iAge: March 2015

Friday, March 27, 2015

Life Expectancy

Life expectancy is akin to the median rather than an average age of death. The median is a statistic, that defines when half a given population is expected to die before that age, and the other half will survive beyond that period. In physics it is close to the half-life of elements. This statistic is not an average (mean), it is a-mid point. Most confuse life expectancy with the average age of death. But it is best described as a mid-point. Gerontologists use life expectancy to define aging of populations. But there are nuances—both statistical and biological—that heed caution about interpreting historical life expectancy data. The problem is that life expectancy is equated with lifespan, and the two are not related.

In 2002, Jim Oeppen and James Vaupel from the Max Planck Institute for Demographic Research showed that life expectancy in some of the world’s developed countries (and Chile) has been increasing steadily by about 2.5 years per decade since the mid-19th century. Although they leave out contradictory evidence from across the world, including a large country like Russia—this argument that life expectancy is constantly improving also ignores latest life expectancy figures from the USA. For Blacks/African Americans in the United States life expectancy is declining. Despite these realities, there is no denying that long-term stable decline in mortality suggests a continued rise in life expectancy. The dispute is not with life expectancy but with lifespan.

Source: Luke Pamer/https://unsplash.com/

Although life expectancy in some selected countries is increasing—and it has been for some years after the second world war—this does not mean that such increases are linear or that the end point has moved—lifespan has remained static. Even though there will be more centenarians both in terms of numbers—prevalence, because we have a larger population—but also in terms of percentage—incidence, because of improved public health—centenarians are exceptional beings. The reality is that human biology will preclude survival to age 100 for most people. Even for those that live to 100, the likelihood that they survive to become supercentenarians (110 years old) is 1 in 6 million. As Fanny Janssen and his colleagues in the Netherlands reported, at some point there will be a wall. A wall that is both biological and psychological.

Studies that show continuing increases in life expectancy cannot be used to argue that there is no lifespan, or that the lifespan can be increased. Life expectancy is an aggregate statistic. In the case where life-expectancy increases and the maximum number of years that you can live remains the same, means that more people reach the end, but they still reach an end. Although life-expectancy algorithm is different from median, and can reflect outliers, changes in life expectancy just tells us that more people are living longer but not to what age. In reality life-expectancy is still an estimate based on earlier survival probabilities. This is the reason it is used in gerontology because it provides an indication of the average person and ignores those exceptional people that live up to and beyond 100 years of age—1 per 25,000—and those who die in infancy—6.15 per 1,000. Especially in the past when there was a high rate of child mortality and very low rate of centenarians, life expectancy was a good estimate. Nowadays it is not. A more appropriate statistics is the modal age of death--the most common age at which people die. What we find is that through time, life expectancy and modal age are converging.

That is just what Juliana da Silva Antero-Jacquemi from the Institute of Biomedical and Epidemiology Research in Sport, France, and her colleagues used. They analyzed 19,012 Olympian competitors and 1,205 supercentenarians—who lived up to 110 years—that died between 1900 and 2013. Although most Olympians had longer life expectancy than most general population, they did not live as long as supercentenarians. However, what they identified is that there was a common death trend between Olympians and centenarians—indicating a similar mortality pressures over both populations that increase with age. The authors argue that mortality trend is better explained by a biological “barrier” model—that there is a static lifespan.

The issue of whether there are limits to life expectancy—a lifespan—received theoretical backing from demographers who argue that fundamental limits to life expectancy are likely. And that this is similarly to be determined, in part, if not on the whole, by our genes which drives an intense search for longevity genes in both animal models and humans. Human family studies have indicated that a modest amount of the overall variation in adult lifespan (approximately 20–30%) is accounted for by genetic factors. Genetic influences on lifespan are minimal prior to age 60 but increase thereafter. Although these studies look at monozygotic twins—identical twins—there might be other confounding factors.

