AGING
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Almost all living organisms pass through a sequence of changes, characterized by growth, development, maturation and senescence. Up until last year the oldest person ever to live was thought to have been a Japanese man who reached 120. However, it was discovered that his birth record was not accurate and, therefore the oldest person ever to live is now living--a woman in France who was born in 1875. The isolated villages in Russia where many people were supposedly very old turned out to be a myth. None of the 500 or so people who said they were between 120 and 170 years old could produce reliable document of birth, marriage, education or military service.
People are living longer. For example, in 1900 only 25% of U.S. population survived to age 65. Now almost 70% survive to this age. Currently about 30% attain age 80 and within a few years 50% will attain age 80. It is speculated that there no person attained the age of 100 before 1800 and no one lived to over 110 prior to 1950.
Three Primitive Questions--The Biology of the Finitude
A Model of Aging (from Gavrilov and Gavrilova, 1991)
The reduction in endogenous causes of death (cancer, heart disease) may have little effect on prolonging life because the speed of transition from the healthy state to the state of "unspecific vulnerability" (also referred to as the "one-foot-in-the-grave" state) determines the size of the death quota. This quota is then distributed among "causes" of death. It is argued that this explains why elimination of individual endogenous causes of death cannot significantly alter the magnitude of the biological component of mortality--organisms will simply die of another competing risk once in the vulnerable state. The future of research on aging and life span prolongation belongs to a strategy founded on explaining the mechanisms which determine the organism's resistance to a broad spectrum of harmful factors and not in eliminating specific causes, per se.
Concept of Maximal Length of Life
One of the most compelling concepts in human biology and demography is maximal length of life or the age limits of the human species. The validity of this concept is viewed by many as self evident because:
"I don't want to achieve immortality through my work. I want to achieve it through not dying." (Woody Allen, Film Director) |
The problem with this concept is that everything we know about the nature of mortality makes it difficult to accept the notion that there is an age--one single year--which some may reach but no one has any chance of surviving. The only valid alternative is the existence of an asymptote to which the probability of dying tends and that may or may not be near unity. Gavrilov and Gavrilova (1991) also reject the notion of a human-specific upper age limit and argue that people die before the age of infinity, not because they cannot pass bounding age, but because the probability of a person riding out the ever present risks of death for that long is infinitesimal. These authors cited over 50 references from the demographic, gerontological, and biological literature containing 28 different estimates of the biological limit to the length of human life ranging from 60 through 200 years. They noted that these values were not measured but prescribed. For example, Fries (1980) based his hypothesis that the maximal life expectancy of humans is around 85 years on the assumption of "ideal societal conditions" but does not specify these conditions (what diet? what patterns of work, leisure, family life?).
The most obvious evidence that the length of human life is limited is that we have not observed extremely long-lived people, say over 130 years old. However, the assumption of a genetically fixed upper bound to life expectancy and life span ignores the likelihood of strong genetic-environment interactions because these interactions likely had relatively little manifest effect until recently. This may account for the upward historical trend of oldest ages. Some demographers have speculated that no one may have lived to age 100 before 1800 or to 110 before 1950. Wilmoth (in press) analyzed data from five countries (Sweden, England and Wales, France, Japan and the United States) and found that the maximum age attained by humans has been increasing for at least 130 years. He suggested that the relevant limit of human life span may be in the pace of improvement rather than in the ultimate level to be attained.
An Exceptional Case of Human Longevity, Jeanne Calment
(Gerontological Society of America, New Orleans, Nov. 23, 1993)
Centenarian Divorce. The French group of demographers and gerontologists studying Madam Calment was also studying the life style and habits of centenarians. A centenarian couple in their study decided to seek a divorce. When asked why they had waited so long to make this decision they responded, "We waited out of consideration for our children. Thus we postponed the decision until they all had died." (story told by K Ritchie over dinner at Gerontological Meeeting in New Orleans, Nov., 1993). |
The oldest age to which any person on record has lived was a French woman, Madam Jeanne Calment, who was born in the small town of Arles on February 21, 1875 and died August 4, 1997 at age 122 years, 164 days.
"The plausibility of certain reported cases of longevity" V. Kannisto. To test the plausibility of a reported extreme age, we first have to determine the universe to which the person belongs. A woman who has reached the age 118 any time after 1950, reached the age 100 between 1931 and 1975. We estimated that in ca. 30 countries with reliable information (combined population 600 million), there were 57,000 such women. Applying and extrapolating the most reliable survival data we find that there was one chance in twenty that one of them would reach the age 118. This is 4 to 20 times the customary confidence limits in statistics and the case is entirely plausible. Using the same method we find it extremely unlikely (probability 0.002) that a man, as has been claimed (Japanese), would have reached the age 120.
