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62-754: TRF may refer to: Medicine and Science [ edit ] Terminal restriction fragments, used in measuring telomere length Thyrotropin-releasing factor , a peptide hormone secreted by the hypothalamus Time-restricted feeding , a type of intermittent fasting Transfer RNA-derived fragment TERF1 , Telomeric repeat-binding factor 1 (also known as TRF1) Places [ edit ] Sandefjord Airport, Torp , Norway, IATA code Thief River Falls, Minnesota , USA Organisations [ edit ] Tactical recognition flash , UK armed forces Texas Renaissance Festival , USA Thoroughbred Retirement Foundation , racehorse rescue organization TRF (group) ,

124-536: A J-pop group Regional Federal Courts (Portuguese: Tribunais Regionais Federais ), Brazilian Federal appellate courts Other [ edit ] Tuned radio frequency receiver , a type of radio Trinidadian Creole , by ISO 639 code TRF1 , French howitzer Thea Realm Fighters , unreleased fighting game for the Atari Jaguar Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with

186-500: A T-loop. G-quadruplexes present an obstacle for enzymes such as DNA-polymerases and are thus thought to be involved in the regulation of replication and transcription. Many organisms have a ribonucleoprotein enzyme called telomerase, which carries out the task of adding repetitive nucleotide sequences to the ends of the DNA. Telomerase "replenishes" the telomere "cap" and requires no ATP. In most multicellular eukaryotic organisms, telomerase

248-506: A T-loop. This loop is analogous to a knot, which stabilizes the telomere, and prevents the telomere ends from being recognized as breakpoints by the DNA repair machinery. Should non-homologous end joining occur at the telomeric ends, chromosomal fusion would result. The T-loop is maintained by several proteins, collectively referred to as the shelterin complex. In humans, the shelterin complex consists of six proteins identified as TRF1 , TRF2 , TIN2 , POT1 , TPP1 , and RAP1 . In many species,

310-584: A group of scientists organized at Geron Corporation by Geron's founder Michael D. West , that tied telomere shortening with the Hayflick limit. The cloning of the catalytic component of telomerase enabled experiments to test whether the expression of telomerase at levels sufficient to prevent telomere shortening was capable of immortalizing human cells. Telomerase was demonstrated in a 1998 publication in Science to be capable of extending cell lifespan, and now

372-492: A major influence on telomere shortening in vivo . There is a multitude of ways in which oxidative stress, mediated by reactive oxygen species (ROS), can lead to DNA damage; however, it is yet unclear whether the elevated rate in telomeres is brought about by their inherent susceptibility or a diminished activity of DNA repair systems in these regions. Despite widespread agreement of the findings, widespread flaws regarding measurement and sampling have been pointed out; for example,

434-411: A mechanism for remembering what replication level they are at. He interpreted his finding that normal cells are mortal, to be an indication of aging at the cellular level. Hayflick demonstrated for the first time that mortal (normal) and immortal (malignant) mammalian cells existed. Hayflick developed the first normal human diploid cell strains for studies on human aging and for research use throughout

496-806: A member of twenty scientific and professional societies in which he has held several high offices including President of the Gerontological Society of America from 1982 to 1983. He was a founding member of the Council of the National Institute on Aging, NIH, and chairman of its executive committee. He was a consultant to the National Cancer Institute and the World Health Organization , and was a member of several scientific advisory boards. He

558-475: A memory and can remember at what doubling level they have reached. He demonstrated that his normal human cell strains were free from contaminating viruses. His cell strain WI-38 soon replaced primary monkey kidney cells and became the substrate for the production of most of the world's human virus vaccines. Hayflick discovered that the etiological agent of primary atypical pneumonia (also called "walking pneumonia")

