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Life-Span Extension

LIFE-SPAN EXTENSION

Opinions about life-span extension range from the optimistic, fanciful thinking of Ben Bova, a noted science fiction writer, who wrote: "The first immortal human beings are probably living among us today. You may be one of them." (Bova, p. 3), to the realistic views of Steve Austad, a respected researcher on the evolution of aging processes, who wrote: "In Westminster Abbey. . . lie the bones of one rather ordinary man.. . .Thomas Parr's only claim to fame is that he managed to convince a gullible seventeenth-century public that he had been alive for more than 150 years" (Austad, p. 1). There has probably been no more consistent and heartfelt fantasy than to imagine living forever in a youthful body full of health and vigor. From the dawn of written language, there are references to such life extension. Do some people show extraordinary life extension? What can people do to maximize their own life potential? What is known about the mechanisms of life extension? These are some of the questions that will be addressed below.

Myths about life extension

Biblical, mythological, and other works frequently refer to long-lived human populations living at some remote time or place, typically during some "Golden Age" of humankind. References to long-lived populations in such far away places as Vilcabamba, Ecuador, the Himalayas, or Soviet Georgia are numerous, but are typically the result of sheer fabrication. Such reports are not scientific and have always failed to be verified. For example, those from the Asian state of Georgia were probable fabrications put in place to elude the Czar's draft during the Crimean War, or for other reasons, and were maintained by the Soviet Union for political purposes.

Scientific analysis of longevity

Demography is the science that deals with human longevity, among other things. Demographers have learned to be very careful about accepting claims of extraordinary longevity, because there is a very human tendency to exaggerate one's age after a certain point. A combination of good documentation and continual historical verification of identity help to rule out those who are making untruthful claims.

Demographers who work on human longevity have documented that the human life expectancy is going up rapidly, and has been doing so since about 1850. Overall mortality rate (the probability of death per year) has shown a consistent decline during the same period. Most of the increase in longevity in the nineteenth and early twentieth centuries resulted from better nutrition and from public health and sanitation measures used to prevent the spread of disease (e.g., inoculations to prevent early childhood diseases). These seemingly simple interventions have almost eliminated early causes of death and are responsible for the increased longevity and decreased early-life mortality seen throughout the twentieth century.

Since 1950, the increase in life expectancy has continued. In this period, the decline in mortality rate in developed countries has occurred largely in the older populations. Indeed, the population of adults age eighty-five and older showed the fastest rate of decline in mortality between 1950 and 2001. There is considerable debate about whether or not there is an upper limit to life span, but since mortality in the oldest cohorts is dropping most rapidly it seems unlikely that there are built-in limits to human longevity.

Centenarians

There are lots of people who manage to live a long time. The century mark has proven itself to be a useful measure of establishing a truly long life. The number of centenarians is growing rapidly, but the longest lived, so far, is Madam Jeanne Louise Calment, who had a validated life span longer than any one else in recorded history, living 122 years, 165 days. Calment was born in Arles, France on February 21, 1875 and died August 4, 1997. She once met Vincent Van Gogh in her father's shop. Calment rode a bicycle to the age of one hundred, but by the time of her death, she was blind, almost deaf, and confined to a wheelchair. Her genes may have contributed to her longevity, as her father lived to the age of ninety-four and her mother to the age of eighty-six.

Even thought Calment holds the record, there are an extraordinary number of centenarians alive in the world today. There are 50,000 in the United States alone, and worldwide there are expected to be millions of centenarians alive by the year 2020. The Living to 100 Web site (www.livingto100.com) includes a method to calculate one's chances of reaching the century mark.

Life-extension strategies that work

Interventions that lead to a longer life span have been sought for ages. There is a huge amount of money to be made by selling over-the-counter drugs, dietary supplements, and nutraceuticals that claim some effect on life extension. Numerous companies and scientists are trying to develop dietary interventions that will prolong life. As of this writing however, there is no scientifically validated dietary supplement that has a significant effect on human longevity. One should be very careful before purchasing any agents that propose to extend longevity, and even more careful before consuming such a product. The FDA does not regulate dietary supplements, health foods, and nutraceuticals, and some of these agents could have a significant negative effect on one's health; others may be addictive.