"I see badly, I hear badly, I can't feel anything, but everything's fine." (J. Calment on 120th birthday, Sacramento Bee, March 14, 1995) |
"Validation of the age of Jeanne Calment" J. M. Andrieux. It is our great advantage that Jeanne Calment was born and lived in the ancient Roman city of Arles (South of France), with its long history of civil administration. It has thus been possible to validate her age by tracing the course of her life via civil and religious documentation and population census data. Not only has it been possible to verify the age of Jeanne Calment with a high level of certainty, but also to provide international guidelines for the validation of cases of extreme longevity.
"Present health status and medical history of Jeanne Calment". B. Forette. The present physical health status of Jeanne Calment is not normal, it is very good, as indicated by all standard clinical parameters. Everyday functioning is surprisingly good as measured by ADLs (activities of daily living). The three principal difficulties with which she is confronted are bilateral cataracts, deafness and an environment which confines her to a chair. The medical history is astonishing by its absence, up until an elbow and hip fracture at the age of 114.
"Smoking History" Madame Jeanne Calment began smoking when she married in 1896 at the age of 21. She smoked no more than 2 cigarettes per day. We do not know whether she inhaled nor do we know what brand she smoked. She quit smoking at about age 113-114 when she broke her hip. She had to quit because her cataracts prevented her from following the cigarette into her mouth.
LONDON (ReuterAugust, 1997). The Guinness Book of Records on Thursday confirmed 116-year-old Canadian Marie Louise Febronie Meilleur as the world's oldest person. She takes over the record from Frenchwoman Jeanne Calment, who died last week at the age of 122. Guinness said it confirmed Meilleur's age after checking her birth and baptism certificates, census records and two marriage certificates. ``We have an extremely stringent process of verification to ensure that only someone whose age can be proved beyond any shadow of doubt can be recognised as the record holder,'' said Guinnesse Keeper of the Records Clive Carpenter. Meilleur, who now lives in a nursing home in Corbeil, north Ontario, has 300 descendants from two marriages. Her family said the secret of her longevity was an active life and hard work. She used to enjoy fishing and still loves the outdoors. Guinness also confirmed that the world's oldest man is 114-year-old Christian Mortensen. The cigar-smoking centenarian emigrated from Skaarup, Denmark, to the United States in 1903 and now lives in San Raphael, California.
Christian Mortensen died April 25, 1998 at age of 115 yrs and 252 days.
AGING THEORIES
Longevity is Moderately Heritable in Twins.
The evidence of human longevity was investigated in a sample of 218 pairs of monozygotic (MZ) and 382 pairs of like-sex dizygotic (DZ) Danish twin pairs. Findings included: (1)Twin similarity for age at death was significant for MZ twins but nonsignificant for DZ twins; (2)The average age difference at deaths for two identical twins, two non-identical twins and two random individuals was 14.1, 18.5 and 19.2 years, respectively; (3)Genetics plays a moderate role in determining a person's longevity. (from McGue et al., 1993 J. Gerontological Soc. Amer. 48, B237) |
CHARACTERISTICS OF AGING
LONG-LIVED MAN. Dr. John W. Rowe, president of the Mount Sinai School of Medicine in New York, provides a thumbnail sketch of the man least likely to have coronary heart disease (the leading cause of death in the United States): "An effeminate (women live longer) municipal worker or embalmer (low stress) with no drive, never has to meet a deadline of any kind, underfed, subsisting on a diet laced with fruit, vegetables and cod-liver oil, with a full head of hair (baldness is a risk factor), hates smoking, avoids TVs and automobiles, works out with his puny muscles, low in income (wealthy people are at higher risk) and blood pressure, who has undergone a prophylactic castration." (from Sac. Bee Supplement Ap. 23, 1989). |
SUCCESSFUL AGING
Age | Stage | Arthero- sclerosis |
Cancer | Oestero- arthritis |
Diabetes | Emphysema | Cirrhosis |
20 | I. Start | elevated cholesterol |
carcinogen exposure |
abnormal cartilage staining |
obesity | smoker | drinker |
30 | II. Discernible | small plaques on arteriogram |
cellular metaplasia |
slight joint space narrowing |
abnormal glucose tolerance |
mild airway obstruction |
fatty liver on biopsy |
40 | III. Subclinical | larger plaques on arteriogram |
increasing metaplasia |
bone spurs |
elevated fastering blood glucose |
X-ray hyperinflation |
enlarged liver |
50 | IV. Threshold | leg pain on excercise |
carcinoma in situ |
mild articular pain |
sugar in urine |
shortness of breath |
upper GI hemo- rrhage |
60 | V. Severe | chest pain |
clinical cancer |
moderate articular pain |
hypoglycemic drug requirement |
recurrent hospitalization |
ascites |
70 | VI. End | stroke, heart attack |
metastatic cancer |
disabled | blindness; neuropathy; nephropathy |
intractable oxygen debt |
jaundice; hepatic coma |
The concept in Table 1 is that chronic diseases develop through a long series of stages. People will live longer and healthier if we can develop ways to either prevent the onset of some of these diseases or reduce the rate of their progression.
