The Future

The case for
defeating death

Can humans outsmart aging? Here's what the science says.
The Future

The case for defeating death

Can humans outsmart aging? Here's what the science says.

The most outspoken opponent of death by aging in the scientific community is probably Aubrey de Grey, a British biologist with a PhD from Cambridge and long, long hair that he ties with a scrunchie. In his mind, aging is unhealthy; a collection of undesirable side effects of being alive. He likens aging to malaria because it kills a lot of people. If you could cure it, wouldn’t you?

“For every day that I bring forward the defeat of aging, I’m saving 100,000 lives,” he said in 2014. “One hundred thousand lives: 30 World Trade Centers.”

There is a growing cohort of well-credentialed scientists investigating radical life extension: geneticist Craig Venter, one of the first to sequence the human genome; biochemist Cynthia Kenyon, who discovered that a mutation in a single gene doubled a worm’s lifespan and is now vice president of aging research at Google sister company Calico; and molecular biologist Bill Andrews, who led the team that discovered the human gene for telomerase, an enzyme considered critical in aging.

Gratitude

Their promises include keeping 90-year-olds as healthy as 50-year-olds, as the Virginia-based Methuselah Foundation says; extending life to 150 years, as Andrews says; and being biologically 25 years old indefinitely, as de Grey says.

We’re taught that death is natural and that trying to escape it is wishful lunacy. However, these researchers have made tangible discoveries. They’ve published studies in highly respected journals and attracted serious amounts of funding. When they say it’s possible to live longer, and maybe forever, it’s tempting to believe them.

After all, we already doubled the average life expectancy once, from the early 1900s to today. Who is to say that we can’t do it again, especially now that we know so much more about aging? Is it possible that the idea of ending death isn’t so crazy after all?

What is aging?

In December, a study from the Salk Institute made waves in the news. Scientists experimented on mice with progeria, a condition that causes premature aging. They were able to genetically engineer the mice so that they could “turn on” four genes linked to aging by exposing the mice to an antibiotic. The progeria mice lived 30 percent longer. Normal mice that were given the treatment appeared rejuvenated and healed faster. “Our study shows that aging may not have to proceed in one single direction,” the lead researcher said.

Every few months, scientists will come out with a new finding that shows how a very specific set of changes slowed down some aspects of aging in animals. Of course, each study is more insightful when viewed as part of the body of anti-aging research as a whole.

To understand what researchers have accomplished in this area, it’s helpful to understand what “aging” means in a scientific context. Specifically, aging refers to the time-related degradation or decline of the bodily functions necessary for survival — the “gradual, progressive deterioration of integrity of across multiple organ systems,” said Dan Belsky, an assistant professor of medicine in the Division of Geriatrics at Duke University School of Medicine. We now know that diseases such as Alzheimer’s, diabetes, heart disease, and cancer are all caused, at least in part, by aging.

As we age, changes occur in our bodies on a cellular level that affect not just our heart and lungs but also our muscles and our nervous system. “These changes affect all of the different systems in our bodies,” said Belsky. “And each of these systems individually begins to work a little less well as we get older, and gradually that produces the burden of dysfunction that ultimately results in disease, disability, and eventually death.”

We also now understand that biological age doesn’t always correspond to clock age. Imagine a pair of twins: One drinks too much, eats poorly, rarely gets enough sleep, and never exercises, while the other does the opposite. The first twin is likely to age faster and develop more of those age-related diseases.

Since what happens to our organs is triggered by our cells, perhaps the biggest breakthrough in our knowledge of aging has been in our understanding of some of the pathways that affect aging on a cellular level.

It took the genetically modified worm two days to age as much as a regular worm ages in one.

The key lies with what scientists call signaling, or how cells communicate to govern basic functions like cell repair and immune response. While errors in cell signaling can cause autoimmune diseases, diabetes, and cancer, it also turns out that modifying signaling pathways can also slow aging, at least in animals. Researchers have identified two age-related signaling pathways: the Insulin/IGF-1 signaling pathway, which is linked to growth and metabolization, and the Target for Rapamycin or TOR, which in addition to growth regulates how cells move, and replicate. The deeper you get into anti-aging science, the more you’ll see these acronyms.

If we can slow down that biological clock enough, the thinking goes, we could delay the onset of old age and the diseases that come with it. Death opponents like Peter Thiel, Larry Ellison, and Larry Page, all of whom are funding anti-aging research, believe that such discoveries, coupled with cures for disease, will amount to a package solution for extending life, possibly forever.

Fasting, gene hacking, and other interventions

Cynthia Kenyon now heads aging research at Calico. In 1993 she was with the University of California at San Francisco, where she started thinking about the fact that different animals have different lifespans. She began to look for the genetic basis of life expectancy by tinkering with the genetic code of a type of roundworm called C. elegans.

Although we mostly think of roundworms as parasites — like heart worms that infect dogs — C. elegans, which according to Kenyon is about the size of a comma in this sentence, is not. Kenyon picked C. elegans for two reasons. First, its average lifespan of two to three weeks makes it easy to measure changes in longevity. Second, an earlier study had discovered a mutant strain of C. elegans that was mysteriously long-lived.

