What's Next for Longevity Research?
What's Next for Longevity Research?
Scientists can dramatically enhance the life spans of a variety of organisms, but they don't yet fully understand how this life extension works. Given the human stakes, should government be doing more to speed the process along?
All things being equal, these are pretty good days to be an elderly American. Not only has average life expectancy been rising steadily since 1950, but, over the past 2 decades, surveys have shown a steady decline in disability among older Americans, a trend that continues unabated. "We haven't seemed to reach a plateau yet," says Harvard University health economist David Cutler, who studies disability among the elderly.
And the good news doesn't stop there: Scientists have discovered a number of ways to slow aging in creatures as different as yeast and mice. This ongoing research into aging and longevity has "immense potential to prevent late-life illnesses and prolong active life" in humans, wrote gerontologist Richard A. Miller of the University of Michigan, Ann Arbor, last November in the health care policy journal The Milbank Quarterly.
This month, Cutler and Miller will enumerate and explore the implications of these promising scientific and demographic trends in a SAGE Crossroads discussion on "Remarkable Trends in Aging Research." Perhaps the most dramatic findings have come from laboratory studies of some of the simplest organisms. Working with yeast, fruit flies, worms, and mice, researchers have generated animals that live two and three times as long as their untreated companions--observations suggesting that an organism's maximum life span is not carved in stone.
The tantalizing question is whether this stunning extension of life span can be achieved in humans. To translate the results of these longevity-boosting animal studies into a treatment that might retard aging in people, scientists first need to home in on the mechanism--or mechanisms--responsible for what's been observed in the lab. "It's no longer respectable to say that aging is immutable," says Miller. "It's time to move on to the next issue, which is, 'How do these changes work?' "
The question is a timely one. Although recent health trends among the elderly have been heartening, some say that the improvement will eventually reach a natural limit. Even assuming that medical scientists manage to conquer leading causes of death such as cancer and heart disease, demographers calculate that people would gain only a few more years of average life expectancy as a result.
For this reason, Miller has called for a "substantial public commitment to working out the mechanism" behind life span extension in laboratory animals. If we want to live longer, he argues, we have to attack the problem at its source: the fundamental mechanism or mechanisms that drive the process of aging. Miller argues that research into the biology of aging could have a bigger bang for the buck than research on individual illnesses. If scientists can figure out how to slow aging, they will simultaneously attack all of the diseases associated with growing old.
Not What But Why
In experimental science, a wide gap often exists between observation and understanding--between seeing what happens in a given experiment and knowing why it happens. Research into the biology of aging, experts concur, is currently straddling this gap. Before any laboratory findings on longevity in animals can be deemed relevant to humans, scientists will have to pinpoint the mechanisms involved and determine whether they operate in people. "If we can discover what regulates the rate of aging, we can then start to intervene," says Huber Warner, associate director of the biology of aging program at the National Institute on Aging (NIA) in Baltimore.
Figuring out how aging works is not as easy as it might sound. In 1935, Cornell University veterinary nutritionist Clive McCay found that subjecting rats to a regime of calorie restriction (CR) extended their life span by 75%--an observation that has since been replicated numerous times (although the results are not always quite so dramatic). But nearly 70 years later, scientists still don't know precisely how CR slows the aging process (see "Counting Up the Calories, Holding Back the Years?").
One possible explanation involves oxidative stress. In a wide range of studies, including those on CR, a longer life span often correlates with increased resistance to so-called oxidative damage, which occurs when destructive molecules released through the process of basic metabolism wreak havoc in cells, hampering their ability to perform crucial tasks. Animals on a CR diet sustain less cellular damage than their well-fed kin do. Many scientists now have a hunch that aging is wholly or partly caused by the vandalism resulting from such oxidative injury.
Oxidative stress might not be the whole story, however. For example, preliminary unpublished data from a study by biochemist Arlan Richardson, director of the Aging Research and Education Center at the University of Texas Health Science Center in San Antonio, show that mice that are engineered to be more susceptible to oxidative stress than normal animals nevertheless enjoy normal life spans. A great deal of work has shown that stress-resistant animals are particularly long-lived. But animals that are more susceptible to stress don't age faster than normal, so perhaps oxidative damage does not drive aging--at least not on its own. Richardson says he doesn't think his study demolishes the oxidative stress hypothesis, just that the two are inconsistent for reasons that aren't yet entirely clear. "I think the verdict is still out on oxidative stress," he says.
Diet and Genes
Some genetic alterations also result in life span extension. The discovery over the past decade of a large number of genetic changes that can prolong life in a variety of animals has spurred scientists to look deeper for explanations of what they're seeing. So far, however, there's a raft of ideas but no clear winner.