The compression of morbidity thesis notes that the species life span if finite while the onset of chronic disease is relatively easilty delayed (Fries 1988). Thus the period from onset of chronic infirmity to death may be shortened, with benefit to both individuals and society.
Vigorous Exercise and Mortality. Study published in J. Amer. Med. Assoc. (April, 1995) found that fates of 17,300 middle-aged men depended upon the amount of vigorous exercise they engaged in. Examples of activity needed to reduce by 25% the chance of dying over a 26-year period included: walking at 4-5 mph for 45 mins five times/wk, playing one hour of singles tennis 3 times/wk, swimming laps for 3 hours/wk, cycling for one hour 3 times/week or jogging at 6-7 mph for 3 hours/wk. |
Fries (1988) characterizes the basic syllogism of the compression of morbidity as follows:
Finite Human Life Span Evidence (1983, Milbank Mem. Fund Qrt. 61, 397):
Death, is that you? When a new disability arrives, I look about me to see if death has come, and I call quietly, "Death, is that you? Are you there?" and so far the disability has answered, "Don't be silly. It's just me." (F. S. Maxwell quoted in "The Fragile Species, Lewis Thomas, 1992. Macmillan) |
Mortality Rates for Centenarians
The mortality rates for centenarians were presented in a workshop on Oldest Old Mortality sponsored by the National Institute on Aging held at Duke University, March, 1993. Note the following: i)the mortality rates are extremely high--30 to 50% or more die at each age; ii)the males and females are relatively similar; and iii)the rates do not increase according to the Gompertz model.
The Baby Boomers and Aging
The 76 million people born in the 19 postwar years from 1946 to 1964 are considered the Baby Boomer generation. Their numbers are 150% of those born in the previous 19 years. The first Boomers will reach 50 in the year 1996 and the last cohort of Boomers in 2014 and will reach age 80 in 2026 and 2044, respectively. Some believe that the Boomers will be candidates for trendsetters as fiftysomethings and beyond (Rukeyser, 1995):
Anderson, W. F. 1995. Gene therapy. Scientific American Sept. 1995. 124-128.
Caskey, C. T. 1993. Presymptomatic diagnosis: a first step toward genetic health care. Science 262:48-49.
Collins, F. and D. Galas. 1993. A new five-year plan for the U.S. human genome project. Science 262: 43-46.
Graubard, S. R. (Ed.). 1986. The Aging Society. Daedalus 115 (Winter, 1986)
Finch, C. 1990. Longevity, Senescence, and the Genome. The University of Chicago Press, Chicago.
Fries, J. F. 1980. Aging, natural death, and the compression of morbidity. New England J. Med. 303:130-135.
Fries, J. F. 1983. The compression of morbidity. Milbank Mem. Fund, Qrt. 61:397-419.
Gavrilov, L. A. and N. S. Gavrilova. 1991. The Biology of Life Span: A Quantitative Approach. Harwood Academic Publishers, Chur, Switzerland.
Hamilton, J. B. & Mestler, G. E. (1969) Mortality and survival: comparison of eunuchs with intact men and women in a mentally retarded population. Journal of Gerontology, 24, 395-411.
Hayflick, L. 1994. How and Why We Age. Ballantine Books, New York.
Hazzard, W. R. (1990) The sex differential in longevity. Principles of Geriatric Medicine and Gerontology. 2nd Edition. (eds. W. R. Hazzard, R. Andres, E. L. Bierman and J. P. Blass) pp. 37-47. McGraw Hill, New York.
McGue, M., J. W. Vaupel, N. Holm and B. Harvald. 1993. Longevity is moderately heritable in a sample of Danish twins born 1870-1880. J. Gerontology 48:B237-B244.
Nesse, R. 1995. Why We Get Sick. Westminster, Maryland: Random House.
Rukeyser, William. 1995. Let's do the hobble. Atlantic Monthly, July, pp16-18.