620-430: A special structure at the ends of chromosomes was independently proposed in 1938 by Hermann Joseph Muller , studying the fruit fly Drosophila melanogaster , and in 1939 by Barbara McClintock , working with maize. Muller observed that the ends of irradiated fruit fly chromosomes did not present alterations such as deletions or inversions. He hypothesized the presence of a protective cap, which he coined "telomeres", from

682-718: A suspected species and tissue dependency of oxidative damage to telomeres is said to be insufficiently accounted for. Population-based studies have indicated an interaction between anti-oxidant intake and telomere length. In the Long Island Breast Cancer Study Project (LIBCSP), authors found a moderate increase in breast cancer risk among women with the shortest telomeres and lower dietary intake of beta carotene, vitamin C or E. These results suggest that cancer risk due to telomere shortening may interact with other mechanisms of DNA damage, specifically oxidative stress. Although telomeres shorten during

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744-480: A year after its founding and for the next 25 years. He developed their technology for growing animal cells in fermentation tanks in which most of their products were produced. Hayflick was one of several prominent biologists featured in the 1995 science documentary Death by Design: The Life and Times of Life and Times . Hayflick died in Sea Ranch, California , on August 1, 2024, at the age of 96. Hayflick

806-404: Is active only in germ cells , some types of stem cells such as embryonic stem cells , and certain white blood cells . Telomerase can be reactivated and telomeres reset back to an embryonic state by somatic cell nuclear transfer . The steady shortening of telomeres with each replication in somatic (body) cells may have a role in senescence and in the prevention of cancer . This is because

868-440: Is also known for his discovery of the cause of primary atypical pneumonia (" walking pneumonia ") in humans. The etiological agent was first thought to be a virus, but Hayflick showed that it was, in fact, a mycoplasma , a member of the smallest free-living class of microorganisms. The etiological agent was named by him as Mycoplasma pneumoniae , and was first grown by Hayflick on a medium he developed and that bears his name. It

930-507: Is dominated by cross-sectional and correlational studies, which makes causal interpretation problematic. A 2020 review argued that the relationship between psychosocial stress and telomere length appears strongest for stress experienced in utero or early life. The phenomenon of limited cellular division was first observed by Leonard Hayflick , and is now referred to as the Hayflick limit . Significant discoveries were subsequently made by

992-458: Is essential for telomere maintenance and capping. Multiple proteins binding single- and double-stranded telomere DNA have been identified. These function in both telomere maintenance and capping. Telomeres form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle, stabilized by telomere-binding proteins . At the very end of the T-loop,

1054-540: Is known for his research in cell biology , virus vaccine development, and mycoplasmology . In 1962 he discovered that, contrary to the prevailing belief at the time, cultured normal human and animal cells have a limited capacity for replication. This discovery, known as the Hayflick limit , overturned a long-held belief bolstered by Alexis Carrel 's work in the early 20th century that claimed that normal cells would proliferate continuously in culture. Hayflick found that only cancer cells are immortal and that normal cells have

1116-603: Is now used for the production of all of the Rubella Virus vaccine used in the Western Hemisphere. WI-38, or new diploid cell strains, are used today for the manufacture of most human virus vaccines produced throughout the world including those for poliomyelitis , rubella, rubeola, varicella, mumps, rabies, adenoviruses and hepatitis A. Over one billion vaccinees have received vaccines produced on WI-38 or foreign versions of Hayflick's original WI-38. Hayflick

1178-649: Is now used worldwide for mycoplasma isolation and research. Hayflick is the recipient of more than twenty-five major awards including the $ 20,000 Brookdale Award and the Kleemeier Award from the Gerontological Society of America, the Biomedical Sciences and Aging Award from the University of Southern California, The Karl August Forster Lectureship of the Academy of Sciences and Literature and

1240-584: Is one of the most cited contemporary scientists in the world in the fields of biochemistry, biophysics, cell biology, enzymology, genetics and molecular biology. Hayflick is the author of over 275 scientific papers, book chapters and edited books of which four papers are among the 100 most cited scientific papers of the two million papers published in the basic biomedical sciences from 1961 to 1978. The inverted microscope that Hayflick modified for use in his tissue culture and mycoplasma work and on which all other such microscopes have been modeled has been acquired by

