AGING
July 12, 2010

Exceptional Human Longevity

Robert J. Pignolo, M.D., Ph.D.
Who are the oldest old – those 100 years of age and older? And what can these centenarians tell us about aging?
Dr. Pignolo is Assistant Professor and Director, Ralston-Penn Clinic for Osteoporosis & Related Bone Disorders, Department of Medicine, Division of Geriatric Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA.

What do the following groups of people have in common: residents of the island of Okinawa in Japan; Sardinians from Italy; and Seventh Day Adventists in Loma Linda, California? Though they may seem incredibly different, these populations all have life-spans that are considered by experts to be exceptionally long (in some cases, individuals can live to be over 100 years old) compared to most others around the world.

Studying the lives of humans around the world, as well as other species who have varying life spans, helps scientists understand the underlying mechanisms of aging: how it works on a cellular level, why it occurs at all, and what we can do to live healthier and longer lives.

What makes these groups so special and what can we learn from centenarians (people who live into their hundreds) about the aging process? Is it their genes, diets, other lifestyle factors, or is it simply luck – that is, have they been able to somehow dodge the diseases that others have fallen victim to along the way? The answer seems to be a little bit of all the above.

Researchers are very interested in learning from centenarians about what they’re doing right – or what they have done right for the preceding century. Studying the lives of humans around the world, as well as other species who have varying life spans, helps scientists understand the underlying mechanisms of aging: how it works on a cellular level, why it occurs at all, and what we can do to live healthier and longer lives.

Aging vs. Senescence

Whether we’re talking about humans or yeast cells, aging refers to any time-related process that occurs during the life of the organism. This includes processes that have any kind of consequence – good, bad, or neutral – . Although it’s often used interchangeably with aging, the term “senescence” is actually a bit different: it refers only to the deteriorative changes that occur over time after a person or other animal is mature. These changes make the organism more vulnerable to disease, as well as decrease the likelihood of survival.

Rates of Senescence and Primary Aging Processes
Interestingly, not every kind of organism seems to age. There is no strong evidence that bacterial prokaryotes (organisms that do not have a cell nucleus) undergo senescence at all. Some single-celled organisms, like budding yeast, are also considered “immortal”, although individual cells within a given population may have a limited life span if it’s measured by the number of times the cell divides.

In multicellular organisms, like humans, senescence is thought to occur in species where the germ cell line is separate from the body cell lines and in those who give birth to separate (and smaller) offspring or, more specifically, in animals whose body cells differentiate and serve separate functions.

Humans, like all other animals with placentas, experience gradual senescence. This form progresses slowly but persistently after the animals is mature.

Senescence typically falls into one of three categories, depending on the kind of animal we’re talking about: it can be rapid, gradual or negligible. In certain animals like roundworms and flies, rapid senescence occurs suddenly, with deteriorative changes happening soon after the animal has matured; in others organisms, like annual plants and Pacific salmon, it occurs just after the animal reproduces. Negligible senescence occurs in long-lived species like clams, trees, fish and reptiles. In these types of organisms, mortality rates don’t seem to increase after the animal is mature. Humans, like all other animals with placentas, experience gradual senescence. This form progresses slowly but persistently after the animals is mature.

It is important to note that measuring life span in various populations can be tricky, since certain kinds of animals often fall victim to predators, infection, and other environmental factors that can lead to a high “accidental” death rate. . Still, despite these issues, senescence is thought to occur mainly as the result of the primary aging processes – that is, aging in the relative absence of disease or injury.

Ways of Measuring the Life Span
There are a few different ways of describing the life span of a particular population. Mean or average life span is the average age that people in a particular group tend to live to be. Life expectancy, a term most of us are familiar with, is the age a person is expected to live to when he or she is born (or at any age, for that matter), based upon the current mortality rate of the population. For example, the life expectancy for a hypothetical group of 70-year-olds would be based on the current death rate among people age 70, 71 and so on, up to the oldest person in the population. Maximum life span is the age of the oldest survivors of a population; for humans, it is usually considered to be the oldest age reached by one in 100 million people, and an improvement in it is evidence of significantly improved health.

The researchers estimated that over the course of human history, the odds of a woman living from birth to age 100 has risen from 1 in 20 million to 1 in 50 in countries like Japan and Sweden, which are considered to be “low mortality” nations.

