Senescence or biological aging is the change in the biology of an organism In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole. An organism may either be unicellular (single-celled) or be composed of, as in humans, many trillions of cells grouped into as it ages after its maturity. Such changes range from those affecting its cells and their function to that of the whole organism. There are a number of theories as to why senescence occurs, including ones that claim it is programmed by gene expression changes and that it is the accumulative damage of biological processes.

The word senescence is derived from the Latin word senex, meaning old man, old age, or advanced in age.

Contents

Cellular senescence

Cellular senescence (upper) Primary mouse embryonic fibroblast cells (MEFs) before senescence. Spindle-shaped. (lower) MEFs became senescent after passages. Cells grow larger, flatten shape and expressed senescence-associated β-galactosidase β-galactosidase, also called beta-gal or β-gal, is a hydrolase enzyme that catalyzes the hydrolysis of β-galactosides into monosaccharides. Substrates of different β-galactosidases include ganglioside GM1, lactosylceramides, lactose, and various glycoproteins. Alternate or nicknames are "beta-gal" or "β-gal". Lactase is (SABG, blue areas), a marker of cellular senescence.

Cellular senescence is the phenomenon by which normal diploid Human germ cells have one complete set of chromosomes from the male or female parent. Germ cells, also called gametes, combine to produce somatic cells. Somatic cells therefore have twice as many chromosomes. The haploid number (n) is the number of chromosomes in a gamete. A somatic cell has twice that many chromosomes (2n) cells The cell is the functional basic unit of life. It was discovered by Robert Hooke and is the functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. Some organisms, such as most bacteria, are unicellular . Other organisms, such as humans, lose the ability to divide Cell division is the process by which a parent cell divides into two or more daughter cells. Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort of cell division in prokaryotes is known as binary, normally after about 50 cell divisions in vitro A procedure performed in vitro is performed not in a living organism but in a controlled environment, such as in a test tube or Petri dish. Many experiments in cellular biology are conducted outside of organisms or cells; because the test conditions may not correspond to the conditions inside of the organism, this may lead to results that do not. Some cells become senescent after fewer replications cycles as a result of DNA double strand breaks, toxins, etc. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the Hayflick limit The Hayflick limit is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length in honour of Dr. Leonard Hayflick Leonard Hayflick , Ph.D., is Professor of Anatomy at the University of California, San Francisco, School of Medicine, and was Professor of Medical Microbiology at Stanford University School of Medicine. He is a past president of the Gerontological Society of America and was a founding member of the council of the National Institute on Aging (NIA) who was the first to publish this information in 1965. In response to DNA Deoxyribonucleic acid ( /diːˌɒksɨˌraɪbɵ.nuːˈkleɪ.ɪk ˈæsɪd/ (help·info)) (DNA) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information. DNA is often compared to a set of damage (including shortened telomeres A telomere is a region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from deterioration. Its name is derived from the Greek nouns telos "end" and merοs (μέρος, root: μερ-) "part"), cells either age or self-destruct (apoptosis Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, loss of cell membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA, programmed cell death Programmed cell-death is death of a cell in any form, mediated by an intracellular program. In contrast to necrosis, which is a form of cell-death that results from acute tissue injury and provokes an inflammatory response, PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle. PCD serves) if the damage cannot be repaired. In this 'cellular suicide', the death of one cell, or more, may benefit the organism as a whole. For example, in plants the death of the water-conducting xylem In vascular plants, xylem is one of the two types of transport tissue, phloem being the other. The word "xylem" is derived from classical Greek ξυλον , "wood", and indeed the best-known xylem tissue is wood, though it is found throughout the plant. Its basic function is to transport water but it also transports some cells (tracheids Tracheids are elongated cells in the xylem of vascular plants that serve in the transport of water and mineral salts. Tracheids are one of two types of tracheary elements, vessel elements being the other. All tracheary elements develop a thick lignified cell wall, and at maturity the protoplast has broken down and disappeared. The presence of and vessel elements A vessel element is one of the cell types found in xylem, the water conducting tissue of plants. Vessel elements are typically found in the angiosperms but absent from most gymnosperms such as the conifers) allows the cells to function more efficiently and so deliver water to the upper parts of a plant.

