Recent trends in Geriatrics and Gerontological Studies - State Level Conference

Meiosis

Sex cells have only one copy of the chromosomes so that when a sperm and egg cell are united the resulting cell and subsequent cells have a normal complement of two sets of chromosomes. In order to do this half of the genetic material is not used during the creation of a sperm or egg cell. This process called meiosis and other aspects of sexual reproduction are extremely complicated as will be summarized below. The purpose of this section is to demonstrate the enormous difficulty nature has endured in order to produce the maximum possible variation in organisms. These extremely complex evolved mechanisms further validate Darwin's theory of natural selection by means of natural variation and also lend credibility to adaptive theories of ageing. Darwin speaks of such aspects of evolution of humans in his later book ‘Descent of Man' (1871). Use of human data in an attempt to prove or disprove theories based on natural selection is therefore highly suspect although commonly done. Animals have special X and Y chromosomes to help manage sexual reproduction. Female humans have two X chromosomes (which are paired and swapped during meiosis like other chromosomes). Males have an X and a Y chromosome. Therefore, progeny always inherit an X chromosome from their female parent and have a 50 percent chance of being either male or female. In humans, the X chromosome is larger and has more genes than the Y chromosome. The gene that triggers “maleness” is on the Y chromosome. One aspect of this arrangement puzzling to geneticists was how females avoid having something like Down's syndrome. Since females have two copies of chromosome X and males only have one copy, females would appear to have 100 % more of some gene products than males (or males have 50% less than females). I know that at this point, some men and women readers will be saying “that explains a lot about women and men respectively. Eventually, it was determined that in females only one of their two X chromosomes is randomly “inactivated” such that, functionally, females only have one X chromosome. X inactivation is another in a long list of evolved complexities associated with sexual reproduction. At least in higher animals, a process similar to X activation inactivates certain genes as development proceeds. As stem cells differentiate into more specialized cells, some genes are marked as inactivated (genetic imprinting) which partly enables the capability for structural and functional differences in different body cells. The inactivation is removes during meiosis and also when cloning animals from differentiated cells such as skin cells. Due to the large differences in genome organization between similar species (e.g. mammals) it is clear that the organization of the genome evolves. This evolution must necessarily be extremely “incremental” (more “tiny steps”) in order to maintain the ability of individual members to interbreed. This entire scenario appears to be incompatible with classical Darwinism as follows. Darwin 's theory holds that mutations that are adverse decrease its fitness. Mutations with positive or minor fitness impact can eventually become widely distributed in a species gene pool. In the above discussion, we have identified a whole family of different types of mutational changes which have no immediate fitness effect but which plausibly benefit or detract from the ability of the organism to subsequently adapt through by reducing or increasing the probability that certain types of subsequent mutation can occur and also altering the probability that certain genes will be inherited in conjunction with specific other genes. In effect, these mutations affect the future of the organism in terms of the descendent species it might produce or the “evolution of its species”. Although such mutations, either beneficial or adverse, could (since they are fitness neutral), spread through the population of a species and could be transmitted to any descendent species, they cannot spread to co-existing species. This suggests that “survival of the species”, that is, species that produce descendent species or which “evolve”, as opposed to becoming static or extinct could play a much more important role relative to “survival of the fittest individual” than contemplated by classical Darwinism. In addition, speciation, per se, is substantially the result of non-fitness mutation changes and itself obviously plays an important role in evolution.” Evolution of the genome” tends to support modifications and adjustments to classical Darwinism such as the selfish gene theory and evolvability theory.

The purpose is to illustrate the complexity that has appeared as we discovered more about the mechanisms whereby evolution of genetic codes actually occurs. Darwin 's analog world is very simple when compared to the digital reality. Breeding experiments and heredity studies are generally confined to exploring variation and natural selection. Variation and natural selection are essentially the easily observable “tip of the iceberg” regarding the mechanics of genetic code evolution. The time scales of these different processes differ enormously. The selection of a trait that was represented in variations could take a relatively few generations. Other traits, produced or affected by non-variable parts of the genome code could be conserved for millions or billions of years. Details of the mechanics of the third, fourth and fifth processes could explain why Darwin 's theory does not work for ageing and other troublesome animal characteristics. Specifically, it appears that evolution could involve much longer times and more complex processes than contemplated by orthodox Darwinism and that therefore the importance of “individual” fitness could be less than considered by Darwin . At the same time, knowledge of these complex processes supports Darwin 's determination that sudden massive mutations were unlikely to have a significant role in evolution.

