Lifespan

The connection between death and aging is so strong that the inevitability of the former governed the way we came to define the latter. When European societies first began keeping public death certificates in the 1600s, aging was a respected cause of death. Descriptions such as “decrepitude” or “feebleness due to old age” were commonly accepted explanations for death. But according to the seventeenth-century English demographer John Graunt, who wrote Natural and Political Observations Mentioned in a Following Index, and Made upon the Bills of Mortality, so were “fright,” “grief,” and “vomiting.”

As we’ve moved forward in time, we’ve moved away from blaming death on old age. No one dies anymore from “getting old.” Over the past century, the Western medical community has come to believe not only that there is always a more immediate cause of death than aging but that it is imperative to identify that cause. In the past few decades, in fact, we’ve become rather fussy about this.

The World Health Organization’s International Classification of Diseases, a list of illnesses, symptoms, and external causes of injury, was launched in 1893 with 161 headings. Today there are more than 14,000, and in most places where records of death are kept, doctors and public health officials use these codes to record both immediate and underlying causes of disability and death.[91 - “You know the cartoon where Bugs Bunny is driving an old car that suddenly falls apart, every bolt sprung, with the last hubcap rattling in a circle until it comes to rest?” Washington Post reporter David Brown wrote in 2010. “Some people die like that, too. The trouble is there’s not a good name for it.” D. Brown, “Is It Time to Bring Back ‘Old Age’ as a Cause of Death?” Washington Post, September 17, 2010, http://www.washingtonpost.com/wp-dyn/content/article/2010/09/17/AR2010091703823.html?sid=ST2010091705724.] That, in turn, helps medical leaders and policy makers around the globe make public health decisions. Broadly speaking, the more often a cause shows up on a death certificate, the more attention society gives to fighting it. This is why heart disease, type 2 diabetes, and dementia are major focuses of research and interventionary medical care, while aging is not, even though aging is the greatest cause of all those diseases.

Age is sometimes considered an underlying factor at the end of someone’s life, but doctors never cite it as an immediate reason for death. Those who do run the risk of raising the ire of bureaucrats, who are prone to send the certificate back to the doctor for further information. Even worse, they are likely to endure the ridicule of their peers. David Gems, the deputy director of the Institute of Healthy Ageing at University College London and the same man who wrote the report from the Royal Society meeting on “the new science of aging,” told Medical Daily in 2015 that “the idea that people die of pure aging, without pathology, is nuts.”[92 - “Really, people don’t die of old age,” Chris Weller wrote on Medical Daily. “Something else has to be going on.” C. Weller, “Can People Really Die of Old Age?,” “The Unexamined Life,” Medical Daily, January 21, 2015, http://www.medicaldaily.com/can-people-really-die-old-age-318528.]

But this misses the point. Separating aging from disease obfuscates a truth about how we reach the ends of our lives: though it’s certainly important to know why someone fell from a cliff, it’s equally important to know what brought that person to the precipice in the first place.

Aging brings us to the precipice. Give any of us 100 years or so, and it brings us all there.

In 1825, the British actuary Benjamin Gompertz, a learned member of the Royal Society, tried to explain this upward limit with a “Law of Human Mortality,” essentially a mathematical description of aging. He wrote, “It is possible that death may be the consequence of two generally co-existing causes; the one, chance, without previous disposition to death or deterioration; the other, a deterioration, or an increased inability to withstand destruction.”[93 - B. Gompertz, “On the Nature of the Function Expressive of the Law of Human Mortality, and on a New Mode of Determining the Value of Life Contingencies,” Philosophical Transactions of the Royal Society 115 (January 1, 1825): 513–85, https://royalsocietypublishing.org/doi/10.1098/rstl.1825.0026.]

The first part of the law says that there is an internal clock that ticks away at random, like the chance a glass at a restaurant will break; essentially a first-order rate reaction, similar to radioactive decay, with some glasses lasting far longer than most. The second part says that, as time passes, due to an unknown runaway process, humans experience an exponential increase in their probability of death. By adding these two components together, Gompertz could accurately predict deaths due to aging: the number of people alive after 50 drops precipitously, but there is a tail at the end where some “lucky” people remain alive beyond what you’d expect. His equations made his relatives, Sir Moses Montefiore and Nathan Mayer Rothschild, owners of the Alliance Insurance Company, a lot of money.