Consider just one example out of many. Martin Holzenberger of the French biomedical research agency INSERM is the lead author of a recent study showing that mice genetically engineered to respond poorly to the hormone insulin-like growth factor 1 (IGF-1), which controls growth and cell division, live 26% longer on average than do normal lab mice (see "All Together Now"). In flies and worms, related genes have a similar effect, an evolutionary commonality that researchers find intriguing.
Holzenberger's mice are also more resistant to oxidative stress than normal. Still, he refuses to chalk up his findings entirely to the oxidative stress hypothesis. In a recent commentary on their work and its implications in the journal Cell Cycle, Holzenberger and his colleague note that another genetically altered mouse strain shows greater resistance to oxidative damage than their engineered mice do, yet it does not live longer than the IGF-1-deficient mutants do. Such findings make it probable that increased stress resistance is just one of several changes in IGF-1 deficient mutants, they said, further noting that the quest for additional mechanisms to explain these mice "has just begun."
Unitarians and Multiplicitists
Still, some researchers who study the biology of aging, including Miller, see the findings of life extension from calorie cutting and genetic manipulations as evidence that a single mechanism--or at least a small number of them--might control an organism's life span. As evidence for their "unitarian" view, these scientists point to the fact that similar findings have been uncovered in disparate animals: Resistance to oxidative stress tends to be associated with life span extension across species, as does impaired response to the hormone IGF-1.
This "unitarian" philosophy remains highly disputed within the field, however. Many researchers are "multiplicitists" who see the biology of aging as deeply complex at the cellular and intracellular level and therefore unlikely to be the result of one or a few key mechanisms. "Life span is the product of many, many things," says Rajindar Sohal, a molecular pharmacologist who studies CR at the University of Southern California in Los Angeles.
Show Me the Money
Whether one mechanism or many drive the aging process, most scientists in the field agree that the research has already shown its medical promise and deserves better federal funding--particularly because, as Miller points out, putting the brakes on aging would also reduce the incidence of a wide range of illnesses that plague the elderly. Because of the potential payback, "it's terribly important to invest more on fundamental research in the processes of aging," says George Martin, a pathologist at the University of Washington, Seattle, who studies aging and Alzheimer's disease. "It will be very cost effective. You might not find a unitary mechanism for everything, but you might find some very important ones that you can deal with for a large segment of the population."
Despite the immense implications of new findings about the biology of aging for humans, Miller argues that basic research in this area remains drastically underfunded and neglected by policymakers. Miller notes in his piece in The Milbank Quarterly that research on aging "receives such a small proportion of government research funding that it cannot be seen in [the] pie chart." The overall budget of NIA is $1 billion a year, approximately 20% of which goes to basic research into the biology of aging, according to NIA's Warner. In comparison, the National Cancer Institute has a budget of roughly $4 billion a year.
According to Warner, many promising research proposals in the biology of aging remain unfunded with the institute's current budget. But that's probably true of every part of the National Institutes of Health: "There's probably not a biomedical constituency that doesn't believe that it's underfunded," he points out.
Why does research into the biology of aging receive such a meager amount of funding? Miller has several ideas. First, he says, politicians tend to be most responsive to voter demands for research into specific diseases such as cancer and Alzheimer's, a nearsightedness shared by pharmaceutical companies. Further complicating matters is the phenomenon of "gerontologiphobia," a fear of the social consequences of life span extension that has been on prominent display by some members of the President's Council on Bioethics and particularly its chair, Leon Kass (see Panel Politics).
Perhaps Miller's most intriguing suggestion, however, is that "scientists and their patrons--even those who have legitimate research interests in interventional gerontology--do not wish to be seen hanging out with snake oil vendors." The vast and highly profitable antiaging medicine industry, which hawks such unproven dietary supplements as melatonin, DHEA, and human growth hormone, casts a long shadow over legitimate scientific research. A
s Miller's words suggest, scientists have recently begun to fight a strong rearguard action against those who currently claim the ability to treat human aging in advance of unambiguous scientific evidence that this is possible. Last year in Scientific American, 51 biogerontologists--including Martin and Sohal--signed a statement entitled "No Truth to the Fountain of Youth," which argued that the public is being deceived by peddlers of quack aging cures. Yet this action has itself triggered criticism. In the journal The Gerontologist, Case Western Reserve University bioethicist Robert H. Binstock writes that by lashing out against antiaging medicine, biogerontologists are merely trying to protect their own sources of research funding.
Battling off perceived hucksters might not be the only way to win greater recognition for the strides that research into the biology of aging has made, however. America is slowly coming around, says Richardson, and politicians will gradually follow suit. "The first thing a society has to do before it tackles a big problem is that they've got to say, 'We don't want to put up with this; we've got to do something about it.' "
And although biogerontologists are still "futzing around with identifying the mechanism" behind retarded aging, Richardson says that this pursuit is already much more respectable than it was 30 years ago. A change in atmosphere, based on legitimate scientific findings, might already be in the works.