Median life span, the age at which there are as many individuals with shorter life spans as there are individuals with longer life spans, and life expectancy are increasing in many populations across the globe. What factors are behind these increases? An important trend is that the number of premature deaths has decreased in recent years, which probably plays a bigger role in longevity than any significant changes to the aging process itself. (Figure 1). Over the last century, there has been a huge decrease in the infant death rate. This has been is due to a number of factors, such as improvements in sanitation, nutrition, and immunization.

Figure 1.
Increase in Average Life Span.
Figure 1

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Increase in average life span (block arrows), but not maximum life span, is the result of protection from premature death.

Median life span and life expectancy are therefore influenced by many factors and are probably not related to primary aging processes. However, in 2008, life expectancy at birth exceeded 80 years in 11 countries around the world. Even more astounding is that in the twentieth century, life expectancy doubled in some developed countries. Although rising life expectancy at birth is not a universal phenomenon, the highest recorded average life expectancy is for Japan, where it continues to rise. In fact, female life expectancy in Japan has risen steadily for the last 160 years at rate of almost 3 months/year. Figure 2 illustrates the average life expectancy in selected developed countries.

Figure 2.
Life Expectancy At Birth (2008).
Figure 2

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Life expectancy at birth in 2008 in five developed countries. Source: U.S. Census Bureau, International Database, assessed on May 27, 2008.

Maximum life span has often been considered a fairly good index of the rate of aging of a population. The maximum life span for any species is usually inversely related to its rate of aging: in other words, the longer a species lives, the slower it tends to age. For example, rats, who have a maximum life span of about five years, are thought to age faster than dogs, whose maximum life span is about 20 years. Any factor that increases the maximum life span of a species is considered to have influenced primary aging processes.

What We Can Learn from Centenarians

That brings us back to centenarians and what their successful aging may tell us about the primary aging processes. One study found that the number of people over one hundred doubled each decade between 1950 and 1990. According to this study, there may be some differences between the sexes in terms of how we age. The researchers estimated that over the course of human history, the odds of a woman living from birth to age 100 has risen from 1 in 20 million to 1 in 50 in countries like Japan and Sweden, which are considered to be “low mortality” nations. About one in every 10,000 people in the United States is at least 100 years old. It is likely that most industrialized countries will soon see similar increases in the number of centenarians, if they have not already.

The maximum human life span is more than 115 years. The oldest recorded ages have been for Jeanne Calment who died at age 121 in France in 1996 and Antonio Todde who died in Sardinia (Italy) in 2002, just two weeks before his 113th birthday. An interesting phenomenon is that although the median length of life and life expectancy for humans have increased greatly over the last 100 years, there has been little, if any, change in the maximum life span. In fact, over long periods of history the maximum human life span has been fairly stable.

Why Some Populations Live Longer

Certain populations of people around the world, like the ones mentioned in the opening of the article, seem to have a leg up on living a long time. Is it just genetics? Researchers have found there seems to be a wide variety of factors behind the longevity of various groups of people.

Factors Among Okinawans
The long-lived Okinawans live by the dietary mantra, “hara haci bu,” or “eat until you are only 80% full.” Their so-called “rainbow diet” consists of a vast array of fruits and vegetables, with most of the protein component of their diets coming from soy rather than from meat or dairy. Perhaps even more important is that the daily calorie intake of the Okinawans is much lower than other populations, which probably accounts for their lower body mass index, or BMI (which tends to be around 20, just on the low side of the normal range).

The long-lived Okinawans live by the dietary mantra, 'hara haci bu,' or 'eat until you are only 80% full.'

The fact that this population tends to have lower BMIs suggests that a modest caloric restriction may be at least partly responsible for their long life spans. More evidence for this idea comes from a recent study of U.S. centenarians born in the 1880s, which found that lean body mass was also associated with extreme longevity. Okinawans also have a slower natural decline of the adrenal hormone dehydroepiandrosterone (DHEA), which is considered a fairly good marker of life span extension; a similar decline in DHEA is also seen in experiments with animals who are put on restricted calorie diets.

Factors Among Sardinians
Compared to men in other locations, men in Sardinia also tend to live long lives. Even Sardinians who emigrated away from the country at 20, 30 or 40 years of age are capable of living extremely long lives. An interesting characteristic of this population, which may help explain their long life spans, is that they appear to be descended from only a few original settlers. Not only this, but they also remained isolated from other populations and practiced interbreeding. Therefore, the origin of the exceptional longevity of Sardinian men may be explained by certain genetic traits that not been completely revealed.