1302-676: Is the Terminal Restriction Fragment (TRF) southern blot. There is a Web-based Analyser of the Length of Telomeres ( WALTER ), software processing the TRF pictures. A Real-Time PCR assay for telomere length involves determining the Telomere-to-Single Copy Gene (T/S) ratio, which is demonstrated to be proportional to the average telomere length in a cell. Tools have also been developed to estimate

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1364-675: Is the oldest scientific award in the United States, established in 1823 in honor of Benjamin Franklin. In the mid-1990s, Hayflick was recruited by Geron founder Michael D. West to join the company's Scientific Advisory Board. In 1997, Hayflick was elected Academician and Foreign Member of the Ukrainian Academy of Medical Sciences. In 1998 he was elected corresponding member of the Société de Biologie of France. In 1999, he

1426-481: Is used to quantify the length of telomeres in human white blood cells. A semi-automated method for measuring the average length of telomeres with Flow FISH was published in Nature Protocols in 2006. While multiple companies offer telomere length measurement services, the utility of these measurements for widespread clinical or personal use has been questioned. Nobel Prize winner Elizabeth Blackburn , who

1488-409: Is variable among taxa and linked to the method used for estimating telomere length. In contrast, the available information shows no sex differences in telomere length across vertebrates. Phylogeny and life history traits such as body size or the pace of life can also affect telomere dynamics. For example, it has been described across species of birds and mammals. In 2019, a meta-analysis confirmed that

1550-526: Is well-recognized as capable of immortalizing human somatic cells. Two studies on long-lived seabirds demonstrate that the role of telomeres is far from being understood. In 2003, scientists observed that the telomeres of Leach's storm-petrel ( Oceanodroma leucorhoa ) seem to lengthen with chronological age, the first observed instance of such behaviour of telomeres. A study reported that telomere length of different mammalian species correlates inversely rather than directly with lifespan, and concluded that

1612-595: The American Academy of Anti-Aging Medicine . Hayflick has written numerous articles criticizing both the feasibility and desirability of human life extension , which have provoked responses critical of his views. Hayflick was born May 20, 1928, in Philadelphia, Pennsylvania . He received his Ph.D. at the University of Pennsylvania in 1956. After receiving a post-doctoral fellowship for study at

1674-573: The Stanford University School of Medicine , Stanford, California. Hayflick resigned from Stanford in 1976 in protest to the behavior of a few of its administrators who were later shown to have wrongly accepted the beliefs of an NIH accountant who was unable to understand the unique concept of title to a self-duplicating biological system. Hayflick sued the NIH, who later agreed that the issue was in dispute. The behavior of Stanford and

1736-533: The University of Texas Medical Branch in Galveston under the tutelage of the renowned cell culturist Charles M. Pomerat (1905–1964), he returned to Philadelphia, where he spent ten years as an Associate Member of the Wistar Institute and two years as an Assistant Professor of Research Medicine at the University of Pennsylvania . In 1968, Hayflick was appointed Professor of Medical Microbiology at

1798-465: The 1991 Sandoz Prize for Gerontological Research, he studied the ageing process for more than fifty years. He is known for discovering that normal human cells divide for a limited number of times in vitro (refuting the contention by Alexis Carrel that normal body cells are immortal ). This is known as the Hayflick limit . His discoveries overturned a 60-year old dogma that all cultured cells are immortal. Hayflick demonstrated that normal cells have

1860-488: The 3'-end of the template (corresponding to the potential 5'-end of the lagging-strand). Originally it was believed that the last primer would sit at the very end of the template, thus, once removed, the DNA-polymerase that substitutes primers with DNA (DNA-Pol δ in eukaryotes) would be unable to synthesize the "replacement DNA" from the 5'-end of the lagging strand so that the template nucleotides previously paired to

