Wise Young
10-13-2001, 01:01 AM
http://www.nature.com/nsu/001005/001005-3.html
The times of our lives
Why do we grow old and die rather than stay young and gorgeous forever, asks Henry Gee? 2 October 2000
HENRY GEE
Why do we grow old and die? Why can't we stay young and gorgeous forever? These are questions that interest everybody, as attested by the plump profits of beauty-products companies.
Evolution has several explanations for our mortality. At root is a division between our 'germ line' -- sperm and egg cells kept healthy and pristine; and the 'soma' -- the body that houses the germ cells.
The idea of lifespan has no meaning in creatures with no distinction between germ line and soma -- such as amoebae that reproduce simply by making more copies of themselves. Such organisms are, in effect, immortal.
For the rest of us, it is possible to argue that once we have done our bit for reproduction, our bodies are expendable and will slowly degenerate until we die.
The three theories of age
There are three interrelated genetic theories to explain ageing and death. The first is the accumulation of mutations in the germ line that become apparent in old age, when most of one's peers have died by accident or predation (the usual fate of creatures in the wild), and when natural selection is too weak to oppose these mutations.
The second idea, related to the first, is that genes with deleterious effects in later life are maintained in the population because of their greater benefits in youth. This 'trade-off' between profit and loss is related to the third theory, which acknowledges that resources are scarce, and must be apportioned between survival and reproduction.
For example, 90% of mice die in their first year, so mechanisms for survival beyond this age benefit very few mice. Therefore natural selection for traits that prolong survival will be relatively weak.
In general, it benefits organisms to devote resources to reproduction at the expense of bodily maintenance. Experiments show that animals kept in equable captivity but prevented from reproduction tend to live longer, and there is some evidence that people who have fewer children, later in life, tend to live longer than those who breed early and often.
But none of this explains why the range of lifespans in organisms, even in captivity, varies so greatly.
Your pet hamster will not live much beyond two years, even with the best veterinary care and protection from your pet cat. Your cat, on the other hand, could live ten times as long as the most geriatric hamster, but will become decrepit when still a teenager in human years. People rarely live longer than a century, when redwoods and giant tortoises are still in the first bloom of youth. The laboratory roundworm Caenorhabditis elegans -- one of the organisms most popular with researchers interested in ageing -- lives around two and a half weeks.
Why are there no centenarian hamsters?
For more than a century it has been known that animals with higher metabolic rates often have shorter lifespans. Although this 'live fast, die young' hypothesis seems true in a very general way -- short-lived shrews have higher metabolisms than long-lived elephants -- it breaks down when examined more closely.
For example, bats and mice have similar metabolic rates, but bats live ten times as long as mice. And many primates and birds have higher metabolisms than would be predicted from their longevity. Human beings (and parrots) are among the longest-living animals.
Nevertheless, metabolism has yielded a valuable clue. Metabolism produces, as by-products, highly reactive substances called 'reactive oxygen species' (ROS). ROS are intensely damaging to cells, tissues and the genetic material DNA. There is increasing evidence that ROS are involved in the physical effects that we associate with ageing, and that their production is associated with metabolic rate.
Studies on animals show that a dramatic decrease in food intake (so-called 'caloric restriction') results in a decrease in metabolic activity, and extends lifespan in some cases. Exposure to ROS has also been linked to the shortening of telomeres -- the regions at the ends of chromosomes whose gradual shortening and decay with each cell division has been implicated in ageing.
A matter of life and death
The connection between ROS and ageing suggests that 'antioxidants' -- substances that protect against ROS -- could be used to delay the effects of ageing. But in matters of life and death, things are, unsurprisingly, not that simple.
There is also increasing evidence that some ROS are vital for life. ROS such as the superoxide anion are used by white blood cells as weapons against infectious agents. Another, nitric oxide, is involved in the regulation of blood pressure. ROS may even regulate metabolic rate itself, forging a further link between the live fast, die young hypothesis and the direct involvement of ROS in ageing.
But why should ROS cause ageing in any case? Why aren't there mechanisms to repair the damage that ROS causes?
To some extent there are -- but even the damage caused by ROS may, paradoxically, have some benefit. In general, ROS contribute to a phenomenon known as 'oxidative stress' -- basically the hard knocks accrued simply by the process of living. The degree to which we suffer from oxidative stress depends on a delicate balance between the effects of ROS and our bodies' responses to them.
Stress busters
Ageing, it appears, is caused not so much by ROS, as by the decreasing ability of the body to respond positively to oxidative stress. Although too much oxidative stress can kill you, a little bit can give you an edge, toning up your biochemistry to respond better in times of acute stress. What won't kill you, as the saying goes, will make you stronger.
