Centenarian

From Wikipedia, the free encyclopedia

Artist Mary Jane Alexander's portraits of centenarians at the Oklahoma Heritage Association

A centenarian is a person who lives to (or beyond) the age of 100 years. Because life expectancies worldwide are below 100 years, the term is invariably associated with longevity. In 2012, the United Nations estimated that there were 316,600 living centenarians worldwide.

As life expectancy is increasing across the world, and the world population has also increased rapidly, the number of centenarians is expected to increase quickly in the future. According to the UK ONS, one-third of babies born in 2013 in the UK are expected to live to 100.

Supercentenarian

A supercentenarian, sometimes hyphenated as super-centenarian, is a human who has lived to the age of 110 or more, something only achieved by about one in 1,000 centenarians. 

Even rarer is a person who has lived to age 115 – there are only 46 people in recorded history who have indisputably reached this age, of whom only Kane Tanaka, Maria Giuseppa Robucci and Shimoe Akiyama are living as of 2019.

Current incidences

Japan currently has the greatest number of known centenarians of any nation with 67,824 according to their 2017 census, along with the highest proportion of centenarians at 34.85 per 100,000 people. Japan started recording its centenarians in 1963. The number of Japanese centenarians in that year was 153, but surpassed the 10,000 mark in 1998; 20,000 in 2003; and 40,000 in 2009.

According to a 1998 United Nations demographic survey, Japan is expected to have 272,000 centenarians by 2050; other sources suggest that the number could be closer to 1 million. The incidence of centenarians in Japan was one per 3,522 people in 2008.

In Japan, the number of centenarians is highly skewed towards females. Japan in fiscal year 2016 had 57,525 female centenarians, while males were 8,167, a ratio of 7:1. The increase of centenarians was even more skewed at 11.6:1.

Centenarian populations by country

The total number of living centenarians in the world remains uncertain. It was estimated by the Population Division of the United Nations as 23,000 in 1950, 110,000 in 1990, 150,000 in 1995, 209,000 in 2000, 324,000 in 2005 and 455,000 in 2009. However, these older estimates did not take into account the contemporary downward adjustments of national estimates made by several countries such as the United States; thus, in 2012, the UN estimated there to be only 316,600 centenarians worldwide.^[1] The following table gives estimated centenarian populations by country, including both the latest and the earliest known estimates, where available.

Country	Latest estimate (year)	Earliest estimate (year)	Centenarians per 100,000 people
Andorra	7 (2002)	–	10.2
Argentina	3,487 (2010)	–	8.7
Australia	4,252 (2011)	50 (1901)	18.8
Austria	1,371 (2014)	232 (1990), 25 (1960)	16.1
Belgium	2,001 (2015)	23 (1950)	16.9
Brazil	23,760 (2010)	–	12.5
Canada	7,569 (2011)	–	22.3
China	48,921 (2011)	4,469 (1990), 17,800 (2007)	3.6
Czech Republic	625 (2011)	404 (2006)	5.9
Denmark	889 (2010)	32 (1941)	16.1
Estonia	150 (2016)	42 (1990)	11.4
Finland	759 (2015)	11 (1960)	13.8
France	21,393 (2016)	100 (1900)	32.1
Germany	17,000 (2012)	232 (1885)	21
Hungary	1,516 (2013)	227 (1990), 76 (1949)	15.3
Iceland	32 (2015)	3 (1960)	9.7
India	27,000 (2015)		2.1
Ireland	389 (2011)	87 (1990)	8.5
Israel	2,143 (2011)		27.6
Italy	19,095 (2015)	19,095 (2015), 99 (1872)	31.5
Japan	67,824 (2017)	54,397 (2013) 111 (1950), 155 (1960)	48
Mexico	7,441 (2010)	2,403 (1990)	6.6
Netherlands	1,743 (2010)	18 (1830)	10.4
New Zealand	297 (1991)	18 (1960)	5.9
Norway	636 (2010)	44 (1951)	13.1
Peru	1,682 (2011)	–	5.6
Poland	2,414 (2009)	500 (1970)	6.3
Portugal	4,066 (2015)	–	38.9
Russia	6,800 (2007)	-	4.8
Singapore	724 (2011)	41 (1990)	13.7
Slovenia	224 (2013)	2 (1953)	10.9
South Africa	15,581 (2011)	-	30.1
South Korea	3,861 (2014)	961	7.7
Spain	17,423 (2016)	4,269 (2002)	37.5
Sweden	2,084 (2017)	46 (1950)	20.6
Switzerland	1,306 (2010)	7 (1860)	16.6
Thailand	23,399 (2014)		35.9
Turkey	5,293 (2015)	-	6.7
United Kingdom	13,780 (2013)	107 (1911)	21.5
United States	72,000 (2015)	53,364 (2010), 2,300 (1950)	22
Uruguay	519 (2011)	–	15.8
World Estimates	451,000 (2015)	316,600 (2012), 23,000 (1950)	6.2

