Werner syndrome

From Wikipedia, the free encyclopedia

Werner syndrome (adult progeria)
Werner syndrome has an autosomal recessive pattern of inheritance.
Specialty	Endocrinology

Werner syndrome (WS), also known as "adult progeria", is a rare, autosomal recessive disorder which is characterized by the appearance of premature aging.

Werner syndrome is named after the German scientist Otto Werner. He identified the syndrome in four siblings observed with premature aging, which he explored as the subject of his dissertation of 1904.

It has a global incidence rate of less than 1 in 100,000 live births (although incidence in Japan and Sardinia is higher, affecting 1 in 20,000–40,000 and 1 in 50,000, respectively). 1,300 cases had been reported as of 2006. Affected individuals typically grow and develop normally until puberty; the mean age of diagnosis is twenty-four, often realized when the adolescent growth spurt is not observed. The youngest person diagnosed was six years old. The median and mean ages of death are 47–48 and 54 years, respectively. The main cause of death is cardiovascular disease or cancer.

Characteristics

Werner syndrome patients exhibit growth retardation, short stature, premature graying of hair, alopecia (hair loss), wrinkling, prematurely aged faces with beaked noses, skin atrophy (wasting away) with scleroderma-like lesions, lipodystrophy (loss of fat tissues), abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the Achilles tendon and malleoli (around ankles). Other symptoms include change in voice (weak, hoarse, high-pitched), atrophy of gonads leading to reduced fertility, bilateral cataracts (clouding of lens), premature arteriosclerosis (thickening and loss of elasticity of arteries), calcinosis (calcium deposits in blood vessels), atherosclerosis (blockage of blood vessels), type 2 diabetes, osteoporosis (loss of bone mass), telangiectasia, and malignancies. The prevalence of rare cancers, such as meningiomas, are increased in individuals with Werner syndrome.

Gene expression

Gene transcription changes found in WS cells are strikingly similar to those observed in normal aging. At the level of gene expression, WRN protein deficiency causes changes in the pattern of gene expression that markedly resemble those of normal old age.

DNA methylation

The blood of WS patients exhibits accelerated DNA methylation changes that are similar to those observed in normal aging according to a molecular biomarker of aging known as epigenetic clock.

Diagnosis and clinical symptoms

The mutation in the WRN gene that causes Werner syndrome is autosomal and recessive, meaning that sufferers must inherit a copy of the gene from each parent. Patients display rapid premature aging beginning in young adulthood, usually in their early twenties. Diagnosis is based on six cardinal symptoms: premature graying of the hair or hair loss, presence of bilateral cataracts, atrophied or tight skin, soft tissue calcification, sharp facial features, and an abnormal, high-pitched voice. Patients are also generally short-statured due to absence of the adolescent growth spurt. Patients also display decreased fertility. The most common symptom of the six is premature graying and loss of hair. This is also generally the earliest observed symptom, with hair loss occurring first on the scalp and the eyebrows.

Werner syndrome patients often have skin that appears shiny and tight, and may also be thin or hardened. This is due to atrophy of the subcutaneous tissue and dermal fibrosis. Over time, the characteristic facial features may be more apparent due to these skin conditions. Other associated skin conditions include ulcers, which are very difficult to treat in Werner syndrome patients, and are caused in part by decreased potential of skin cells for replication.

WS cataracts are distinctly different from those of normal aging. They are associated with problems in the lens posterior cortex and subcapsular regions. These cataracts are generally treatable with cataract surgery, which should restore normal vision.

Symptoms become apparent in the late teens and early twenties and continue to progress. Most patients live to about fifty years of age. The most common causes of death for people are associated diseases and complications, especially atherosclerosis and cancer.

Associated diseases

Werner syndrome patients are at increased risk for several other diseases, many associated with aging. Atherosclerosis, the thickening of artery walls due to cholesterol buildup, is one common complication. While normal atherosclerosis generally involves the major arteries, smaller arterioles are more likely to be affected. It is possible nervous system disorders are associated. Brain atrophy is present in 40% of patients. Osteoporosis, the loss of bone mineral density common in post-menopausal women, is another common symptom. In contrast with the normal population, the rate of osteoporosis is especially high for male patients. Diabetes mellitus is another common accompaniment. Skin ulcers occur in about 75% of patients – and can be difficult to treat. If skin ulcers become badly infected or develop gangrene, they often require amputation. Unlike most other related diseases and complications, these ulcers are not associated with normal aging.

Patients are also at an increased risk of cancer, especially malignant melanoma. Soft-tissue sarcomas are the most common cancer types. Other types of skin cancer, other epithelial cancers such as thyroid and liver cancers, MDS (myelodysplastic syndrome), and MFH (malignant fibrous histiocytoma) are also prevalent among. Mutations in the WRN gene, especially single-nucleotide polymorphisms (SNPs), are associated with many of the cancers and other associated diseases. WRN SNPs correlate with cancers such as sarcomas and non-Hodgkin lymphomas, as well as diabetes and cardiovascular problems including atherosclerosis.

Causes

Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the gene, WRN, the only gene currently attributed to cause Werner syndrome. WRN, which lies on chromosome 8 in humans, encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases. RecQ helicases are a special type of helicase that function at unique times during DNA repair of doubled stranded breaks, which are a form of DNA damage that results in a break of both strands of DNA. Thus, RecQ helicases are important for maintaining DNA stability, and loss of function of these helicases has important implications in the development of Werner syndrome. In addition to the central domain, there are three exonuclease domains at the N-terminus and a Helicase and Ribonuclease D C-terminal (HRDC) domain at the C-terminus.

When functioning normally, the WRN gene and associated protein are important for maintaining genome stability. WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication. Specifically, the WRN protein has an important role in responding to replication malfunctions, particularly double-stranded breaks, and stalled replication machinery. WRN may reactivate replication by preventing unwanted recombination processes from occurring or by promoting recombination, depending on the type of DNA damage. In addition, the WRN protein physically interacts with or binds to several other proteins that are involved in processing DNA. For example, the WRN protein binds to RPA, which stimulates WRNp's helicase activity. WRNp also physically interacts with p53, a tumor suppressor gene that stops the formation of tumors and the progression of cancers, which inhibits the exonuclease activity of the WRNp. Since WRNp's function depends on DNA, it is only functional when localized to the nucleus.

