Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism. There are a number of hypotheses as to why senescence occurs; for example, some posit it is programmed by gene expression changes, others that it is the cumulative damage caused by biological processes. Senescence is not the inevitable fate of all organisms. A variety of organisms, including some cold-blooded animals, have negligible senescence. Whether senescence as a biological process can be slowed down, halted or even reversed, is a subject of current scientific speculation and research. ^[1]

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

Cellular senescence[link]

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 (SABG, blue areas), a marker of cellular senescence.

Cellular senescence is the phenomenon by which normal diploid cells lose the ability to divide, normally after about 50 cell divisions in vitro. Some cells become senescent after fewer replication 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 in honour of Dr. Leonard Hayflick, co-author with Paul Moorhead, of the first paper describing it in 1961.^[2]. In response to DNA damage (including shortened telomeres), cells either age or self-destruct (apoptosis, programmed cell death) if the damage cannot be easily 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 cells (tracheids and vessel elements) allows the cells to function more efficiently and so deliver water to the upper parts of a plant. The ones that do not self-destruct remain until destroyed by outside forces.

Aging of the whole organism[link]

Organismal senescence is the aging of whole organisms. In general, aging is characterized by the declining ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases. Death is the ultimate consequence of aging, though "old age" is not a scientifically recognized cause of death because there is always a specific proximal cause, such as cancer, heart disease, or liver failure. Aging of whole organisms is therefore a complex process that can be defined as "a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability".^[3]

Differences in maximum life span among 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 80 years.^[4] These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair, antioxidant enzymes, and rates of free radical production.

Supercentenarian 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 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".^[5]

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

Theories of aging[link]

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 because it prevents the onset of cancer. In a few simple species, such as Hydra, senescence is negligible and cannot be detected. All such species have no "post-mitotic" cells; they reduce the effect of damaging free radicals by cell division and dilution. They are biologically immortal but not immortal in the traditional sense as they will eventually fall prey to trauma or disease. Moreover, average lifespans can vary greatly within and between species. This suggests that both genetic and environmental factors contribute to aging.

In general, theories that explain senescence have been divided between the programmed and stochastic 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 that affect the systems responsible for maintenance, repair, and defense responses. The Reproductive-Cell Cycle Theory suggests that aging is caused by changes in hormonal signaling over the lifespan^[6]. 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, damage to tissues and cells by oxygen radicals (widely known as free radicals countered by the even more well-known antioxidants), and cross-linking.

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[link]

A gene can be expressed at various stages of life. Therefore, natural selection can support lethal and harmful alleles, if their expression occurs after reproduction. Senescence may be the product of such selection.^[7][8][9] 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 [by whom?] 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^[10]), 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 allow—even cause—age-related mortality.

Peter Medawar formalised this observation in his mutation accumulation theory of aging.^[11][12] "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 under 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 only live 2–3 years even under optimum conditions. The explanation is that bats have fewer predators, and therefore low extrinsic mortality. More individuals survive to later ages, so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations equates to slower aging and therefore a longer lifespan. Birds are also warm-blooded and are similar in size to many small mammals, yet often live 5–10 times as long. They have less predation pressure than ground-dwelling mammals. Seabirds, which, in general, have the fewest predators of all birds, live longest.

When examining the body-size vs. lifespan relationship, one also observes that predatory mammals tend to live longer than prey mammals 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 their sociality, help 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^[13] 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. Thus, harmful biological changes in old age may result from selection for pleiotropic genes that are beneficial early in life but harmful later on. 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[link]

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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^[14]). 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 stilbenoid 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^[14]). 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.^[15] 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.

According to the GenAge database of aging-related genes there are over 700 genes associated with aging in model organisms: 555 in the soil roundworm (Caenorhabditis elegans), 87 in the bakers' yeast (Saccharomyces cerevisiae), 75 in the fruit fly (Drosophila melanogaster) and 68 in the mouse (Mus musculus).^[16] The following is a list of genes connected to longevity through research^{[citation needed]} on model organisms:

Cellular senescence[link]

As noted above, senescence is not universal. It was once thought that senescence did not occur in single-celled organisms that reproduce through the process of cellular mitosis.^[17] Recent investigation has unveiled a more complex picture. Single cells do accumulate age-related damage. On mitosis the debris is not evenly divided between the new cells. Instead it passes to one of the cells leaving the other cell pristine. With successive generations the call population becomes a mosaic of cells with half ageless and the rest with varying degrees of senescence. ^[18]

Moreover, cellular senescence is not observed in several 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.