There is a problem with estimating age at very old age. In 1986, given continued reports of claims of extreme age, Norris and Ross McWhirter, the editors of the Guinness Book of World Records, noted the need to validate such assertions when they repeatedly stated that there is no single subject is more obscured by obfuscation than the extremes of human longevity. And the inaccuracy increases with the older the person is reported to be. Stephen Coles reports how the U.S. Census Bureau dropped its estimate of centenarians from 2,700 in 1990 to 1,400 centenarians in 2000 after checking the dates of birth with the claimed ages at the Social Security Administration. However, even this conservative number was found to be inflated as there were only 139 persons aged 110 or older. And then, even this number is likely to be exaggerated since the true number, based on physician uncertainty about their age, is more likely to be between 75 and 100 persons.

One of the classic example of such uncertainty occurred in the 1973 issue of National Geographic when Alexander Leaf gave a detailed account of his journeys to regions of purported long-living people: the Hunzas in Pakistan, the Abkhazians in the Soviet Union, and Ecuadorians in Vilcabamba. According to this article, there were ten times more centenarians in these countries than in most Western countries despite poor sanitation, prevalence of infectious diseases, high infant mortality, illiteracy, and a lack of modern medical care. Unfortunately in 2009, a fantastic age claim by Sakhan Dosova of Kazakhstan, age “130 years” was supported in an issue of Scientific American, despite the lack of early-life documentation.

These inaccuracies in reporting extreme long age have received a lot of attention from demographers. Eventually a resurgence of longevity myths in the 1970s were finally debunked which lead to Alexander Leaf himself acknowledging that people lied to him in order for them to improve their social status and to promote local tourism. More recently demographers have become increasingly concerned with the accuracy of unprecedented growth of extreme longevity in developed countries. As a consequence more careful checks are being implemented which has resulted in a systematic refutation of numerous cases of extreme age since they appeared to be undocumented or exaggerated. One such example was when in 1999, Sardinian data was presented showing extreme male longevity. This pushed demographers to assess the validity of the data and lead to the development of a robust methodology for asserting the true age of participants.

Life expectancy vs. Lifespan

One of the most persuasive arguments that lifespan is separate from life expectancy is that even if we eliminate most diseases associated with age, we will still die. Of course, we can only do this statistically. Kenneth Manton and his colleagues from Duke University eliminated one disease at a time in their statistical modeling. What they found is that if we eliminate all of age-related diseases we expect to see those over 87 years of age to live an addition 5.7 years for males (estimated for 1987) and 6.5 years for females. This is about the same improvement in life expectancy at 65 in the last 100 years in the USA (5.7 years.) If you are 65 years old today, you have a 50/50 chance of living an additional 5.7 years than if you were living in the 1900s. In the last hundred years, the great improvement in life expectancy is not amongst older adults, but among newborns and infants and have very little to do with clinical care at later ages. Statistically, as we have shown before, if we live longer than the life expectancy, the statistic of life expectancy at birth will not change, and life expectancy at other ages will only improve slightly.

Most older adults suffer from not just one, but multiple, health conditions. So if we conjecture that we can cure one disease, say cancer, we will still be faced—sooner rather than later—with another disabling disease that might kill us slower. Douglas Manuel with the Institute for Clinical Evaluative Sciences, Toronto, Canada, and his colleagues calculated what happens when they eliminated specific killer diseases from their data. They reported that by eliminating cancer they predicted that one ﬁfth of the years of life gained would be spent in poor health—and increased cost. On the other hand, eliminating musculoskeletal conditions, would result in a year of good health for women and under half a year for men. And that is what we are finding across the world. Even if we eliminated all diseases we might improve the life expectancy but not lifespan. Life expectancy and lifespan, despite their close association are separate statistical and theoretical constructs.

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Note: Life expectancy is a statistical formula to enumerate the average life left. Although it is different from median, the two are in reality very similar and produce very similar results. It is much easier to see life expectancy as a median, a mid-point because it illustrates how we can have an increase in life-expectancy and yet our maximum life that we can attain remains static.