All things being equal, these are pretty good days to be an elderly American. Not only has average life expectancy been rising steadily since 1950, but, over the past 2 decades, surveys have shown a steady decline in disability among older Americans, a trend that continues unabated. "We haven't seemed to reach a plateau yet," says Harvard University health economist David Cutler, who studies disability among the elderly.
And the good news doesn't stop there: Scientists have discovered a number of ways to slow aging in creatures as different as yeast and mice. This ongoing research into aging and longevity has "immense potential to prevent late-life illnesses and prolong active life" in humans, wrote gerontologist Richard A. Miller of the University of Michigan, Ann Arbor, last November in the health care policy journal The Milbank Quarterly.
This month, Cutler and Miller will enumerate and explore the implications of these promising scientific and demographic trends in a SAGE Crossroads discussion on "Remarkable Trends in Aging Research." Perhaps the most dramatic findings have come from laboratory studies of some of the simplest organisms. Working with yeast, fruit flies, worms, and mice, researchers have generated animals that live two and three times as long as their untreated companions--observations suggesting that an organism's maximum life span is not carved in stone.
The tantalizing question is whether this stunning extension of life span can be achieved in humans. To translate the results of these longevity-boosting animal studies into a treatment that might retard aging in people, scientists first need to home in on the mechanism--or mechanisms--responsible for what's been observed in the lab. "It's no longer respectable to say that aging is immutable," says Miller. "It's time to move on to the next issue, which is, 'How do these changes work?' "
The question is a timely one. Although recent health trends among the elderly have been heartening, some say that the improvement will eventually reach a natural limit. Even assuming that medical scientists manage to conquer leading causes of death such as cancer and heart disease, demographers calculate that people would gain only a few more years of average life expectancy as a result.
For this reason, Miller has called for a "substantial public commitment to working out the mechanism" behind life span extension in laboratory animals. If we want to live longer, he argues, we have to attack the problem at its source: the fundamental mechanism or mechanisms that drive the process of aging. Miller argues that research into the biology of aging could have a bigger bang for the buck than research on individual illnesses. If scientists can figure out how to slow aging, they will simultaneously attack all of the diseases associated with growing old.
Not What But Why
In experimental science, a wide gap often exists between observation and understanding--between seeing what happens in a given experiment and knowing why it happens. Research into the biology of aging, experts concur, is currently straddling this gap. Before any laboratory findings on longevity in animals can be deemed relevant to humans, scientists will have to pinpoint the mechanisms involved and determine whether they operate in people. "If we can discover what regulates the rate of aging, we can then start to intervene," says Huber Warner, associate director of the biology of aging program at the National Institute on Aging (NIA) in Baltimore.
Figuring out how aging works is not as easy as it might sound. In 1935, Cornell University veterinary nutritionist Clive McCay found that subjecting rats to a regime of calorie restriction (CR) extended their life span by 75%--an observation that has since been replicated numerous times (although the results are not always quite so dramatic). But nearly 70 years later, scientists still don't know precisely how CR slows the aging process (see "Counting Up the Calories, Holding Back the Years?").
One possible explanation involves oxidative stress. In a wide range of studies, including those on CR, a longer life span often correlates with increased resistance to so-called oxidative damage, which occurs when destructive molecules released through the process of basic metabolism wreak havoc in cells, hampering their ability to perform crucial tasks. Animals on a CR diet sustain less cellular damage than their well-fed kin do. Many scientists now have a hunch that aging is wholly or partly caused by the vandalism resulting from such oxidative injury.
Oxidative stress might not be the whole story, however. For example, preliminary unpublished data from a study by biochemist Arlan Richardson, director of the Aging Research and Education Center at the University of Texas Health Science Center in San Antonio, show that mice that are engineered to be more susceptible to oxidative stress than normal animals nevertheless enjoy normal life spans. A great deal of work has shown that stress-resistant animals are particularly long-lived. But animals that are more susceptible to stress don't age faster than normal, so perhaps oxidative damage does not drive aging--at least not on its own. Richardson says he doesn't think his study demolishes the oxidative stress hypothesis, just that the two are inconsistent for reasons that aren't yet entirely clear. "I think the verdict is still out on oxidative stress," he says.
Diet and Genes
Some genetic alterations also result in life span extension. The discovery over the past decade of a large number of genetic changes that can prolong life in a variety of animals has spurred scientists to look deeper for explanations of what they're seeing. So far, however, there's a raft of ideas but no clear winner.
Consider just one example out of many. Martin Holzenberger of the French biomedical research agency INSERM is the lead author of a recent study showing that mice genetically engineered to respond poorly to the hormone insulin-like growth factor 1 (IGF-1), which controls growth and cell division, live 26% longer on average than do normal lab mice (see "All Together Now"). In flies and worms, related genes have a similar effect, an evolutionary commonality that researchers find intriguing.