The Selfish gene theory of evolution: Darwin 's theory proposes survival and to a lesser extent, reproductive capacity as the factors driving evolution. However, Darwin makes it clear that the way these factors work is to increase the probability that an organism's genes will be propagated to a larger number of future organisms. We could therefore simplify and restate Darwin 's theory to read that any characteristic can be evolved that aids an organism in propagating its genes. Richard Dawkins developed and popularized this approach in his book The Selfish gene (1976). Dawkins wrote this book at least partly in order to debunk group selection theory by showing that troublesome evolved traits such as altruism could be explained more or less within Darwin 's theory (“neo-Darwinism”) without invoking group selection. In Dawkins' view, it is the genes that are actually competing and struggling for survival. Individual organisms only live for momentary periods genes “live” for millions or even billions of years. Animals and humans are “survival machines” whose purpose is to propagate genes and whose every characteristic is evolved to propagate their underlying genes. You will recall that altruism involves an animal protecting or otherwise helping an unrelated animal. Although an animal protecting its mate or progeny does not help the animal itself to survive or reproduce, most people would agree that such behavior helps the animal propagate its genes by increasing the probability that the animal's own progeny will survive. The tradeoff is between the increased survival risk to the parent (bad) and the decreased survival risk of the progeny (good). Such behavior is not really “altruism”. What happens if an animal protects progeny of another animal, maybe a niece or nephew as has been observed? Now it is risking its own life, probably the lives of its own progeny that would not survive without their parent and the possibility of subsequent progeny of its own, but there does not appear to be any compensating benefit in a strictly Darwinian sense.

Effects of Ageing

One of the main objections to adaptive theories of ageing is the relatively insignificant effect ageing has on fitness because of the alleged “declining fitness effect of adverse events with age”. Some traditional biologists dismiss adaptive theories for this reason. However, the traditional view of the effect of ageing on fitness is overly simplified. In the following sections we shall see how characteristics of actual animals greatly increase the impact of ageing on animal populations. In the wild, animals die mainly of predator attack, warfare and their inability to obtain food, disease and environmental conditions. Ageing causes weakness, reduced agility and mobility, increased susceptibility to adverse environmental conditions, deterioration of senses and reduced reproductive effectiveness. It is therefore clear that , in wild populations, well prior to the occurrence of “programmed death”, ageing causes greatly increased probability of death from the causes listed above. Ageing does not have to directly by itself cause death in order to result in death and thus have an impact on evolution. Ageing just has to increase the probability of death from the listed causes. If a lion is chasing 150 wild beasts in the Serengeti which one is going to be caught? The one that is just a little bit slower or a little bit less lucky. After thousands of years, the luck part averages out. Therefore, we can think of genetically programmed ageing as causing programmed weakness, programmed increased susceptibility to disease and programmed death”. As natural selection, acting during millions of years can select between very small advantages or disadvantages, even a very small weakness, agility loss or other deterioration, such as might occur in even a relatively young animal could have a significant effect on an animal's survival or breeding probability and thereby evolution. The effect of ageing in actual wild animals on fitness and thereby natural selection is therefore not insignificant. Studies on large wild animals such as those of Anne Loison of the Norwegian Institute for Nature Research confirm that death rates increases with age beginning at rather young ages. Another aspect of the performance deterioration caused by ageing is that it generally gradually increases. The Earth is thought to have existed for about 4.5 billion years. Life on Earth has been evolving for may be 4 billion years. Of this period, good scientific records have been kept for about 200 years. Photography has only been available for about 150 years. We only have good, direct, recorded observations for about 0.000005 % of the process! Fossils convey only a tiny fraction of the information that could be extracted from observations of living animals. Although there are detailed observations of recent humans, humans are not “wild” animals and are therefore not as subject to natural selection as wild animals. Detailed observations of wild animals are difficult and expensive to do without disturbing the “wildness” of the animals. Data is sparse. Funding is limited. Progress has been glacial. Origin is still the most respected work. Darwin is still the most respected researcher. If we had a time machine and could determine what descendents of the non-ageing sturgeon and compare what the ageing fish had produced several hundred million years from now we could prove the theory. It is therefore apparent that solutions to the question “what causes ageing” may be as unlikely to come from evolutionary biology alone in the next 140 years as they have been in the previous 140 years.

