The time of your life
Cells hold clues to a healthy old age
The small, silvery-yet-colorful fish paused in patrolling his tank for a moment to eyeball me, perhaps assessing a threat. After a split second of scrutiny, he resumed his patrol of the tank. Around him, row upon row of similar tanks, stacked 10 feet high, hold similar fish, doing similar fishy things. The dim lighting and sounds of bubbling, flowing, fresh water hint at a spalike atmosphere curiously in sync with the real purpose behind the tanks: to understand — and perhaps even slow (or stop?) — human aging.
If you feel like you’ve stumbled into a science fiction tale, don’t be alarmed. Immortality is a concept both alluring and frightening. And yet some animals seem to have achieved the impossible. The “immortal jellyfish,” for example, responds to aging or injury by rewinding time, reverting to an immature polyp state and then re-maturing to generate new, healthy medusas wafting gracefully on the ocean currents. Barring predation by hungry tuna, turtles or sharks, a single individual could conceivably continue this stately cycle of not-quite-death followed by triumphant rebirth for, well, forever.
These animals have conquered the passage of time in ways that make our heads spin and our souls hopeful. Could we someday stop the aging clock and achieve the same fate?
It’s a question humans have struggled with since the dawn of recorded history but, unlike our now-deceased predecessors, our generation is closer to grabbing the golden ring than ever before.
“Ways of prolonging human life span are now within the realm of possibility,” says professor of genetics and newbie fish keeper Anne Brunet, PhD. Brunet, who is an associate director of Stanford’s Paul F. Glenn Center for the Biology of Aging, focuses her research on genes that control the aging process in animals such as the minnowlike African killifish I’d watched fiercely guarding his territory.
The killifish is especially important to researchers like Brunet because it has an extremely variable, albeit short, life span. One strain from eastern Zimbabwe completes its entire life cycle — birth, maturity, reproduction and death — within about three to four months. Another strain can live up to nine months.
It’s also a vertebrate, meaning it belongs to the same branch of the evolutionary tree as humans. This gives it a backbone up over more squishy models of aging like fruit flies or roundworms — translucent, 1-millimeter-long earth dwellers you could probably find in your compost pile if you felt like digging.
The killifish is a relative newcomer on the aging scene, however. Brunet and her colleagues are working to sequence the fish’s genome and to learn more about why some strains live longer than others by comparing their genomes. They’d also like to devise ways to swap out specific genes to create designer strains for study.
“We’d like to identify genes specific to vertebrates that regulate life span,” says Brunet. “These fish are so like us, and they breed and develop much more quickly than other laboratory animals like mice. Worms and flies have been revolutionary in moving the field forward, but they lack key tissues, organs and systems that are critical to human life. They don’t have bones, or the same type of blood or an adaptive immune system. We are really in love with this fish because it will allow us to quickly test some fundamental concepts of aging.”
Learning how our cells and tissues change with the passage of time, and how these changes compare with those seen in other species, may help us identify crucial genes or pathways that could be tweaked to prolong our lives, and our health. That’s because aging is the single biggest risk factor for the development of chronic diseases from diabetes to cancer to heart disease. Interfering or modulating the natural aging process may be one way to reduce our risk of many devastating, life-shortening conditions.
It may also help answer one of the biggest biological questions of all, and one that’s recently incited keen interest among savvy investors.
“We don’t really know what aging is,” says Thomas Rando, MD, PhD, professor of neurology and director of the Glenn Center. “We don’t know what it really means to ‘die from old age.’ We understand development as a biological program — how we are conceived, develop and mature — but aging remains, fundamentally, a biological mystery. But the interest in the private sector in this research is almost unimaginable compared to just 10 years ago.”
Aging is inherently interesting, because we’re all doing it. Like it or not, our bodies are slowly winding down as time passes. But what actually happens in our tissues and cells? It’s clear that we are subject to a plethora of depressing outcomes, including sagging tissues (hello, wrinkles), reduced cognitive capacity (where did I put my car keys?) and a slowing metabolism that (tragically) favors belly padding over muscle building.
