Sci. Aging Knowl. Environ., 28 June 2006
On the eve of its termination, SAGE KE takes a look at the future of research on aging
When SAGE KE was born in late 2001, nobody knew that it suffered from a premature aging disease that would prove fatal before its 5th birthday. Ironically, the site is dying as research on aging seems to be hitting its prime. To get a sense of what the future might hold, SAGE KE canvassed more than three dozen leading scientists in the field. We asked them to identify the most important unanswered questions that are likely to be resolved--or at least addressed--in the next 5 to 10 years.
The responses were conservative. Although our sources tended to hold great hope that research would continue trekking toward an understanding of the basic mechanisms of aging and possible ways to manipulate the process, no one predicted dramatic breakthroughs. The responses were also diverse, suggesting that workers in the field are not focused on a single problem or quest.
One question does loom over the field, however, according to almost half of our 16 respondents. Could the life-stretching genes and biochemical pathways that scientists have fingered in model organisms give humans extra time? The answer could dictate how long--and how well--people live in the future, says evolutionary biologist Steven Austad of the University of Texas Health Sciences Center in San Antonio. If the functions overlap, "there will be lots and lots of drug targets for slowing human aging." But if humans are idiosyncratic, such compounds will be elusive, he says. Results so far are mixed.
Fiddling with these genes and pathways certainly can keep lab animals fresh well past their usual expiration date. Scientists know the most about how squelching the insulin/insulin-like growth factor 1 (IGF-1) pathway lengthens life in nematodes (see Antebi Perspective). Worms with a handicapped daf-2 gene, which encodes one protein in the pathway, can endure more than twice as long as normal. Like a stretch in boot camp, these genetic alterations toughen the animals, fortifying their defenses against stresses such as heat and reactive oxygen species, waste products of metabolism that might promote aging (see "The Two Faces of Oxygen"). Flies with similar perturbations also flit unusually long. In mammals, separate insulin and IGF-1 pathways operate--and mice gain from shackling either one. Animals with half the normal amount of the IGF-1 receptor not only outlast normal rodents, but like long-lived worms and flies, they also shrug off reactive oxygen species (see "One for All"). Mice that carry one faulty copy of the insulin receptor scamper longer than normal, but they develop a condition called insulin resistance that can lead to diabetes (see "Turning a Daf Ear to Stress"). Deleting the receptor from only fat cells, however, enables the animals to live 20% longer and to eat heartily without packing on blubber or becoming insulin resistant (see "Lasting Without Fasting").
Another life-giver is Sir2p, a yeast enzyme that helps shut down genes. Boosting output of the protein increases the number of times a yeast cell can reproduce, a measure of longevity in the fungus (see Kaeberlein Perspective). Extra amounts of the worm version of Sir2p also promote survival. Sir2p belongs to a family of enzymes called sirtuins--mammals sport a version of the enzyme called SIRT1. Several labs have engineered mice that overproduce SIRT1 to find out whether extra quantities of the protein help mice nibble and sniff longer. It's too early to say anything about life span, says molecular biologist Leonard Guarente of the Massachusetts Institute of Technology in Cambridge, but some of the physiological results look promising. However, some research suggests that SIRT1 might work differently than its relatives in yeast and worms. The nematode edition of the protein dampens the insulin/IGF-1 pathway, but SIRT1 might exert the opposite effect in mice (see "Tuning Up the Pancreas" and "Uncoupling Insulin"). Other life-extending pathways from model organisms include the TOR pathway, which responds to food availability (see Kapahi and Zid Perspective and "More Without TOR"), and the Ras pathway (see Longo Perspective).
Humans carry many of the same genes as model organisms--including those for insulin, IGF-1, and SIRT1--and our versions appear to orchestrate at least some similar chemical changes, says molecular biologist Matt Kaeberlein of the University of Washington, Seattle. "I'm cautiously optimistic" that tweaking these pathways will buy us extra time, he says. So far, the evidence that they play a role in human longevity is slim. Some studies hint that people with a sluggish insulin or IGF-1 pathway gain time, but those results are controversial (see "Will Humans Join the Club?" and "Power to the People").
Although scientists have pored over such pathways, these networks aren't necessarily the most important for aging, and they might not provide the most promising targets for boosting our life spans. Several of our respondents argue that researchers need to look beyond these few pathways--and even beyond the usual roster of lab denizens--to understand and possibly manipulate aging. For example, Kaeberlein has teamed with Brian Kennedy, also of the University of Washington, and colleagues to search worms and yeast for undiscovered longevity-promoting genes. They are studying a panel of more than 4000 yeast variants, each of which lacks a different gene (see "A Methodical March Toward Immortality"). The group is also using small RNA molecules to block every nematode gene, one at a time. These approaches might uncover previously unknown aging-related genes that researchers can evaluate in mammals.