How to live longer?

Eat less: Research on animals has shown that the only surefire way to extend life is through dietary or calorific restriction – eat nutritious food just enough to stay alive. You won't have energy to do much though. Be popular, have good social networks, a happy marriage and close family contacts promote longer life. Walk more for exercise and quit smoking. Is it an investment too far? The prospects for a longer life currently seem rosy at least if you are a laboratory mouse. This year has seen headlines about mice engineered to produce lots of antioxidants who can live 20 % longer than usual and equally impressive gains for animals altered to produce high levels of a peptide hormone known as Klotho, after the minor Greek deity. Ultra-low calorie diets, big doses of Vitamin E and even transferring ovaries from a younger mouse into elderly females also seem to extend lifespan. Shepherds may say that sheep are just looking for new ways to die but mice seem to be susceptible to almost anything that can make them live a bit longer. So what are the prospects for a rather larger mammal that normally lives 70-80 years rather than the mouse's two and very occasionally makes it to 120 before keeling over? Will what works in mice work in humans? There are well publicized optimists who think it will. The most often quoted is Aubrey de Grey of Cambridge proponent of a big expansion of research on what he called Strategies for Engineered Negligible Senescence. He is also one of the leading lights of the Methuselah Mouse Prize which is offered to the scientific team that develops the longest-lived mouse. Many researchers in biogerontology are skeptical about his predictions. Professor Kirkwood the author of the influential ‘disposable soma' theory of ageing that the body decays because there is little genetic interest in keeping it going beyond reproductive age. This means that he sees no programmed limit to lifespan in mice or people. Ageing is a biological sin of omission not commission. So perhaps we could block whatever is doing the damage. He stresses “this does not imply that major increases in lifespan are imminent. As we grow older the accumulated burden of molecular and cellular damage increases and going gets harder”. Martin Brand of the Medical Research Council's Dunn Human Nutrition Unit in Cambridge also urges caution. “There have been spectacular increases in lifespan caused by simple treatments and mutations in model organisms,” he concedes. He is however mindful that flies and mice in the laboratory tend to live shorter lives than wilds strains. “I worry that these results can be explained as putting right bad husbandry of the model organisms rather than affecting ageing itself. However, the most basic argument against major extension of lifespan for humans is a general one that the eventual triumph of entropy can only be delayed not denied. Doug Wallace of the University of California, Irvine, is an expert on how damage accumulates in the energy-generating organelles, the mitochondria, through the action of mitochondrially generated reactive oxygen species one of the main classes of free radical. They damage not only enzymes that generate energy but also the mitochondrial DNA (mtDNA) that preserves the information needed to repair the organelle. “Once the mtDNA becomes sufficiently compromised, the mitochondrial power plants go off-line and the cellular, tissue and organ systems fail.” he says. Professor Wallace also believes mitochondrial degradation is crucial, he does not believe that preventing it would open the path to immortality. Instead, he reads the mitochondrial story as an example of a broader principle. He argues that lifespan is determined by the balance between the processes that degrade our bodies' systems and the investments our cells can make in maintenance and repair. Those investments cover both the DNA coding for the machinery needed to monitor and correct cellular damage plus the allocation of resources, particularly energy, to actually make the repairs (including repairs to DNA itself). “It follows that the longer the individuals wish to extend life the greater the resources that will be needed to achieve the end” he says. So in the end the cost will exceed the benefit. In other words fix the damage to the mitochondria and something else will bring the system to a halt instead;” as each life-limiting process is countered some other process will become limiting.” So while all these researchers believe the current results are valuable for advancing understanding of ageing and age-related diseases, they do not think they hold the key to a society where death comes only through accident or ennui.