Inside our cells, the situation looks even more dire. DNA mutations begin to accumulate, our cells’ energy factories begin to wind down, and proteins policing gene expression appear to “forget” how to place the chemical tags on DNA that serve as runway lights for the appropriate production of proteins.
The protein production, transportation and degradation network that cells depend on to deliver these molecular workhorses to all parts of the cell at exactly the right times also falls into disarray. Proteins are degraded too soon, or begin to clump together in awkward bundles that interfere with cellular processes. These events have obvious, previously inescapable, outcomes.
“As we age, time becomes compressed and we tend to develop many chronic diseases or health problems simultaneously,” says Brunet. “Many elderly people are dealing with a constellation of health conditions. We’d like to imagine ways to stretch out the healthy period of our lives, so it comprises more of the totality. This is something we call ‘health span,’ and it would be tremendously advantageous to stretch out that portion of our lives.”
The Glenn Center was created in 2011 with a $5 million grant to Rando from the Glenn Foundation for Medical Research. He and his colleagues are hardly alone in wondering whether it’s possible to slow or stop the aging clock. Nationwide, both public and private efforts have been launched to better understand and prolong our golden years. In 2012, the National Institutes of Health created the Geroscience Interest Group to bring together experts from across the agency to create a framework to advance aging research. In 2013, tech industry giant Google backed the creation of an independent research and development company called Calico (short for California Life Company) to investigate the basic biology of aging, and in 2014 Calico joined forces with research pharmaceutical company AbbVie to tackle age-related diseases, such as cancer and neurodegeneration, to the tune of at least $500 million.
Human genomics pioneer Craig Venter, PhD, threw his hat into the ring in early 2014 with La Jolla, Calif.-based Human Longevity Inc., which secured $70 million in initial funding for its plans to sequence up to 40,000 human genomes each year to learn more about cancer, the microbiome and possible stem cell therapies for the diseases of aging.
Nonprofit efforts have also sprung up during the past few years, such as the SENS Research Foundation (SENS stands for the Strategies for Engineered Negligible Senescence, or preventing or reversing cellular aging). Founded in 2009 in part by gerontologist Aubrey De Grey, PhD, SENS funds research at universities around the world as well as at its own facility in Mountain View, Calif.
Even NIH director Francis Collins, MD, PhD, has a particular interest. His research focuses on understanding a genetic condition called progeria, in which children age extremely rapidly, often dying of apparent old age in their early teens. Progeria is caused by a mutation in a single gene called lamin A that makes a protein that stabilizes the structure of a cell’s nucleus. It’s thought that when the nucleus deforms it causes a cascade of changes that leads to premature aging.
Associated with the growth in funding is an expansion in laboratory research that suggests the possibility of intervening in the aging process and extending the human health span, says Rando, who is also a practicing neurologist. “It may one day be possible to avoid chronic diseases, living into old age free from dementia, diabetes and heart disease. Our tissues will still age, but we may be able to delay or prevent the onset of the decline in function that comes with passing years.”
So what’s changed? Humans have grappled with mortality for hundreds, if not thousands, of years. Ancient humans propounded myriad ways to live longer, from a subsistence-only diet to bathing in or drinking magical water (the Fountain of Youth, anyone?) to alchemy or transfusions with the blood of children. Longevity has been sometimes associated with devout spirituality, or with capacious sexual appetites. Geographic location and climate were viewed as critical; both mild and stringent weather were at times considered beneficial. In short, if you can think of it, humans have likely tried it.
We can chuckle at some of these suggestions. Others, however, are somewhat unnervingly close to promising paths of current research. Calorie restriction has been shown to increase the lives of mice and other lab animals, and Rando, together with neuroscientist Tony Wyss-Coray, PhD, are among several researchers who have shown that the blood of young mice contains factors that help the muscles and brains of aging mice perform better.