Limiting total food intake, however, does have some beneficial effect. Around 1930, Clive McCay discovered that feeding rats a diet complete in vitamins and minerals, but low in total calories, resulted in a prolonged period of life. Since then, numerous studies have observed life extension in a variety of different species, both mammals and invertebrates, and the effects of caloric restriction (CR) on extending life span have been widely validated. There is anecdotal evidence that humans who practice CR are healthier and may have longer life spans; unfortunately, few people have the ability to eat 40 percent less than that eaten by the average person every day, for the rest of their lives. At least one start-up biotech company is attempting to overcome this problem using pharmaceuticals that will mimic the effect of CR.

Scientifically, caloric restriction (also called dietary restriction or food restriction) refers to the method of extending mean and maximal life span by reducing caloric intake of a test animal. This is the only widely validated means of life extension in mammals. (Genetic methods and drug interventions are beginning to be studied in invertebrates.) CR is not starvation, but a reduction in caloric intake that typically results in consumption of only about 60 percent of the normal ad libitum diet. Numerous physiological functions are changed by CR; indeed, it is difficult to find a change associated with aging that is not slowed by CR. This has been one of the real difficulties in studying CR, for almost everything responds. Typical CR animals look and behave much younger than their chronological age would suggest, and this is true at the organ, cellular, and molecular levels. CR works best if the animal is restricted early in life (just after puberty), but even CR initiated late in life can have an effect on longevity that is almost proportional to the amount of time the animal is on CR. A typical CR mouse or rat lives about 30 percent longer and is much more lean and active at later stages of life. However, CR is often associated with reproductive sterility.

It has been quite difficult to reliably study CR in humans, or to convince people to initiate a CR diet for themselves. Numerous proponents have tried to maintain CR for themselves, but the results are not systematic or generally convincing. The National Institutes of Health (NIH) is currently funding CR research on macaques and rhesus monkeys to see if the observations made in rodents can be extended to primates. The results seem to suggest that CR works in primates as well.

Lifestyle choices to maximize life span

Choosing long-lived parents is currently the best method of insuring one's longevity. For now, there's not much people can do to ensure that the genes they got from their parents were the best possible. Each of us is responsible for maximizing our own life span (or not) as we see fit. Interventions to rectify such hereditary defects are probably at least a few decades away; but there's a lot a person can do to maximize the effect of his or her genes. The most important things to do to ensure that one reaches a maximum life span are to avoid unhealthy habits, such as smoking; excessive use of drugs like alcohol, narcotics, or marijuana; and overeating or consuming fatty foods. Regular exercise is also recommended.

Assuming that one wants to extend his or her life, as the comedian Woody Allen put it, "by not dying," rather than through one's children or works, what can be done? Not smoking, eating a healthy diet that's light in fats and total calories, getting plenty of exercise, staying happy, and having friends all may help. Some people recommend certain dietary supplements, such as vitamin E and a half an aspirin tablet daily. There are no magic bullets, however, at least not yet. Advice changes, and it's best to stay up to date; several websites maintained by responsible organizations include those of the American Federation for Aging Research (www.infoaging.org), the National Institute on Aging (www.nih.gov/nia/), and the Gerontological Association of America (www.geron.org).

Evolution of longevity

After the end of the reproductive period, an organism, be it mouse or human, can no longer contribute to the evolutionary pool in any sort of direct way, so there is little reason to think that evolution would select for individuals who live well past the age of reproduction. Moreover, since most organisms in the wild die from infection, accident, or predation, most scientists working on aging think that there is no selection for a program that kills an organism. Genes that regulate longevity also function to do other things as well, and their effects on longevity are thought to be secondary to these other actions. A small, but very vocal, subgroup disagrees strongly with this view, arguing that aging is genetically programmed. One of the best arguments against genetic programming is that no one has been able to eliminate the aging program in any species. In other words, no immortal organisms have been found, and most scientists think that they never will be. Other processes sometimes associated with aging are programmed, including programmed cell senescence, also called the Hayflick limit, and programmed cell death (apoptosis ). These processes can be completely eliminated in the lab, but no one has turned a mortal organism into an immortal one.

