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A Look at Centenarians…
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Older Mothers Live Longer
Reviewing the pedigrees of our centenarian subjects, we noted one female subject who apparently had a child at the age of 52 years. While this initially startled us, we realized that a history of older maternal age among our centenarian subjects would make sense since having a child at an older age (naturally, without technological assistance with fertility) would reflect a reproductive system that was aging relatively slowly and an absence of age-related diseases that would adversely impact upon fertility. These qualities in turn would bode well for the ability to achieve exceptional longevity. Based upon the data we collected, we concluded that if you are a woman who naturally had a child in her forties, you are four times more likely to become a centenarian compared to women who did not have children after the age of forty. It is important to note that we believe that it is not the act of having a child in your forties that promotes long life, but rather that having a child late in life is an indicator that the woman’s reproductive system is aging slowly. A slow rate of aging would therefore predict the woman’s subsequent ability to achieve very old age.
Male Centenarians Fare Better
Although men make up a small proportion of centenarians, they tend to be better off than their female counterparts in terms of both physical and cognitive function. At first, this seems paradoxical because so many more women achieve extreme old age. One explanation may be that compared with women, men must be in particularly good condition to achieve extreme old age. Women, on the other hand, seem to be physiologically stronger in old age and more likely than men to be able to live with chronic illnesses and disabilities. These observations may indicate a demographic crossover in which women are better off than men in younger old age and men, although fewer in number, are functionally better off in extreme old age.
The underlying reasons that women generally live longer than men and, at least before menopause, are significantly less likely to develop heart disease and stroke are unclear. Estrogen, which has been suggested to be a powerful antioxidant, has been implicated as an important reason. Another possible reason is that women, because of menses, are more iron deficient than men for a 30- to 40-year period. Iron is a critical catalyst in mitochondrial production of free radicals as a byproduct of metabolism; perhaps a reduction in available iron leads to less free-radical production. For example, iron deficiency has been associated with significant reductions in levels of oxidized low-density lipoprotein cholesterol, an essential component of atherosclerotic plaque production.
Winning the Lottery
Recently we studied 444 centenarian pedigrees containing 2,092 siblings and compared their survival experience with that of the general population born around the same time in 1900. From young adulthood all the way into very old age, the centenarians and their siblings maintained, from year to year, half the mortality rate of their peers. That year to year survival advantage eventually translated into the siblings of centenarians having a tremendous overall survival advantage in living to 100 years. The male siblings ended up having a 17 times greater probability and the female siblings an 8 times greater probability of living to 100 compared to the general public born around the same time.
We suspect that the ability to live to 100 results from getting a combination of factors correct. These factors, such as specific genetic traits or lack or presence of certain health related behaviors need not be rare; in fact, they might be quite common. However, like the lottery, it is getting the right combination of these factors and behaviors that becomes the rare event. It further makes sense that the actual factors and the correct combination of those factors likely varies significantly from one person to the next. Furthermore, some factors such as lacking a genetic predisposition to early heart disease or smoking tobacco are likely more potent and ubiquitously important than others.
Genes Predisposing to Exceptional Longevity
The discovery of genetic variations that explain even 5% to 10% of the variation in survival to extreme old age could yield important clues about the cellular and biochemical mechanisms that affect basic mechanisms of aging and susceptibility to age-associated diseases. Until recently, only one genetic variation had been repeatedly shown to be associated with exceptional longevity, but even that finding may vary according to ethnicity and other factors. Francois Schachter and colleagues noted that a variation of apolipoprotein E, called ƒ, becomes markedly less frequent with advancing age. This variation is well known for its association with heart disease and Alzheimer’s disease and thus it makes sense that it would be found less frequently among centenarians.
Since then, several other genes playing roles primarily in cardiovascular disease (microsomal transferase protein and cholesteryl ester transfer protein) have emerged as being important to achieving exceptional longevity. It should not be a surprise that factors related to cardiovascular disease figure so prominently. Heart attacks and congestive heart failure are the number one killer of older people in industrialized countries.
There are likely two types of genes influencing longevity. One is the type that has already been discovered; that is, “disease genes” that have variations that make it more likely for a person to develop a specific disease. Centenarians are more likely to lack such variations. The other type of gene, as of yet not discovered has been called a “longevity enabling gene.” Such genes would influence aging at its most basic levels, thus affecting the rate of aging and how it increases a person¡¦s susceptibility to age-related diseases.
Discovering genes that could impart the ability to live to old age while compressing the period of disability toward the end of life yields important insight into how the aging process increases susceptibility to diseases associated with aging and how this susceptibility might be modulated. The hope, of course, is that these gene discoveries will help identify drug targets and create drugs that would allow persons to become more centenarian-like by maximizing the period of their lives spent in good health.