Genetics of Longevity

The most persuasive argument for the genetic influence on lifespan is the different lifespan of species. The best explanation we have of this absolute and static lifespan is the concept of the Hayflick Limit—a genetic program that kills cells. In 1961—going against the thinking at the time—biologists Leonard Hayflick and Paul Moorhead noticed that their cell cultures were dying after replicating (mitosis) a certain number of times. But during this period Alex Carrel—a Nobel Prize winner in surgery—held the thinking that cells are naturally immortal. We do bad things to them to them. Taking a direct leaf from the biblical story of Adam and Eve, we are held responsible for our own mortality. In contrast, Hayflick demonstrated that normal human fibroblasts cells divide about 70 times in 3 percent oxygen—which is the same as human internal conditions—before stopping replicating. This stopping of replication has become the Hayflick Limit. Refuting the idea that normal cells are immortal and establishing a biological basis for lifespan—the Hayflick Limit has established itself as the primary theory of what determines human lifespan.

The mechanism was not yet known at the time of this observation. But in 1971, a Russian scientist Alexey Olovnikov, hypothesized the involvement of the end caps of the DNA that controlled this Hayflick Limit. Elizabeth Blackburn and Carol Greider—who won the Nobel Prize in Biology for their studies—later confirmed this in 1984. They found evidence of proteins called telomeres at the end of the DNA which get shorter with every division (mitosis) until they get too short to allow for more replication. This telomeric theory identifies the mechanism of how the Hayflick Limit exists.

Although this is an eloquent theory, there is large variance in correlating telomere length with aging and with lifespan. Firstly, telomeres are not proportional to longevity. There are three main arguments against using telomeres as the sole explanation of lifespan. Nuno Gomez from the University of Texas Southwestern Medical Center and his colleagues, undertook the largest comparative study involving over 60 mammalian species, and they reported that telomere length inversely correlates with lifespan. They also found that while telomerase—an enzyme that promotes the re-growth of telomeres—correlates with size of the species. The larger the species, the more telomerase, and therefore there is more maintenance of telomeres. In addition, it seems that telomeres do not provide a complete understanding of lifespan. The second argument against the telomeric theory of lifespan comes from the Italian biologist Giuseppina Tesco and her colleagues in 1998—refuting earlier studies—found that fibroblast taken from centenarians showed no difference in the number of replications compared to cells from younger donors. It could be that within the body, cells can be replaced with new ones—rather than simply renewed.

Adult stem cells have been identified In many organs and tissues of older adults, including brain, bone marrow, peripheral blood, teeth, heart, gut, liver, blood vessels, skeletal muscle, skin, ovarian epithelium, and testis. They are thought to reside in a “stem cell niche" which is a specific area within each tissue. We all have these and yet some of us seem to use them up quicker, perhaps we started with fewer stem cells, or perhaps theenvironment that we live in degraded them faster. Older adults are more likely to have used up their supply of stem cell or experienced more stressors that damaged their stem cells. Once stem cells run out or become disabled, they cannot be replaced by the body. So there is also a limit for the utility of our endowed stem cells. The third argument comes from Leonard Hayflick himself, who observed that assuming human fibroblasts endure 70 divisions, there are more than enough cells for several lifetimes. So although the Hayflick Limit predicts that there has to be a lifespan—an upper limit to longevity—the evidence suggests that that limit could not have yet been achieved.

Aside from the genetic explanations of lifespan there is also the observable reality of demography—the study of changes and patterns in population. An earlier theoretical observation made by a British actuary Benjamin Gompertz was published in 1825. He observed a law of geometric progression in death rates as we grow older. The insight was a mathematical formulae which has the probability of dying doubling about every 7 or 8 years following puberty. This is known as the Gompertz curve and is constant in all observations of human (and most other species) mortality. The only modification to this curve is that it is shifting to the right allowing later—delayed—death mortality. This has been predicted through the rectangularization of this curve. While the decline at the end of life has been termed as the entropy in the life table. This theory argues that the Gompertz curve will be pushed up but that the lifespan will remain virtually unchanged, making a rectangular path. Under such a scenario, most people will live up to a maximum lifespan and then die. Until then, the life expectancy will increase but the age of death will remain virtually static and always below 122.

Some geneticists argue that we have not achieved the theoretical lifespan. As a consequence these scientists claim that we can increase the lifespan. There are many studies in this area but three act as seminal archetypes of the type of work being conducted.

