A series of changes in the body which are related to increasing mortality with increasing age. Modern views hold that it is essentially a continuing and increasing failure of adaptability to environmental variations. When the range of environments to which the body can adapt is less than the minimum range normally experienced, death results. In the past, many causes of this decreased adaptability have been suggested, but modern theory suggests that it is due ultimately to errors in the replication of DNA in cell division and/or errors in the production of proteins and enzymes by cells. These errors accumulate as a result of mutation in the hereditary material as the individual becomes older.
(Discuss)In biology, senescence is the combination of processes of deterioration which follow the period of development of an organism.
Cellular senescence is the phenomenon where cells lose the ability to divide. In response to DNA damage (including shortened telomeres) cells either senesce or self-destruct (apoptosis) if the damage cannot be repaired. Organismal senescence is the aging of whole organisms.
Aging is generally characterized by the declining ability to respond to stress, increasing homeostatic imbalance and increased risk of disease. Because of this, death is the ultimate consequence of aging. Differences in maximum life span between species correspond to different "rates of aging". For example, inherited differences in the rate of aging make a mouse elderly at 3 years and a human elderly at 90 years. These genetic differences affect a variety of physiological processes, probably including the efficiency of DNA repair, antioxidant enzymes, and rates of free radical production.
Some researchers in gerontology (specifically biogerontologists) regard aging itself as a "disease" that may be curable, although this view is controversial. To those who accept the view, aging is an accumulation of damage to macromolecules, cells, tissues and organs.
Genetic and environmental interventions are known to affect the life span of model organisms. This gives many hope that human aging can be slowed, halted, or reversed.
Theories of aging
The process of senescence is complex, and may derive from a variety of different mechanisms and exist for a variety of different reasons. However, senescence is not universal, and scientific evidence suggests that cellular senescence evolved in certain species as a mechanism to prevent the onset of cancer. they reduce the effect of damaging free radicals by cell division and dilution. This suggests that both genetic and environmental factors contribute to aging.
Theories that explain senescence can generally be divided between the programmed and error theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the life span. Error theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples which range from damage to deoxyribonucleic acid (DNA), damage to tissues and cells by oxygen radicals (widely known as free radicals countered by the even more well known antioxidants), and cross-linking.
Gerontologists also theorise that one potential cause of senescence is the accumulation of mutations in DNA, eventually leading to the progressive loss of key genes.
Evolutionary theories
Theories of the evolution of aging seek to explain why we don't live forever, and provide a reasonable explanation for the huge variation in lifespan between (often closely-related) species.
The geneticist J. Since few were alive at older ages and their contribution to the next generation was therefore small relative to the large cohorts of younger age groups, the force of selection against such late-acting deleterious mutations was correspondingly small.
Peter Medawar formalised this observation in his mutation accumulation theory of aging. This is called 'extrinsic mortality.' Young cohorts, not depleted in numbers yet by extrinsic mortality, contribute far more to the next generation than the few remaining older cohorts, so the force of selection against late-acting deleterious mutations, which only affect these few older individuals, is very weak.
The major testable prediction made by this model is that species which have high extrinsic mortality in nature will age more quickly and have shorter intrinsic lifespans. This is because there is too little time before death occurs by extrinsic causes for the effects of deleterious mutations to be expressed and, therefore, selected against. There is a correlation among mammals between body size and lifespan, such that larger species live longer than smaller species in controlled/optimum conditions, but there are notable exceptions. Fewer late-acting deleterious mutations = slower aging = longer lifespan.
Also, when examining the body-size vs.
Another evolutionary theory of aging was proposed by George C. But because many more individuals are alive at young ages than at old ages, even small positive effects early can be strongly selected for, and large negative effects later may be very weakly selected against. Therefore negative effects in old age may reflect the result of natural selection for pleiotropic genes which are beneficial early in life.
Ultimately, lifespan differences among species are due to genetics, but this does not explain the "how" question of aging.
The Evolution Inbreed Theory of Aging: This theory proposes that aging has evolved to reduce the impact of inbreeding.
Gene regulation
A number of genetic components of aging have been identified using model organisms, ranging from the simple budding yeast Saccharomyces cerevisiae to worms such as Caenorhabditis elegans and fruit flies (Drosophila melanogaster). Study of these organisms has revealed the presence of at least two conserved aging pathways.