Factors Among Seventh Day Adventists
Seventh Day Adventists, many of whom live in Loma Linda, California, also live 5-10 years longer than fellow citizens of the area. Some of their religious practices may help explain their impressive longevity: some of these practices include no drinking of alcohol or smoking, and many congregants observe the vegetarian diet that the church advises. Spiritual life remains the centerpiece of their daily living. In fact, regular churchgoers of any faith live longer compared to non-churchgoers. Seventh Day Adventists have also been shown to have significantly lower levels of stress hormones, which could contribute to their longevity.

Biomarkers: Helping Determine One’s “Real Age”

True biomarkers of aging, if identified, would help doctors determine a person’s “real” or biological age, and therefore be able to estimate one’s life expectancy. Reliable biomarkers would also make tracking the roles of different factors or “interventions” on the aging process much easier. To be effective, a biomarker of aging would have to include several features. First, a strong, measurable relationship between the biomarker and the age of the population would have to be demonstrated. Second, the biomarker would have to be unaffected by the presence of disease. Third, confidence that an age-related alteration in the parameter is not secondary to metabolic or nutritional changes. (For example, someone who is malnourished can be susceptible to disease and die—this has nothing to do with aging. So a biomarker that changes with nutritional changes is really not a good biomarker for aging.) And finally, factors that influence the rate at which people age would likewise affect the particular biomarker.

The Changes of Age
Most organisms, humans included, display a wide variety of physical and physiological (internal body processes) changes with age. Some of these changes are obviously negative in the sense that they cause the aging person to decline in overall functioning. Some changes may be due to the aging process itself, but they may also be the result of disease, exposure to toxins, the body’s response to injury or other physiological problem, or to some combination of the above. A challenge to researchers who study basic aging is determining which of the many characteristics of aged individuals actually relate to aging per se and therefore make up the primary aging processes.

Although mortality rates for many diseases increase with age, at least one estimate predicts that eliminating heart disease and cancer as causes of death would only add about ten years to the average life span and would probably not affect maximum life span at all.

What actually happens to people as they age? Aside from the obvious increase in mortality rate, which we’ve already discussed, there are some biological changes that are pretty much inevitable as we get older. One is changes to the tissues of the body (seen in the development of wrinkles), which comes from modifications in their biochemical make-up (such as shifts in the structure of collagen, as well as increases in lipofuscin a.k.a the “age pigment,”). Other age-related changes include things like decline in kidney function, the maximum rate at which they heart can pump blood during exercise, and changes in the way the liver metabolizes medications. As a person ages, there is also, of course, an increased risk of developing certain diseases like heart disease, type II diabetes, osteoporosis, and Alzheimer's disease.

Biomarkers Don't Tell The Whole Story
Although these “characteristics” of aging are widespread, there are also exceptions that make using them as biomarkers perhaps not such a good bet. For example, though the mortality rate for humans rises exponentially as one ages, there comes a point, at a very advanced age, where it no longer increases so quickly. Also, some of the changes mentioned above, like changes in tissue composition and in the way the heart responds during exercise, may vary widely between individuals. Not only this, but they can also vary within one person, i.e., from organ to organ. Although mortality rates for many diseases increase with age, at least one estimate predicts that eliminating heart disease and cancer as causes of death would only add about ten years to the average life span and would probably not affect maximum life span at all.



Centenarians Get Diseases, Too – But Often Later Than Most of Us

In centenarians, the age that one is typically struck with common age-related diseases (not including cognitive impairment) was found to vary , with 24% of males and 43% of females attaining at least one diagnosis prior to the age of 80. About 43% of all centenarians experienced delayed onset of age-related disease until they were at least 80 years old. Approximately 30% of male centenarians and 15% of female centenarians escaped any diagnosis by age 100. This suggests that the onset of age-related problems, for both men and women, is fairly variable – but earlier onset of these conditions (prior to the age of 80) does not prevent people from living exceptionally long lives.