Sacher, G. A. 1978. Longevity and aging in vertebrate evolution. BioScience 28:497-501.
Siebert, C. 1995. The DNA we've been dealt. NY Times Sunday Magazine. 50-57, 64, 74, 93-95.
Williams, G. C. and R. M. Nesse. 1991. The dawn of Darwinian medicine. Quarterly Review of Biology 66:1-22.
Data from surveys on attitudes and intentions are usually poor predictors of behavior. A woman may do well in predicting her future fertility given her present circumstances; she may not, however, clearly foresee her future circumstances, which of course would have greater bearing on her future fertility than would her present situation (Bennett, 1983).
REPRODUCTIVE TERMINOLOGY
Fig. 1. Schematic age-specific fertility schedule for females in developed countries. |
The three components of birth interval:
Conception
Lifetime | |
---|---|
Sperm | 24 to 48 hours |
Ovum | 12 to 24 hours |
METHODS OF FERTILITY CONTROL
CONTRACEPTIVE METHODS (after Djerassi 1989):
Hellin's Rule--the ratio of of twin births to single births is 1 out of 86, of triplet births is 1 out of 862 (= 1 out of 7,396), quadruplet births is 1 out of 863 (= 1 out of 636,056) and so forth. |
TREATMENTS OF INFERTILITY
CONVENTIONAL
IN VITRO FERTILIZATION
An estimated 65,000 children are born each year as a result of artificial insemination and other methods using stored sperm. However, human in vitro (test tube) fertilization (IVF) is surprisingly unsuccessful (Winston and Handyside 1993). In the U.S. the overall birth rate per IVF treatment cycle is 14% from 16,405 oocyte retrievals. Superovulation hopefully leads to fertilization of several oocytes, and it is common to transfer several embryos to the uterus, anticipating that at least one will implant. Pregnancy resulted from 13% (184 out of 1436) of transfers when three or fewer embryos were transferred and around 25% when four to six embryos were transferred. Of triplets and quadruplets born after IVF, from 65 to 75% required admission to intensive care. The quality of both the embryo and the uterine environment affects success.
In Vitro Fertilization Research Trends (from Winston and Handyside 1993).
Who's your father? "One can imagine a scenario in the post-nuclear family age in which both partners are infertile: an egg donor here, a sperm donor there, nine months with a surrogate mom and a bouncing miracle baby born, ready to be raised by a nanny." from P. Orenstein, Looking for a Donor to Call Dad. New York Times Sunday Magazine, June 18, 1995. |
In 1990 in the U.S. nearly 26,000 stimulation cycles were reported to the IVG-Embryo Transfer Registry, from which there were 5,150 pregnancies and slightly less than 4,000 live births. Assuming that around 10% of couples suffer infertility involuntarily, there may be upwards of 2 million women in the U.S. that will be candidates for IFV treatment.
SEX RATIO AND SEX PRESELECTION
Sex preselection represents a potential extension of fertility control. Numerous studies have attested to the presence of sex preferences and thus it seems reasonable to suppose that in societies practicing extensive family limitation and birth spacing, many couples would be inclined to take advantage of techniques of sex preselection.
Wives tales:
Two types of goals are commonly recognized:
STOPPING RULES
Couples who deliberately interrupt their childbearing when a minimum number of sons, or a minimum number of daughters are obtained may be said to be following a "stopping rule." The question is whether stopping rules affect the sex ratio at birth which is normally 105 boys to 100 girls or 51.2% boys and 48.8% girls. If couples prefer to have boys, then stopping rules will result in skewing the sex ratio slightly toward girls. For example, if a set of couples are following the stopping rule of no more children after the second son is born, the effect is to lower, not raise the sex ratio. This result follows because couples predisposed to have daughters will have to bear more children on the average in order to bear two sons than will couples predisposed to have boys.
But even when no couples are predisposed to having more daughters than sons, the consequences of the stopping rule of 2 sons has a minimal effect on the sex ratio. The table below presents the results of a computer simulation where 4,995 families were created using the stopping rule of 2 sons. The simulation was based on the assumption that there is a 50:50 chance of having a boy and that the couple continues having more children until the 2 boys are born. Note the following: i)51% of all families consist of either 2 children (2 boys) or 3 children (2 boys & 1 girl); ii)18.5% of all families consist of 2 boys and 2 girls. Thus a total of 69.5% of all families consist of 2 girls or less; iii)however, the remaining 30.5% of families consist of 5 or more children and thus contain more girls than boys. One of the nearly 5,000 families required the birth of 15 children to obtain their 2 boys; iv)of the 19,675 children born, there were 9,990 boys (2 boys/family X 4,995 families) and therefore 9,685 girls (19,675 children minus 9,990 girls). Thus the sex ratio of the population of 4,995 families is 50.8% boys and 49.2% girls. The results reveal that the ratio is nearly 50:50 despite a rule (stop at 2 sons) whose effect which, at least on first approximation, would appear to skew the population toward mostly males.
