Senescence 146539 225712804 2008-07-15T01:09:14Z Phenylalanine 5382478 /* See also */ fixed wikilink {{dablink|For the science of the care of the elderly, see [[geriatrics]]; for the study of aging in humans, see [[gerontology]]; for experimental gerontology, see [[life extension]]}} '''Senescence''' refers to the biological processes of a living [[organism]] approaching an advanced age (i.e., the combination of processes of deterioration which follow the period of development of an organism). The word ''senescence'' is derived from the Latin word ''senex'', meaning "old man" or "old age" or "advanced in age". ==Cellular senescence== [[Image:SABG MEFs.jpg|thumb|right|250px|'''Cellular senescence'''<br/>(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 [[Beta-galactosidase|β-galactosidase]] (SABG, blue areas), a marker of cellular senescence.]] ''Cellular senescence'' is the phenomenon where normal diploid differentiated [[cell (biology)|cells]] lose the ability to divide after about 50 cell divisions. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the [[Hayflick limit]] in honour of [[Leonard Hayflick|Dr.&nbsp;Leonard Hayflick]] who was the first to publish this information in 1965. In response to [[DNA]] damage (including shortened [[telomere]]s) cells either age or self-destruct ([[apoptosis]], [[programmed cell death]]) if the damage cannot be repaired. In this 'cellular suicide', the death of one, or more, cells may benefit the organism as a whole. For example, in plants the death of the water-conducting [[xylem]] cells ([[tracheid]]s and [[vessel element]]s) 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. The term ''aging'' has become so commonly equated with ''senescence'' that the terms will be used interchangeably in this article. [[Aging]] is generally characterized by the declining ability to respond to stress, increasing [[homeostasis|homeostatic]] imbalance and increased risk of [[aging-associated diseases]]. Because of this, [[death]] is the ultimate consequence of aging. Differences in [[maximum life span]] among species correspond to different "rates of aging". For example, [[Biological inheritance|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, including the efficiency of [[DNA repair]], [[antioxidant]] [[enzyme]]s, and rates of [[radical (chemistry)|free radical]] production. [[Image:Ann Pouder.jpg|thumbnail|200px|right|[[Supercentenarian]] Ann Pouder ([[8 April]], [[1807]] &ndash; [[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]] rises rapidly with age. Some animals, such as some reptiles and fish, age slowly. Some even exhibit "negative senescence", in which mortality falls with age, in disagreement with the Gompertz-Makeham "law".<ref> New Scientist, 10 Aug. 2007, pp. 36-9.[http://www.newscientist.com/channel/life/mg19526161.800-evolutions-greatest-mistakes.html;jsessionid=BMLEODOGCGLO]</ref> ==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]]. In a few simple species, senescence is negligible and cannot be detected. All such species have no "post-[[mitosis|mitotic]]" cells; they reduce the effect of damaging [[Free-radical theory|free radicals]] by cell division and dilution. Such species are not immortal, however, as they will eventually fall prey to [[physical trauma|trauma]] or [[disease]]. Moreover, average lifespans can vary greatly within and between [[species]]. This suggests that both [[nature versus nurture|genetic and environmental factors]] contribute to aging. Traditionally, theories that explain senescence have generally been divided between the programmed and [[stochastic]] theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the life span. This regulation would depend on changes in [[gene expression]] 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 which range from damage to [[deoxyribonucleic acid|DNA]], damage to tissues and cells by oxygen [[radical (chemistry)|radicals]] (widely known as [[Free-radical theory|free radicals]] countered by the even more well known [[antioxidants]]), and [[cross-linking]]. Conversely, 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. {{Fact|date=June 2007}} ===Evolutionary theories=== {{Main|Evolution of ageing}} 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 which 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]]. Essentially, aging is therefore the result of investing resources in reproduction, rather than maintenance of the body (the "Disposable Soma" theory<ref>Kirkwood, T.B.L. 1977. Evolution of aging. ''Nature'', '''270''': 301-304. [http://www.nature.com/nature/journal/v270/n5635/abs/270301a0.html]</ref>), 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, or more specific, theories of aging exist, and are not necessarily mutually exclusive. The geneticist [[J. B. S. Haldane]] wondered why the dominant mutation which causes [[Huntington's disease]] remained in the population, 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, probably reasonably, 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. And it is these later-acting deleterious mutations which are believed to cause, or perhaps more correctly allow, age-related mortality. [[Peter Medawar]] formalised this observation in his [[mutation accumulation theory]] of ageing<ref>Medawar, P. B., 1946 Old age and natural death. Mod. 1:30-56.