The length of the telomere strand has senescence effects, telomere shortening activate extensive alterations in alternative RNA splicing that produce senescence toxins such as progerin that degrades the tissue and makes it more susceptible to failure.^[19]

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.^[20] This simple observation suggests that reactivation of telomerase in healthy individuals could greatly increase their cancer risk.

A research team led by Darren J. Baker and Jan M. van Deursen at the Mayo Clinic in Rochester, Minn., purged all the senescent cells in mice by giving them a drug that forces the cells to self-destruct. The mice’s tissues showed a major improvement in the usual burden of age-related disorders. They did not develop cataracts, avoided the usual wasting of muscle with age, and could exercise much longer on a mouse treadmill. They retained the fat layers in the skin that usually thin out with age and, in people, cause wrinkling.^{[citation needed]}

Chemical damage[link]

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^[21](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.^[22] 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.^[23] (For a critique of the Rate of Living Hypothesis see Living fast, dying when?^[24])

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 termed oxidative stress are linked to the potential benefits of dietary polyphenol antioxidants, for example in coffee^[25], red wine and tea.^[26]

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.^[27]

Reliability theory[link]

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[link]

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,^[28] 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[link]

• Accelerated aging diseases (DNA repair-deficiency disorders)
• Advanced adult
• Ageing
• Ageing brain
• Calorie restriction
• DNA damage theory of aging
• Evolution of ageing
• Fisher's reproductive value
• Immortality
• Life extension
• List of life extension-related topics
• Maximum life span
• Mitohormesis
• Plant senescence
• Progeria, a disease in which symptoms resembling aspects of aging are manifested in childhood
• Reliability theory of aging and longevity
• SAGE KE
• Strategies for Engineered Negligible Senescence (SENS)
• Sub-lethal damage
• Telomere
• Stem cell theory of aging

References[link]

External links[link]

Look up senescence in Wiktionary, the free dictionary.

• AgeLab (Massachusetts Institute of Technology)
• Senescence at the Open Directory Project
• Aging Cell

Aubrey de Grey
In Los Angeles, California, 2008
Born	(1963-04-20) 20 April 1963 (age 49) London, England
Residence	Cambridge, England
Nationality	British
Education	MA, PhD (Cantab)
Alma mater	Trinity Hall, Cambridge
Occupation	Chief Science Officer of the SENS Foundation
Known for	Work in Biogerontology, Strategies for Engineered Negligible Senescence (SENS)
Spouse	Adelaide Carpenter[1]

Aubrey David Nicholas Jasper de Grey (born 20 April 1963) is an English author and theoretician in the field of gerontology, and the Chief Science Officer of the SENS Foundation. He is editor-in-chief of the academic journal Rejuvenation Research, author of The Mitochondrial Free Radical Theory of Aging (1999) and co-author of Ending Aging (2007). He is perhaps best known for his view that human beings could, in theory, live to lifespans far in excess of that which any authenticated cases have lived to today.

De Grey's research focuses on whether regenerative medicine can thwart the aging process. He works on the development of what he calls "Strategies for Engineered Negligible Senescence" (SENS), a tissue-repair strategy intended to rejuvenate the human body and allow an indefinite lifespan. To this end, he has identified seven types of molecular and cellular damage caused by essential metabolic processes. SENS is a proposed panel of therapies designed to repair this damage.^[2]

De Grey is a fellow of the Gerontological Society of America, the American Aging Association, the Institute for Ethics and Emerging Technologies, and an advisor to the Singularity Institute for Artificial Intelligence.^[3] He has been interviewed in recent years in a number of news sources, including CBS 60 Minutes, the BBC, The New York Times, Fortune Magazine, The Washington Post, TED, Popular Science, The Colbert Report, Time, and the Skeptics' Guide to the Universe.