Table 1. Results of computer simulation of 4,995 families using a stopping rule of 2 boys.
No. Children in family (1) | Total number of families (2) | Total number of children (3) | Percent of all families (4) | No. girls in family (5) | No. boys in family (6) |
2 | 1,255 | 2,510 | 25.1% | 0 | 2 |
3 | 1,295 | 3,885 | 25.9 | 1 | 2 |
4 | 926 | 3,704 | 18.5 | 2 | 2 |
5 | 629 | 3,145 | 12.6 | 3 | 2 |
6 | 380 | 2,280 | 7.6 | 4 | 2 |
7 | 224 | 1,568 | 4.5 | 5 | 2 |
8 | 135 | 1,080 | 2.7 | 6 | 2 |
9 | 77 | 693 | 1.5 | 7 | 2 |
10 | 38 | 380 | .8 | 8 | 2 |
11 | 16 | 176 | .3 | 9 | 2 |
12 | 11 | 132 | .2 | 10 | 2 |
13 | 5 | 65 | .1 | 11 | 2 |
14 | 3 | 42 | .1 | 12 | 2 |
15 | 1 | 15 | .0 | 13 | 2 |
4,995 | 19,675 | 100.0 | |||
Woman only produces X gametes (XX zygote; homogametic sex); Men produces X and Y gametes (XY zygotes; heterogametic sex).
Approaches to Sex Preselection:
Old Wives' tales. Couples who pay to choose the sex of their child may be wasting their money, say Britain's sperm experts. Sex choice clinics claim that "male" sperm bearing the Y chromosome swim faster through viscous solutions of human albumin and so can be separated from "female" sperm bearing an X chromosome. But, according to John Aitken of the Universisty of Edinburgh, there is no good scientific data to confirm that X- and Y-bearing sperm do swim at different rates. Clinics that claim to select the sex of the sperm with an accuracy of over 70% use their own data. Researchers at the University of Edinburgh ended up with 50:50 male and female sperm using the same techniques.(New Scientist, 30 January, 1993).
But there may be hope for the future. Methods for producing sex-selected cattle semen are close to becoming commercially availableXY, Inc. of Fort Collins, Colorado. The method involves sorting sperm by flow cytometry, in which cells are stained with a flourescent dye and then passed through a laser beam. Cattle X sperm contain about 4% more DNA than Y sperm do, so the dye makes the X sperm glow more brightly (1997 Science 276: 1503). |
Consequences of Sex Pre-selection {(2,1) indicates 2 boys and 1 girl; B-G indicates the birth order of boy then girl}:
PATERNITY RIGHTS
A man who agrees to help a woman bear a child by donating sperm has a constitutional right to claim fatherhood, according to the Supreme Court. Under past Supreme Court rulings, unwed fathers who had an extended relationship with a woman were deemed to have a constitutional right to claim fatherhood of any child that is produced. These rulings involved children conceived through sexual intercourse, but Oregon courts said that the same principles apply to artificial insemination. In 1986, the California state courts issued a similar ruling. Though the state law said sperm donors do not have paternity rights, the state courts said this law covered only artificial insemination supervised by a doctor. A man who agreed to help a woman become impregnated without a doctor's involvement retained the right to seek paternity in court. (Sacramento Bee, April 24, 1990)
SUGGESTED READING
Alexander, N. J. Future contraceptives. Scientific American Sept. 1995. 136-141.
Bongaarts, J. and R. G. Potter. 1983. Fertility, Biology, and Behavior. An Analysis of the Proximate Determinants. Academic Press, New York.
Djerassi, C. 1989. The bitter pill. Science 245:356-361.
Ellison, P. T. 1994. Advances in human reproductive ecology. Annual Review of Anthropology 23:255-275.
Maranto, G. 1995. Delayed childbearing. The Atlantic Monthly. June issue. pp. 55-66.
Roush, W. 1996. Fertile results: bringing up baby (eggs). Science 271:594-595.
Westoff, C. F. and R. R. Rindfuss. 1974. Sex preselection in the United States: some implications. Science 184:633-636.
Winston, R. M. L. and A. H. Handyside. 1993. New challenges in human in vitro fertilization. Science 260:932-936.