DNA repair processes

The finding that WRN protein interacts with DNA-PKcs and the Ku protein complex, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for WRN protein in the DNA repair process of non-homologous end joining (NHEJ). WRN protein also physically interacts with the major NHEJ factor X4L4 (XRCC4-DNA ligase 4 complex). X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.

WRN protein appears to play a role in resolving recombination intermediate structures during homologous recombinational repair (HRR) of DNA double-strand breaks.

WRN protein participates in a complex with RAD51, RAD54, RAD54B and ATR proteins in carrying out the recombination step during inter-strand DNA cross-link repair.

Evidence was presented that WRN protein plays a direct role in the repair of methylation induced DNA damage. This process likely involves the helicase and exonuclease activities of WRN protein that operate together with DNA polymerase beta in long patch base excision repair.

Effects on cell structure and function

Mutations which cause Werner syndrome all occur at the regions of the gene which encode for protein, and not at non-coding regions. There are 35 different known mutations of WRN, which correspond to stop codons, insertions, or deletions that result in a frameshift mutation. These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA (mRNA), which increases the rate at which they are degraded. With less mRNA, less is available to be translated into the WRNp protein. Mutations may also lead to the truncation (shortening) of the WRNp protein, leading to the loss of its nuclear localization signal sequence, thus it is no longer transported into the nucleus where it interacts with the DNA. This leads to a reduction in DNA repair. Furthermore, mutated proteins are more likely to be degraded than normal WRNp. Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increasing the survival of these dysfunctional cells. Cells of affected individuals also have reduced lifespan in culture, have more chromosome breaks and translocations and have extensive deletions.

Patients with Werner syndrome lose the RecQ helicase activity in the WRN protein because of the loss of its C-terminus region, but the mechanism by which this happens is unclear. The loss of the helicase activity can have far-reaching consequences in terms of cell stability and mutation. One instance of these consequences involves telomeres. It is thought that the WRN helicase activity is important not only for DNA repair and recombination, but also for maintaining telomere length and stability. Thus, WRN helicase is important for preventing catastrophic telomere loss during DNA replication. In a normal cell, the telomeres (the ends of chromosomes) undergo repeated shortening during the cell cycle, which can prevent the cell from dividing and multiplying. This event can be counteracted by telomerase, an enzyme that extends the ends of the chromosomes by copying the telomeres and synthesizing an identical, but new end that can be added to the existing chromosome. However, patients with Werner syndrome often exhibit accelerated telomere shortening, indicating that there may be a connection between the loss of the WRN helicase activity and telomere and cell instability. While evidence shows that telomere dysfunction is consistent with the premature aging in WS, it has yet to be determined if it is the actual cause of the genomic instability observed in cells and the high rate of cancer in WS patients.

Without the WRN protein, the interwoven pathways of DNA repair and telomere maintenance fail to suppress cancer and the aging symptoms seen in patients with WS. Events such as rapid telomere shortening cause Werner syndrome cells to exhibit low responses to overall cellular stress. In addition to telomere dysfunction, over-expression of oncogenes and oxidation can induce this type of response. High stress causes a synergistic effect, where WS cells become even more sensitive to agents that increase cell stress and agents that damage DNA. As a result, WS cells show a drastic reduction in replicative lifespan and enter into a stage of aging prematurely. The accumulation of these damaged cells due to telomere shortening over many years may be indicative of why Werner syndrome symptoms only appear after an individual is about twenty years old.

Protection of DNA against oxidative damage

WRN protein was found to have a specific role in preventing or repairing DNA damages resulting from chronic oxidative stress, particularly in slowly replicating cells. This finding suggested that WRN may be important in dealing with oxidative DNA damages that underlie normal aging.

Treatment

A cure for Werner syndrome has not yet been discovered. It is often treated by managing the associated diseases and relieving symptoms to improve quality of life. The skin ulcers that accompany WS can be treated in several ways, depending on the severity. Topical treatments can be used for minor ulcers, but are not effective in preventing new ulcers from occurring. In the most severe cases, surgery may be required to implant a skin graft or amputate a limb if necessary. Diseases commonly associated with Werner syndrome such as diabetes and cancer are treated in generally the same ways as they would be for a non-Werner syndrome individual. A change in diet and exercise can help prevent and control arteriosclerosis, and regular cancer screenings can allow for early detection of cancer.

There is evidence that suggests that the cytokine-suppressive anti-inflammatory drug SB203580 may be a possible therapeutic option for patients with Werner's syndrome. This drug targets the p38 signaling pathway, which may become activated as a result of genomic instability and stalled replication forks that are characteristic mutations in WS. This activation of p38 may play a role in the onset of premature cell aging, skin aging, cataracts, and graying of the hair. The p38 pathway has also been implicated in the anti-inflammatory response that causes atherosclerosis, diabetes, and osteoporosis, all of which are associated with Werner's syndrome. This drug has shown to revert the aged characteristics of young WS cells to those seen in normal, young cells and improve the lifespan of WS cells in vitro. SB203580 is in the clinical trial stages, and the same results have not yet been seen in vivo.

In 2010, vitamin C supplementation was found to reverse the premature aging and several tissue dysfunctions in a genetically modified mouse model of the disease. Vitamin C supplementation also appeared to normalize several age-related molecular markers such as the increased levels of the transcription factor NF-κB. In addition, it decreases activity of genes activated in human Werner syndrome and increases gene activity involved in tissue repair. Supplementation of vitamin C is suspected to be beneficial in the treatment of human Werner syndrome, although there was no evidence of anti-aging activity in nonmutant mice. In general, treatments are available for only the symptoms or complications and not for the disease itself.