</ref> <ref>{{cite book | first=Peter B. | last=Medawar | year=1952 | title=An Unsolved Problem of Biology | publisher=H. K. Lewis | location=London}}</ref>. "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 typically 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 only affect 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 which have high [[extrinsic mortality]] in nature will age more quickly and have shorter [[intrinsic lifespan]]s. This is borne out among mammals, the most well 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 similarly sized, yet bats live much, 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 ageing = longer lifespan. Birds are also warm-blooded and similarly sized to many small mammals, yet live often 5–10 times as long. They clearly have fewer predation pressures compared with ground-dwelling mammals. And [[seabird]]s, which generally have the fewest predators of all birds, live longest. Also, when examining the body-size vs. lifespan relationship, 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 ageing was proposed by [[George C. Williams]] (Williams 1957) <ref>Williams, G. C., 1957 Pleiotropy, natural selection and the evolution of senescence. Evolution 11:398-411.</ref> 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 [[pleiotropy|pleiotropic]] genes which 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=== {{Citations missing|date=July 2008}} 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 [[Nicotinamide adenine dinucleotide|NAD]]+-dependent histone deacetylase. In yeast, Sir2 is required for genomic silencing at three loci: the yeast mating [[locus (genetics)|loci]], the [[telomere]]s and the [[ribosomal DNA]] (rDNA). In some species of yeast replicative aging may be partially caused by [[homologous recombination]] between rDNA repeats; [[excision (genetics)|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 [[titration|titrating]] away (competing for) essential [[nucleotide|nuclear factors]]. ERCs have not been observed in other species of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans. Extrachromosomal circular DNA (eccDNA) has been found in worms, flies and humans. The 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. The mechanisms by which Sir2 homologues in higher organisms regulate lifespan is unclear, but the human SIRT1 protein has been demonstrated to [[deacetylate]] [[p53]], Ku70, and the [[forkhead box proteins|forkhead]] family of [[transcription factor]]s. SIRT1 can also regulate acetylates such as [[P300/CBP|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 [[mitochondria]]l free [[radical (chemistry)|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 growth factor|insulin-like signaling]] in worms, flies and mice are associated with extended lifespan. In yeast, Sir2 activity is regulated by the nicotinamidase PNC1. PNC1 is transcriptionally [[upregulation|upregulated]] under stressful conditions such as [[caloric restriction]], [[heat shock]], and [[osmotic shock]]. By converting [[nicotinamide]] to [[niacin]], it removes nicotinamide, which inhibits 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 [[grape]]s, was reported to extend the lifespan of yeast, worms, and flies. It has been shown to activate Sir2 and therefore mimics the effects of calorie restriction. 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<ref>{{cite journal |author=Ryley J, Pereira-Smith OM|title=Microfluidics device for single cell gene expression analysis in Saccharomyces cerevisiae |journal=Yeast |volume=23 |issue=14-15 |pages=1065-73 |year=2006 |pmid=17083143}}</</ref>. 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{{Fact|date=July 2008}} 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(genetics)|cat1]] || [[p66shc]] | || [[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]] || || || |- | || || [[AMPK|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]] <ref>Gavrilov, L. A., Gavrilova, N. S., 2001 [http://longevity-science.org/JTB-01.pdf The reliability theory of aging and longevity]. Journal of Theoretical Biology 213(4): 527-545. PMID 11742523</ref> <ref>F. Yaghmaie, O. Saeed, S.A. Garan, M.A. Voelker, A.M. Gouw, W. Freitag, H. Sternberg and P.S. Timiras "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17034982 Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice]". ''International Journal of Developmental Neuroscience'', Vol. 24, Issue 7, 2006, pp. 431-436</ref>. Moreover, cellular senescence is not observed in many organisms, including [[perennial]] plants, [[sea sponge|sponge]]s, [[coral]]s, and [[lobster]]s. In those species where cellular senescence is observed, cells eventually become post-[[mitotic]] when they can no longer replicate themselves through the process of [[mitosis|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]] [[mutation]]s and would therefore be in danger of becoming [[cancer]]ous if cell division continued. Lately the role of [[telomere]]s in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of [[cloning]]. The successive shortening of the [[chromosome|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 "[[biological immortality|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 [[genetic engineering|genetically engineer]] all cells in the human body to have this capability by employing [[gene therapy]] and thereby stop or reverse aging, effectively making the entire organism potentially immortal. [[Cancer]] cells are usually immortal. This evasion of cellular senescence is the result, in about 85% of tumors, of up-activation of their [[telomerase]] genes <ref name="pmid10647931">{{cite journal |author=Hanahan D, Weinberg RA |title=The hallmarks of cancer |journal=Cell |volume=100 |issue=1 |pages=57–70 |year=2000 |pmid=10647931|doi=10.1016/S0092-8674(00)81683-9}}</ref>. This simple observation suggests that reactivation of telomerases in healthy individuals could greatly increase their cancer risk. <!--Is immortality of the cancer cells what makes them so deadly?