Conclusion

Defect theories generally suggest that medical intervention in the ageing process is impossible. Ageing is the result of a fundamental limitation or a defect so severe that evolution has been unable to find a solution. Believers in defect theories logically tend to also believe that anti-ageing research is a foolish waste of time and money, a “chase after the fountain of youth”. Future theories are much more optimistic regarding prospects for medical intervention. Intervention would involve finding ways to interfere with the “ageing program” or slow the operation of an “ageing mechanism” without adverse side effects, a problem similar to other medical problems such as treating infectious diseases and cancer. Theories also affect research by suggesting “where to look” for places at which intervention could be applied. Darwin's Dilemma Darwin's theory of evolution published in 1859, In ‘The Origin of Species' Darwin's natural selection or “survival of the fittest” theory was obviously incompatible with feature theories of ageing. In no plausible way ageing assists individual survival or propagation. When cited at a time as evidence Darwin's theory was proved incorrect, nevertheless it supported feature theories despite incompatibility. This incompatibility has affected ageing theories for more than 140 years. Any feature theory of ageing must invoke at least an adjustment to natural selection theory. A number of other apparent natural selection incompatibilities especially in the area of behaviors have been observed. Weismann proposed a feature theory in which animals were genetically programmed to die. Purpose was to enhance the process of evolution and thereby benefit the species. The “programmed death” theory achieved little scientific support primarily because of the conflict with Darwin's theory. Starting in 1952, three “evolutionary” defect theories (mutation accumulation, antagonistic pleiotropy and disposable soma) appeared based on the ‘declining evolutionary importance of older individuals”. These evolutionary theories despite various logical flaws, better fit the observed loose relationship between organism development time and life span while not violating ”orthodox Darwinism”. Ageing Theory Status “Main line” consensus of current biologists heavily favors the evolutionary defect theories. Earlier “wear out” and accumulations of damage theories have little current scientific credibility. Advances in genetics sciences may eventually solve a 140 year controversy. Some genetic discoveries appear to be incompatible with natural selection theory and provide support for various adjustments. Some species have been identified that apparently do not age. Older individuals do not appear to be weaker, less agile, less reproductive and more susceptible to disease or otherwise less fir than younger animals. Some species with age of oldest recorded specimen: #Lake Sturgeon 152 years, # Aldabra Tortoise 152 years, #Yellow eye Rockfish 140 years, #Common U.S. Eastern Box Tuttle is also long-lived 100 years. ‘Natural selection' and ‘survival of the fittest' is valid in natural environment but for animals in zoos or human in present

Earth is not like natural environment. Immunization against deadly diseases, discovery of wonderful drugs improved longevity of the rich people but adverse environmental conditions, genetically engineered bacteria, viruses, nuclear bombs and deadly poisonous chemicals for warfare, natural disasters etc. lessened and made uncertain the life-spans of all organisms.

References

1. Kirkwood T. Time of Our Lives: The Science of Human Ageing. Oxford :Oxford University Press; 2002
2. Wallace DC' – A mitochondrial paradigm of metabolic and degenerative diseases, ageing nad cancer; a dawn for evolutionary medicine. Annu Rev Genel 2005, 39..339-407
3. Bordone L, Guarente L. Calorie restriction, SIRJ1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 2005;6(4):298-306
4. The Origin of Species – Charles Darwin, 1859 http://www.literature.org/authors/darwin-charles/ the-origin-of-species/

1. The Descent of Man – Charles Darwin, 1871
2. No Truth to the Fountain of Youth – Olshansky, Hayflick and Carnes, Scientific American June 2002 (reprinted July 2004 Vol 14 No. 3 )
3. Ageing as an Evolved Characteristic – Weismann's Theory Reconsidered Theodore, C.Goldsmith Medical Hypotheses 2004 62-2 304:308
4. The Evolution of Ageing – How Darwin's dilemma is affecting your chance for a longer and healthier life – Theodore C. Goldsmith; ISBN:0-595-28069-2 6/20/2003 paperback
5. Genetics of Aging: Caleb E. Finch and Rudolph E. Tanzi:SCIENCE, Vol. 278,17 OCTOBER P-408 1997; www.science.mag.org

1. The Selfish Gene, Richard Dawkins, 1976 revised edition 1986, Oxford University Press ISBN:0-19-286092-5