Recognition worldwide

In many countries, people receive a gift or congratulations from state institutions on their 100th birthday.

Europe

Swedish centenarians receive a telegram from the King and Queen of Sweden.

Centenarians born in Italy receive a letter from the President Of The Republic Of Italy. 

In the United Kingdom and the other Commonwealth realms, the British (and Commonwealth) monarch sends greetings (formerly as a telegram) on the 100th birthday and on every birthday beginning with the 105th. The tradition of Royal congratulations dates from 1908, when the Secretary for King Edward VII sent a congratulatory letter to Reverend Thomas Lord of Horncastle in a newspaper clipping, declaring, "I am commanded by the King to congratulate you on the attainment of your hundredth year, after a most useful life." The practice was formalized from 1917, under the reign of King George V, who also sent congratulations on the attainment of a 60th Wedding anniversary. Queen Elizabeth II sends a greeting card style with the notation: "I am so pleased to know that you are celebrating your one-hundredth birthday, I send my congratulations and best wishes to you on such a special occasion", thereafter each few years the card is updated with a current picture of the Queen to ensure people do not receive the same card more than once. The Queen further sends her congratulations on one's 105th birthday and every year thereafter as well as on special wedding anniversaries; people must apply for greetings three weeks before the event, on the official British Monarch's website.

Centenarians born in Ireland receive a €2,540 "Centenarians' Bounty" and a letter from the President of Ireland, even if they are resident abroad.

Greeting Card sent from former US President Gerald Ford and first lady Betty Ford

United States

In the United States, centenarians traditionally receive a letter from the President, congratulating them for their longevity.

Asia

Japanese centenarians receive a silver cup and a certificate from the Prime Minister of Japan upon the Respect for the Aged Day following their 100th birthday, honoring them for their longevity and prosperity in their lives.

Worldwide cultural traditions and rituals

An aspect of blessing in many cultures is to offer a wish that the recipient lives to 100 years old. Among Hindus, people who touch the feet of elders are often blessed with "May you live a hundred years". In Sweden, the traditional birthday song states, May he/she live for one hundred years. In Judaism, the term May you live to be 120 years old is a common blessing. In Poland, Sto lat, a wish to live a hundred years, is a traditional form of praise and good wishes, and the song "sto lat, sto lat" is sung on the occasion of the birthday celebrations—arguably, it is the most popular song in Poland and among Poles around the globe. 

Chinese emperors were hailed to live ten thousand years, while empresses were hailed to live a thousand years. In Italy, "A hundred of these days!" (cento di questi giorni) is an augury for birthdays, to live to celebrate 100 more birthdays. Some Italians say "Cent'anni!", which means "a hundred years", in that they wish that they could all live happily for a hundred years. In Greece, wishing someone Happy Birthday ends with the expression να τα εκατοστήσεις (na ta ekatostisis), which can be loosely translated as "may you make it one hundred birthdays". In Sri Lanka, it is a custom to bless as " you may live 220 instead of 120".

Centenarians in antiquity

While the number of centenarians per capita was much lower in ancient times than today, the data suggest that they were not unheard of. Estimates of life expectancy in antiquity are far lower than modern values mostly due to the far greater incidence of deaths in infancy or childhood. Those who lived past early childhood had a reasonable chance of living to a relatively old age. The assumption of what constitutes "old age", or being "elderly", at least, seems to have remained unchanged since antiquity, the line being generally drawn at either sixty or sixty-five years; Psalm 90:10 in the Hebrew Bible appears to give seventy to eighty years as the natural life expectancy of a person surviving into old age, "The years of our life are seventy, or even by reason of strength eighty". A survey of the lifespans of male individuals with entries in the Oxford Classical Dictionary (i.e., a sample pre-selected to include those who lived long enough to attain historical notability) found a median lifespan of 72 years, and a range of 32 to 107 years, for 128 individuals born before 100 BC (though the same study found a median lifespan of 66 years for 100 individuals born after 100 BC but no later than 602 AD); by comparison, male individuals listed in Chambers Biographical Dictionary who died between 1900 and 1949 had a median lifespan of 71.5 years, with a range between 29 and 105 years. The author of the 1994 study concluded that it was only in the second half of the 20th century that medical advances have extended the life expectancy of those who live into adulthood.