The first type is a classic experiment by Michael Rose who began manipulating the life spans of fruit flies by allowing them to reproduce only at late ages. This forced researchers to pay attention to the survival and reproductive vigor of the flies through their middle age. The subsequent progeny of flies evolved longer life spans and greater reproduction over the next dozen generations.

The second type of experiment uses examples from nature, which they then emulated in the laboratory and involved growth hormones. At U.C San Francisco Cynthia Kenyon chemically knocked out certain genes in flatworms, the gene daf-2 which partially disables receptors that are sensitive to two hormones – insulin and a growth hormone called IGF-1. This mutation—which was original seen in nature and then replicated in the laboratory—nearly doubled the flatworms’ lifespan. These long-lived worms looked and acted younger than their control group, implying that extending the lifespan also extends healthy life.

Then there is the genetic observation with mice, in particular the work done by Richard Miller, and his infamous mouse called Yoda (who is now deceased.) Like other dwarf mice, Yoda had a natural genetic mutation that obstructs the production of growth and thyroid hormones. Dwarf mice tend to grow to only about a third the size of normal mice, which helps them live about 40 percent longer. There are three types of mice that share this longevity characteristic. The Snell and Ames dwarf mice have been bred to inherit mutations in Pit-1 and Prop1 genes, respectively, which disrupt the embryonic development of the pituitary gland. While the Laron dwarf mouse has a targeted gene deletion of either the growth hormone receptor (GHR-KO) or the growth hormone binding protein (GHBP-KO). So even though this mouse produces growth hormone, it is still growth-restricted because it is unable to respond to the hormone. The common denominator in all these mice is that they have stunted growth which correlates with increased lifespan.

Increasing the lifespan in all cases of genetic studies—manipulation or observation—is related to stunted growth or late life progeny. It has been argued that this delayed growth stamps an expiration date onto our genes. If we are stunted in growth or our parents delayed producing us, then our body seems to know that it needs to live longer in order to pass on its genes. There are two complementary theories that explain these observations.

The theory of Antagonistic Pleiotropy argues that some genes have contradictory effects at different age. Genes which might enhance your reproductive success—genes that increase testosterone in men, resulting in more muscle mass and masculine secondary sexual characteristics—may at the same time have detrimental effects on survival later in life—in testosterone example elevated risk of cancer. Natural selection tends to favor these kinds of genes because they maximize fitness, as higher mortality in the post-reproduction stage will have little impact on fitness compared to increased number of offspring. The second theory is the Disposable Soma Theory. This theory states that—given that there are finite resources to maintain and repair cells and organs, the body does a balancing act—the body protects itself just long enough so that we are able to pass on our genes. A similar argument is made by Leonard Hayflick to distinguish age related changes from lifespan who argues that longevity—whish is distinct from age changes—is indirectly determined by the genome.

Another area of research that compliments the genetic work on life span is the burgeoning research on Caloric Restriction (CR). Initially discovered in 1935 in mice, CR has been shown to increase the lifespan in yeast, insect, and in non-human primates. In humans CR is still undergoing testing, although initial results suggest prolongation of life as well as prevention of age-related are likely outcomes. The mechanism seems to emulate the genetic work of life prolongation, in that the CR elicits a hormesis event—a low level stressor that stimulates positive response where epigenetic switches are triggered.

As with all genetic work there are many confounders. From the genotype to the phenotype and then there is the environment. Even if we accept that stunted growth might improve lifespan, other factors might negate such gains. And that is the case with a southern Ecuador group where more than 250 individuals are thought to have Laron syndrome—IGF-1 deficiency in primary growth hormone—which is caused by a mutation in the growth hormone receptor gene with affected individuals growing to less than 4 feet tall. Although Laron patients appear to be protected against developing cancer. However, this apparent protection does not translate to a longer lifespan due to trauma and alcoholism. There is a schism between lifespan and theoretical lifespan…human behavior.