Early life and education[link]

De Grey was born and brought up in London, England.^{[citation needed]} He told The Observer that he never knew his father, and that his mother, an artist, hothoused him in the areas she herself was the weakest: science and mathematics.^[1] He was educated at Sussex House School and Harrow School. He went to the University of Cambridge, graduating in 1985 with a BA in computer science from Trinity Hall.

Career[link]

After graduation in 1985, de Grey joined Sinclair Research Ltd as an AI/software engineer. In 1986, he co-founded Man-Made Minions Ltd to pursue the development of an automated formal program verifier. He met his wife, fruit-fly geneticist Adelaide Carpenter, at a graduate party in Cambridge, and through her was introduced to the science of anti-aging, when her boss needed someone who knew about computers and biology to take over the running of a database on fruit flies.^[4] From 1992 until 2006, he was in charge of software development at the university's Genetics Department for the FlyBase genetic database.^[5]

In 1999, his book The Mitochondrial Free Radical Theory of Aging was published, in which he writes that obviating damage to mitochondrial DNA might by itself extend lifespan significantly, though he said it was more likely that cumulative damage to mitochondria is a significant cause of senescence, but not the single dominant cause. On the basis of the book, the University of Cambridge awarded de Grey a PhD in 2000.^[6]

Strategies[link]

De Grey argues that the fundamental knowledge needed to develop effective anti-aging medicine mostly already exists, and that the science is ahead of the funding. He works to identify and promote specific technological approaches to the reversal of various aspects of aging, or, as de Grey puts it, "the set of accumulated side effects from metabolism that eventually kills us,"^[7] and for the more proactive and urgent approaches to extending the healthy human lifespan. Regarding this issue, de Grey is a supporter of life extension.

As of 2005, his work centered upon a detailed plan called Strategies for Engineered Negligible Senescence (SENS), which is aimed at preventing age-related physical and cognitive decline. In March 2009, he co-founded the SENS Foundation, a non-profit organization based in California, United States, where he currently serves as Chief Science Officer. The Foundation "works to develop, promote and ensure widespread access to regenerative medicine solutions to the disabilities and diseases of ageing,"^[8] focusing on the Strategies for Engineered Negligible Senescence. Before March 2009, the SENS research program was mainly pursued by the Methuselah Foundation, co-founded by de Grey.

A major activity of the Methuselah Foundation is the Methuselah Mouse Prize,^[9] a prize designed to hasten the research into effective life extension interventions by awarding monetary prizes to researchers who stretch the lifespan of mice to unprecedented lengths. De Grey stated in March 2005 "if we are to bring about real regenerative therapies that will benefit not just future generations, but those of us who are alive today, we must encourage scientists to work on the problem of aging." The prize reached 4.2 USD million in February 2007.

In 2005, he was the subject of two highly critical editorials accompanying an article in MIT's Technology Review.^[10]

In 2007, de Grey wrote the book Ending Aging with the assistance of Michael Rae.^[11] It provides a detailed account of the science, politics and social challenges of the entire SENS agenda.^[12]

In a 2008 broadcast on the Arte German & French TV, de Grey confirmed that according to him, the first human who will live up to 1,000 years is probably already alive now, and might even be today between 50 and 60 years old.^[13]

Pro-aging trance[link]

The "pro-aging trance" is a term coined by Grey to describe "the impulsion to leap to embarrassingly unjustified conclusions in order to put the horror of aging out of one’s mind".^[14] According to de Grey, the pro-aging trance or "pro-aging edifice"^[15] is a psychological strategy which people use in order to cope with aging, and which is rooted in the belief that aging is immutable and unavoidable. De Grey refers, in this regard, to the general public's ambivalence towards aging. For example, he states that life extension is often viewed as prolonging, rather than postponing, the period of decrepitude characteristic of old age, a belief that de Grey calls the "Tithonus error", in reference to the myth of Tithonus. He describes this attitude as a rational response to the perceived inevitability of aging. However, de Grey believes that defeating aging is feasible and that the pro-aging trance represents a huge barrier to combating aging.^[16]

The seven types of aging damage proposed by de Grey (The Seven Deadly Things)[link]

1. Cancer-causing nuclear mutations/epimutations:

   These are changes to the nuclear DNA (nDNA), the molecule that contains our genetic information, or to proteins which bind to the nDNA. Certain mutations can lead to cancer, and, according to de Grey, non-cancerous mutations and epimutations do not contribute to aging within a normal lifespan, so cancer is the only endpoint of these types of damage that must be addressed.