Ben Bova was right about one thingall people have the potential to be immortal. To be more precise, one part of each person has that potential: the germ line. Obviously, one part of the human must in some sense be immortal or human life would not exist today. However, the indefinite life of the germ line does not mean that any biological component in the process is really immortal. The somatic part of the germ line wears out; men accumulate mutations in their sperm, and women go through menopause. Menopause is not something that is unique to humans; numerous other species also show a cessation of reproduction in females late in life. Numerous arguments have been put forward arguing that menopause provides advantages to humans over evolutionary time periods, but there is little direct support for this notion and certainly no need that it be true. Modern medical interventions have already extended the reproductive life of women into their sixties using a variety of in vitro fertilization technologies and appropriate hormone treatments.

Genetic effects on life extension

Scientists have discovered that the genetic constitution of an organism can have a significant effect on its longevity. In humans, only a small fraction of the life span seems to be under genetic control, but this estimate could be wrong for many reasons. Geneticists who study humans are interested to know how much of the variation in individual longevity is controlled by the genes of the individual and how much is environmental. To answer this question, geneticists estimate something called heritability. For example, if on average, two Americans chosen at random will differ in life span by ten years, then heritability is a way of saying how much of that variation is due to environment and how much is due to genetic influences. (In this case, environment means the external environment as well as the stochastic differences within the animal, tissue or cell). The best current estimates are that genetics has a significant, but modest, effect on overall longevity, explaining only about 20 percent of the variation.

This estimate does not mean that aging is controlled by 20 percent of the genes, or that 20 percent of life is genetically programmed and the rest determined by environment. There are good reasons to suppose that centenarians have been blessed with very good genes (actually we all have the same genes, but centenarians have good versions called alleles ). So in a centenarian, forty or fifty years of life could result from genetic effects. It's impossible to be certain, but many groups are looking for these genes.

Life extension as a way to find aging genes

Scientists use life extension as a way to find genes that affect aging. Johnson and Wood proposed in 1982 that genetic variants that lengthen life could be found. Most genetic alterations shorten life, because these mutants reduce overall health and fitness. Indeed, it is counterintuitive that a genetic mutant could actually lead to longer than normal life, because mutations are generally thought of as bad. However, to the species, the length of an individual life does not matter at all. Scientists have used this strategy very effectively and have discovered numerous genes that lengthen life span.

Aside from caloric restriction, genetic manipulation is the only intervention that has been widely shown to actually extend longevity. Initial studies used naturally occurring genetic variants of longevity genes and combined them to yield longer-lived populations. Later, mutations in individual genes were shown to generate even longer life spans than possible in strains developed using this polygenic approach. In invertebrates, and especially in the small nematode worm called Caenorhabditis elegans, genetic variants leading to prolonged life have been produced for almost two decades. Other model organisms, in addition to the nematode, that are used to study genetic interventions include yeast and the fruit fly. These studies are yielding dozens of genes that affect longevity and slow down the rate of aging.

Several steps must be taken to characterize a longevity mutant. First, it must be verified that the longevity change is real and is passed on to the offspring. If it is, and if the mutation can be assigned a position in the chromosomes of the animal, then a mutational event has likely been found. Then the scientist would want to fish out the larger piece of DNA that carries the genetic mutants and figure out what this larger piece of DNA (the gene) does. Since almost all genes code for protein, this means finding out what the protein does, using both biochemical and genetic tricks.

The future

Many companies are trying to extend the life of short-lived species by using drug treatments. Such a strategy could possibly lead to drugs that lead to life prolongation and slower rates of aging. It was shown in 2000 that life extension can be achieved by drug treatment, at least in invertebrates. This is a natural extension of the genetic approach, using life span as a marker. Such a strategy could possibly lead to drugs that prolong life and slow rates of aging. For now, this still seems a distant pipe dream. However, the production of such drugs could be common in the future.

Thomas E. Johnson

See also Centenarians; Compression of Morbidity; Evolution of Aging; Fruit Flies, Drosophilia; Genetics: Longevity Assurance; Life Expectancy; Nematodes; Nutrition; Nutrition, Caloric Restriction; Pathology of Aging, Animal Models.

BIBLIOGRAPHY

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Austad, S. N. Why We Age. New York: John Wiley, 1997.

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