Not surprisingly, a plethora of genes and proteins have been found that link lifespan extension with the ability to resist oxidative stress. For instance, Simon Melov of the Buck Institute for Age Research in California, and colleagues reported in Science1 that C. elegans worms live 44% longer than normal when treated with substances that mimic the activities of two ROS-fighting enzymes, catalase and superoxide dismutase.
Other lifespan-extending mutations in C. elegans concern proteins that reduce metabolic rate (thus lowering the production of ROS). In the fly Drosophila, life-extending mutations also affect resistance to oxidative stress. Flies with a mutation in the methuselah gene live much longer than normal, and are resistant to heat stress and also to the pesticide paraquat -- which kills by generating a flood of ROS.
But flies and worms are a long way from humans. Until last year, reports of life-extending genetic mutations in mammals were lacking. Then Pier Giuseppe Pelicci of the European Institute of Oncology in Milan, Italy, and colleagues reported in Nature2 that mice lacking a certain protein were resistant to oxidative stress and lived longer than normal mice. The protein p66shc is involved in the biochemical pathway that responds to the activities of ROS.
The current wisdom is that ROS, oxidative stress, and the biochemical response to this stress are key determinants of longevity. But they are not the only ones, and many questions remain, including the degree to which any of these findings are applicable to humans.
Great expectations
Human life expectancy has increased hugely over the past century, despite our almost total ignorance of the underlying biochemistry. Since 1900, life expectancy for a baby born in the United States has increased from 47 to 76 years, a rise of 62% -- much more than many of the increases reported for flies and worms in the laboratory.
The cause of this shift cannot be found in any particular genetic mutation, but in the overall improvement in public access to adequate food, clean water and healthcare.
Most human beings are not so blessed. According to figures from the World Health Organization, people born today in Sierra Leone will be lucky to reach their 40th birthday. Life expectancy in Africa and countries such as Russia are declining for a variety of reasons, ranging from AIDS to economic hardship. The leading cause of death among young black men in the United States is gunshot wounds.
One might argue that before we seek to find ways to increase the maximum possible human lifespan from Jeanne Calment's current record of 122 years, we should ensure that more people get the chance to enjoy even that allotted span.
References
1. Melov, S. et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science 289, 1567-1569 (2000). 2. Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313 (1999).
Nature News Service / Macmillan Magazines Ltd 2001
The times of our lives
Why do we grow old and die rather than stay young and gorgeous forever, asks Henry Gee? 2 October 2000
HENRY GEE
Why do we grow old and die? Why can't we stay young and gorgeous forever? These are questions that interest everybody, as attested by the plump profits of beauty-products companies.
Evolution has several explanations for our mortality. At root is a division between our 'germ line' -- sperm and egg cells kept healthy and pristine; and the 'soma' -- the body that houses the germ cells.
The idea of lifespan has no meaning in creatures with no distinction between germ line and soma -- such as amoebae that reproduce simply by making more copies of themselves. Such organisms are, in effect, immortal.
For the rest of us, it is possible to argue that once we have done our bit for reproduction, our bodies are expendable and will slowly degenerate until we die.
The three theories of age
There are three interrelated genetic theories to explain ageing and death. The first is the accumulation of mutations in the germ line that become apparent in old age, when most of one's peers have died by accident or predation (the usual fate of creatures in the wild), and when natural selection is too weak to oppose these mutations.
The second idea, related to the first, is that genes with deleterious effects in later life are maintained in the population because of their greater benefits in youth. This 'trade-off' between profit and loss is related to the third theory, which acknowledges that resources are scarce, and must be apportioned between survival and reproduction.
For example, 90% of mice die in their first year, so mechanisms for survival beyond this age benefit very few mice. Therefore natural selection for traits that prolong survival will be relatively weak.
In general, it benefits organisms to devote resources to reproduction at the expense of bodily maintenance. Experiments show that animals kept in equable captivity but prevented from reproduction tend to live longer, and there is some evidence that people who have fewer children, later in life, tend to live longer than those who breed early and often.
But none of this explains why the range of lifespans in organisms, even in captivity, varies so greatly.
Your pet hamster will not live much beyond two years, even with the best veterinary care and protection from your pet cat. Your cat, on the other hand, could live ten times as long as the most geriatric hamster, but will become decrepit when still a teenager in human years. People rarely live longer than a century, when redwoods and giant tortoises are still in the first bloom of youth. The laboratory roundworm Caenorhabditis elegans -- one of the organisms most popular with researchers interested in ageing -- lives around two and a half weeks.
Why are there no centenarian hamsters?