2. Mitochondrial mutations:

   Mitochondria are components in our cells that are important for energy production. They contain their own genetic material, and mutations to their DNA can affect a cell’s ability to function properly. Indirectly, these mutations may accelerate many aspects of aging.

3. Intracellular aggregates:

   Our cells are constantly breaking down proteins and other molecules that are no longer useful or which can be harmful. Those molecules which can’t be digested simply accumulate as junk inside our cells. Atherosclerosis, macular degeneration and all kinds of neurodegenerative diseases (such as Alzheimer's disease) are associated with this problem.

4. Extracellular aggregates:

   Harmful junk protein can also accumulate outside of our cells. The amyloid senile plaque seen in the brains of Alzheimer’s patients is one example.

5. Cell loss:

   Some of the cells in our bodies cannot be replaced, or can only be replaced very slowly - more slowly than they die. This decrease in cell number causes the heart to become weaker with age, and it also causes Parkinson's disease and impairs the immune system.

6. Cell senescence:

   This is a phenomenon where the cells are no longer able to divide, but also do not die and let others divide. They may also do other things that they’re not supposed to, like secreting proteins that could be harmful. Immune senescence and type 2 diabetes are caused by this.^{[citation needed]}

7. Extracellular crosslinks:

   Cells are held together by special linking proteins. When too many cross-links form between cells in a tissue, the tissue can lose its elasticity and cause problems including arteriosclerosis and presbyopia.^[7]

Criticism[link]

[edit] Technology Review debate

A debate over the legitimacy of de Grey's proposals for combating aging was published in MIT's Technology Review. In the end, none of the challengers to de Grey were able to convince the judges that SENS was "so wrong that it is unworthy of learned debate," though the judges noted that "the proponents of SENS have not made a compelling case for SENS."

EMBO Reports[link]

An article about SENS published in the viewpoint section of EMBO Reports by 28 scientists concluded that none of de Grey's therapies "has ever been shown to extend the lifespan of any organism, let alone humans".^[17] The SENS Foundation, of which de Grey was a co-founder, seems to agree with the EMBO Report as it states, "If you want to reverse the damage of aging right now I'm afraid the simple answer is, you can't." ^[18] Nonetheless, De Grey argues that this reveals a serious gap in understanding between basic scientists and technologists and between biologists studying aging and those studying regenerative medicine.^[19] The 15-member Research Advisory Board of his own SENS Foundation have signed an endorsement of the plausibility of the SENS approach.^[20]

Recorded public appearances[link]

See also[link]

• Regenerative Medicine
• List of life extension topics

References[link]

External links[link]

v t e Life extension Issues Anti-oxidants · Calorie restriction · Cryonics · Exercise · Free-radical theory · Gerontology · Glycation · Indefinite lifespan · Index of life extension-related articles · Longevity · Mind uploading · Rejuvenation · Senescence · Stem cell treatments · Strategies for Engineered Negligible Senescence · Suspended animation People Bill Andrews · Aubrey de Grey · Terry Grossman · Leonard Hayflick · Denham Harman · Saul Kent · Ray Kurzweil · Marios Kyriazis · Durk Pearson · Sandy Shaw · Roy Walford · Michael D. West Organizations Alcor Life Extension Foundation · Alliance for Aging Research · American Academy of Anti-Aging Medicine · American Aging Association · American Cryonics Society · Cryonics Institute · Cryonics Society · Immortalist Society · Immortality Institute · KrioRus · Life Extension Foundation · Methuselah Foundation · SENS Foundation · Sierra Sciences Books Life Extension (1982) · The First Immortal (1998) · Fantastic Voyage (2004) · Ending Aging (2007) Categories Life extension