Lifespan

Lifespan is described by The Oxford English dictionary as “The length of time for which a person or animal lives or a thing functions.” Pragmatically, lifespan is defined as the period that the longest living member of a species has lived. Sometimes lifespan—or Maximum Lifespan—is used to refer to the longest period of time that a member of a species can live to. Scientists have not yet determined what the maximum length of time a human can live up to. This is an active theoretical field, and is home to lively speculation among some gerontologists. When it comes to humans, the oldest person that has ever lived defines lifespan. Verified by the Guinness World Records and the Gerontology Research Group, Jeanne Louise Calment, a French woman from Arles, lived to 122 years and 164 days. This lifespan remains the definition of human lifespan since her death in 1997.
In this regard, lifespan is an outlier—an extreme case of longevity. It is different from longevity, mean life span, average life span, life expectancy, individual lifespan, average age of death, average life expectancy and median age of death.
After the second World War, Max Klieber, a Swiss agricultural chemist, predicted that mass determines metabolism, and metabolism determines longevity. Larger animals tend to live longer. This theory has been elaborated in 2000 when a study that looked at nearly 4,100 longevity records of the highest documented age for a variety of fish, reptile, amphibian, bird, and mammalian species that included humans. There were four primary findings. First, longevity is positively correlated with body size between orders (e.g. the smaller rodents are shorter lived than the larger cetaceans) though not necessarily within orders—a biological grouping. As an example, longevity is not correlated with body size among seals and walruses. Second, animals that fly (i.e. birds and bats), or armored (turtles; armadillos) or live underground (moles; mole rats) tend to live longer than is predicted from body size alone. Third, there is great variance within species, so that lifespans vary by a factor of over 50 in mammals, herps and fish; and by over 15-fold in birds. Body size, metabolic rate, brain size all positively correlated with life span. Fourth, primates are long-lived mammals, the great apes (i.e. gorillas; chimpanzees) are long lived primates, and humans are extraordinarily long-lived great apes; human longevity exceeds nearly all other species both relatively and absolutely.
There is something uniquely human about great longevity, although it is not an exclusive characteristic of humans.
There are still some species that we have not yet observed a lifespan for. There are other species for whom we have not been able to observe mortality and therefore we do not have a lifespan for. There is a small jellyfish called turritopsis nutricula, that seems to regenerate itself from an adult back to an adolescent. A constant process of metamorphosis. These are also species that exhibit minimal aging. Kleiber’s Law was complicated by the work of Caleb Finch from the University of Southern California who—while researching aging among animals—found insignificant aging among rougheye rockfish (who can live up to 205 years), sturgeon (150 years for females), giant tortoise (152 years), bivalves and possibly lobsters. These included no observable age-related increases in mortality rate or decreases in reproduction rate after maturity, and no observable age-related decline in physiological capacity or disease resistance. Finch coined the term "negligible senescence" to describe very slow aging.
There have been three primary approaches to the study of lifespan; Genetic, Biological, and demographic using life expectancy and age of death. However, a new twist to lifespan studies emerged in a 2012 study by Kyung-Jin Min from the Inha University, and his Korean colleagues. These authors reported that during Chosun Dynasty between 14th to early 20th centuries Korean eunuchs lived 14 to 19 years longer than other (intact) men. Researchers were able to identify 81 eunuchs, who were castrated as boys, and determined that they lived to an average age of 70, significantly longer than other men of similar social status. Three of the eunuchs lived to 100. This is a centenarian rate that's far higher than would be expected today (one in 25,000.) Historically, but as recent as the 19th century, eunuchs were common across the world. Castrati boys—castrated beforepuberty—were among the most prized singers especially in catholic churches in Italy—the Sistine Chapel retained the last of the castrati singers—and Opera houses in Vienna. Elsewhere eunuchs were hired staff in harems and imperial palaces in Africa, China, Korea, Japan, and the rest of Asia and the Middle East. As well as in Europe and Russia.