Instead of fixating on worms and flies for clues about how to put the brakes on aging, researchers should scrutinize organisms outside the traditional lab clique, says gerontologist Richard Miller of the University of Michigan, Ann Arbor. Nature often makes long-lasting animals from early-dying ancestors, he says. Among mammals, for instance, dogs that survive for 10 years and humans that can last past 70 evolved from the same "small, scared creatures that didn't live very long." The question scientists need to tackle, he argues, is whether this life-span bonus always relies on the "same bag of tricks." Researchers have pinpointed characteristics of Methuselah-like lab organisms, such as upgraded DNA repair and pumped-up oxidant defenses. They can test whether the same mechanisms operate in the wild by measuring, say, whether long-lived creatures deploy more antioxidant enzymes compared to their short-lived relatives. If persistent animals depend on the same few improvements, nature might have a longevity recipe that researchers could try to duplicate in humans. If species follow different routes to long life, we might find other possible ways to prolong our survival.
Most genes that influence aging came to light by chance or because they fall in known longevity pathways, notes evolutionary biologist Daniel Promislow of the University of Georgia, Athens. But evolutionists might someday be able to predict which genes are likely to falter late in life and drive bodily deterioration, he says. Aging occurs because natural selection's power over an organism wanes during its lifetime, according to evolutionary theory (see "Aging Research Grows Up"). Scientists postulate that two types of genes affect aging. One kind is beneficial early in life but turns traitor later on. The second kind exerts no effect in youth but acts up at older ages. To classify genes into these categories, researchers can compare the effect of mutations across species, says Promislow. Some DNA alterations change the amino-acid sequence of a protein, but others don't. If a gene falls into the "good early/bad late" category, it should show relatively few mutations that alter the amino-acid sequence; natural selection would favor stability because the protein confers benefits during youth. A gene that misbehaves only at advanced ages should amass relatively more protein-altering DNA changes because it lies beyond natural selection's reach. If known age-promoting genes tend to fall into one or the other category, unknown ones might be expected to fall into that same category. By tracing the evolutionary history of established "aging" genes, therefore, researchers might be able to narrow down the candidate list of genes that spur breakdown.
If researchers devise drugs that extend life span, they'll still need to demonstrate that we can gain extra time without sacrificing health or fertility, says neurologist Thomas Rando of Stanford University, who worries that "the enticement of life-span extension" is overshadowing possible side effects of manipulating genetic pathways. Ask biologists whether extra longevity is free, and they'll start bickering about arcane points such as how to spot a sick nematode. Scientists who argue that the costs are small point to work such as a 2003 study by Cynthia Kenyon of the University of California, San Francisco, and colleagues. The team hobbled daf-2 and deleted the animals' gonads, yielding a superworm that survived a record 124 days, 100 days beyond control nematodes. Moreover, the wonder worms ate and slithered around normally (see "Guinness-Bound"). Researchers who argue that the costs could be significant hold up a 2004 study that found that seemingly hale, long-lived worms can't compete against normal nematodes (see "Paying the Price"). If extra time does carry a cost, "the implications are that living longer doesn't necessarily mean living better," says Rando.
Adding years to our lives might not be as simple as designing a drug to throttle IGF-1 or galvanize SIRT1, cautions neuroscientist Rudolph Tanzi of Harvard University. That approach assumes that a few master genes control longevity. Some scientists argue for the existence of such genes. In people, the E2 version of the ApoE gene might qualify, because it's unusually abundant in people who live past 100. However, Tanzi suspects that these genes extend survival not because they slow the overall rate of bodily deterioration but because they guard against lethal diseases of old age. For instance, evidence suggests that the E2 variant of ApoE might stall heart disease and Alzheimer's disease, two leading killers of older folks, Tanzi says. We don't know what snuffs out elderly nematodes, he notes, but the worm crowd has begun to address the issue. As normal nematodes get old, the nervous system remains intact, but the muscles crumble, Monica Driscoll of Rutgers University in Piscataway, New Jersey, and colleagues found. A faulty version of the age-1 gene buys the worms extra time and keeps their muscles buff, suggesting that deterioration of this tissue fells the creatures (see "Strong Spirit, Weak Flesh").