Reliable references to individuals in antiquity who lived past 100 years are quite rare, but they do exist. Regnal dates of Bronze Age monarchs are notoriously unreliable; the sixth dynasty Egyptian ruler Pepi II sometimes listed as having lived c. 2278 – c. 2184 BC, as he is said to have reigned for 94 years,^[73] but alternative readings cite a reign of just 64 years.

Diogenes Laërtius (c. AD 250) gives one of the earliest references regarding the plausible centenarian longevity given by a scientist, the astronomer Hipparchus of Nicea (c. 185 – c. 120 BC), who, according to the doxographer, assured that the philosopher Democritus of Abdera (c. 470/460 – c. 370/360 BC) lived 109 years. All other ancient accounts of Democritus appear to agree that the philosopher lived at least 90 years. The case of Democritus differs from those of, for example, Epimenides of Crete (7th and 6th centuries BC), who is said to have lived an implausible 154, 157 or 290 years, depending on the source. Other ancient Greek philosophers thought to have lived beyond the age of 90 include Xenophanes of Colophon (c. 570/565 – c. 475/470 BC), Pyrrho of Ellis (c. 360 - c. 270 BC), and Eratosthenes of Cirene (c. 285 – c. 190 BC). Hosius of Córdoba, the man who convinced Constantine the Great to call the First Council of Nicaea, reportedly lived to age 102. 

A rare record of an ordinary person who lived to be a centenarian is the tombstome of Roman British legionary veteran Julius Valens, inscribed "VIXIT ANNIS C".

In the medieval period, Albert Azzo II, Margrave of Milan (d. 1097) is reported by Bernold of Constance as having lived past 100 years (iam maior centenario).

Research

Research in Italy

Research in Italy suggests that healthy centenarians have high levels of both vitamin A and vitamin E and that this seems to be important in causing their extreme longevity. Other research contradicts this, however, and has found that this theory does not apply to centenarians from Sardinia, for whom other factors probably play a more important role. A preliminary study carried out in Poland showed that, in comparison with young healthy female adults, centenarians living in Upper Silesia had significantly higher red blood cell glutathione reductase and catalase activities, although serum levels of vitamin E were not significantly higher. Researchers in Denmark have also found that centenarians exhibit a high activity of glutathione reductase in red blood cells. In this study, the centenarians having the best cognitive and physical functional capacity tended to have the highest activity of this enzyme.

Other research has found that people whose parents became centenarians have an increased number of naïve B cells. It is well known that the children of parents who have a long life are also likely to reach a healthy age, but it is not known why, although the inherited genes are probably important. A variation in the gene FOXO3 A is known to have a positive effect on the life expectancy of humans, and is found much more often in people living to 100 and beyond - moreover, this appears to be true worldwide.

Men and women who are 100 or older tend to have extroverted personalities, according to Thomas T. Perls, the director of the New England Centenarian Study at Boston University. Centenarians will often have many friends, strong ties to relatives and high self-esteem. In addition, some research suggests that the offspring of centenarians are more likely to age in better cardiovascular health than their peers.

DNA repair

Lymphoblastoid cell lines established from blood samples of centenarians have significantly higher activity of the DNA repair protein PARP (Poly ADP ribose polymerase) than cell lines from younger (20 to 70 years old) individuals. The lymphocytic cells of centenarians have characteristics typical of cells from young people, both in their capability of priming the mechanism of repair after H₂O₂ sublethal oxidative DNA damage and in their PARP capacity. PARP activity measured in the permeabilized mononuclear leukocyte blood cells of thirteen mammalian species correlated with maximum lifespan of the species. These findings suggest that PARP mediated DNA repair activity contributes to the longevity of centenarians, consistent with the DNA damage theory of aging.