1922-459: The Greek telos (end) and meros (part). In the early 1970s, Soviet theorist Alexey Olovnikov first recognized that chromosomes could not completely replicate their ends; this is known as the "end replication problem". Building on this, and accommodating Leonard Hayflick 's idea of limited somatic cell division, Olovnikov suggested that DNA sequences are lost every time a cell replicates until

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1984-527: The NIH was later condemned by 85 prominent biologists who viewed him as having been "exonerated" by subsequent events. In 1982 he moved to the University of Florida , Gainesville, where he became Director of the Center for Gerontological Studies and Professor of Zoology in the College of Liberal Arts and Sciences and Professor of Microbiology and Immunology in the College of Medicine. In 1988, Hayflick joined

2046-863: The Regenerative Medicine Secretariat for his "...discovery of the finite replicative capacity of normal human diploid cells..." A third Annual Hayflick Lecture was established at the Friedrich Schiller University in 2013. Hayflick was a Fellow of the American Association for the Advancement of Science , an Honorary Member of the Tissue Culture Association and, according to the Institute of Scientific Information,

2108-887: The University of Mainz, Germany, the Samuel Roberts Noble Foundation Research Recognition Award, the Lifetime Achievement Award of the Society for In Vitro Biology, the Sandoz Prize from the International Association of Gerontology , and the Presidential Award from The International Organization for Mycoplasmology . Hayflick, together with Paul Moorhead, were awarded the prestigious John Scott Award in 2014. This

2170-400: The contribution of telomere length to lifespan remains controversial. There is little evidence that, in humans, telomere length is a significant biomarker of normal aging with respect to important cognitive and physical abilities. Experimentally verified and predicted telomere sequence motifs from more than 9000 species are collected in research community curated database TeloBase . Some of

2232-429: The end replication problem and therefore do not age. Olovnikov suggested that in germline cells, cells of vegetatively propagated organisms, and immortal cell populations such as most cancer cell lines, an enzyme might be activated to prevent the shortening of DNA termini with each cell division. In 1975–1977, Elizabeth Blackburn , working as a postdoctoral fellow at Yale University with Joseph G. Gall , discovered

2294-407: The eukaryotic chromosomes in structure and function. The known structures of bacterial telomeres take the form of proteins bound to the ends of linear chromosomes, or hairpin loops of single-stranded DNA at the ends of the linear chromosomes. At the very 3'-end of the telomere there is a 300 base pair overhang which can invade the double-stranded portion of the telomere forming a structure known as

2356-525: The experimentally verified telomere nucleotide sequences are also listed in Telomerase Database website (see nucleic acid notation for letter representations). Preliminary research indicates that disease risk in aging may be associated with telomere shortening, senescent cells , or SASP ( senescence-associated secretory phenotype ). Several techniques are currently employed to assess average telomere length in eukaryotic cells. One method

2418-537: The exposure to stressors (e.g. pathogen infection, competition, reproductive effort and high activity level) was associated with shorter telomeres across different animal taxa. Studies on ectotherms , and other non-mammalian organisms, show that there is no single universal model of telomere erosion; rather, there is wide variation in relevant dynamics across Metazoa , and even within smaller taxonomic groups these patterns appear diverse. Leonard Hayflick Leonard Hayflick (May 20, 1928 – August 1, 2024)

2480-467: The faculty of the University of California, San Francisco, where he was Professor of Anatomy. Hayflick was a member of numerous national and international scientific and public boards of directors and committees. He has been on the Editorial Boards of more than ten professional journals. Hayflick was Editor-in-Chief of the international journal "Experimental Gerontology" for 13 years. He was

