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.
© USA Copyrighted 2015 Mario D. Garrett
Further Readings
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