Lifespan

WHY TREATING ONE DISEASE AT A TIME HAS LITTLE IMPACT ON LIFESPAN. The graph shows an exponential increase in disease as each year passes after the age of 20. It’s hard to appreciate exponential graphs. If I were to draw this graph with a linear Y-axis, it would be two stories tall. What this means is your chance of developing a lethal disease increases by a thousandfold between the ages of 20 and 70, so preventing one disease makes little difference to lifespan.

Source: Adapted from A. Zenin, Y. Tsepilov, S. Sharapov, et al., “Identification of 12 Genetic Loci Associated with Human Healthspan,” Communications Biology 2 (January 2019).

Thanks to statins, triple-bypass surgeries, defibrillators, transplants, and other medical interventions, our hearts are staying alive longer than ever. But we haven’t been nearly so attentive to our other organs, including the most important one of all: our brains. The result is that more of us are spending more years suffering from brain-related maladies, such as dementia.

Eileen Crimmins, who studies health, mortality, and global aging at the University of Southern California, has observed that even though average lifespans in the United States have increased in recent decades, our healthspans have not kept up. “We have reduced mortality more than we prevented morbidity,” she wrote in 2015.[102 - As treatments for patients with disease have prolonged their lives, so the amount of disease in society has augmented. This situation means that the only way to increase the human healthspan will be by “‘delaying aging,’ or delaying the physiological change that results in disease and disability,” the author argues. Along with scientific breakthroughs, changes in socioeconomic inequalities, lifestyle, and behavior can contribute to improving both healthspan and lifespan. E. M. Crimmins, “Lifespan and Healthspan: Past, Present, and Promise,” Gerontologist 55, no. 6 (December 2015): 901–11, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861644/.]

So prevalent is the combined problem of early mortality and morbidity that there is a statistic for it: the disability-adjusted life year, or DALY, which measures the years of life lost from both premature death and poor state of health. The Russian DALY is the highest in Europe, with twenty-five lost years of healthy life per person. In Israel, it is an impressive ten years. In the United States, the number is a dismal twenty-three.[103 - According to the World Health Organization, one DALY can be thought of as one lost year of “healthy” life. The sum of these DALYs across the population, or the burden of disease, can be thought of as a measurement of the gap between current health status and an ideal health situation in which the entire population lives to an advanced age, free of disease and disability. “Metrics: Disability-Adjusted Life Year (DALY),” World Health Organization, https://www.who.int/healthinfo/global_burden_disease/metrics_daly/en/.]

The average age of death can vary rather significantly over time, and is affected by many factors, including the prevalence of obesity, sedentary lifestyles, and drug overdoses. Similarly, the very idea of poor health is both subjective and measured differently from place to place, and so researchers are divided on whether the DALY is rising or declining in the United States. But even the more optimistic assessments suggest that the numbers have largely been static in recent years. To me, that in itself is an indictment of the US system; like other advanced countries, we should be making tremendous progress toward reducing the DALY and other measures of morbidity, yet, at best, it seems we’re treading water. We need a new approach.

It doesn’t take studies and statistics to know what’s happening, though. It’s all around us, and the older we get, the more obvious it becomes. We get to 50 and begin to notice we look like our parents, with graying hair and an increasing number of wrinkles. We get to 65, and if we haven’t faced some form of disease or disability yet, we consider ourselves fortunate. If we’re still around at 80, we are almost guaranteed to be combating an ailment that has made life harder, less comfortable, and less joyful. One study found that 85-year-old men are diagnosed with an average of four different diseases, with women of that age suffering from five. Heart disease and cancer. Arthritis and Alzheimer’s. Kidney disease and diabetes. Most patients have several additional undiagnosed diseases, including hypertension, ischemic heart disease, atrial fibrillation, and dementia.[104 - And almost everyone at that age spends a considerable part of his or her life visiting the doctor. According to the study, published in 2009 by the British Medical Journal, 94 percent of 85-year-olds had had contact with a doctor in the past year, and one in ten was in institutional care. J. Collerton, K. Davies, C. Jagger, et al., “Health and Disease in 85 Year Olds: Baseline Findings from the Newcastle 85+ Cohort Study,” British Medical Journal, December 23, 2009, https://www.bmj.com/content/339/bmj.b4904.] Yes, these are different ailments with different pathologies, studied in different buildings at the National Institutes of Health and in different departments within universities.

But aging is a risk factor for all of them.

In fact, it’s the risk factor. Truly, by comparison, little else matters.

The final years of my mother’s life serve as a good example. Like almost everyone else, I recognized that smoking would increase my mother’s chances of getting lung cancer. I also knew why: cigarette smoke contains a chemical called benzo(a)pyrene, which binds to guanine in DNA, induces double-strand breaks, and causes mutations. The repair process also causes epigenetic drift and metabolic changes that cancer cells thrive on, in a process we’ve called geroncogenesis.[105 - The possibility that both genetic and epigenetic aging are needed for a tumor to develop we’ve termed “geroncogenesis,” and it explains why tumors don’t occur in young people even after extreme sun exposure, why it often takes decades for DNA damage to lead to a tumor even if you avoid the sun later in life, and why cancers often have an unusual metabolism (named after the physicist Otto Warburg), one that directly consumes glucose, has decreased mitochondrial activity, and uses less oxygen to make energy, similar to the metabolism of old cells.]