2542-536: The last primer would not be replicated. It has since been questioned whether the last lagging strand primer is placed exactly at the 3'-end of the template and it was demonstrated that it is rather synthesized at a distance of about 70–100 nucleotides which is consistent with the finding that DNA in cultured human cell is shortened by 50–100 base pairs per cell division . If coding sequences are degraded in this process, potentially vital genetic code would be lost. Telomeres are non-coding, repetitive sequences located at

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2604-413: The length of telomere from whole genome sequencing (WGS) experiments. Amongst these are TelSeq, Telomerecat and telomereHunter. Length estimation from WGS typically works by differentiating telomere sequencing reads and then inferring the length of telomere that produced that number of reads. These methods have been shown to correlate with preexisting methods of estimation such as PCR and TRF. Flow-FISH

2666-595: The lifetime of an individual, it is telomere shortening-rate rather than telomere length that is associated with the lifespan of a species. Critically short telomeres trigger a DNA damage response and cellular senescence . Mice have much longer telomeres, but a greatly accelerated telomere shortening-rate and greatly reduced lifespan compared to humans and elephants. Telomere shortening is associated with aging, mortality, and aging-related diseases in experimental animals. Although many factors can affect human lifespan, such as smoking, diet, and exercise, as persons approach

2728-591: The loss reaches a critical level, at which point cell division ends. According to his theory of marginotomy, DNA sequences at the ends of telomeres are represented by tandem repeats, which create a buffer that determines the number of divisions that a certain cell clone can undergo. Furthermore, it was predicted that a specialized DNA polymerase (originally called a tandem-DNA-polymerase) could extend telomeres in immortal tissues such as germ line, cancer cells and stem cells. It also followed from this hypothesis that organisms with circular genome, such as bacteria, do not have

2790-411: The parent strands. This is a consequence of its unidirectional mode of DNA synthesis: it can only attach new nucleotides to an existing 3'-end (that is, synthesis progresses 5'-3') and thus it requires a primer to initiate replication. On the leading strand (oriented 5'-3' within the replication fork), DNA-polymerase continuously replicates from the point of initiation all the way to the strand's end with

2852-445: The primer (made of RNA ) then being excised and substituted by DNA. The lagging strand, however, is oriented 3'-5' with respect to the replication fork so continuous replication by DNA-polymerase is impossible, which necessitates discontinuous replication involving the repeated synthesis of primers further 5' of the site of initiation (see lagging strand replication ). The last primer to be involved in lagging-strand replication sits near

2914-495: The sequence repeats are enriched in guanine , e.g. TTAGGG in vertebrates , which allows the formation of G-quadruplexes , a special conformation of DNA involving non-Watson-Crick base pairing. There are different subtypes depending on the involvement of single- or double-stranded DNA, among other things. There is evidence for the 3'-overhang in ciliates (that possess telomere repeats similar to those found in vertebrates ) to form such G-quadruplexes that accommodate it, rather than

2976-435: The single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA, and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop. Apart from the end replication problem, in vitro studies have shown that telomeres accumulate damage due to oxidative stress and that oxidative stress-mediated DNA damage has

3038-560: The telomeres act as a sort of time-delay "fuse", eventually running out after a certain number of cell divisions and resulting in the eventual loss of vital genetic information from the cell's chromosome with future divisions. Telomere length varies greatly between species, from approximately 300 base pairs in yeast to many kilobases in humans, and usually is composed of arrays of guanine -rich, six- to eight-base-pair-long repeats. Eukaryotic telomeres normally terminate with 3′ single-stranded-DNA overhang ranging from 75 to 300 bases, which

3100-688: The termini of linear chromosomes to act as buffers for those coding sequences further behind. They "cap" the end-sequences and are progressively degraded in the process of DNA replication. The "end replication problem" is exclusive to linear chromosomes as circular chromosomes do not have ends lying without reach of DNA-polymerases. Most prokaryotes , relying on circular chromosomes, accordingly do not possess telomeres. A small fraction of bacterial chromosomes (such as those in Streptomyces , Agrobacterium , and Borrelia ), however, are linear and possess telomeres, which are very different from those of