Aging of the whole organism

Organismal senescence is the aging of whole organisms. In general, aging Ageing or aging (American and Canadian English) is the accumulation of changes in an organism or object over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Some dimensions of ageing grow and expand over time, while others decline. Reaction time, for example, may slow with age, while is characterized by the declining ability to respond to stress, increased homeostatic Homeostasis is the property of a system, either open or closed, that regulates its internal environment and tends to maintain a stable, constant condition. Typically used to refer to a living organism, the concept came from that of milieu interieur that was created by Claude Bernard and published in 1865. Multiple dynamic equilibrium adjustment imbalance, and increased risk of aging-associated diseases An aging-associated disease is a disease that is seen with increasing frequency with increasing senescence. Age-associated diseases are to be distinguished from the aging process itself because all adult animals age, but not all adult animals experience all age-associated diseases. Aging-associated diseases do not refer to age-specific diseases,. Death Death is the termination of the biological functions that define a living organism. The word refers both to a particular process and to the condition that results thereby. The nature of the latter has been for millennia a central concern of the world's religious traditions and of philosophical enquiry. Belief in some kind of afterlife or rebirth is the ultimate consequence of aging, though "old age" is not a scientifically recognized cause of death The following is a list of the causes of human deaths worldwide for the year 2002, arranged by their associated mortality rates. There were 57,029,000 deaths tabulated for that year. Some causes listed include deaths also included in more specific subordinate causes , and some causes are omitted, so the percentages do not sum to 100. According to because there is always a specific proximal cause, such as cancer Cancer /ˈkænsər/ (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties, heart disease Heart disease or cardiopathy is an umbrella term for a variety of different diseases affecting the heart. As of 2007, it is the leading cause of death in the United States, England, Canada and Wales, killing one person every 34 seconds in the United States alone.[verification needed], or liver failure Liver failure is the inability of the liver to perform its normal synthetic and metabolic function as part of normal physiology. Two forms are recognised:.

Differences in maximum life span In animal studies, maximum life span is often taken to be the mean life span of the most long-lived 10% of a given cohort. By another definition, however, maximum life span corresponds to the age at which the oldest known member of a species or experimental group has died. Calculation of the maximum life span in the former sense depends upon among species correspond to different "rates of aging". For example, inherited Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause a species to evolve. The study of heredity in biology is called genetics, differences in the rate of aging make a mouse A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse (Mus musculus). It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles. They are known to invade homes for food and occasionally shelter elderly at 3 years and a human Humans are a species of animal known taxonomically as Homo sapiens , and are the only extant member of the Homo genus of bipedal primates in Hominidae, the great ape family. However, in some cases "human" is used to refer to any member of the genus Homo elderly at 80 years.[citation needed] These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day, antioxidant An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions that damage cells. Antioxidants terminate these chain reactions by enzymes Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at significant rates. Since enzymes are selective for their, and rates of free radical In chemistry, radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Radicals may have positive, negative or zero charge. By convention, metals and their ions or complexes with unpaired electrons are not radicals. The unpaired electrons cause radicals to be highly chemically reactive production.

Supercentenarian A supercentenarian is someone who has reached the age of 110 years. This age is achieved by only one in a thousand centenarians. [citation needed] Furthermore, only 2% of supercentenarians live to be 115.[citation needed] Ann Pouder (8 April 1807 – 10 July 1917) photographed on her 110th birthday. A heavily lined face is common in human senescence.

Senescence of the organism gives rise to the Gompertz–Makeham law of mortality, which says that mortality rate Mortality rate is a measure of the number of deaths in some population, scaled to the size of that population, per unit time. Mortality rate is typically expressed in units of deaths per 1000 individuals per year; thus, a mortality rate of 9.5 in a population of 100,000 would mean 950 deaths per year in that entire population. It is distinct from rises rapidly with age.

Some animals, such as some reptiles and fish, age slowly (negligible senescence) and exhibit very long lifespans. Some even exhibit "negative senescence", in which mortality falls with age, in disagreement with the Gompertz–Makeham "law".[1]

Whether replicative senescence (Hayflick limit) plays a causative role in organismal aging is at present an active area of investigation.