--> ===Chemical damage=== [[Image:Edward S. Curtis Collection People 086.jpg|thumb|200px|Elderly Klamath woman photographed by Edward S. Curtis in 1924]] The earliest aging theory was the ''Rate of Living Hypothesis'' described by [[Raymond Pearl]] in 1928<ref>{{cite book | first=Raymond | last=Pearl | year=1928 | title=The Rate of Living, Being an Account of Some Experimental Studies on the Biology of Life Duration | publisher=Alfred A. Knopf | location=New York}}</ref>, 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). (The idea had been posited earlier by [[Max Rubner]]). While there is likely some validity to this theory, in the form of various types of specific damage detailed below which, all other things being equal 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. Similarly, metabolic rate is a poor predictor of lifespan for birds, bats and other species which presumably have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates. With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived [[biopolymer]]s, such as structural [[protein]]s or [[DNA]], caused by ubiquitous chemical agents in the body such as [[oxygen]] and [[sugar]]s, are in part responsible for aging. The damage can include breakage of biopolymer chains, [[cross-linking]] of biopolymers, or chemical attachment of unnatural substituents ([[hapten]]s) 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 (chemistry)|radical]] and eventually other reactive species including other [[peroxide]]s and [[singlet oxygen]], which can in turn generate [[radical (chemistry)|free radical]]s capable of damaging structural proteins and DNA. Certain metal [[ion]]s found in the body, such as [[copper]] and [[iron]], may participate in the process. (In [[Wilson's disease]], a [[genetic disorder|hereditary defect]] which 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 antioxidant]]s {{Fact|date=February 2007}}. [[Sugar]]s such as [[glucose]] and [[fructose]] can react with certain [[amino acid]]s 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 ''[[Advanced glycation endproduct|glycoxidation]]''. [[radical (chemistry)|Free radicals]] can damage [[protein]]s, [[lipids]] or [[DNA]]. [[Glycation]] mainly damages proteins. Damaged proteins and lipids accumulate in [[lysosome]]s 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 [[enzyme]]s reduces cellular functionality. [[Lipid]] [[redox|peroxidation]] of the inner [[mitochondria]]l 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 disease]]s" 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.<ref>http://pubs.niaaa.nih.gov/publications/arh23-4/272-283.pdf</ref> ===Reliability theory=== {{main|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 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 (engineering)|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. It also explains why organisms "prefer" to die according to the [[Gompertz law]], while technical devices usually fail according to the [[Weibull distribution|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. ===Neuro-endocrine-immunological theories=== Senescence may also simply be a result of wear and tear overwhelming repair mechanisms. It is also possible that senescence is a mechanism to control the development and spread of [[cancer]]; if cells have built-in limits to how many times they can replicate, they must somehow overcome this before they can spread indefinitely. ==Miscellaneous== Recently, early senescence has been alleged to be a possible unintended outcome of early [[cloning]] experiments. Most notably, 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 (e.g. by [[Kerry Lynn Macintosh]] in her book, ''Illegal Beings: Human Clones and the Law''), and Dolly's creator, [[Ian Wilmut|Dr.&nbsp;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 ([[genetics|genetic]]) disorders, each called [[progeria]], has been known for some time. Sufferers exhibit symptoms resembling [[Accelerated aging disease|accelerated aging]], including wrinkled skin. The cause of [[Progeria|Hutchinson&ndash;Gilford progeria syndrome]] was reported in the journal ''[[Nature (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== {{wiktionary}} <div class="references" style="-moz-column-count:3; column-count:3;"> * [[Advanced adult]] * [[Aging]] * [[Aging and memory]] * [[Aging-associated diseases]] * [[Aging brain]] * [[Aging DNA]] * [[Aging Research Centre]] {ARC} * [[American Academy of Anti-Aging Medicine]] * [[American Aging Association]] * [[American Federation for Aging Research]] * [[Gerontology|Biogerontology]] * [[Calorie restriction]] * [[DNA damage theory of aging]] * [[DNA repair]] * [[Evolution of ageing]] * [[Strategies for Engineered Negligible Senescence]] (SENS) * [[Fisher's reproductive value]] * [[Life extension]] * [[List of life extension-related topics]] * [[Maximum life span]] * [[Mitohormesis]] * [[Network Theory of Aging]] * [[Plant senescence]] * [[Progeria]] * [[Real death]] * [[Rejuvenation (aging)|Rejuvenation]] * [[Reliability theory of aging and longevity]] * [[SAGE KE]] * [[Sub-lethal damage]] </div> ==References== {{reflist}} ==External links== *[http://web.mit.edu/agelab AgeLab] ([[Massachusetts Institute of Technology|MIT]]). *[http://www.arclab.org Aging Research Centre (ARC)] *[http://www.worldhealth.net/ American Academy of Anti-Aging Medicine] *[http://www.afar.org/ American Federation for Aging Research] *[http://www.grg.org Gerontology Research Group] Site also has the official tables of known supercentenarians. *[http://www.fli-leibniz.de/index_en.php Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI)] *[http://www.longevitymeme.org/ Longevity Meme (Longevity Activism)] *[http://longevity-science.org/ Longevity Science] *[http://www.benbest.com/lifeext/aging.html Mechanisms of Aging] *[http://ouroboros.wordpress.com/ Ouroboros Anti-Aging Research News] Written by scientists for scientists *[http://ieet.org/index.php/IEET/more/scientistsantiaging/ 54 Scientists' Open Letter on Aging Research] *[http://www.senescence.info senescence.info] Educational resource on the science of aging. 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