Japanese Bio-Study

Many experts attribute Japan's high life expectancy to the typical Japanese diet, which is particularly low in refined simple carbohydrates, and to hygienic practices. The number of centenarians in relation to the total population was, in September 2010, 114% higher in Shimane Prefecture than the national average. This ratio was also 92% higher in Okinawa Prefecture. In Okinawa, studies have shown five factors that have contributed to the large number of centenarians in that region:

1. A diet that is heavy on grains, fish, and vegetables and light on meat, eggs, and dairy products.
2. Low-stress lifestyles, which are proven significantly less stressful than that of the mainland inhabitants of Japan.
3. A caring community, where older adults are not isolated and are taken better care of.
4. High levels of activity, where locals work until an older age than the average age in other countries, and more emphasis on activities like walking and gardening to keep active.
5. Spirituality, where a sense of purpose comes from involvement in spiritual matters and prayer eases the mind of stress and problems.

Although these factors vary from those mentioned in the previous study, the culture of Okinawa has proven these factors to be important in its large population of centenarians.

A historical study from Korea found that male eunuchs in the royal court had a centenarian rate of over 3%, and that eunuchs lived on average 14 to 19 years longer than uncastrated men.

Centenarian controversy in Japan

The number of Japanese centenarians was called into question in 2010, following a series of reports showing that hundreds of thousands of elderly people had gone "missing" in the country. The deaths of many centenarians had not been reported, casting doubt on the country's reputation for having a large population of centenarians.

In July 2010, Sogen Kato, a centenarian listed as the oldest living male in Tokyo, registered to be aged 111, was found to have died some 30 years before; his body was found mummified in his bed, resulting in a police investigation into centenarians listed over the age of 105. Soon after the discovery, the Japanese police found that at least 200 other Japanese centenarians were "missing", and began a nationwide search in early August 2010.

Epigenetic studies

By measuring the biological age of various tissues from centenarians, researchers may be able to identify tissues that are protected from aging effects. According to a study of 30 different body parts from centenarians and younger controls, the cerebellum is the youngest brain region (and probably body part) in centenarians (about 15 years younger than expected ) according to an epigenetic biomarker of tissue age known as epigenetic clock.

These findings could explain why the cerebellum exhibits fewer neuropathological hallmarks of age related dementias compared to other brain regions. Further, the offspring of semi-supercentenarians (subjects who reached an age of 105–109 years) have a lower epigenetic age than age-matched controls (age difference=5.1 years in peripheral blood mononuclear cells) and centenarians are younger (8.6 years) than expected based on their chronological age.

Media references

Centenarians are often the subject of news stories, which often focus on the fact that they are over 100 years old. Along with the typical birthday celebrations, these reports provide researchers and cultural historians with evidence as to how the rest of society views this elderly population. Some examples:

• 107-year-old Arkansas man Monroe Isadore dies in shootout with SWAT
• 101-year-old Nepalese man Funchu Tamang was rescued from the Nepal earthquake in 2015
• In 2015, Japanese man Hidekichi Miyazaki, a masters athlete, became the world's oldest sprinter upon winning the 100m at the age of 105, earning a place in the Guinness World Record book
• William A."Bill" Del Monte, the last known survivor of the 1906 San Francisco earthquake, died at a retirement faculty in Marin County in 2016 at the age of 109.
• In 2015, Mieko Nagaoka, a 100-year-old Japanese woman, became the first centenarian to complete a 1500m swim in a 25-meter pool; specifically, she completed 30 laps of the pool in 1 hour, 15 minutes, 54 seconds, in a masters event in Matsuyama, Japan.
• In May 2015 Marjorie "Bo" Gilbert, from South Wales, became the first centenarian to appear in the magazine Vogue, when she was featured as part of an advertisement for the department store Harvey Nichols.
• On April 30, 2016, Ida Keeling became the first woman in history to complete a 100-meter run at the age of 100. Her time of 1:17.33 was witnessed by a crowd of 44,469 at the 2016 Penn Relays.
• In 2017, Julia Hawkins (age 101) became the oldest woman ever in the USA Track and Field Outdoors Masters Championships, and ran the 100 meters in 40.12 seconds. Previously that year she had run the 100 meters in 39.62 seconds. That is a new world record for women 100 or older.

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 .