Kenyon and researchers in her lab began by changing genes in C. elegans specimens at random to see if the changes would make the worms live longer. They eventually discovered that damaging a single gene called daf-2 doubled C. elegans’ lifespan. And it wasn’t just that the modified worms lived longer; they actually aged more slowly. A two-week-old genetically modified C. elegans moved faster and was a lot more spry than its untreated cousin. Kenyon found that it took the genetically modified worm two days to age as much as a regular worm ages in one.

The discovery wasn’t limited to C. elegans. When the researchers modified the equivalent gene in flies and in mice, they also lived longer. Perhaps most interestingly, the daf-2 gene modifies a hormone receptor in worms that is very similar to the Insulin/IGF-1 receptor in humans. Centenarians, humans that manage to live to 100 years and beyond, are more likely to carry mutations that reduce the activity of the IGF-1 receptors than those who die younger. At the same time, similar studies in yeast have shown that if you genetically alter TOR signaling pathways so that they communicate less, the yeast also lived longer. In total, the research suggests if you can find ways of calming down these signaling pathways you might be able to slow down aging.

Genetic modification of people creates a number of ethical and practical concerns, so a lot of the immediate focus on anti-aging science is on interventions that calm down the TOR and IGF-1 signal pathways but don’t involve altering our genes.

One way of reducing signal TOR pathways is unpleasant if you enjoy eating. Studies have shown that mice fed 65 percent less food lived up to 60 percent longer. Thankfully, researchers have found other interventions, that work on the same pathway. Rapamycin, an anti-rejection drug used by kidney transplant patients, has increased lifespan in mice by up to 14 percent; low-dose Aspirin increased worm lifespan by 23 percent.
At the same time, anti-aging proponents are enthusiastic about chemical interventions, including Vitamin D, Metformin, and Acarbose, that work along the same IG-1 pathway that Kenyon discovered with her genetic experiments. Vitamin D increased lifespan in worms by 31 percent, while Metformin and Acarbose, prescription drugs designed to treat type 2 diabetes, increased lifespans in mice by about 5 percent. A separate study out of the UK found that diabetic patients treated with Metformin lived longer than nondiabetics, when they should have died eight years earlier. If the drug was just treating their diabetes, they should have died at roughly the same age as nondiabetics — not outlived them.

A national clinical trial called Targeting Aging with Metformin, or TAME, to test Metformin’s anti-aging effects in humans has received FDA approval. “What we want to show is that if we delay aging, that’s the best way to delay disease,” Dr. Nir Barzilai, one of the researchers on the study, told Nature.

There is another strategy that does not involve signaling pathways.

If you’ve ever wondered why kids seem to have so much energy while you struggle to get through the day, at least part of the difference lies in your mitochondria. Their mitochondria — cellular power plants — are more efficient than ours. As we get older, for reasons that still aren’t well understood, the mitochondria doesn’t work as well, causing changes that trickle up to the organ level.

In the past few years, sirtuins, a type of protein that manages a host of cell processes including those processes in the mitochondria linked to aging, have come to the fore. While the role of sirtuins in aging is still controversial, researchers have found that powering up an organism’s sirtuins might be able to not just slow aging but reverse it. Mice fed sirtuin activators have been found to live 16 to 20 percent longer. The first clinical study on nicotinamide mononucleotide (NMD) began this year in Japan.

Taken together, these lifestyle, medicinal, and genetic interventions have allowed earthworms to live as much as 10-times longer, while extending the lifespan of mice by 15 to 20 percent. That doesn’t mean any of these interventions will work in humans, but it gives anti-aging scientists a place to start.

“Ten years ago, we would have been hard-pressed to come up with anything but exercise and diet,” said Brian Kennedy, a professor at the Buck Institute for Research on Aging who has been in the field for more than 20 years. “Now we have probably 10 or 15 different interventions that might work.”

Wishful thinking

The theory goes that if we can find which of these interventions work best in humans and tack on some cloned organ replacements for when some parts inevitably wear out, it would allow for the development of a holistic, effective combination that would end aging, or at least slow it to a crawl. Unfortunately, the prospect is still backed more by wishful thinking than hard science.

The rise and fall of resveratrol, an extract most commonly found in wines, is a cautionary tale.

In numerous studies on animals, resveratrol was found to extend life by 70 percent in yeast and 59 percent in fish. Another study found that resveratrol improved the health and longevity of mice eating a high-calorie diet — seemingly explaining the French paradox, whereby French people have low rates of heart disease despite a high-fat diet. Forget cake, went the thinking, let them drink wine. Sales of resveratrol supplements shot up to $30 million a year.

Alas, the effects in humans haven’t held up. A 2014 study published in JAMA tracked older adults in the notoriously wine-swilling region of Chianti, Italy, and found that those with higher levels of resveratrol didn’t live any longer. Early research around whether resveratrol might help prevent or fight cancer is mixed. “Resveratrol supplementation in animal models of cancer has shown positive, neutral, as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors,” write the authors of a 2014 review.