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 In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are often used, such as based on similarity of DNA or because it prevents the onset of cancer Cancer /ˈkænsər/ (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties. In a few simple species, such as Hydra Hydra is a genus of simple fresh-water animal possessing radial symmetry. Hydras are predatory animals belonging to the phylum Cnidaria and the class Hydrozoa. They can be found in most unpolluted fresh-water ponds, lakes and streams in the temperate and tropical regions by gently sweeping a collecting net through weedy areas. They are usually a, senescence is negligible Negligible refers to the quantities so small that they can be ignored when studying the larger effect. Although related to the more mathematical concepts of infinitesimal, the idea of negligibility is particularly useful in practical disciplines like physics, chemistry, mechanical and electronic engineering, computer programming and in everyday and cannot be detected. All such species have no "post-mitotic Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly equal shares of these cellular components. Mitosis and" cells; they reduce the effect of damaging free radicals The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most biologically-relevant free radicals are highly reactive. For by cell division and dilution. Such species are not immortal, however, as they will eventually fall prey to trauma Physical trauma refers to a physical injury, generally of a considerable degree. A trauma patient is someone who has suffered serious and life-threatening physical injury, with the potential for secondary complications such as shock, respiratory failure and death or disease A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal disfunctions, such as autoimmune diseases. Moreover, average lifespans can vary greatly within and between species In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are often used, such as based on similarity of DNA or. This suggests that both genetic and environmental factors The nature versus nurture debates concern the relative importance of an individual's innate qualities versus personal experiences ("nurture", i.e. empiricism or behaviorism) in determining or causing individual differences in physical and behavioral traits contribute to aging.

In general, theories that explain senescence have been divided between the programmed and stochastic Stochastic means random. A stochastic process is one whose behavior is non-deterministic, in that a system's subsequent state is determined both by the process's predictable actions and by a random element. However, according to M. Kac and E. Nelson, any kind of time development (be it deterministic or essentially probabilistic) which is theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the lifespan. This regulation would depend on changes in gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as rRNA genes or tRNA genes, the product is a functional RNA. The process of gene expression is used by all known life - eukaryotes , prokaryotes (bacteria that affect the systems responsible for maintenance, repair, and defense responses. Stochastic theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples of which ranging from damage to DNA The DNA damage theory of aging proposes that aging is a consequence of unrepaired DNA damage accumulation. Damage in this context includes chemical reactions that mutate DNA and/or interfere with DNA replication. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear, damage to tissues and cells by oxygen radicals In chemistry, radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Radicals may have positive, negative or zero charge. By convention, metals and their ions or complexes with unpaired electrons are not radicals. The unpaired electrons cause radicals to be highly chemically reactive (widely known as free radicals countered by the even more well-known antioxidants An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions that damage cells. Antioxidants terminate these chain reactions by), and cross-linking Cross-links are bonds that link one polymer chain to another. They can be covalent bonds or ionic bonds. "Polymer chains" can refer to synthetic polymers or natural polymers . When the term "cross-linking" is used in the synthetic polymer science field, it usually refers to the use of cross-links to promote a difference in the.

However, aging is seen as a progressive failure of homeodynamics (homeostasis) involving genes for the maintenance and repair, stochastic events leading to molecular damage and molecular heterogeneity, and chance events determining the probability of death. Since complex and interacting systems of maintenance and repair comprise the homeodynamic (old term: homeostasis) space of a biological system, aging is considered to be a progressive shrinkage of homeodynamic space mainly due to increased molecular heterogeneity.[citation needed]

Evolutionary theories

Main article: Evolution of aging Historically, ageing was first likened to "wear and tear": living bodies get weaker just as with use a knife's edge becomes dulled or with exposure to air and moisture iron objects rust. But this idea was discredited in the 19th century when the second law of thermodynamics was formalized. Entropy must increase inevitably within a closed

A gene can be expressed at various life-stages. Therefore, natural selection can support lethal and harmful alleles, if their expression occurs after reproduction. Senescence is the product of such selection.[2][3][4] In addition, aging is believed to have evolved because of the increasingly smaller probability of an organism still being alive at older age, due to predation and accidents, both of which may be random and age-invariant. It is thought that strategies that result in a higher reproductive rate at a young age, but shorter overall lifespan, result in a higher lifetime reproductive success and are therefore favoured by natural selection. In essence, aging is, therefore, the result of investing resources in reproduction, rather than maintenance of the body (the "Disposable Soma" theory[5]), in light of the fact that accidents, predation, and disease will eventually kill the organism no matter how much energy is devoted to repair of the body. Various other theories of aging exist, and are not necessarily mutually exclusive.