The combination of genetic and epigenetic changes induced by years of exposure to cigarette smoke increases the chances of developing lung cancer about fivefold.

That’s a big increase. And because of it—and the devastatingly high health costs associated with treating cancer—the majority of the world’s nations sponsor smoking cessation programs. Most countries also put health warnings on cigarette packaging, some with horrific color pictures of tumors and blackened extremities. Most countries have passed laws against certain kinds of tobacco advertising. And most have sought to decrease consumption through punitive taxes.[106 - According to the World Health Organization, “The State of Global Tobacco Control,” 2008, http://www.who.int/tobacco/mpower/mpower_report_global_control_2008.pdf.]

All of that to prevent a fivefold increase in a few kinds of cancer. And having watched my mother suffer from that kind of cancer, I’ll be the first to say it’s totally worth it. From both an economic and emotional point of view, these are good investments.

But consider this: though smoking increases the risk of getting cancer fivefold, being 50 years old increases your cancer risk a hundredfold. By the age of 70, it is a thousandfold.[107 - R. A. Miller, “Extending Life: Scientific Prospects and Political Obstacles,” Mil-bank Quarterly 80, no. 1 (March 2002): 155–74, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690099/; graph redrawn from D. L. Hoyert, K. D. Kochanek, and S. L. Murphy, “Deaths: Final Data for 1997,” National Vital Statistics Report 47, no. 19 (June 30, 1999):1–104, https://www.ncbi.nlm.nih.gov/pubmed/10410536.]

Such exponentially increasing odds also apply to heart disease. And diabetes. And dementia. The list goes on and on. Yet there is not a country in the world that has committed any significant resources to help its citizens combat aging. In a world in which we seem to agree on very little, the feeling that “it’s just the way it goes” is almost universal.

A GLORIOUS FIGHT

Aging results in physical decline.

It limits the quality of life.

And it has a specific pathology.

Aging does all this, and in doing so it fulfills every category of what we call a disease except one: it impacts more than half the population.

According to The Merck Manual of Geriatrics, a malady that impacts less than half the population is a disease. But aging, of course, impacts everyone. The manual therefore calls aging an “inevitable, irreversible decline in organ function that occurs over time even in the absence of injury, illness, environmental risks, or poor lifestyle choices.”

Can you imagine saying that cancer is inevitable and irreversible? Or diabetes? Or gangrene?

I can. Because we used to say that.

All of these may be natural problems, but that doesn’t make them inevitable and irreversible—and it sure doesn’t make them acceptable. The manual is wrong about aging.

But being wrong has never stopped conventional wisdom from negatively impacting public policy. And because aging isn’t a disease by the commonly accepted definition, it doesn’t fit nicely into the system we’ve built for funding medical research, drug development, and the reimbursement of medical costs by insurance companies. Words matter. Definitions matter. Framing matters. And the words, definitions, and framing we use to describe aging are all about inevitability. We didn’t just throw in the towel before the fight began, we threw it in before we even knew there was a fight to be had.

But there is a fight. A glorious and global one. And, I think, a winnable one.

There’s no good reason why we have to say that something that happens to 49.9 percent of the population is a disease while something that happens to 50.1 percent of the population is not. In fact, that’s a backward way of approaching problems that lends itself to the whack-a-mole system of medicine we’ve set up in hospitals and research centers around the world.

Why would we choose to focus on problems that impact small groups of people if we could address the problem that impacts everyone—especially if, in doing so, we could significantly impact all those other, smaller problems?

We can.

I believe that aging is a disease. I believe it is treatable. I believe we can treat it within our lifetimes. And in doing so, I believe, everything we know about human health will be fundamentally changed.

If you are not yet convinced that aging is a disease, I want to let you in on a secret. I have a window into the future. In 2028, a scientist will discover a new virus, called LINE-1. It will turn out that we are all infected with it. We get it from our parents. It will turn out that the LINE-1 virus is responsible for most other major diseases: diabetes, heart disease, cancer, dementia. It causes a slow, horrible chronic disorder, and all humans eventually succumb to it, even if they have a low-grade infection. Fortunately, the world pours billions of dollars into finding a cure. In 2033, a company will succeed in making a vaccine that prevents LINE-1 infections. New generations who are vaccinated at birth will live fifty years longer than their parents did—it will turn out that that’s our natural lifespan and we had no idea. The new generation of healthy humans will pity previous generations, who blindly accepted that physical decline at 50 was natural and an 80-year life was a life well lived.

Of course, this is a science fiction story I just invented. But it might be truer than you think.

