. Because their likelihood of being killed or eaten is high, mice invest evolutionary energy into fast reproduction. Naked mole rats, on the other hand, protect themselves from predators by living underground so can invest more evolutionary energy into living longer lives.25 Gorbunova and her scientist husband Andrei Seluanov are now exploring whether they can engineer some of the unique genetic structures of the naked mole rats into mice to see if those mice live longer.
Other examples of related animals with dramatically different life spans are the hard clam, Mercenaria mercenaria in scientific lingo, and its closely related Icelandic quahog clam, or Arctica islandicaI. The hard clam can live about forty years. Its cousin the Icelandic quahog clam can live over five hundred. No one really knows just how long a quahog clam can live because the Icelandic researchers who in 2006 discovered a 507-year-old quahog (they calculated how old it was by counting the growth rings on its shell) ended up killing it accidentally when they brought it up from the ocean floor and opened it to measure its age. Oops.
A major study used a battery of tests to compare these quahog clams to their shorter-lived hard clam relatives and found that the Icelandic quahogs’ remarkable resistance to oxidative stress—the damage done to cells when they are exposed to electronically unstable molecules called free radicals that accrue in all animals over time—was likely a major factor in their extreme longevity.26 This finding pointed researchers toward exploring oxidative stress as a potential systemic element in the aging process of other animals, including us.
My favorite example of an animal that shows us how little we know about aging and what might be possible is Turritopsis dohrnii, the immortal jellyfish.
It’s hard not to get excited about the Turritopsis dohrnii. Like all jellyfish, it starts out as a fertilized egg, out of which a larva emerges that then sinks to the ocean floor. There, it grows into a colony of polyps that spawn multiple, genetically identical jellyfish. But when faced with physical adversity or a lack of food, the Turritopsis dohrnii, unlike other jellyfish, turns from being an adult jellyfish back into a polyp, kind of like an adult human turning back into an embryo.
Comparing the biology of the immortal jellyfish to the biology of other subspecies of non-immortal jellyfish has helped scientists explore how the next generation of research into how induced pluripotent stem cells might help unlock secrets of cellular regeneration and rejuvenation, keys to extending human life.27
Humans and jellyfish separated in our evolutionary journey about six hundred million years ago. That’s a lot of years. But understanding more about what enables naked mole rats to live long and cancer-free, for quahog clams to slow their metabol
ism and protect their cells from oxidation, and for immortal jellyfish to continually regenerate themselves is already generating clues about how aging happens and how the process might be manipulated for us.28
Most of my childless friends often come away, like me, from visits with other people’s small children with the same wind-blown look on our faces. These awesome kids with so much darn energy, our internal dialogue goes, are great for an hour or two but would be overwhelming were they our full-time responsibility. (This feeling, of course, largely explains why some of us remain childless!) But the biological underpinnings of all this energy has big implications for aging.
All animals live on energy, but our ability to process the energy resources we have are limited. At every moment, our cells need to figure out how to allocate the energy they have. There are two main options: growth or repair. When we are young, we need lots of energy to grow into ourselves. That’s why young people, for example, have such a high metabolism, seem hyperactive, and burn a lot of calories. But burning this much energy also comes at a cost. Like constantly driving a car at full throttle, it wears out our cells. But cells have another option: to allocate energy more conservatively toward repair, kind of like the quahog clams, or like we do in the face of calorie restriction or other stress. This is equivalent to when your computer shifts to screensaver mode to conserve electricity or when your grandmother drives her car twenty miles an hour and carefully parks it in her garage.
Cells do this by regulating the uptake of glucose, the sugar we need to survive. Normally, cells use glucose aggressively for growth, but in times of scarcity, our cells shift into repair mode. The animal models showed that when the roundworms, fruit flies, and mice shifted from growth mode to repair mode, they were not only better able to survive hardship but also lived longer and healthier lives. When scientists like biologist Cynthia Kenyon (then a scientist at University of California, San Francisco, but now with Google Calico) used new tools to turn on and off the genetic switches that these experiments identified, they found that a few genetic changes to the Daf-2 and Daf-16 genes could shift cells from growth to repair mode and double the life spans of C. elegans roundworms.29 This led to the increasing realization that the aging process is regulated by the equivalent of knobs that can be turned.