In the 18th century there was a Christian sect called the Skoptzy, also known as the White Doves, whose male members—in order to attain their ideal of sanctity—subjected themselves to castration. They believed that the Messiah would not come until the Skoptsy numbered 144,000 (Rev. 14:1,4). Further East, in China, eunuchs played a more central role in government. Although in this context, castration was mostly apunishment, some subjected themselves to the procedure in order to gain employment. At the same time, during the Ottoman period, especially from the 16th century on, black eunuchs from Ethiopia or Sudan were in charge of the harem in the Ottoman court. Many of these boys were castrated at a monastery in Upper Egypt by Coptic priests. The practice was pervasive and endemic.
But the first time that eunuchs featured in longevity debates was with the observation by Serge Abrahamovitch Voronoff in the early 1900s. And it was not a positive observation. Voronoff—a French surgeon of Russian descent—worked at a hospital in Cairo from 1896 to 1910 where he had the opportunity to observe eunuchs. He noted their obesity, lack of body hair, and broad pelvises, as well as their flaccid muscles, lethargic movements, memory problems, and lowered intelligence. He concluded that the absence of testicles was responsible for aging and that their presence should prompt bone, muscle, nerve, and psychological development. He saw aging as the result of the lack of substance from the testicles and ovaries. This is all before we knew abouthormones. Voronoff gained fame for his technique of grafting monkey testicle tissue on to the scrotum of men to increase the lifespan. Voronoff and his predecessor and mentor Charles-Édouard Brown-Séquard—although ridiculed at the time—developed the field of endocrinology, the study of hormones. Voronoff observations was that castration had retarding effects. In 1999 Jean Wilson and Claus Roehrborn investigated the long-term effects of castration and concluded enlargement of the pituitary gland and decreased bone mineral density. There were also some reported growth of breasts in the Ottoman court eunuchs, which is also evident in photographs of Skoptzy men and Chinese eunuchs. Shrinkage of the prostate was common among eunuchs. However the authors could not resolve whether lifespan differed in their study. Such a study was done earlier in 1969, by James Hamilton and Gordon Mestler from the Department of Anatomy, State University of New York College of Medicine. In the turn of the 1900 it was common practice to castrate cognitively challenged children, a practice encouraged by the strong eugenics movement at that time. The study looked at mortality of patients in a mental institution with a population of 735 intact White males, 883 intact White females, and 297 White eunuchs. They reported that survival was significantly better in eunuchs than in intact males and females. This survival advantage started at age 25 years and continued throughout their life. The life expectancy for eunuchs was 69.3 years compared to 55.7 years in intact males. Males castrated at 8-14 years of age—before sexual maturation—were longer lived than males castrated at 20-39 years of age—after sexual maturation. Castration reduced the age of death by 0.28 years for every year of castration from age 39 and younger.
There are many changes that happen as a result of castration. The world was very different 600 years or even 100 years ago. In most cases it was a very violent world where men suffered early mortality through wars, famine, and petty violence. Eunuchs, because of their demeanor might have escaped that onslaught of violence. They might also have had more nurturing qualities that extended to looking after themselves better. We will never know.
What we observe in science tells us a very different story. Pragmatically we know that sex, and the activity surrounding sex, increases longevity. Howard Friedman in the Longevity Project longitudinal study provided our first glimpse into female orgasms and longevity. The study which was begun in 1921 by Lewis Terman of Stanford University, California looked at 1548 children with high intelligence born around 1910. Now in their nineties, the study morphed into a gerontological study. One of the interesting and pertinent findings was that women who had a higher frequency of orgasm tended to live longer than their less fulfilled sisters. No data on men was collected from this study. But a separate study in in the town of Caerphilly in south Wales, England, provided evidence for males as well. George Davey Smith from Department of Social Medicine, University of Bristol,, England, and his colleagues interviewed nearly 1,000 men about their sexual frequency, then followed up on their death records ten years later. The results determined that men who had two or more orgasms a week had died at a rate half that of the men who had orgasms less than once a month. And importantly there was a dose effect, where the more times these men had orgasms the longer they lived. These observations have been replicated in Sweden and in the USA for both male and female.

The most conclusive evidence on what promotes lifespan however comes from the masters of longevity themselves—centenarians. In the Blue Zones the cluster of centenarians teach us about the pragmatisms of living longer and sexual activity is a significant part of their life.

© USA Copyrighted 2015 Mario D. Garrett