A few recent studies have suggested that the so-called selfish genes we all carry in our genome, actually called LINE-1 elements, replicate and cause cellular havoc as we get older, accelerating our physical demise. We’ll discuss them in more detail later, but for now, it’s the idea I want to focus on because it raises important questions: Does it matter whether LINE-1 comes from your parents directly or via a virus? Would you want to eradicate LINE-1 from humanity or let it grow in your kids and inflict horrible diseases on them? Would you say that LINE-1 causes a disease or not?

If not, is it simply because more than half of all people carry it?

Whether it’s a virus, a selfish DNA element, or simply the makeup of our cells that causes these health problems, what’s the difference? The end result is the same.

The belief that aging is a natural process is deep-rooted. So even if I’ve somewhat convinced you that aging should be considered a disease, let’s do another thought experiment.

Imagine that everyone on our planet typically lives to 150 years in good health. Your family, though, doesn’t. You become wrinkled, gray-haired, diabetic, and frail at 80. Upon seeing these poor, unfortunate souls in this poor, unfortunate state of existence, what doctor would not diagnose your family with a disease, name it after him- or herself, and publish horrid photos of you with your eyes blacked out in medical journals? Communities would raise money to understand and find a cure for your family’s wretched inheritance.

That was exactly what happened when the German physician Otto Werner first described a condition that causes people to look and feel as though they are 80 when they are in their 40s. That’s Werner syndrome, the disease I was studying when I first arrived at MIT in the 1990s. Nobody said I was studying something that is inevitable or irreversible. Nobody said it was crazy to call Werner syndrome a disease or to work to find a breakthrough therapy. Nobody told me or the Werner patients that “that’s just the way it goes.”

In front of us is the deadliest and costliest disease on the planet, a disease that almost no one is working on. It is as if the planet is in a stupor. If your first thought is “But I don’t want to live past 90,” let me assure you: I don’t want you to live a year longer than you wish.

But before you make your decision, let’s do one final thought experiment.

Imagine that a clerk at City Hall has found a mistake on your birth certificate. It turns out that you are actually 92 years old.

“You’ll get a new one in the mail,” the clerk says. “Have a nice day.”

Do you feel any different now that you are 92? Nothing else has changed in your life—just a few numbers on your identification. Do you suddenly want to kill yourself?

Of course not. When we stay healthy and vibrant, as long as we feel young physically and mentally, our age doesn’t matter. That’s true whether you are 32, 52, or 92. Most middle-aged and older adults in the United States report feeling ten to twenty years younger than their age, because they still feel healthy. And feeling younger than your age predicts lower mortality and better cognitive abilities later in life.[108 - Using a survey of 593 people that was then repeated four years later, the authors explored the role of “subjective age” (meaning how old an individual feels in contrast to his or her biological age) in shaping the process of aging. A. E. Kornadt, T. M. Hess, P. Voss, and K. Rothermund, “Subjective Age Across the Life Span: A Differentiated, Longitudinal Approach,” Journals of Gerontology: Psychological Sciences 73, no. 5 (June 1, 2018): 767–77, http://europepmc.org/abstract/med/27334638.] It’s a virtuous cycle, as long as you keep pedaling.

But no matter how you feel at this moment in your life, even with a positive outlook and a healthy lifestyle, you have a disease. And it’s going to catch up to you, sooner rather than later, unless something is done.

I acknowledge that calling aging a disease is a radical departure from the mainstream view of health and well-being, which has established an array of medical interventions addressing the various causes of death. That framework evolved, however, largely because we didn’t understand why aging occurs. Up until very recently, the best thing we had was a list of aging hallmarks. The Information Theory of Aging could change that.

There is nothing wrong with using the hallmarks to guide interventions. We can probably have a positive impact on people’s lives by addressing each of them. It’s possible that interventions aimed at slowing telomere deterioration will improve people’s long-term well-being. Maintaining proteostasis, preventing deregulation of nutrient sensing, thwarting mitochondrial dysfunction, stopping senescence, rejuvenating stem cells, and decreasing inflammation might all be ways to delay the inevitable. Indeed, I work with students, postdocs, and companies around the globe that are developing solutions to each one of these hallmarks and hope to continue.[109 - “David A. Sinclair’s Past and Present Advisory Roles, Board Positions, Funding Sources, Licensed Inventions, Investments, Funding, and Invited Talks,” Sinclair Lab, Harvard Medical School, November 15, 2018, https://genetics.med.harvard.edu/sinclair-test/people/sinclair-other.php.] Anything we can do to alleviate suffering we should do.

But we’re still building nine dams on nine tributaries.

In coming together to tackle the “new science of aging,” as the attendees of the Royal Society meeting termed this fight in their 2010 meeting, increasing numbers of scientists are starting to acknowledge the possibility and potential inherent in heading upstream.

Together we can build a single dam—at the source. Not just intervene when things go wrong. Not just slow things down. We can eliminate the symptoms of aging altogether.