Humans and worms likely perish from different causes--the heartless creatures don't have to fret about clogged arteries, for example. The genes and pathways that lengthen worm life will do the same for humans only if they defer our senior ailments, Tanzi says. If they don't, "we'll have to conquer aging disease by disease." We can improve the health of elderly folks by determining what genes make people vulnerable to late-life illnesses, he says. New gene chips that allow researchers to scan the entire genome for DNA alterations might help. For example, by comparing genetic profiles of patients who have heart disease to the profiles of their siblings with clear arteries, researchers might be able to finger genes that increase susceptibility to fatty buildup, he says. Once doctors learn what ailments a person is prone to, they can prescribe remedies--such as a low-fat diet and cholesterol-lowering drugs--to reduce the risk. "We are entering the pioneering days of the next big phase of preventive medicine," he says.
Because age is a huge risk factor for Alzheimer's disease, diabetes, and other illnesses, many researchers argue that slowing basic aging mechanisms is the key to preventing these killers. But seniors' increased vulnerability to such diseases doesn't establish the existence of these mechanisms, counters Tanzi: The reason these killers wait to strike is because years of exposure to environmental and physical factors--such as bad diet and stress--are necessary before the susceptibility genes can make trouble.
The Longevity Diet
Forget about tricky genetic manipulations. We might be able to live longer just by eating less--a lot less. Another key question, says Guarente, is whether humans can gain from the spartan diet known as calorie restriction. CR works wonders for mice and many other lab animals. Trimming rodents' food consumption can boost their longevity by more than one-third (see Masoro Review). The animals also reap benefits such as reduced blood sugar and insulin, and they are less susceptible to cancer and other late-life diseases. Early results suggest that CR spurs the same salutary metabolic changes in our primate kin (see "Monkey in the Middle"), although it fails for some species, such as Medflies (see "Not in Medflies").
Whether CR stretches people's lives is uncertain, and we might never know because the necessary studies require so much time, says Kaeberlein. However, researchers can gauge whether slashing calories helps fend off diseases of old age, as it does in mice. The first randomized trial of CR provides promising results, showing that cutting back on food for only 1 year increases responsiveness to insulin and trims harmful blood fats, changes that might reduce the risk for diabetes and heart disease (see "Craving an Answer").
Even if CR does work for humans, extreme calorie cutting is arduous, and few people are likely to have the fortitude to stick with the regimen. It can also impair fertility, quash libido more effectively than a photo of Orson Welles in a Speedo, foul up body temperature control, and trigger other problems (see "Dietary Drawbacks"). So another question is whether scientists can pinpoint molecules that deliver CR's benefits without requiring us to give up cake. Such substitutes are "a potentially less draconian pathway to the postponement of disease and the enhancement of the life spans of human beings," says pathologist George Martin of the University of Washington, Seattle, SAGE KE's editor-in-chief.
Researchers are encouraged because studies by Guarente, molecular geneticist David Sinclair of Harvard Medical School in Boston, and others link CR to sirtuins. For example, Guarente's group found that yeast cells need Sir2p to benefit from going hungry--although work by Kennedy, Kaeberlein, and colleagues questions the enzyme's role in CR (see "Calorie Restriction Un-SIR-tainty", "Craving an Answer", Kaeberlein letter to Science, and Lamming letter to Science). Moreover, Sinclair and colleagues have isolated a compound in red wine that stimulates sirtuins and adds time for yeast, worm, and flies (see "Raise a Glass to Long Life" and "Resveratrol to the Rescue"). Researchers are trying to develop other small molecules that prolong life yet avoid the disadvantages of CR. Accomplishing that goal would generate a "revolution in how we treat diseases," says Sinclair, because the drugs might defer age-related killers such as cancer and heart disease. Medicines that extend our lives by 20% to 30% by mimicking CR could be on the pharmacy shelves within a decade, Kaeberlein says.
A mechanic who fixes a car's broken timing belt but overlooks its cracked radiator has done only half the job. Similarly, researchers who want to get older organisms running smoothly again need to pin down the kinds of damage their cells incur. Scientists have focused on how cells safeguard DNA (see Sinclair Perspective) battered by reactive oxygen species, notes molecular biologist Douglas Gray of the Ottawa Health Research Institute in Canada. But they've paid less attention to how old cells deal with the marred proteins, fats, and even organelles such as mitochondria that clutter them. A key question, he says, is how much of aging's toll stems from broken DNA and how much from damage to other cellular components.
Cells dump worn-out proteins by feeding them into the proteasome, a molecular trash disposal (see Gray Review). Membrane-bound bags can also snarf up part of the cell's contents, including flawed proteins, through a process called autophagy (see Cuervo Perspective). Both mechanisms can falter with time, leaving cells vulnerable to addled proteins. These defective molecules might pose a greater risk for neurons than does DNA damage, Gray says, because these cells don't divide. Researchers are just starting to gauge the importance of protein damage for aging by deleting genes that orchestrate autophagy and proteasome activity.