Background and history

Otto Werner was the first to observe Werner syndrome in 1904 as a part of his dissertation research. As a German ophthalmologist, Werner described several progeria-like features and juvenile cataracts in many of his patients. He noticed these symptoms particularly in a family with four sequential children who all showed the characteristics of the syndrome at around the same age. He assumed the cause to be genetic, though most of his evidence was clinical. Between 1934 and 1941, two internists from New York, Oppenheimer and Kugel, coined the term "Werner Syndrome," igniting a wave of interest and research on the disease. During that time, Agatson and Gartner suggested a possible link between Werner's syndrome and cancer. However, It was not until 1966 that there was a general consensus on the autosomal recessive mode of inheritance for the syndrome. By 1981, geneticists had located the WRN gene on chromosome 8, leading to its cloning in 1996. This cloning of the WRN was significant because it revealed the predicted WRN protein was made from a family of DNA helicases. Prior to 1996, Werner syndrome was thought to be a model for accelerated aging. Since the discovery of the gene, it has become clear that the premature aging displayed in Werner syndrome is not the same, on a cellular level, as normal aging. The role of WRN in DNA repair and its exonuclease and helicase activities have been the subject of many studies in recent years.

Since the initial discovery in 1904, several other cases of Werner syndrome have been recorded. Many of these cases have occurred in Japan, where a founder effect has caused a higher incidence rate than in other populations. The incidence rate of Werner syndrome in Japan is approximately 1 case per 100 thousand people (1:100,000), a large contrast with the rate of incidence for the rest of the world, which is between 1:1,000,000 and 1:10,000,000. A founder effect is also apparent in Sardinia, where there have been 18 recorded cases of Werner syndrome.

Popular culture

On the episode "Stargazer in a Puddle" from the television series Bones, the victim has Werner syndrome, the team discovering in the course of the investigation that her mother killed her daughter because she was dying of another disease and worried that her daughter would have nobody to look after her afterwards, with the tragic twist that the mother began to recover from her disease after her daughter's death. 

Werner syndrome is featured in the 1996 film Jack, starring Robin Williams, in which his character ages four times faster than normal. 

In an early cutscene from the game Metal Gear Solid 4, Otacon cites "classic Werner syndrome" as the most likely cause of Solid Snake's premature aging, though he goes on to say that testing had been inconclusive. It is however later said that Solid Snake's body, created as a genetically engineered clone, had been designed to break down quickly. 

In season 3 episode 9, "The Ballad of Kevin and Tess", of the TV series The 4400, Kevin is said to have Werner syndrome to hide his real condition from the public. 

In The Invisible Man season 1 episode 6, "Impetus", the new character Gloria has an experimentally altered type of Werner syndrome that causes it to become contagious.

The central character in Gail Tsukiyama's novel DREAMING WATER (2002) has Werner's syndrome.

In season 1 episode 8 Cold Comfort from TV series Dark Angel, a character has a "form of progeria, similar to Werner syndrome", due to genetic manipulation. With an appropriate treatment, her condition seems to be stabilized. 

In *Resident Evil: The Final Chapter* (2016), the deadly "T-Virus," which causes the viral pandemic in the Resident Evil (film series), is revealed to be the cure for "adult progeria." James Marcus originally develops the virus to cure his young daughter Alicia Marcus. 

Ratsasan (2018) Tamil movie, features a young man born with Werner's and is a victim of childhood bullying due to his appearance and has bad experience proposing to a girl, who turns into serial killer and hunts down and kills school girls.

Progeria

From Wikipedia, the free encyclopedia

Progeria
Synonyms	Hutchinson–Gilford progeria syndrome (HGPS), progeria syndrome
A young girl with progeria (left). A healthy cell nucleus (right, top) and a progeric cell nucleus (right, bottom).
Pronunciation	/proʊˈdʒɪəriə/
Specialty	Medical genetics
Symptoms	Growth delay, short height, small face, hair loss
Complications	Heart disease, stroke, hip dislocations
Usual onset	9–24 months
Causes	Genetic
Diagnostic method	Based on symptoms, genetic tests
Differential diagnosis	Hallermann–Streiff syndrome, Gottron's syndrome, Wiedemann–Rautenstrauch syndrome
Treatment	Mostly symptomatic
Medication	Lonafarnib
Prognosis	Average age of death is 13 years
Frequency	Rare (1 in 18 million)

Progeria is an extremely rare autosomal dominant genetic disorder in which symptoms resembling aspects of aging are manifested at a very early age. Progeria is one of several progeroid syndromes. Those born with progeria typically live to their mid-teens to early twenties. It is a genetic condition that occurs as a new mutation, and is rarely inherited, as carriers usually do not live to reproduce. Although the term progeria applies strictly speaking to all diseases characterized by premature aging symptoms, and is often used as such, it is often applied specifically in reference to Hutchinson–Gilford progeria syndrome (HGPS).

Progeria was first described in 1886 by Jonathan Hutchinson. It was also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson–Gilford progeria syndrome. The word progeria comes from the Greek words "pro" (πρό), meaning "before" or "premature", and "gēras" (γῆρας), meaning "old age". Scientists are interested in progeria partly because it might reveal clues about the normal process of aging.

Signs and symptoms

Children with progeria usually develop the first symptoms during their first few months of life. The earliest symptoms may include a failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy, additional conditions become apparent usually around 18–24 months. Limited growth, full-body alopecia (hair loss), and a distinctive appearance (a small face with a shallow recessed jaw, and a pinched nose) are all characteristics of progeria. Signs and symptoms of this progressive disease tend to become more marked as the child ages. Later, the condition causes wrinkled skin, atherosclerosis, kidney failure, loss of eyesight, and cardiovascular problems. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is prevalent. People diagnosed with this disorder usually have small, fragile bodies, like those of elderly people. The face is usually wrinkled, with a larger head in relation to the body, a narrow face and a beak nose. Prominent scalp veins are noticeable (made more obvious by alopecia), as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population. Individuals usually retain typical mental and motor development.

Cause

In normal conditions, the LMNA gene codes for a structural protein called prelamin A which undergoes a series of processing steps before attaining its final form, called lamin A. In one of these steps, after prelamin A is made in the cytoplasm, an enzyme called farnesyl transferase attaches a farnesyl functional group to its carboxyl-terminus. The farnesylated prelamin A is then transported through a nuclear pore to the interior of the nucleus. The farnesyl group allows prelamin A to attach temporarily to the nuclear rim. Once the protein is attached, it is cleaved by a protease, thereby removing the farnesyl group along with a few adjacent amino acids. Failure to remove this farnesyl group permanently affixes the protein to the nuclear rim. After cleavage by the protease, prelamin A is referred to as lamin A. Lamin A, along with lamin B and lamin C, makes up the nuclear lamina, which provides structural support to the nucleus. 

Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered to be a point mutation in position 1824 of the LMNA gene, in which cytosine is replaced with thymine. This mutation creates a 5' cryptic splice site within exon 11, resulting in an abnormally short mature mRNA transcript. This mRNA strand, when translated, yields an abnormal variant of the prelamin A protein whose farnesyl group cannot be removed. Because its farnesyl group cannot be removed, this abnormal protein, referred to as progerin, is permanently affixed to the nuclear rim, and therefore does not become part of the nuclear lamina. Without lamin A, the nuclear lamina is unable to provide the nuclear envelope with adequate structural support, causing it to take on an abnormal shape. Since the support that the nuclear lamina normally provides is necessary for the organizing of chromatin during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide.

To date over 1,400 SNPs in the LMNA gene are known. They can manifest as changes in mRNA, splicing, or protein amino acid sequence (e.g. Arg471Cys, Arg482Gln, Arg527Leu, Arg527Cys, Ala529Val). 

Progerin may also play a role in normal human aging, since its production is activated in typical senescent cells.

Unlike other "accelerated aging diseases" (such as Werner syndrome, Cockayne syndrome or xeroderma pigmentosum), progeria may not be directly caused by defective DNA repair. Because these diseases cause changes in different aspects of aging, but never in every aspect, they are often called "segmental progerias."

Diagnosis

Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. A genetic test for LMNA mutations can confirm the diagnosis of progeria.

Treatment

No treatment has yet proven effective. Most treatment options have focused on reducing complications (such as cardiovascular disease) with coronary artery bypass surgery and low-dose aspirin.

Growth hormone treatment has been attempted. The use of Morpholinos has also been attempted in mice and cell cultures in order to reduce progerin production. Antisense Morpholino oligonucleotides specifically directed against the mutated exon 11–exon 12 junction in the mutated pre-mRNAs were used.

Potential therapeutic targets for the inhibition of progerin farnesylation

A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models. A Phase II clinical trial using the FTI lonafarnib began in May 2007. In studies on the cells another anti-cancer drug, rapamycin, caused removal of progerin from the nuclear membrane through autophagy. It has been proved that pravastatin and zoledronate are effective drugs when it comes to the blocking of farnesyl group production. 

Farnesyltransferase inhibitors (FTIs) are drugs that inhibit the activity of an enzyme needed in order to make a link between progerin proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can occur because that attachment takes place and the nucleus is not in a normal state. Lonafarnib is an FTI, which means it can avoid this link, so progerin can not remain attached to the nucleus rim and it now has a more normal state. 

Studies of sirolimus, an mTOR Inhibitor, demonstrate that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are: abolishment of nuclear blebbing, degradation of progerin in affected cells and reduction of insoluble progerin aggregates formation. These results have been observed only in vitro and are not the results of any clinical trial, although it is believed that the treatment might benefit HGPS patients.

The delivery of lonafarnib is not approved by the US Food and Drug Administration (FDA). Therefore, it can only be used in certain clinical trials. Until treatment with FTIs is thoroughly tested in progeria children in clinical trials, its effects on humans cannot be known, although its effects on mice seem to be positive. A 2012 clinical trial found that it improved weight gain and other symptoms of progeria.

Prognosis

As there is no known cure, few people with progeria exceed 13 years of age. At least 90 percent of patients die from complications of atherosclerosis, such as heart attack or stroke.

Mental development is not adversely affected; in fact, intelligence tends to be average to above average. With respect to the features of aging that progeria appears to manifest, the development of symptoms is comparable to aging at a rate eight to ten times faster than normal. With respect to features of aging that progeria does not exhibit, patients show no neurodegeneration or cancer predisposition. They also do not develop conditions that are commonly associated with aging, such as cataracts (caused by UV exposure) and osteoarthritis.

Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems. Sufferers of progeria have normal reproductive development and there are known cases of women with progeria who had delivered healthy offspring.

Epidemiology

A study from the Netherlands has shown an incidence of 1 in 4 million births. Currently, there are about 100 known cases in the world. Approximately 140 cases have been reported in medical history. However, the Progeria Research Foundation believes there may be as many as 150 undiagnosed cases worldwide. 

Classical Hutchinson–Gilford progeria syndrome is usually caused by a sporadic mutation taking place during the early stages of embryo development. It is almost never passed on from affected parent to child, as affected children rarely live long enough to have children themselves. 

There have been only two cases in which a healthy person was known to carry the LMNA mutation that causes progeria. These carriers were identified because they passed it on to their children. One family from India has five children with progeria, though not the classical HGPS type. This family was the subject of a 2005 Bodyshock documentary titled The 80 Year Old Children. The Vandeweert family of Belgium has two children, Michiel and Amber, with classic HGPS.

Society and culture

Notable cases

In 1987, twelve-year-old Mickey Hays, who had progeria, appeared along with Jack Elam in the documentary I Am Not a Freak. Elam and Hays first met during the filming of the 1986 film The Aurora Encounter, in which Hays was cast as an alien. The friendship that developed lasted until Hays died in 1992, age 20. Elam said, "You know I've met a lot of people, but I've never met anybody that got next to me like Mickey."

Harold Kushner's 1978 book When Bad Things Happen to Good People, which explores God and the problem of evil, was written in response to his 14-year-old son's death due to progeria. 

South African hip-hop artist Leon Botha was one of the oldest known progeria sufferers, surviving to the age of 26 before his death in June 2011.

Meg Casey, a Milford, Connecticut artist and spokesperson for disabled people, was born October 1, 1955 and died May 26, 1985. She survived for 29 years with progeria.