“It’s clear that, as we age, our cells and tissues change,” says Rando. “The fundamental question is ‘To what extent are these changes reversible?’ This research shows that it’s possible to drive cells from an old state to a young state with factors that circulate in the blood.”
Researchers have also identified geographic locations they’ve termed blue zones that harbor more than their fair share of centenarians (the Italian island of Sardinia, for one, and the Okinawa region of Japan). Stuart Kim, PhD, professor of developmental biology and of genetics, recently sequenced the whole genomes of 17 “supercentenarians” (individuals at least 110 years old) to identify longevity-associated genes. The participants in the study were unusually healthy for their advanced age, and only one had cancer, diabetes or another age-related disease.
The study was unable to pinpoint with certainty any reasons these people were so long lived, perhaps because there are simply too few individuals to study. It’s also possible that their good fortune is due to a plethora of influences. In other words, winning the longevity lottery requires a rare, felicitous combination of environment, genes and simple good luck.
“The process of aging is very complex,” says professor of medicine Steven Artandi, MD, PhD, who, with Brunet, is also an associate director of the Glenn Center. “It seems like there’s no single cellular variable that is changing with time that is the main trigger for aging. But starting at about ages 30 or 40, we experience a gradual physiological decline. The ends of our chromosomes shorten, the proteins in our cells begin to clump, our cells’ energy factories begin to become dysfunctional and we begin to accrue damage to our DNA. We begin to exhibit cognitive, metabolic and respiratory decline.”
If that’s not insult enough, there’s proof that, at least in some ways, aging is an active, deliberate process.
Individual human chromosomes are made of single DNA strands that are tens or hundreds of millions of nucleotides long. At each end is a protective cap called a telomere, which in humans is only about 8,000 nucleotides. Every time a cell divides, it loses a tiny snippet of DNA from the ends of the telomeres. This loss appears to act as a cellular clock, restricting any one cell to a limited number of cell divisions. When the telomeres become too short, the cell stops dividing.
The telomere may be an internal timekeeper, but recent research suggests its length is also affected by external factors. In the past few years, researchers have associated shortened telomeres with a huge variety of environmental influences, from consuming sugary soft drinks to depression in young girls to the perception of race discrimination by African-American men. Conversely, other research has suggested that a reduction in stress acts to slow telomere shortening.
All this hasn’t escaped the notice of the biotech industry, which has spawned several companies offering to measure people’s telomeres and make predictions about their future health. But Artandi cautions that much still needs to be learned about the association.
“The average telomere length varies dramatically among individuals,” he says. “A 30-year-old person could have the same telomere length as a 50-year-old person, with no identifiable effects on his or her health. What might be more interesting would be to track the rate of shortening over time in an individual. Rapid shortening could indicate more rapid aging, and an increased likelihood of developing diseases of aging such as heart disease and cancer. But much more research remains to be done.”
Telomeres shorten with each cell division, except when they don’t. An enzyme called telomerase lovingly repairs telomeres in embryonic stem cells and sperm cells to keep them in tip-top shape. As far as their chromosomal ends go, those cells don’t appear to age at all.
“Nature knows how to solve the problem of telomere shortening,” says Artandi. (Without this attention, we’d age across generations as our children inherited progressively shortened telomeres.) “But it chooses not to do so in most tissues. We don’t know why this is.”
The short-lived killifish may offer clues. Unlike laboratory mice, which have extremely long telomeres (about 100,000 nucleotides), the fish sport telomeres that are comparable in size to those of humans, making them more amenable to study.
The indomitable fish could also shed light with their ability to stop the clock for months at a time. They can survive for months or years as embryos in a kind of suspended, seemingly ageless, animation called diapause when their puddly playgrounds evaporate in the hot African sun. The tactic allows them to leapfrog into the next generation without missing a beat when the rains come again. Cell growth and development largely stops during this time and, intriguingly, those individuals that emerge after years of diapause live just as long, and appear just as healthy, as those that were out of commission for only a few short weeks.