Part of the problem with aging experiments is that humans live too long. A mouse lives for about two years; extending its life by 20 percent extends it by about five months. That’s pretty easy to study and repeat under controlled conditions. It’s much harder to repeat the same experiment in people.

Scientists would have to wait for their subjects to die, at which point their own mortality becomes an issue. A proper experiment might require generations of scientists in order to study its subjects’ lifespans.

Scientists would have to wait for their subjects to die, at which point their own mortality becomes an issue.

Anti-aging researchers could stick to working with the elderly, but that would make it impossible to test preventative techniques. Meanwhile, interventions in young people present ethical issues. Testing, say, a gene therapy on a healthy young person is potentially pretty risky.

The best solution is to find a way of measuring biological aging without having to wait for people to actually get old. To that end, researchers are searching for a marker that reflects biological age.

There are some promising candidates, like telomeres, the caps at the end of chromosomes that shrink as we age. Scientists are also looking at methylation epigenetic clocks. Our DNA or genes are mostly fixed, but which parts of those genes get expressed can change over time due to environmental factors. Epigenetics is the study of those changes. If genetics were sheet music, DNA would be the notes, but epigenetics are the set of instructions — the time signature, the tempo — that tell us how those notes are played. Methylation, or adding methyl groups to cellular DNA, is how epigenetic changes are made, but as we get older, DNA methylation slows down. A methylation epigenetic clock would be able to take the information we know about methylation and epigenetics and correlate that to a biological age.

Other promising potential timers include inflammatory cytokine profiles, which characterize the traits of cytokines, proteins involved in cell signaling, that are linked to aging and metabolomic markers, which look for the fingerprints left behind by cellular processes like aging.

Until a good metric is pinned down, we won’t know which, if any, anti-aging measures work in humans.

Is dying natural?

Our understanding of aging remains a bit like our understanding of sleep. It’s a fundamental aspect of being alive, but we don’t really understand how or why. We can see people aging, and we’re beginning to be able to understand the markers of aging, but we don’t really understand why we age. Is aging a bug in the human experience or a feature?

Earlier this year, researchers at Albert Einstein University published a study, based on existing lifespan data, positing that humans have a natural maximum lifespan of about 115 years. Although more of us are living into our 70s, the number of us making it to 100 and beyond has remained flat in comparison. “We wanted to see what progress is being made, or in this case, not being made in terms of human longevity,” said Brandon Millholland, a lead author on the study.

The reason, the researchers theorize, is not because death is the goal, but rather that aging is a byproduct of the genetic codes that frame our life — development, birth, growth, reproduction. The codes that give us life include imperfections that cause our death. And, while science may make it possible to extend life beyond those natural limits, we will still ultimately be constrained by them — like trying to build a skyscraper on the foundation of a ranch house. It’s not that no one can live longer than 115 — Millholland puts the likelihood of someone making it to 125 at 1 in 10,000 — it’s just statistically improbable.

This may seem at odds with human history. American life expectancy has increased from an average of 47 years in the early 1900s to 78.7 years today, suggesting that human lifespan is malleable. That would be the wrong conclusion, however. The increase in life expectancy, which is the average of lifespans, was largely due to a decline in child mortality, as public health, hygiene, and medicine slashed the number of children who die before their fifth birthdays. People who survived into adulthood could reasonably expect to live into their 40s, 50s, and even 60s, and sometimes even beyond. Thomas Jefferson was 83 when he died, Ben Franklin was 84, and John Adams lived till 90. Jeanne Louise Calment of France, who died at age 122 and holds the record for oldest confirmed human lifespan, was born in 1845. “Her record is probably going to remain unbroken for a very long time,” said Millholland.

The emerging anti-aging lobby isn’t just talking about doubling lifespans, either. It is talking about extending them indefinitely — longer than 4,000-year-old black coral or a 2,000-year-old sponge or Creme Puff, the 38-year-old cat. To date, no studies have been able to keep organisms alive indefinitely or identify anything that does this in the wild. The only biologically immortal living creature that we know of is the cancer cell, and it tends to kill its host.

Most of the scientists doing the everyday work of aging research didn’t get involved because of a thirst for eternal life. Kennedy first started looking at yeast out of scientific curiosity and later because it became apparent that aging is the primary risk factor for many of our most pressing chronic diseases. Belsky’s work focuses on health disparities — specifically on why people with lower incomes tend to suffer from a wide range of chronic, disabling health conditions. One possible reason is that they’re experiencing an accelerated pace of so-called “biological aging.”

None of the gerontologists I talked to would speak about immortality, preferring to stick to talking about slowing aging and extending health. Even de Grey eschews the term, which he calls “a religious word.”

A popular quote dubiously attributed to Ralph Waldo Emerson asks, “What would be the use of eternity to a person who cannot use well one half hour?” For most of us, the goal isn’t to live longer but to live better. And, if all of this attention on immortality leads to funding sound research, we may all find ourselves living longer, healthier lives.

Kendra Pierre-Louis is a New York City based science writer. You can find more of her work on her website​. Illustration by Aaron Fernandez.

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