The geneticist J. B. S. Haldane wondered why the dominant mutation that causes Huntington's disease remained in the population, and why natural selection had not eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10–20 years. Haldane assumed that, in human prehistory, few survived until age 45. 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. However, if a mutation affected younger individuals, selection against it would be strong. Therefore, late-acting deleterious mutations could accumulate in populations over evolutionary time through genetic drift. This principle has been demonstrated experimentally.[citation needed] And it is these later-acting deleterious mutations that are believed to cause—even allow—age-related mortality.

Peter Medawar formalised this observation in his mutation accumulation theory of aging.[6][7] "The force of natural selection weakens with increasing age—even in a theoretically immortal population, provided only that it is exposed to real hazards of mortality. If a genetic disaster… happens late enough in individual life, its consequences may be completely unimportant". The 'real hazards of mortality' are, in typical circumstances, predation, disease, and accidents. So, even an immortal population, whose fertility does not decline with time, will have fewer individuals alive in older age groups. 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 affect only these few older individuals, is very weak. The mutations may not be selected against, therefore, and may spread over evolutionary time into the population.

The major testable prediction made by this model is that species that have high extrinsic mortality in nature will age more quickly and have shorter intrinsic lifespans. This is borne out among mammals, the best-studied in terms of life history. 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. For instance, many bats and rodents are of similar size, yet bats live much longer. For instance, the little brown bat, half the size of a mouse, can live 30 years in the wild. A mouse will live 2–3 years even with optimum conditions. The explanation is that bats have fewer predators, so therefore low extrinsic mortality. Thus, more individuals survive to later ages, so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations = slower aging = longer lifespan. Birds are also warm-blooded and are of similar size to many small mammals, yet live often 5–10 times as long. They have fewer predation pressures compared with ground-dwelling mammals. And seabirds, which, in general, have the fewest predators of all birds, live longest.

Also, when examining the body-size vs. lifespan relationship, one will observe that predator mammals tend to have longer lifespans than prey animals in a controlled environment such as a zoo or nature reserve. The explanation for the long lifespans of primates (such as humans, monkeys, and apes) relative to body size is that their intelligence and often sociality helps them avoid becoming prey. Being a predator, being smart, and working together all reduce extrinsic mortality.

Another evolutionary theory of aging was proposed by George C. Williams[8] and involves antagonistic pleiotropy. A single gene may affect multiple traits. Some traits that increase fitness early in life may also have negative effects later in life. 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. Williams suggested the following example: Perhaps a gene codes for calcium deposition in bones, which promotes juvenile survival and will therefore be favored by natural selection; however, this same gene promotes calcium deposition in the arteries, causing negative effects in old age. Therefore, negative effects in old age may reflect the result of natural selection for pleiotropic genes that are beneficial early in life. In this case, fitness is relatively high when Fisher's reproductive value is high and relatively low when Fisher's reproductive value is low.

Gene regulation

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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. In yeast, Sir2 is required for genomic silencing at three loci: The yeast mating loci, the telomeres and the ribosomal DNA (rDNA). In some species of yeast, replicative aging may be partially caused by homologous recombination between rDNA repeats; excision of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). 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. ERCs have not been observed in other species (nor even all strains of the same yeast species) of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans (they have not been shown to accumulate in mammals in a similar manner to yeast). Extrachromosomal circular DNA (eccDNA) has been found in worms, flies, and humans. The origin and role of eccDNA in aging, if any, 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 (though, in flies, this finding has not been replicated by other investigators, and the activator of Sir2 resveratrol does not reproducibly increase lifespan in either species[9]). Whether the Sir2 homologues in higher organisms have any role in lifespan is unclear, but the human SIRT1 protein has been demonstrated to deacetylate p53, Ku70, and the forkhead family of transcription factors. SIRT1 can also regulate acetylates such as CBP/p300, and has been shown to deacetylate specific histone residues.

RAS1 and RAS2 also affect aging in yeast and have a human homologue. RAS2 overexpression has been shown to extend lifespan in yeast.