Holzenberger's mice are also more resistant to oxidative stress than normal. Still, he refuses to chalk up his findings entirely to the oxidative stress hypothesis. In a recent commentary on their work and its implications in the journal Cell Cycle, Holzenberger and his colleague note that another genetically altered mouse strain shows greater resistance to oxidative damage than their engineered mice do, yet it does not live longer than the IGF-1-deficient mutants do. Such findings make it probable that increased stress resistance is just one of several changes in IGF-1 deficient mutants, they said, further noting that the quest for additional mechanisms to explain these mice "has just begun."
Unitarians and Multiplicitists
Still, some researchers who study the biology of aging, including Miller, see the findings of life extension from calorie cutting and genetic manipulations as evidence that a single mechanism--or at least a small number of them--might control an organism's life span. As evidence for their "unitarian" view, these scientists point to the fact that similar findings have been uncovered in disparate animals: Resistance to oxidative stress tends to be associated with life span extension across species, as does impaired response to the hormone IGF-1.
This "unitarian" philosophy remains highly disputed within the field, however. Many researchers are "multiplicitists" who see the biology of aging as deeply complex at the cellular and intracellular level and therefore unlikely to be the result of one or a few key mechanisms. "Life span is the product of many, many things," says Rajindar Sohal, a molecular pharmacologist who studies CR at the University of Southern California in Los Angeles.
Show Me the Money
Whether one mechanism or many drive the aging process, most scientists in the field agree that the research has already shown its medical promise and deserves better federal funding--particularly because, as Miller points out, putting the brakes on aging would also reduce the incidence of a wide range of illnesses that plague the elderly. Because of the potential payback, "it's terribly important to invest more on fundamental research in the processes of aging," says George Martin, a pathologist at the University of Washington, Seattle, who studies aging and Alzheimer's disease. "It will be very cost effective. You might not find a unitary mechanism for everything, but you might find some very important ones that you can deal with for a large segment of the population."
Despite the immense implications of new findings about the biology of aging for humans, Miller argues that basic research in this area remains drastically underfunded and neglected by policymakers. Miller notes in his piece in The Milbank Quarterly that research on aging "receives such a small proportion of government research funding that it cannot be seen in [the] pie chart." The overall budget of NIA is $1 billion a year, approximately 20% of which goes to basic research into the biology of aging, according to NIA's Warner. In comparison, the National Cancer Institute has a budget of roughly $4 billion a year.
According to Warner, many promising research proposals in the biology of aging remain unfunded with the institute's current budget. But that's probably true of every part of the National Institutes of Health: "There's probably not a biomedical constituency that doesn't believe that it's underfunded," he points out.
Why does research into the biology of aging receive such a meager amount of funding? Miller has several ideas. First, he says, politicians tend to be most responsive to voter demands for research into specific diseases such as cancer and Alzheimer's, a nearsightedness shared by pharmaceutical companies. Further complicating matters is the phenomenon of "gerontologiphobia," a fear of the social consequences of life span extension that has been on prominent display by some members of the President's Council on Bioethics and particularly its chair, Leon Kass (see Panel Politics).
Perhaps Miller's most intriguing suggestion, however, is that "scientists and their patrons--even those who have legitimate research interests in interventional gerontology--do not wish to be seen hanging out with snake oil vendors." The vast and highly profitable antiaging medicine industry, which hawks such unproven dietary supplements as melatonin, DHEA, and human growth hormone, casts a long shadow over legitimate scientific research. A
s Miller's words suggest, scientists have recently begun to fight a strong rearguard action against those who currently claim the ability to treat human aging in advance of unambiguous scientific evidence that this is possible. Last year in Scientific American, 51 biogerontologists--including Martin and Sohal--signed a statement entitled "No Truth to the Fountain of Youth," which argued that the public is being deceived by peddlers of quack aging cures. Yet this action has itself triggered criticism. In the journal The Gerontologist, Case Western Reserve University bioethicist Robert H. Binstock writes that by lashing out against antiaging medicine, biogerontologists are merely trying to protect their own sources of research funding.
Battling off perceived hucksters might not be the only way to win greater recognition for the strides that research into the biology of aging has made, however. America is slowly coming around, says Richardson, and politicians will gradually follow suit. "The first thing a society has to do before it tackles a big problem is that they've got to say, 'We don't want to put up with this; we've got to do something about it.' "
And although biogerontologists are still "futzing around with identifying the mechanism" behind retarded aging, Richardson says that this pursuit is already much more respectable than it was 30 years ago. A change in atmosphere, based on legitimate scientific findings, might already be in the works.
Comentários
Postar um comentário