What Gompertz could not have known, but would have appreciated, is that most organisms obey his law: flies, roundworms, mice, even yeast cells. For larger organisms, we don’t know exactly what the two clocks are, but we do know in yeast cells: the chance clock is the formation of an rDNA circle, and the exponential clock is the replication and exponential increase in the numbers of rDNA circles, with the resulting movement of Sir2 away from the silent mating-type genes that causes sterility.[94 - D. A. Sinclair and L. Guarente, “Extrachromosomal rDNA Circles—A Cause of Aging in Yeast,” Cell 91, no. 7 (December 26, 1997): 1033–42, https://www.ncbi.nlm.nih.gov/pubmed/9428525.]

Humans are more complicated, but in the nineteenth century, British mortality rates were becoming amenable to simple mathematical modeling because they were increasingly avoiding not-from-aging deaths: childbirth, accidents, and infections. This increasingly revealed the underlying and exponential incidence of death due to internal clocks as being the same as it ever was. During those times, the probability of dying doubled every eight years, an equation that left very little room for survivors after the age of 100.

That cap has generally held true ever since, even as the global average life expectancy jumped twenty years between 1960 and today.[95 - Based on global population estimates and census reports, among other sources, the World Bank plotted out a fifty-six-year period ending in 2016 that showed life expectancy increasing from 52 to 72. “Life Expectancy at Birth, Total (Years),” The World Bank, https://data.worldbank.org/indicator/SP.DYN.LE00.IN.] That’s because all that doubling adds up quickly. So even though most people who live in developed nations can now feel confident that they will make it to 80, these days the chances that any of us will reach a century is just 3 in 100. Getting to 115 is a 1-in-100-million proposition. And reaching 130 is a mathematical improbability of the highest order.

At least it is right now.

THE MORTAL BREEZE

Back in the mid-1990s, when I was pursuing my PhD at Australia’s University of New South Wales, my mother, Diana, was found to have a tumor the size of an orange in her left lung.

As she was a lifelong smoker, I’d suspected it was coming. It was the one thing we had argued about more than anything else. When I was a young boy, I used to steal her cigarettes and hide them. It infuriated her. The fact that she didn’t respond to my pleas to stop smoking infuriated me, too.

“I have lived a good life. The rest is a bonus,” she would say to me in her early 40s.

“Do you know how lucky you are to have been born? You’re throwing your life away! I won’t come visit you in hospital when you get cancer,” I would say.

When the cancer finally arrived about a decade later, I wasn’t angry. Tragedy has a way of vanquishing anger. I drove to the hospital, determined to solve any problem.

My mother was responsible for her own actions, but she was also a victim of an unscrupulous industry. Tobacco alone doesn’t kill people; it’s the combination of tobacco, genetics, and time that most often leads to death. She was diagnosed with cancer at the age of 50. That’s twenty-one years earlier than the first diagnosis in the average lung cancer patient. It’s also how old I am now.

In one way of thinking, my mother was unfortunate to develop cancer at such a young age. After her back was opened up, rows of ribs were cut from her spine, and major arteries were rerouted, she lived the rest of her life with just one lung, which certainly impacted her quality of life and ensured that she had only a few years of good life left.

On the genetics front, my mother was also unfortunate. Everyone in my family, from my grandmother to my youngest son, has had their genes analyzed by one of the companies that offer these services. When my mother had hers done, she learned, albeit after she had cancer, that she had inherited a mutation in the SERPINA1 gene, which is implicated in chronic obstructive pulmonary disease or emphysema. That meant her clock was ticking even faster. After her left lung was removed, her right lung was the sole provider of oxygen, but the deficiency in SERPINA1 meant that white blood cells attacked her remaining lung, destroying the tissue as if it were an invader. Eventually the lung gave out.[96 - I inherited the SERPINA1 mutation from my mother. Even though I have never smoked, I find it hard to breathe in some situations, such as when I am visiting a place with substantial pollution. Armed with this information, I avoid breathing in dust and other contaminants when possible. I feel empowered knowing the genetic instructions within each of my cells, an experience that previous generations never had.]