Life According to Sam was a 2013 documentary on Foxborough High School (Foxborough, Massachusetts) student Sam Berns. He was age 17 when he died of the disease, January 10, 2014, and a fan of the New England Patriots. Had he lived another day, he would have served as the team's honorary captain in their playoff game versus the Indianapolis Colts. Produced by Sean Fine and Andrea Nix, the film explains progeria and follows the process of finding a cure for it. In an interview, Berns had said that the most important thing people should know about him is that he had a very happy life.

Popular culture

Perhaps one of the earliest influences of progeria on popular culture occurred in the 1922 short story The Curious Case of Benjamin Button by F. Scott Fitzgerald (and later released as a feature film in 2008). The main character, Benjamin Button, is born as a 70-year-old man and ages backwards; it has been suggested that this was inspired by progeria.

Charles Dickens may have described a case of progeria in the Smallweed family of Bleak House, specifically in the grandfather and his grandchildren, Judy and twin brother Bart.

A 2009 Bollywood movie, Paa, was made about the condition; in it, the lead (Amitabh Bachchan) played a 12-year-old child affected by progeria. 

In the 1983 film The Hunger, progeria was the focus of study by Susan Sarandon's character, Dr. Sarah Roberts. 

The 1984 film The Three Wishes of Billy Grier stars Ralph Macchio as a teenager who tries to fulfill his wishes before he dies from the disease.

The 1996 movie Jack deals with the eponymous character (Robin Williams) who has a genetic disorder similar to progeria and the difficulties he faces fitting into society. 

The 2006 movie Renaissance deals with progeria. 

In Tad Williams' novel series Otherland, one of the main characters suffers from progeria. 

In Chuck Palahniuk's 2005 novel Haunted the main villain is Mr. Whittier, a 13-year-old sufferer of progeria. Mr. Whittier tricked middle-aged married women to sleep with him by telling them that he was an 18-year-old virgin, he then blackmailed them into giving him money by telling them that he would charge them with statutory rape if they did not. 

The 2012 Philippine melodrama series, Lorenzo's Time is about a young boy who is placed in cryonics to save him from Progeria.

Research

Several discoveries have been made that have led to greater understandings and perhaps eventual treatment for this disease.

A 2003 report in Nature said that progeria may be a de novo dominant trait. It develops during cell division in a newly conceived zygote or in the gametes of one of the parents. It is caused by mutations in the LMNA (lamin A protein) gene on chromosome 1; the mutated form of lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who did not know anything about progeria until her own son, Sam, was diagnosed at 22 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.

Lamin A

Lamin A is a major component of a protein scaffold on the inner edge of the nucleus called the nuclear lamina that helps organize nuclear processes such as RNA and DNA synthesis.

Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein, now lamin A, is no longer membrane-bound and carries out functions inside the nucleus.

In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing. This results in the symptoms of progeria, although the relationship between the misshapen nucleus and the symptoms is not known. 

A study that compared HGPS patient cells with the skin cells from young and elderly normal human subjects found similar defects in the HGPS and elderly cells, including down-regulation of certain nuclear proteins, increased DNA damage, and demethylation of histone, leading to reduced heterochromatin. Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes. These studies suggest that lamin A defects are associated with normal aging.

Mouse model

Confocal microscopy photographs of the descending aortas of two 15-month-old progeria mice, one untreated (left) and the other treated with the FTI drug tipifarnib (right)

 

Untreated cells from children with the genetic disease progeria (left) compared to similar cells treated with FTIs

 

A mouse model of progeria exists, though in the mouse, the LMNA prelamin A is not mutated. Instead, ZMPSTE24, the specific protease that is required to remove the C-terminus of prelamin A, is missing. Both cases result in the buildup of farnesylated prelamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing. Fong et al. use a farnesyl transferase inhibitor (FTI) in this mouse model to inhibit protein farnesylation of prelamin A. Treated mice had greater grip strength and lower likelihood of rib fracture and may live longer than untreated mice.

This method does not directly "cure" the underlying cause of progeria. This method prevents prelamin A from going to the nucleus in the first place so that no prelamin A can build up on the nuclear membrane, but equally, there is no production of normal lamin A in the nucleus. Lamin A does not appear to be necessary for life; mice in which the Lmna gene is knocked out show no embryological symptoms (they develop an Emery–Dreifuss muscular dystrophy-like condition postnatally). This implies that it is the buildup of prelamin A in the wrong place, rather than the loss of the normal function of lamin A, that causes the disease.

It was hypothesized that part of the reason that treatment with an FTI such as alendronate is inefficient is due to prenylation by geranylgeranyltransferase. Since statins inhibit geranylgeranyltransferase, the combination of an FTI and statins was tried, and markedly improved "the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss, and bone defects".

DNA repair

Repair of DNA double-strand breaks can occur by either of two processes, non-homologous end joining (NHEJ) or homologous recombination (HR). A-type lamins promote genetic stability by maintaining levels of proteins that have key roles in NHEJ and HR. Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and have increased sensitivity to DNA damaging agents. In progeria, the inability to adequately repair DNA damages due to defective A-type lamin may cause aspects of premature aging.

Epigenetic clock analysis of human HGPS

Fibroblast samples from children with Hutchinson–Gilford progeria syndrome exhibit accelerated epigenetic aging effects according to the epigenetic clock for skin & blood samples .

Disposable soma theory of aging

From Wikipedia, the free encyclopedia

The disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. Formulated by Thomas Kirkwood, the disposable soma theory explains that an organism only has a limited amount of resources or "soma" that it can allocate to its various cellular processes. Therefore, a greater investment in growth and reproduction would result in reduced investment in DNA repair maintenance, leading to increased cellular damage, shortened telomeres, accumulation of mutations, compromised stem cells, and ultimately, senescence. Although many models, both animal and human, have appeared to support this theory, parts of it are still controversial. Specifically, while the evolutionary trade-off between growth and aging has been well established, the relationship between reproduction and aging is still without scientific consensus, and the cellular mechanisms largely undiscovered.

Background and history

British biologist Thomas Kirkwood first proposed the disposable soma theory of aging in a 1977 Nature review article. The theory was inspired by Leslie Orgel's Error Catastrophe Theory of Aging, which was published fourteen years earlier, in 1963. Orgel believed that the process of aging arose due to mutations acquired during the replication process, and Kirkwood developed the disposable soma theory in order to mediate Orgel's work with evolutionary genetics.