Other genes regulate aging in yeast by increasing the resistance to oxidative stress. Superoxide dismutase, a protein that protects against the effects of mitochondrial free radicals, can extend yeast lifespan in stationary phase when overexpressed.

In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway. Mutations that affect insulin-like signaling in worms, flies, and the growth hormone/IGF1 axis in mice are associated with extended lifespan. In yeast, Sir2 activity is regulated by the nicotinamidase PNC1. PNC1 is transcriptionally upregulated under stressful conditions such as caloric restriction, heat shock, and osmotic shock. By converting nicotinamide to niacin, nicotinamide is removed, inhibiting the activity of Sir2. A nicotinamidase found in humans, known as PBEF, may serve a similar function, and a secreted form of PBEF known as visfatin may help to regulate serum insulin levels. It is not known, however, whether these mechanisms also exist in humans, since there are obvious differences in biology between humans and model organisms.

Sir2 activity has been shown to increase under calorie restriction. Due to the lack of available glucose in the cells, more NAD+ is available and can activate Sir2. Resveratrol, a polyphenol found in the skin of red grapes, was reported to extend the lifespan of yeast, worms, and flies (the lifespan extension in flies and worms have proved irreproducible by independent investigators[9]). It has been shown to activate Sir2 and therefore mimics the effects of calorie restriction, if one accepts that caloric restriction is indeed dependent on Sir2.

Gene expression is imperfectly controlled, and it is possible that random fluctuations in the expression levels of many genes contribute to the aging process as suggested by a study of such genes in yeast.[10] Individual cells, which are genetically identical, none-the-less can have substantially different responses to outside stimuli, and markedly different lifespans, indicating the epigenetic factors play an important role in gene expression and aging as well as genetic factors.

The following is a list of genes connected to longevity through research[citation needed] on model organisms: the filamentous fungus (Podospora anserina), bakers' yeast (Saccharomyces cerevisiae), the soil roundworm (Caenorhabditis elegans), the fruit fly (Drosophila melanogaster), and the mouse (Mus musculus).

Podospora Saccharomyces Caenorhabditis Drosophila Mus
grisea LAG1 daf-2 sod1 Prop-1
LAC1 age-1/daf-23 cat1 p66shc (Not independently verified)
pit-1 Ghr
RAS1 daf-18 mth mclk1
RAS2 akt-1/akt-2
PHB1 daf-16
PHB2 daf-12
CDC7 ctl-1
BUD1 old-1
RTG2 spe-26
RPD3 clk-1
HDA1 mev-1
SIR2
aak-2
SIR4-42
UTH4
YGL023
SGS1
RAD52
FOB1

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.[11] Moreover, cellular senescence is not observed in many organisms, including perennial plants, sponges, corals, and lobsters. 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. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres. Some cells do not age and are, therefore, described as being "biologically immortal". It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability. 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, therefore, stop or reverse aging, effectively making the entire organism potentially immortal.

Cancer cells are usually immortal. In about 85% of tumors, this evasion of cellular senescence is the result of up-activation of their telomerase genes.[12] This simple observation suggests that reactivation of telomerase in healthy individuals could greatly increase their cancer risk.

Whether cell senescence plays any role in organismal aging is at present unknown, and is an active area of investigation. Mouse mutants lacking telomerase do not immediately show accelerated aging.

Chemical damage

Elderly Klamath woman photographed by Edward S. Curtis in 1924

One of the earliest aging theories was the Rate of Living Hypothesis described by Raymond Pearl in 1928[13](based on earlier work by Max Rubner), which states that fast basal metabolic rate corresponds to short maximum life span.

While there may be some validity to the idea that for various types of specific damage detailed below that are by-products of metabolism, all other things being equal, a fast metabolism may reduce lifespan, in general this theory does not adequately explain the differences in lifespan either within, or between, species. Calorically-restricted animals process as much, or more, calories per gram of body mass, as their ad libitum fed counterparts, yet exhibit substantially longer lifespans.[citation needed] . Similarly, metabolic rate is a poor predictor of lifespan for birds, bats and other species that, it is presumed, have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates.[14] More recently, it was shown that, when modern statistical methods for correcting for the effects of body size and phylogeny are employed, metabolic rate does not correlate with longevity in mammals or birds.[15] (For a critique of the Rate of Living Hypothesis see Living fast, dying when?[16])

With respect to specific types of chemical damage caused by metabolism, 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. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural substituents (haptens) to biopolymers.