As many as 25% of centenarians have normal cognitive function. Among centenarians who do develop cognitive problems, the vast majority of don’t develop problems until they are about 92 on average. There are centenarians who demonstrate no evidence of neurodegenerative disease, and there are some who, despite having some of the markers of Alzheimer’s disease, do not actually meet the criteria for dementia.

Cancer and the Heart
The average age of cancer diagnosis is also significantly delayed in centenarians. Supercentenarians, which is defined as those who live past 110 years of age, delay and even escape diagnosis of vascular disease. Many can still function independently or require only minimal assistance.

One theory, called “compression of morbidity,” tries to explain how just how people with exceptional longevity live longer than regular folk. If people live longer, they would have lower morbidity by “compressing” the number of years they would suffer from chronic diseases and associated disability.

As many as 25% of centenarians have normal cognitive function...There are centenarians who demonstrate no evidence of neurodegenerative disease, and there are some who, despite having some of the markers of Alzheimer’s disease, do not actually meet the criteria for dementia.

There’s actually some evidence to support this hypothesis. Disability has been declining by about 2% per year, and mortality has declined by 1% per year during this same period. With the fastest growing segment of the American population being 85 years and older, however, there is some concern that “compression of morbidity” (and disability) might not hold true for those who survive to exceptional old age. Delaying serious health problems from age-onset diseases occurs in many of those who survive to very old age; for others who survive to extreme old age, delays in disabilities alone seem to be the important factor.

The Genetics Behind Long Life

As mentioned, one component of longevity seems to be purely genetic. This idea is supported by the fact that within a species, life span is fairly consistent, and by the fact that identical twins tend to live to more similar ages than do fraternal twins or non-twin siblings. Likewise, exceptional longevity seems to be a trait that runs within families. Twin studies have shown us that genetic differences likely account for about 25% of the variation in adult human life span. The children of centenarians have increased odds of surviving to 100 years and like their parents have a reduced risk for age-related diseases. Compared to others who lived at the same time and in the same place as the ancestors of Jeanne Calment, she had an extraordinary group of long-lived relatives within her family’s last five generations. This was particularly true of her father’s side of the family, which suggests that she must have inherited some part of her longevity from her (paternal) genes. Other research has shown certain genes and pathways (like the apolipoprotein E gene, insulin/insulin-like growth factor-1, and anti-inflammatory cytokines) have also been linked to the aging process.

For more information, the GenAge database (http://genomics.senescence.info/genes/) gives a complete listing of genes analyzed for their possible association with human longevity http://genomics.senescence.info/genes/longevity.html).

Evolution and Longevity
Does longevity have some evolutionary function or advantage? As mentioned earlier, for many species, the risk of mortality increases after reproduction takes place. Evolutionarily, this may be because there is more pressure for an organism to have genes that boost his or her ability to reproduce during younger years. In other words, genes that help the organism out early on in life – particularly reproductively-speaking – would be favored over the history of evolution, even if they should lead to negative health effects later in life. (We might add that genes that lead to poor health in later life would never be phased out over evolutionary history because they wouldn’t affect an individual’s ability to reproduce) However, genes that reduce health problems in both the young and the old would be more likely to stick around, and could increase both reproductive success and longevity.

Much of the evidence for the evolutionary theory of aging comes from studies of flies and “lower” mammals. In these cases, extended life spans have been brought about by reduced pressure for early reproduction either intentionally (by experimenters in the case of the fly) or naturally (in the case of certain mammals). Similarly, the incredibly long lives of birds and turtles, compared to mammals, is thought to be related to genes that favor reproduction later in life, regardless of whether the animals have many predators or not.

There may be similar evolutionary explanations for humans’ increasing life spans. Some researchers feel that our longer lives may be linked to the increasingly longer periods that women are able to have children. The length of a woman’s post-reproductive life span is mirrored in the reproductive “success” of her own children – and in the survival of her grandchildren, a phenomenon that is known as the “grandmother hypothesis”, and may be more relevant in the case of maternal grandmothers. In a study of centenaries who lived in the U.S in the 1980s, large numbers of children, but not martial status, was associated with long life spans.

“Interventions” in the Aging Process: Can We Slow It Down?

As mentioned in the case of the Okinawans, most likely dietary therapy to slow down many aspects of aging in humans and other mammals is caloric restriction. A 30 to 60 percent reduction of calories can produce extensions of both average and maximum life span (Figure 3).