Ah, to Be Young Again
Meanwhile, back at the auto shop, tweaking longevity pathways might transform us from economy models that break down when the warranty ends into sturdy Lexuses that resist the assaults of time. But even Lexuses need repairs. As an alternative approach to fighting aging, some researchers are trying to figure out how to refurbish our bodies by rejuvenating cells or replacing fraying tissues and organs. One method involves using stem cells to engineer new organs and tissues. This field of regenerative medicine is embryonic, and the much-touted cells might never live up to the hype, says Kaeberlein. But if "stem cells can be used effectively to replace aging tissues and organs, these technologies have the potential to be far more effective at increasing 'healthspan' than do 'CR mimetics' or therapies based on slowing aging or age-associated declines," says Kaeberlein. That's because mimicking CR can only increase life span by so much, whereas regenerative medicine doesn't have such a limit, he says. We might not live into the next millennium, but we could gain more than the 30% to 50% bonus offered by CR. Researchers might be able to grow fresh tissue in the lab and transplant it into deteriorating bodies. But they might also be able to coax oldsters' stem cells to begin dividing again. For example, Rando's group has found that muscle-repairing satellite cells slow down with age, but permanently activating a receptor on the cells' surface can keep them reproducing at a youthful pace (see "Many Roads to Ruin"). This work suggests that modifying the cells' environment--perhaps with therapeutic compounds--could restore their vigor.
Sprucing up telomeres, the molecular caps that protect the tips of chromosomes, could also grant cells and people new life. In most kinds of cells, telomeres shorten with each division (see "More Than a Sum of Our Cells"). Once the structures hit a minimum length, many types of cells enter senescence, a semiretirement in which they can no longer divide. Senescence might weaken the immune system and organs such as the liver and skin that depend on continued cell renewal. Shrinking telomeres occur during aging and in rare diseases such as dyskeratosis congenita, in which patients develop anemia and abnormal skin pigmentation. Within 10 years, predicts cell biologist Jerry Shay of the University of Texas Southwestern Medical School in Dallas, patients with these illnesses could head to the hospital for a telomere tune-up. Doctors could remove blood cells, dose them with a substance that spurs telomeres to grow, and return them to the patient. Then researchers will need to determine whether a modification of that approach could refresh some types of cells hammered by aging.
Quick, Call an Endocrinologist
Big telomeres might grant long life. But a big body might do the opposite, says physiologist Andrzej Bartke of the Southern Illinois School of Medicine in Springfield. To understand the factors that shape our life span, researchers need to pin down how hormones such as growth hormone (GH) alter aging, he says. Many seniors seem sure they know and are taking GH as an antiaging tonic (see "Growing Pains" and "Drug Bust"). But scientists aren't certain. Although the notion that growth shrinks life span is controversial, strong evidence from animals supports the assertion, Bartke says. For example, dwarf mice that either produce too little GH or don't respond normally to it can live 50% longer than normal (see Bartke Viewpoint). And small, yappy dogs outlive large ones. Researchers have battled over the human data that link GH to life span (see "The Shrimps Shall Inherit the Earth"), but it should be possible to design a test of whether growing more means living less, Bartke says. In your face, Shaq.
Parents who complain that their children took years off their lives could be right, at least in a way. The reproductive system influences life span, but the details of the interaction remain uncertain, says biodemographer James Carey of the University of California, Davis (see Tatar Perspective). For instance, worms survive longer if researchers obliterate the germ cells that spawn the creatures' sperm and eggs. And implanting ovaries from young mice into older females jacks up rodent longevity (see "Youthful Infusion"). Dissecting the mechanism behind these changes in longevity might supply hints about the reproductive system's role in life-stretchers such as CR, Carey says.
Scientists can't tackle any of these issues without money. A final question is whether policymakers will recognize the importance of research on ways to slow aging and pony up the cash, says biodemographer S. Jay Olshansky of the University of Illinois, Chicago. With the baby boomers' massive Medicare bills looming, the payoff from increasing how long seniors can remain healthy would be enormous, he says. If enough funding is available, "there is a high probability that scientists in the field will succeed in creating [life-extending] interventions in humans," he says.
If researchers nab the grants that enable them to answer their big questions, the achievements will come too late to save SAGE KE. But they might give some of its readers extra time.
June 28, 2006
After SAGE KE's death, Mitch Leslie, a writer in Portland, Oregon, plans to enter the dauer state for a few months.Citation: M. Leslie, Death-Bed Prophecy. Sci. Aging Knowl. Environ. 2006 (10), nf17 (2006).
Science of Aging Knowledge Environment. ISSN 1539-6150