In another way of thinking, though, my mother was very lucky—she had the come-to-God moment that many smokers need to go to battle with the tremendously powerful forces of addiction in time to save herself, and she spent another two decades on this planet. She traveled the world, visiting eighteen different countries. She met her grandchildren. She saw me give a TED Talk at the Sydney Opera House. For this we must certainly credit the doctors who removed her cancerous lung, but we should also acknowledge the positive impact of her age. One of the best ways to predict whether someone will survive a disease, after all, is to take a look at how old he or she is when diagnosed—and my mother was, relatively speaking, very young.

This is key. We know that smoking accelerates the aging clock and makes you more likely to die than a nonsmoker—15 years earlier, on average. So, we have fought it with public health campaigns, class action lawsuits, taxes on tobacco products, and legislation. We know that cancer makes you more likely to die, and we’ve fought it with billions of dollars’ worth of research aimed at ending it once and for all.

We know that aging makes you more likely to die, too, but we’ve accepted it as part of life.

It’s also worth noting that even before my mother was diagnosed with lung cancer—indeed, even before the cancerous cells in her lungs began growing out of control—she was aging. And in that way, of course, she was hardly unique. We know that the process of aging begins long before we notice it. And with the unfortunate exceptions of those whose lives are taken by the early onset of a hereditary ailment or a deadly pathogen, most people begin to experience at least some of the effects of aging long before they are impacted by the accumulation of diseases we commonly associate with growing old. At the molecular level, this starts to happen at a time in our lives that many of us still look and feel young. Girls who go through puberty earlier than normal, for example, have an accelerated epigenetic clock. At that age, we can’t hear the mistakes of the concert pianist.[97 - A. M. Binder, C. Corvalan, V. Mericq, et al., “Faster Ticking Rate of the Epigenetic Clock Is Associated with Faster Pubertal Development in Girls,” Epigenetics 13, no. 1 (February 15, 2018): 85–94, https://www.tandfonline.com/doi/full/10.1080/15592294.2017.1414127.] But they are there, even as a teenager.

In our 40s and 50s, we don’t often think about what it feels like to grow old. When I give talks about my research, sometimes I bring an “age suit” and ask a young volunteer to wear it. A neck brace reduces mobility in the neck, lead-lined jackets and wraps all over the body simulate weak muscles, earplugs reduce hearing, and ski goggles simulate cataracts. After a few minutes of walking around in the suit, the test subject is very relieved to take it off—and fortunately can do so.

“Imagine wearing it for a decade,” I say.

To put yourself into an aged mind-set, try this little experiment. Using your nondominant hand, write your name, address, and phone number while circling your opposite foot counterclockwise. That’s a rough approximation of what it feels like.

Different functions peak at different times for different people, but physical fitness, in general, begins to decline in our 20s and 30s. Men who run middle-distance races, for instance, are fastest around the age of 25, no matter how hard they train after that. The best female marathoners can stay competitive well into their late 20s and early 30s, but their times begin to rise quickly after 40. Occasionally, exceptionally fit outliers—such as National Football League quarterback Tom Brady, National Women’s Soccer League defender Christie Pearce, Major League Baseball outfielder Ichiro Suzuki, and tennis legend Martina Navratilova—demonstrate that professional athletes can stay competitive into their 40s, but almost no one remains at the highest levels of these or most other professional sports much past their mid-40s. Even someone as resilient as Navratilova peaked when she was in her early 20s through her early 30s.

There are some simple tests to determine how biologically old you probably are. The number of push-ups you can do is a good indicator. If you are over 45 and can do more than twenty, you are doing well. The other test of age is the sitting-rising test (SRT). Sit on the floor, barefooted, with legs crossed. Lean forward quickly and see if you can get up in one move. A young person can. A middle-aged person typically needs to push off with one of their hands. An elderly person often needs to get onto one knee. A study of people 51 to 80 years found that 157 out of 159 people who passed away in 75 months had received less than perfect SRT scores.

Physical changes happen to everyone. Our skin wrinkles. Our hair grays. Our joints ache. We start groaning when we get up. We begin to lose resilience, not just to diseases but to all of life’s bumps and bruises.