One of these pathways involves the gene Sir2, a NAD+-dependent histone deacetylase. Yeast replicative aging is caused by homologous recombination between rDNA repeats; These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by titrating away (competing for) essential nuclear factors. While ERCs are not believed to contribute to aging in higher organisms such as human, extrachromosomal circular DNA (eccDNA) has been found in worms, flies and humans. The role of eccDNA in aging is unknown.
Despite the lack of a connection between circular DNA and aging in higher organisms, extra copies of Sir2 are capable of extending the lifespan of both worms and flies.
Other genes regulate aging in yeast by increasing the resistance to oxidative stress.
In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway.
It is not known, however, whether these mechanisms also exist in humans since there are obvious differences in biology between humans and model organisms.
Cellular senescence
As noted above, senescence is not universal, and senescence is not observed in single-celled organisms that reproduce through the process of cellular mitosis. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis -- i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted above) it is widely believed that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would therefore be in danger of becoming cancerous if cell division continued.
Lately the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. It is further theorized that it will eventually be possible to genetically engineer all cells in the human body to have this capability by employing gene therapy and thereby stop or reverse ageing, effectively making the entire organism potentially immortal.
Chemical damage
The earliest aging theory was the Rate of Living Hypothesis posited by Raymond Pearl in 1928, based on the idea that fast basal metabolic rate corresponds to short maximum life span (much as a rapidly running machine will experience more damage from wear). (m=1) Denham Harman's free-radical theory of aging later provided a plausible causal mechanism for Pearl's hypothesis, but glycation and other sources of damage can also contribute.
It is suggested that damage to long-lived biopolymers, such as structural proteins or DNA, caused by ubiquitous chemical agents in the body such as oxygen and sugars, are in part responsible for aging.
Under normal aerobic conditions, approximately 4% of the oxygen metabolized by mitochondria is converted to superoxide ion which can subsequently be converted to hydrogen peroxide, hydroxyl radical and eventually other reactive species including other peroxides and singlet oxygen, which can in turn generate free radicals capable of damaging structural proteins and DNA.
Sugars such as glucose and fructose can react with certain amino acids such as lysine and arginine and certain DNA bases such as guanine to produce sugar adducts, in a process called glycation. These adducts can further rearrange to form reactive species which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. There is evidence that sugar damage is linked to oxidant damage in a process termed glycoxidation.
Free radicals can damage proteins, lipids or DNA. It is probably no accident that nearly all of the so-called "accelerated aging diseases" are due to defective DNA repair enzymes.
Reliability theory
Main article: Reliability theory of aging and longevity.
Reliability theory suggests that biological systems start their adult life with a high load of initial damage. Reliability theory is a general theory about systems failure. Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy.
Reliability theory also predicts the late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as an inevitable consequence of redundancy exhaustion at extreme old ages. The theory explains why mortality rates increase exponentially with age (the Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems. Reliability theory allows to specify conditions when organisms die according to the Weibull law: organisms should be relatively free of initial flaws and defects. The theory makes it possible to find a general failure law applicable to all adult and extreme old ages, where the Gompertz and the Weibull laws are just special cases of this more general failure law. The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age (compensation law of mortality), and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels.
Neuro-endocrine-immunological theories
Senescence may also simply be a result of wear and tear overwhelming repair mechanisms.
Miscellaneous
Recently, early senescence has been alleged to be a possible unintended outcome of early cloning experiments.
A set of rare hereditary (genetic) disorders, each called progeria, has been known for some time. Sufferers exhibit symptoms resembling accelerated aging, including wrinkled skin. This report suggests that DNA damage, not oxidative stress, is the cause of this form of accelerated aging.
Artificially-induced senescence, as a means of control over artificially-created humans, or androids, is a central plot motivation in the renowned 1982 science fiction film "Blade Runner", loosely based on Philip K.
Resveratrol, a polyphenol found in the skin of red grapes, was reported to extend the lifespan of yeast, worms, and flies, although this conclusion has since failed to be validated in yeast and has yet to be verified in flies.
A centenarian is a person who has attained the age of 100 years or more.
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