For more than a century it has been known that animals with higher metabolic rates often have shorter lifespans. Although this 'live fast, die young' hypothesis seems true in a very general way -- short-lived shrews have higher metabolisms than long-lived elephants -- it breaks down when examined more closely.
For example, bats and mice have similar metabolic rates, but bats live ten times as long as mice. And many primates and birds have higher metabolisms than would be predicted from their longevity. Human beings (and parrots) are among the longest-living animals.
Nevertheless, metabolism has yielded a valuable clue. Metabolism produces, as by-products, highly reactive substances called 'reactive oxygen species' (ROS). ROS are intensely damaging to cells, tissues and the genetic material DNA. There is increasing evidence that ROS are involved in the physical effects that we associate with ageing, and that their production is associated with metabolic rate.
Studies on animals show that a dramatic decrease in food intake (so-called 'caloric restriction') results in a decrease in metabolic activity, and extends lifespan in some cases. Exposure to ROS has also been linked to the shortening of telomeres -- the regions at the ends of chromosomes whose gradual shortening and decay with each cell division has been implicated in ageing.
A matter of life and death
The connection between ROS and ageing suggests that 'antioxidants' -- substances that protect against ROS -- could be used to delay the effects of ageing. But in matters of life and death, things are, unsurprisingly, not that simple.
There is also increasing evidence that some ROS are vital for life. ROS such as the superoxide anion are used by white blood cells as weapons against infectious agents. Another, nitric oxide, is involved in the regulation of blood pressure. ROS may even regulate metabolic rate itself, forging a further link between the live fast, die young hypothesis and the direct involvement of ROS in ageing.
But why should ROS cause ageing in any case? Why aren't there mechanisms to repair the damage that ROS causes?
To some extent there are -- but even the damage caused by ROS may, paradoxically, have some benefit. In general, ROS contribute to a phenomenon known as 'oxidative stress' -- basically the hard knocks accrued simply by the process of living. The degree to which we suffer from oxidative stress depends on a delicate balance between the effects of ROS and our bodies' responses to them.
Stress busters
Ageing, it appears, is caused not so much by ROS, as by the decreasing ability of the body to respond positively to oxidative stress. Although too much oxidative stress can kill you, a little bit can give you an edge, toning up your biochemistry to respond better in times of acute stress. What won't kill you, as the saying goes, will make you stronger.
Not surprisingly, a plethora of genes and proteins have been found that link lifespan extension with the ability to resist oxidative stress. For instance, Simon Melov of the Buck Institute for Age Research in California, and colleagues reported in Science1 that C. elegans worms live 44% longer than normal when treated with substances that mimic the activities of two ROS-fighting enzymes, catalase and superoxide dismutase.
Other lifespan-extending mutations in C. elegans concern proteins that reduce metabolic rate (thus lowering the production of ROS). In the fly Drosophila, life-extending mutations also affect resistance to oxidative stress. Flies with a mutation in the methuselah gene live much longer than normal, and are resistant to heat stress and also to the pesticide paraquat -- which kills by generating a flood of ROS.
But flies and worms are a long way from humans. Until last year, reports of life-extending genetic mutations in mammals were lacking. Then Pier Giuseppe Pelicci of the European Institute of Oncology in Milan, Italy, and colleagues reported in Nature2 that mice lacking a certain protein were resistant to oxidative stress and lived longer than normal mice. The protein p66shc is involved in the biochemical pathway that responds to the activities of ROS.
The current wisdom is that ROS, oxidative stress, and the biochemical response to this stress are key determinants of longevity. But they are not the only ones, and many questions remain, including the degree to which any of these findings are applicable to humans.
Great expectations
Human life expectancy has increased hugely over the past century, despite our almost total ignorance of the underlying biochemistry. Since 1900, life expectancy for a baby born in the United States has increased from 47 to 76 years, a rise of 62% -- much more than many of the increases reported for flies and worms in the laboratory.
The cause of this shift cannot be found in any particular genetic mutation, but in the overall improvement in public access to adequate food, clean water and healthcare.
Most human beings are not so blessed. According to figures from the World Health Organization, people born today in Sierra Leone will be lucky to reach their 40th birthday. Life expectancy in Africa and countries such as Russia are declining for a variety of reasons, ranging from AIDS to economic hardship. The leading cause of death among young black men in the United States is gunshot wounds.
One might argue that before we seek to find ways to increase the maximum possible human lifespan from Jeanne Calment's current record of 122 years, we should ensure that more people get the chance to enjoy even that allotted span.
References
1. Melov, S. et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science 289, 1567-1569 (2000). 2. Migliaccio, E. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313 (1999).
Nature News Service / Macmillan Magazines Ltd 2001