Fortunately, a hip fracture for a teenager is a very rare event that nearly everyone is expected to bounce back from. At 50, such an injury could be a life-altering event but generally not a fatal one. It’s not long after that, though, that the risk factor for people who suffer a broken hip becomes terrifyingly high. Some reports show that up to half of those over the age of 65 who suffer a hip fracture will die within six months.[98 - Women over 65 are more prone to hip fractures, with sepsis being the main cause of death. Researchers have linked the sepsis to poor medical care, a lack of family support, and dementia. “Time wise, mortality was found to be higher within the first six months, with 10 deaths (50%), and within the first year, with six deaths (30%).” J. Negrete-Corona, J. C. Alvarano-Soriano, and L. A. Reyes-Santiago, “Hip Fracture as Risk Factor for Mortality in Patients over 65 Years of Age. Case-Control Study” (abstract translation from Spanish), Acta Ortopédica Mexicana 28, no. 6 (November–December 2014): 352–62, https://www.ncbi.nlm.nih.gov/pubmed/26016287, (Spanish) http://www.medigraphic.com/pdfs/ortope/or-2014/or146c.pdf.] And those who survive often live the rest of their lives in pain and with limited mobility. At 88, my grandmother Vera tripped on a rumpled carpet and broke her upper femur. During surgery to repair the damage, her heart stopped on the operating table. Though she survived, her brain had been starved for oxygen. She never walked again and died a few years later.

Wounds also heal much more slowly with age—a phenomenon first scientifically studied during World War I by the French biophysicist Pierre Lecomte du Noüy, who noted a difference in the rate of healing between younger and older wounded soldiers. We can see this in even starker relief when we look at the differences in the ways children and the elderly heal from wounds. When a child gets a cut on her foot, a noninfected wound will heal quite quickly. The only medicine most kids need when they get hurt like this is a kiss, a Band-Aid, and some assurance that everything will be okay. For an elderly person, a foot injury is not just painful but dangerous. For older diabetics, in particular, a small wound can be deadly: The five-year mortality rate for a foot ulcer in a diabetic is greater than 50 percent. That’s higher than the death rates for many kinds of cancer.[99 - Up to 74 percent of patients who have a foot amputated due to diabetes die within five years of surgery. The authors argue for more aggressive focus on the issue by doctors and patients alike. “New-onset diabetic foot ulcers should be considered a marker for significantly increased mortality and should be aggressively managed locally, systemically, and psychologically.” J. M. Robbins, G. Strauss, D. Aron, et al., “Mortality Rates and Diabetic Foot Ulcers: Is It Time to Communicate Mortality Risk to Patients with Diabetic Foot Ulceration?,” Journal of the American Podiatric Medical Association 98, no. 6 (November–December 2008): 489–93, https://www.ncbi.nlm.nih.gov/pubmed/19017860.]

Chronic foot wounds, by the way, are not rare; we just don’t hear much about them. They almost always begin with seemingly benign rubbing on increasingly numb and fragile soles—but not always. My friend David Armstrong, at the University of Southern California, a passionate advocate for increasing our focus on preventing diabetic foot injuries, often tells the story of one of his patients, who had a nail stuck in his foot for four days. The patient noticed it only because he wondered where the tapping sound on the floor was coming from.

Small and large diabetic foot wounds rarely heal. They can look as though someone has taken an apple corer to the balls of both feet. The body doesn’t have enough blood flow and cell regeneration capacity, and bacteria thrive in this meaty, moist environment. Right now, 40 million people, bedridden and waiting for death, are living this nightmare. There’s almost nothing that can be done for them except to cut back the dead and dying tissue, then cut some more, and then some more. From there, robbed of upright mobility, misery is your bedfellow and thankfully death is nigh. In the United States alone, each year, 82,000 elderly people have a limb amputated. That’s ten every hour. All this pain, all this cost, comes from relatively minor initial injuries: foot wounds.

The older we get, the less it takes for an injury or illness to drive us to our deaths. We are pushed closer and closer to the precipice until it takes nothing more than a gentle wind to send us over. This is the very definition of frailty.

If hepatitis, kidney disease, or melanoma did the sorts of things to us that aging does, we would put those diseases on a list of the deadliest illnesses in the world. Instead, scientists call what happens to us a “loss of resilience,” and we generally have accepted it as part of the human condition.

There is nothing more dangerous to us than age. Yet we have conceded its power over us. And we have turned our fight for better health in other directions.

WHACK-A-MOLE MEDICINE

There are three large hospitals within a few minutes walk of my office. Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, and Boston Children’s Hospital are focused on different patient populations and medical specialties, but they’re all set up the same way.