Principles

The disposable soma theory of aging acts on the premise that there is a tradeoff in resource allocation between somatic maintenance and reproductive investment. Too low an investment in self-repair would be evolutionarily unsound, as the organism would likely die before reproductive age. However, too high an investment in self-repair would also be evolutionarily unsound due to the fact that one's offspring would likely die before reproductive age. Therefore, there is a compromise and resources are partitioned accordingly. However, this compromise is thought to damage somatic repair systems, which can lead to progressive cellular damage and senescence. Repair costs can be categorized into three groups: (1) the costs of increased durability of nonrenewable parts; (2) the costs of maintenance involving cell renewal, and (3) the costs of intracellular maintenance. In a nutshell, aging and decline is essentially a tradeoff for increased reproductive robustness in youth.

Mechanisms

The IGF-1 pathway, which represses FOXO, thus preventing gene expression of longevity-inducing proteins.

Growth and somatic maintenance

Much research has been done on the antagonistic effects of increased growth on lifespan. Specifically, the hormone insulin-like growth factor 1 (IGF-1), binds to a cell receptor, leading to a phosphorylation cascade. This cascade results in kinases phosphorylating forkhead transcription factor (FOXO), deactivating it. Deactivation of FOXO results in an inability to express genes involved in responding to oxidative stress response, such as antioxidants, chaperones, and heat-shock proteins. Additionally, uptake of IGF-1 stimulates the mTOR pathway, which activates protein synthesis (and therefore growth) through upregulation of the translation-promoting S6K1, and also inhibits autophagy, a process necessary for recycling of damaged cellular products. Decline of autophagy causes neurodegeneration, protein aggregation and premature aging. Lastly, studies have also indicated that the mTOR pathway also alters immune responses and stimulates cyclin-dependent kinase (CDK) inhibitors such as p16 and p21. This leads to alteration of the stem-cell niche and results in stem cell exhaustion, another theorized mechanism of aging.

Reproduction and somatic maintenance

The mechanism of why reproduction inhibits lifespan with regards to multicellular organisms is still unclear. Although many models do illustrate an inverse relationship, and the theory makes sense from an evolutionary perspective, the cellular mechanisms have yet to be explored. However, with regards to cellular replication, the progressive shortening of telomeres is a mechanism which limits the amount of generations of a single cell may undergo. Furthermore, in unicellular organisms like Saccharomyces cerevisiae, the formation of extrachromosomal rDNA circles (ERCs) in mother cells (but not daughter cells) upon every subsequent division is an identifiable type of DNA damage that is associated with replication. These ERCs accumulate over time and eventually trigger replicative senescence and death of the mother cell.

Evidence

Growth and aging

There is a large body of evidence indicating the negative effects of growth on longevity across many species. As a general rule, individuals of a smaller size generally live longer than larger individuals of the same species.

Animal models

In dwarf models of mice, such Snell or Ames mice, mutations have arisen, either rendering them incapable of producing IGF-1 or unable to have adequate receptors for IGF-1 uptake. Furthermore, mice injected with growth hormone have been shown to have progressive weight loss, roughing of the coat, curvature of the spine, enlargement of the organs, kidney lesions and increased cancer risk. This effect is also seen in different breeds of dogs, where smaller breeds of dogs typically live significantly longer compared to their larger counterparts. Selectively bred for their small size, smaller dog breeds like the Chihuahua (average lifespan of 15–20 years) have the B/B genotype for the IGF-1 haplotype, reducing the amount of IGF-1 produced. Conversely, large dogs like the Great Dane (average lifespan of 6–8 years) are homozygous for the IGF-1 I allele, which increases the amount of IGF-1 production.

Human models

Initially, it was believed that growth hormone actually prolonged lifespan due to a 1990 study that indicated that injection of growth hormone to men over 60 years of age appeared to reverse various biomarkers implicated in aging, such as decreased muscle mass, bone density, skin thickness, and increased adipose tissue. However, a 1999 study found that administering growth hormone also significantly increased mortality rate. Recent genomic studies have confirmed that the genes involved in growth hormone uptake and signaling are largely conserved across a plethora of species, such as yeast, nematodes, fruit flies, mice and humans. These studies have also shown that individuals with Laron syndrome, an autosomal recessive disorder resulting in dwarfism due to defects in growth hormone receptors, have increased lifespan. Additionally, these individuals have much lower incidences of age-related diseases such as type 2 diabetes and cancer. Lastly, human centenarians around the world are disproportionately of short stature, and have low levels of IGF-1.

Reproduction and aging

Numerous studies have found that lifespan is inversely correlated with both the total amount of offspring birthed, as well as the age at which females first gives birth, also known as primiparity. Additionally, it has been found that reproduction is a costly mechanism that alters the metabolism of fat. Lipids invested in reproduction would be unable to be allocated to support mechanisms involved in somatic maintenance.

Animal models

The disposable soma theory has been consistent with the majority of animal models. It was found in numerous animal studies that castration or genetic deformities of reproduction organs was correlated with increased lifespan. Moreover, in red squirrels, it was found that females with an early primiparity achieved the highest immediate and lifetime reproductive success. However, it was also found that these same individuals had a decreased median and maximum lifespan. Specifically squirrels who mated earlier had a 22.4% rate of mortality until two years of age compared to a 16.5% rate of mortality in late breeders. In addition, these squirrels had an average maximum lifespan of 1035 days compared to an average maximum lifespan of 1245 days for squirrels that bred later.

In another study, researchers selectively bred fruit flies over three years to develop two different strains, an early-reproducing strain and a late-reproducing strain. The late-reproducing line had a significantly longer lifespan than the early-reproducing line. Even more telling was that when the researchers introduced a mutation in the ovarian-associated gene ovoD1, resulting in defective oogenesis, the differences in lifespan between the two lines disappeared. The researchers in this case concluded that "aging has evolved primarily because of the damaging effects of reproduction earlier in life".