“These fish can live almost four times their normal adult life span in diapause,” says Brunet. “We don’t really know how organisms survive in this kind of suspended animation, or exactly how they choose to enter and exit. Could understanding this better teach us something about immortality?”
Just as killifish embryos respond to seasonal rains by emerging from diapause, the health of humans is also affected by the environment. Smoking, chronic disease and obesity have all been shown to exacerbate aging-related damage in our cells. Conversely, diets in which calorie intake is severely restricted have been shown not just to reduce telomere shortening and cellular senescence, but to also significantly increase life span in a variety of laboratory animals, including the killifish. (No second helpings of fish flakes for you!) The cells and tissues of these animals continue to look like those of their younger counterparts even as the months and years pile on — indicating that the animals are experiencing not just an increase in life span, but also in the health span coveted by scientists and laypersons alike.
Researchers are also still grappling with the fact that different species of animals, and even plants, exhibit vastly different life spans. Killifish are the most short-lived of all the vertebrates that can be bred in captivity, but other organisms live for decades or even centuries. The Methuselah tree, a bristlecone pine in the mountains of eastern California, is thought to be about 5,000 years old; a colony of quaking aspen trees in Utah may have originated as many as 80,000 years ago.
“We really don’t understand why some organisms evolved to have extremely long lives, while others are very short,” says Artandi, “just like we don’t understand why some people age very well, and others don’t.”
“There is something across the entire spectrum of the animal kingdom that puts the ‘stopping point,’ or maximum life span, in vastly different places,” says Rando. “We’d like to know why this is. But this is a very interesting, and difficult, question. We are not even sure where this stopping point is in humans.” The oldest human with a reliably recorded age was Jeanne Calment, who died in France in 1997 at the age of 122; many researchers believe the maximum human life span to be around 120 years.
Part of the trouble in identifying a maximum life span in humans lies in the difficulty of separating aging itself from the diseases that accompany it. Do we get diseases because we age? The winding down of the body’s clock clearly affects many biological processes, including our ability to fight off infection or to regenerate healthy muscle. However, some conditions, such as chronic inflammation, actually increase the accumulation of age-associated changes in our cells — having a disease can actually age us. It seems like a no-win situation. But we’re getting better at staving off some of the more preventable causes of death.
“Average life expectancy doubled during the past thousand years, and doubled again during the past hundred,” says Rando. At the end of 2014, researchers at the Global Burden of Disease Study announced that the average human life expectancy had reached 71.5 years — a number that would have been nearly unthinkable just a few decades ago. With continued improvement, will we eventually find ourselves bouncing off an internal maximum life span that has yet to be defined? And if so, what then?
In October 2013, the trans-NIH Geroscience Interest Group held a summit to identify ways in which researchers from many different disciplines could work together to identify the molecular causes of aging and the relationship between aging and chronic disease, and to investigate approaches to attack root causes that could not only prolong life, but improve health. Many of the suggestions involved new ideas such as studying the development of chronic diseases in aging, rather than young, laboratory mice; to use genetically diverse, rather than identical, laboratory animals; and to pay closer attention to companion animals like dogs to learn more about how our shared environment affects aging. In November 2014, the group published its recommendations in a commentary in Cell.
“We have high hopes that our research strategy will help move collaborative efforts to the next level,” said Brian Kennedy, PhD, president and CEO of the Buck Institute and the lead author of the commentary in an accompanying press release. “What has come out of our work is a keen understanding that the factors driving aging are highly intertwined and that in order to extend health span we need an integrated approach to health and disease with the understanding that biological systems change with age.”
The researchers identified seven intertwined “pillars of aging” for targeted research, including adaptation to stress, stem cells and regeneration, metabolism, macromolecular damage, inflammation, epigenetics (the process by which cells control when and where genes are expressed based on chemical signposts on their DNA) and a concept called proteostasis, which describes the intricate dance in which proteins are made, transported and degraded within a cell.