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. Certain metal ions found in the body, such as copper and iron, may participate in the process. (In Wilson's disease, a hereditary defect that causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes are termed oxidative damage and are linked to the benefits of nutritionally derived polyphenol antioxidants[citation needed].

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. People with diabetes, who have elevated blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed glycoxidation.

Free radicals can damage proteins, lipids or DNA. Glycation mainly damages proteins. Damaged proteins and lipids accumulate in lysosomes as lipofuscin. Chemical damage to structural proteins can lead to loss of function; for example, damage to collagen of blood vessel walls can lead to vessel-wall stiffness and, thus, hypertension, and vessel wall thickening and reactive tissue formation (atherosclerosis); similar processes in the kidney can lead to renal failure. Damage to enzymes reduces cellular functionality. Lipid peroxidation of the inner mitochondrial membrane reduces the electric potential and the ability to generate energy. It is probably no accident that nearly all of the so-called "accelerated aging diseases" are due to defective DNA repair enzymes.

It is believed that the impact of alcohol on aging can be partly explained by alcohol's activation of the HPA axis, which stimulates glucocorticoid secretion, long-term exposure to which produces symptoms of aging.[17]

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. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that composed entirely 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.

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. It also explains why organisms "prefer" to die according to the Gompertz law, while technical devices usually fail according to the Weibull (power) law. Reliability theory allows to specify conditions when organisms die according to the Weibull distribution: 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.

Miscellaneous

Recently, a kind of early senescence has been alleged to be a possible unintended outcome of early cloning experiments. The issue was raised in the case of Dolly the sheep, following her death from a contagious lung disease. The claim that Dolly's early death involved premature senescence has been vigorously contested,[18] and Dolly's creator, Dr. Ian Wilmut has expressed the view that her illness and death were probably unrelated to the fact that she was a clone.

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. The cause of Hutchinson–Gilford progeria syndrome was reported in the journal Nature in May 2003. This report suggests that DNA damage, not oxidative stress, is the cause of this form of accelerated aging.

See also

Look up senescence in Wiktionary, the free dictionary.

References

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  5. ^ Kirkwood TB (November 1977). "Evolution of ageing". Nature 270 (5635): 301–4. doi:10.1038/270301a0. PMID 593350.
  6. ^ Medawar PB (1946). "Old age and natural death". Modern Quarterly 1: 30–56.
  7. ^ Medawar, Peter B. (1952). An Unsolved Problem of Biology. London: H. K. Lewis. [page needed]
  8. ^ Williams, George C. (December 1957). "Pleiotropy, Natural Selection, and the Evolution of Senescence". Evolution 11 (4): 398–411. doi:10.2307/2406060. http://www.devonescent.org/pdfs/Williams57.pdf.
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  11. ^ Gavrilov LA, Gavrilova NS (December 2001). "The reliability theory of aging and longevity". Journal of Theoretical Biology 213 (4): 527–45. doi:10.1006/jtbi.2001.2430. PMID 11742523.
  12. ^ Hanahan D, Weinberg RA (January 2000). "The hallmarks of cancer". Cell 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9. PMID 10647931.
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  14. ^ Brunet-Rossinni AK, Austad SN (2004). "Ageing studies on bats: a review". Biogerontology 5 (4): 211–22. doi:10.1023/B:BGEN.0000038022.65024.d8. PMID 15314271.
  15. ^ de Magalhães JP, Costa J, Church GM (1 February 2007). "An analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts" (). The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 62 (2): 149–60. PMID 17339640. PMC 2288695. http://biomed.gerontologyjournals.org/cgi/pmidlookup?view=long&pmid=17339640.
  16. ^ Speakman JR, Selman C, McLaren JS, Harper EJ (1 June 2002). "Living fast, dying when? The link between aging and energetics". The Journal of Nutrition 132 (6 Suppl 2): 1583S–97S. PMID 12042467. http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=12042467.
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  18. ^ Lynn Macintosh, Kerry (2005). Illegal Beings: Human Clones and the Law. Cambridge: Cambridge University Press. ISBN 0521853281. [page needed]

External links

Categories: Gerontology | Aging

 

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