If we were to take a walk into the lobby of Brigham and Women’s and head over to the sign by the elevator, we’d get a lay of this nearly universal medical landscape. On the first floor is wound care. Second floor: orthopedics. Third floor: gynecology and obstetrics. Fourth floor: pulmonary care.

At Boston Children’s, the different medical specialties are similarly separated, though they are labeled in a way more befitting the young patients at this amazing hospital. Follow the signs with the boats for psychiatry. The flowers will take you to the cystic fibrosis center. The fish will get you to immunology.

And now over to Beth Israel. This way to the cancer center. That way to dermatology. Over here for infectious diseases.

The research centers that surround these three hospitals are set up in much the same way. In one lab you’ll find researchers working to cure cancer. In another they’re fighting diabetes. In yet another they’re working on heart disease. Sure, there are geriatricians, but they almost always take care of the already sick, thirty years too late. They treat the aged—not the aging. No wonder so few doctors today are choosing to specialize in this area of medicine.

There’s a reason why hospitals and research institutions are organized in this way. Most of our modern medical culture has been built to address medical problems one by one—a segregation that owes itself in no small part to our obsession with classifying the specific pathologies leading to death.

There was nothing wrong with this setup when it was established hundreds of years ago. And by and large, it still works today. But what this approach ignores is that stopping the progression of one disease doesn’t make it any less likely that a person will die of another. Sometimes, in fact, the treatment for one disease can be an aggravating factor for another. Chemotherapy can cure some forms of cancer, for instance, but it also makes people’s bodies more susceptible to other forms of cancer. And as we learned in the case of my grandmother Vera, something as seemingly routine as orthopedic surgery can make patients more susceptible to heart failure.

Because the stakes are so exceptionally high for the individual patients being treated in these places, a lot of people don’t recognize that a battle won on any of these individual fronts won’t make much of a difference against the Law of Human Mortality. Surviving cancer or heart disease doesn’t substantially increase the average human lifespan, it just decreases the odds of dying of cancer or heart disease.

The way doctors treat illness today “is simple,” wrote S. Jay Olshansky, a demographer at the University of Illinois. “As soon as a disease appears, attack that disease as if nothing else is present; beat the disease down, and once you succeed, push the patient out the door until he or she faces the next challenge; then beat that one down. Repeat until failure.”[100 - Have we made a deal with the medical devil that’s backfired? Olshansky certainly thinks so, contrasting the quest for human longevity and health to the dark narrative of Faust’s ultimately pyrrhic deal with Mephistopheles. “It’s possible that humanity has squeezed about as much healthy life out of public health interventions as possible and that the human body is now running up against inherent limits that the genetically fixed attributes of our biology impose.” S. J. Olshansky, “The Future of Health,” Journal of the American Geriatrics Society 66, no. 1 (December 5, 2017): 195–97, https://onlinelibrary.wiley.com/doi/full/10.1111/jgs.15167.]

The United States spends hundreds of billions of dollars each year fighting cardiovascular disease.[101 - The numbers are indeed staggering: close to 800,000 Americans die annually of cardiovascular-related diseases; medical costs related to cardiovascular issues are expected to be over $818 billion by 2030 and lost productivity costs above $275 billion. “Heart Disease and Stroke Cost America Nearly $1 Billion a Day in Medical Costs, Lost Productivity,” CDC Foundation, April 29, 2015, https://www.cdcfoundation.org/pr/2015/heart-disease-and-stroke-cost-america-nearly-1-billion-day-medical-costs-lost-productivity.] But if we could stop all cardiovascular disease—every single case, all at once—we wouldn’t add many years to the average lifespan; the gain would be just 1.5 years. The same is true for cancer; stopping all forms of that scourge would give us just 2.1 more years of life on average, because all other causes of death still increase exponentially. We’re still aging, after all.

Aging in its final stages is nothing like a bushwalk, where a bit of rest, a drink of water, a nutritional bar, and some fresh socks can get you another dozen miles before sunset. It’s more like a fast sprint over an ever-higher and ever-closer set of hurdles. One of those hurdles will eventually send you for a tumble. And once you’ve fallen one time, if you do get up, the odds of falling again just keep getting higher. Take away one hurdle, and the path forward is really no less precarious. That’s why the current solutions, which are focused on curing individual diseases, are both very expensive and very ineffective when it comes to making big advances in prolonging our healthspans. What we need are medicines that knock down all the hurdles.