So far Brunet and her killifish-loving colleagues have focused on several genes involved in these pathways, including the gene for telomerase. They’ve homed in on genes known to play roles in epigenetics and nutrient sensing, paying particular attention to a cascade of signals initiated by insulin and the insulinlike growth factor receptor that modulates the hormone’s effect on cells. (Mutation in the receptor molecule extends by two to three times the life span of laboratory roundworms, and mutations in insulin or the receptor have a similar effect in fruit flies and laboratory mice.) In fact, many genes associated with aging are involved in some way with common metabolic processes.
In addition to playing a role in normal aging, there’s fascinating evidence that organisms have evolved to manipulate these processes to their advantage. In 2013, Brunet showed that male roundworms, for example, actively secrete pheromones to shorten the life span of the egg layers after eggs are produced. It appears that the male worms have devised a calculated plan to off the baby makers to keep them from consuming valuable resources or mating with a competitor.
“In worms, once the male has mated and eggs are produced, the mother can be discarded,” Brunet says. “The C. elegans mother is not needed to care for the baby worms. Why should it be allowed to stay around and eat? Also, if she dies, no other male can get to her and thus introduce his genes into the gene pool.”
Will we one day be able to so casually (but perhaps with more compassion?) tweak our own life spans with simple medications? And what would be the ethical and societal implications of such an intervention? Will access be limited to a privileged few with the know-how to ask and the means to pay? Or will such treatments come to be regarded as the standard of care, covered by health insurance and dispensed as casually as vaccines and vitamins?
Bioethicist Christopher Scott, PhD, specializes in such thought-provoking questions. “Longevity research could be considered the newest iteration of ‘enhancing life’ technologies,” says Scott, “connected deeply to what some call a moral imperative to portray aging as the ultimate enemy of humanity. But highly consequential decisions (funding research, creating new companies, establishing new scientific disciplines), technological inventions and social changes are being pursued on the tacit assumption that such decisions, inventions and changes will lead to a healthier, longer life and the promise of a better future. In ethics, I think these assumptions are largely unexplored and unacknowledged.”
“We’re going at this because it seems the right thing to do,” says Rando. “But we’re not sure what we’re going to end up with. What kind of health span will we achieve? Is extending life span worthwhile if we can’t control the development of diseases like Alzheimer’s, which is extremely prevalent in the very old?” Conversely, if we begin to live much longer, perhaps humans will begin to develop entirely new diseases that are as unheard of now as cancer was in the Stone Age.
Scott also wonders whether the longevity research attracting attention today will manage to escape the commercialism and over-promises that beset similar research on aging conducted in the previous two decades. Those findings spawned a multibillion-dollar industry peddling largely useless nutraceuticals and pseudomedicine to legions of baby boomers eager to tack on at least a few more years to their lives.
“I’m fascinated by how quickly longevity research has taken off,” says Scott. “One question is whether the promise of healthy life spans will outrun the reality of the science. It will be interesting to see whether longevity research will somehow duck the ethical and social issues that plagued aging research, or whether a supercharged repeat is in store.”
Swimming in their tanks, the killifish are oblivious to the hype. But like humans, killifish age visibly. They lose muscle mass, their shimmering colors dim and their backbones begin to hunch. They move more slowly, conserving energy. Internally, they develop cancerous tumors of the liver and kidney and even cataracts in their eyes. Eventually they just stop swimming.
Death may come more quickly for the killifish than for any other vertebrate. Odds are that the darting, silvery individual that paused to give me the fish-eye in early October has already passed on. But he, and others like him, have already achieved a kind of immortality — living on as tiny data points and annotations in the laboratory notebooks of researchers like Brunet, Rando and Artandi, who are keeping their eyes on the real prize: unlocking the mysteries of longevity and health.