Prominent aging researcher Steven Austad also performed a large-scale ecological study on the coast of Georgia in 1993. Austad isolated two opossum populations, one from the predator-infested mainland and one from the predator-absent nearby island of Sapelo. According to the disposable soma theory, a genetically isolated population subject to low environmentally-induced mortality would evolve delayed reproduction and aging. This is because without the pressure of predation, it would be evolutionarily advantageous to allocate more resources to somatic maintenance than reproduction, as early offspring mortality would be low. As predicted, even after controlling for predation, the isolated population had a longer lifespan, delayed primiparity, and reduced aging biomarkers such as tail collagen cross-linking.

Human models

In general, only a few studies exist in human models. It was found that castrated men live longer than their fertile counterparts. Further studies found that in British women, primiparity was earliest in women who died early and latest in women who died at the oldest ages. Furthermore, increased number of children birthed was associated with a decreased lifespan. A final study found that female centenarians were more likely to have children in later life compared average, especially past the age of 40. The researchers discovered that 19.2% of female centenarians had their first child after the age of 40, compared to 5.5% of the rest of the female population.

Relationship between cell damage and aging

The naked mole rat has a disproportionately long life of 30 years through efficient cellular repair mechanisms.

 

There are numerous studies that support cellular damage, often due to a lack of somatic maintenance mechanisms, as a primary determinant for aging, and these studies have given rise to the free radical theory of aging and the DNA damage theory of aging. One study found that the cells of short-living rodents in vitro show much greater mutation rates and a general lack of genome surveillance compared to human cells and are far more susceptible to oxidative stress. Other studies have been conducted on the naked mole rat, a rodent species with remarkable longevity (30 years), capable of outliving the brown rat (3 years) by ten-fold. Additionally, almost no incidence cancer has ever been detected in naked mole rats. Nearly all of the differences found between these two organisms, which are otherwise rather genetically similar, was in somatic maintenance. Naked mole rats were found to have higher levels of superoxide dismutase, a reactive oxygen species clearing antioxidant. In addition, naked mole rats had higher levels of base excision repair, DNA damage response signaling, homologous recombination repair, mismatch repair, nucleotide excision repair, and non-homologous end joining. In fact, many of these processes were near or exceeded human levels. Proteins from naked mole rats were also more resistant to oxidation, misfolding, ubiquitination, and had increased translational fidelity.

Further studies have been conducted on patients with Hutchinson-Gilford Progeria Syndrome (HGPS), a condition that leads to premature aging. Patients with HGPS typically age about seven times faster than average and usually succumb to the disease in their early teens. Patients with HGPS have cellular defects, specifically in the lamin proteins, which regulate the organization of the lamina and nuclear envelope for mitosis.

Lastly, as mentioned previously, it has been found that the suppression of autophagy is associated with reduced lifespan, while stimulation is associated with extended lifespan. Activated in times of caloric restriction, autophagy is a process that prevents cellular damage through clearance and recycling of damaged proteins and organelles.

Criticism

One of the main weaknesses of the disposable soma theory is that it does not postulate any specific cellular mechanisms to which an organism shifts energy to somatic repair over reproduction. Instead, it only offers an evolutionary perspective on why aging may occur due to reproduction. Therefore, parts of it are rather limited outside of the field of evolutionary biology.

Caloric restriction

Schematic showing the reallocation of energy investment towards self-repair during caloric restriction.

 

Critics have pointed out the supposed inconsistencies of the disposable soma theory due to the observed effects of caloric restriction, which is correlated with increased lifespan. Although it activates autophagy, according to classical disposable soma principles, with less caloric intake, there would less total energy to be distributed towards somatic maintenance, and decreased lifespan would be observed (or at least the positive autophagic effects would be balanced out). However, Kirkwood, alongside his collaborator Darryl P. Shanley, assert that caloric restriction triggers an adaptive mechanism which causes the organism to shift a higher proportion of resources to somatic maintenance, away from reproduction. This theory is supported by multiple studies, which show that caloric restriction typically results in impaired fertility, but leave an otherwise healthy organism. Evolutionarily, an organism would want to delay reproduction to when resources were more plentiful. During a resource-barren period, it would evolutionarily unwise to invest resources in progeny that would be unlikely to survive in famine. Mechanistically, the NAD-dependent deacetylase Sirtuin 1 (SIRT-1) is upregulated during low-nutrient periods. SIRT-1 increases insulin sensitivity, decreases the amount of inflammatory cytokines, stimulates autophagy, and activates FOXO, the aforementioned protein involved in activating stress response genes. SIRT-1 is also found to result in decreased fertility.

In additional to differential partitioning of energy allocation during caloric restriction, less caloric intake would result in less metabolic waste in the forms of free radicals like hydrogen peroxide, superoxide and hydroxyl radicals, which damage important cellular components, particularly mitochondria. Elevated levels of free radicals in mice has been correlated with neurodegeneration, myocardial injury, severe anemia, and premature death.

The Grandmother hypothesis

Another primary criticism of the disposable soma theory is that it fails to account for why women tend to live longer than their male counterparts. Afterall, females invest significantly more resources into reproduction and according to the classical disposable soma principles, this would compromise energy diverted to somatic maintenance. However, this can be reconciled with the grandmother hypothesis. The Grandmother Hypothesis states that menopause comes about into older women in order to restrict the time of reproduction as a protective mechanism. This would allow women to live longer and increase the amount of care they could provide to their grandchildren, increasing their evolutionary fitness. And so, although women do invest a greater proportion of resources into reproduction during their fertile years, their overall reproductive period is significantly shorter than men, who are able of reproduction during and even beyond middle age. Additionally, males invest more resources into growth, and have significantly higher levels of IGF-1 compared to females, which is correlated with decreased lifespan. Other variables such as increased testosterone levels in males are not accounted for. Increased testosterone is often associated with reckless behavior, which may lead to a high accidental death rate.

Contradicting models

A few contradicting animal models weaken the validity of the disposable soma theory. This includes studies done on the aforementioned naked mole rats. In these studies, it was found that reproductive naked mole rats actually show significantly increased lifespans compared to non-reproductive individuals, which contradicts the principles of disposable soma. However, although these naked mole rats are mammalian, they are highly atypical in terms of aging studies and may not serve as the best model for humans. For example, naked mole rats have a disproportionately high longevity quotient and live in eusocial societies, where breeding is usually designated to a queen.