Figure 3.
Extension of Average and Maximum Life Spans.
Figure 3

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Extension of average and maximum life spans (block arrows) [e.g., by interventions such as caloric restriction] is thought to reflect changes in primary aging processes.

The life-lengthening effect of calorie restriction has been shown in experiments using a variety of species including worms, flies, fish, rodents, and in non-human primates. One study in rhesus monkeys showed that even when their calories were reduced when they were adults, they had fewer incidents of age-related deaths. Even more, the onset of age-related diseases like diabetes, cancer, cardiovascular disease, and neurological disease was delayed in monkeys who ate lower calorie diets. Even short-term studies on calorie restriction in humans have shown encouraging results (for instance, markers of delayed aging like improvements in blood glucose and insulin levels have been reported).

While calorie restriction may seem like an easy means to slow down the aging process (though maybe not the most desirable one), it’s important to note that the degree of caloric restriction that would be needed to achieve a true anti-aging effect is probably too severe to be practical for most of us. Therefore, it’s important for researchers to figure out exactly why calorie restriction works, and how it changes the age-dependent processes that cause functional decline.

There may be other dietary approaches that could extend maximum life span, but more research is still needed to understand how and why they work. One method is a low-methionine diet; methionine is an essential amino acid found in certain seeds, nuts, and meats. The life-lengthening effects of this diet seem to be totally separate from calorie restriction. Dietary supplementation with antioxidants has not yet been shown to significantly change median or maximum life span.

While calorie restriction may seem like an easy means to slow down the aging process (though maybe not the most desirable one), it’s important to note that the degree of caloric restriction that would be needed to achieve a true anti-aging effect is probably too severe to be practical for most of us.

The National Institute of Aging has organized a massive study of pharmaceuticals that have the potential to extend life span in various strains of mice. Of the drugs being tested, aspirin and nordihydroguaiaretic acid, a potent antioxidant, have been found to lead to significantly longer life spans in male mice, while rapamycin (an immunosuppressant drug used to prevent rejection in organ transplantation) leads to an increase in life span in both sexes. Other compounds currently being tested as part of this initiative can be found at http://www.nia.nih.gov/ResearchInformation/ScientificResources/CompoundsInTesting.htm.

Can We Tweak the Genes?
Some studies on mice have suggested that genetic manipulations can have some influence on life span in both mammals and invertebrates. The "Ames dwarf" mutation leads to developmental problems with the pituitary gland when mice receive two copies of the mutant gene. As a result, mice with two copies of the gene have a near-total absence of growth hormone, prolactin, and thyroid-stimulating hormone – they also have a one-third reduction in normal body weight. These mice can have up to a 68% increase in life span, depending on sex. Another mouse mutation, the "Snell dwarf" mutant, leads to low levels of growth hormone, a very small body size, and dramatic life span extension. Long-lived strains of fruit flies and round worms have been bred in the laboratory as well. Length of life has been increased in round worms and yeast cells by specific mutations in single genes, and fruit flies’ lives can be lengthened when they are made to overexpress two enzymes, superoxide dismutase and catalase. It is unclear how these genetic changes actually relate to human longevity.

Other changes like reduction in body temperature and increasing exercise have also been shown to affect life span. As examples, a low body temperature increases life span in many animals whose body temperatures change along with the environment (like certain lizards) and voluntary exercise in rats increases average life span. Habitual exercise does increase healthy life span in humans but whether it also extends the maximum length of life remains up for debate..

Summary

Centenarians are a rare breed: they are survivors, who escaped infant mortality, infectious illnesses in the pre-antibiotic era, as well as fatal outcomes of common age-related diseases. They exhibit an impressive delay of the onset of age-related illnesses – or they escape manage to survive that the diseases that typically cause mortality in other people at earlier ages. The mechanisms of extreme long life appear to be varied, (Figure 4), and can be accomplished by different combinations of genes, environment and chance that vary with culture and geography. It will be interesting, in coming years, to follow researchers as they continue to uncover just how we age – and perhaps understand the secrets of centenarians – and determine just what we may be able to do to live longer, healthier lives.

Figure 4.
Multiple Pathways To Exceptional Longevity.
Figure 4

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Multiple pathways to exceptional longevity are possible. Interactions among pro-longevity factors are shown by arrows. Solid lines indicate currently non-modifiable factors; dashed lines indicate modifiable factors.

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