Sex biases and environment

The disposable soma theory is tested disproportionately on female organisms for the relationship between reproduction and aging, as females carry a greater burden in reproduction. Additionally, for the relationship between growth and aging, studies are disproportionately conducted on males, to minimize the hormonal fluctuations that occur with menstrual cycling. Lastly, genetic and environmental factors, rather than reproductive patterns, may explain the variations in human lifespan. For example, studies have shown that poorer individuals, to whom nutritious food and medical care is less accessible, typically have higher birth rates and earlier primiparity.

Stem cell theory of aging

From Wikipedia, the free encyclopedia

 

The stem cell theory of aging postulates that the aging process is the result of the inability of various types of stem cells to continue to replenish the tissues of an organism with functional differentiated cells capable of maintaining that tissue's (or organ's) original function. Damage and error accumulation in genetic material is always a problem for systems regardless of the age. The number of stem cells in young people is very much higher than older people and this cause a better and more efficient replacement mechanism in the young contrary to the old. In other words, aging is not a matter of the increase of damage, but a matter of failure to replace it due to decreased number of stem cells. Stem cells decrease in number and tend to lose the ability to differentiate into progenies or lymphoid lineages and myeloid lineages.

 

Maintaining the dynamic balance of stem cell pools requires several conditions. Balancing proliferation and quiescence along with homing and self-renewal of hematopoietic stem cells are favoring elements of stem cell pool maintenance while differentiation, mobilization and senescence are detrimental elements. These detrimental effects will eventually cause apoptosis.

There are also several challenges when it comes to therapeutic use of stem cells and their ability to replenish organs and tissues. First, different cells may have different lifespans even though they are originated from the same stem cells, meaning that aging can occur differently in cells that have longer lifespans as opposed to the ones with shorter lifespans. Also, continual effort to replace the somatic cells may cause exhaustion of stem cells.

Research

Some of the proponents of this theory have been Norman E. Sharpless, Ronald A. DePinho, Huber Warner, Alessandro Testori  and others. Warner came to this conclusion after analyzing human case of Hutchinson's Gilford syndrome and mouse models of accelerated aging. 

Stem cells will turn into certain cells as the body needs them. Stem cells divide more than non stem cells so the tendency of accumulating damage is greater. Although they have protective mechanisms, they still age and lose function. Matthew R. Wallenfang, Renuka Nayak and Stephen DiNardo showed this in their study. According to their findings, it is possible to track male GSCs labeled with lacZ gene in Drosophila model by inducing recombination with heat shock and observe the decrease in GSC number with aging. In order to mark GSCs with lacZ gene, flip recombinase (Flp)-mediated recombination is used to combine a ubiquitously active tubulin promoter followed by an FRT (flip recombinase target) site with a promotorless lacZ ORF (open reading frame) preceded by an FRT site. Heat shock is used to induce Flp recombinase marker gene expression is activated in dividing cells due to recombination. Consequently, all clone of cells derived from GSC are marked with a functional lacZ gene. By tracking the marked cells, they were able to show that GSCs do age.

Another study in a mouse model shows that stem cells do age and their aging can lead to heart failure. Findings of the study indicate that diabetes leads to premature myocyte senescence and death and together they result in the development of cardiomyopathy due to decreased muscle mass.

Behrens et al. have reviewed evidence that age-dependent accumulation of DNA damage in both stem cells and cells that comprise the stem cell microenvironment is responsible, at least in part, for stem cell dysfunction with aging.

Hematopoietic stem cell aging

Hematopoietic stem cells (HSCs) regenerate the blood system throughout life and maintain homeostasis . DNA strand breaks accumulate in long term HSCs during aging. This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence. DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by non-homologous end joining (NHEJ). Lig4 deficiency in the mouse causes a progressive loss of HSCs during aging. These findings suggest that NHEJ is a key determinant of the ability of HSCs to maintain themselves over time.

Hair follicle stem cell aging

A key aspect of hair loss with age is the aging of the hair follicle. Ordinarily, hair follicle renewal is maintained by the stem cells associated with each follicle. Aging of the hair follicle appears to be primed by a sustained cellular response to the DNA damage that accumulates in renewing stem cells during aging. This damage response involves the proteolysis of type XVII collagen by neutrophil elastase in response to the DNA damage in the hair follicle stem cells. Proteolysis of collagen leads to elimination of the damaged cells and then to terminal hair follicle miniaturization.

Evidence against the theory

Diseases such as Alzheimer's disease, end-stage renal failure and heart disease are caused by different mechanisms that are not related to stem cells. Also, some diseases related to hematopoietic system, such as aplastic anemia and complete bone marrow failure, are not especially age-dependent. Aplastic Anemia is often an adverse effect of certain medications but as such it cannot really be considered as evidence against the stem cell theory of aging. The cellularity of the bone marrow does decrease with age and can be usually calculated by the formula 100-age, and this seems consistent with a stem cell theory of aging . A dog study published by Zaucha J.M, Yu C. and Mathioudakis G., et al. also shows evidence against the stem cell theory. Experimental comparison of the engraftment properties of young and old marrow in a mammal model, the dog, failed to show any decrement in stem cell function with age.

Other theories of aging

The aging process can be explained with different theories. These are evolutionary theories, molecular theories, system theories and cellular theories. The evolutionary theory of ageing was first proposed in the late 1940s and can be explained briefly by the accumulation of mutations (evolution of ageing), disposable soma and antagonistic pleiotropy hypothesis. The molecular theory of ageing includes phenomena such as gene regulation (gene expression), codon restriction, error catastrophe, somatic mutation (accumulation of genetic material damage) and dysdifferentiation (DNA damage theory of aging). The system theories include the immunologic approach to ageing, rate-of-living and the alterations in neuroendocrinal control mechanisms. (Seehomeostasis). Cellular theory of ageing can be categorized as telomere theory, free radical theory (free-radical theory of aging) and apoptosis. The stem cell theory of aging is also a sub-category of cellular theories.