3162-512: The title TRF . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=TRF&oldid=1233895599 " Category : Disambiguation pages Hidden categories: Articles containing Portuguese-language text Short description is different from Wikidata All article disambiguation pages All disambiguation pages Telomere#Measurement The existence of

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3224-469: The unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends. Blackburn, Carol Greider , and Jack Szostak were awarded the 2009 Nobel Prize in Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase . During DNA replication, DNA polymerase cannot replicate the sequences present at the 3' ends of

3286-434: The upper limit of human life expectancy , longer telomeres may be associated with lifespan. Meta-analyses found that increased perceived psychological stress was associated with a small decrease in telomere length—but that these associations attenuate to no significant association when accounting for publication bias . The literature concerning telomeres as integrative biomarkers of exposure to stress and adversity

3348-461: The world. Prior to his seminal research, all cultured cell lines were immortal and aneuploid . One of these new cell strains, developed by Hayflick and his colleague Paul Moorhead at the Wistar Institute in Philadelphia , Pennsylvania, called WI-38 , has become the most widely used and highly characterized normal human cell population in the world. Hayflick had found that his normal cell strain WI-38

3410-576: Was Chairman of the Scientific Review Board of the American Federation for Aging Research where he was also a vice president and a Member of the board of directors. He was also recruited by Michael D. West , founder of Geron ( Nasdaq :  GERN ) and current CEO of BioTime , to join the company's Scientific and Clinical Advisory Board, on which he served from 1991–2000. Hayflick was also a consultant at Genentech from

3472-496: Was accessioned by the Smithsonian Institution in 2009. Hayflick developed the first practical method for producing powdered cell culture media in 1965. This method is now used worldwide for the production of many tons of powdered media annually for use in research laboratories and commercial production facilities. The technique is not patented and Hayflick received no remuneration from this invention. Hayflick

3534-602: Was an American anatomist who was Professor of Anatomy at the UCSF School of Medicine , and was Professor of Medical Microbiology at Stanford University School of Medicine. He was also past president of the Gerontological Society of America and was a founding member of the council of the National Institute on Aging (NIA). The recipient of a number of research prizes and awards, including

3596-473: Was capable of growing all of the then known human viruses. He hypothesized that because WI-38 was free from contaminating viruses, it could replace the then widely used primary monkey kidney cells, which contained several dangerous contaminating viruses. Indeed, WI-38 became used worldwide for human virus vaccine manufacture, to the benefit of billions of people. Hayflick produced the first oral polio vaccine ever made on his normal human cell strain WI-38. WI-38

3658-565: Was co-founder of one company, promoted the clinical utility of telomere length measures. During the last two decades, eco-evolutionary studies have investigated the relevance of life-history traits and environmental conditions on telomeres of wildlife. Most of these studies have been conducted in endotherms , i.e. birds and mammals. They have provided evidence for the inheritance of telomere length; however, heritability estimates vary greatly within and among species. Age and telomere length often negatively correlate in vertebrates, but this decline

3720-501: Was not a virus as previously believed. He was the first to cultivate the causative organism called a mycoplasma , the smallest free-living organism, which Hayflick isolated on a unique culture medium that bears his name. He named the organism Mycoplasma pneumoniae . In 1959, Hayflick developed the first inverted microscope for use in cell culture research. To this day, all inverted microscopes used in cell culture laboratories worldwide are descended from this prototype. His microscope

3782-652: Was presented with the van Weezel Award by the European Society for Animal Cell Technology and the Lord Cohen of Birkenhead Medal by the British Society for Research on Ageing . The American Aging Association established an Annual Hayflick Lectureship in 1997. A second Annual Hayflick Lecture was established by the University of Alabama at Birmingham in 2000. Hayflick was the recipient of the 2001, $ 10,000 Life Extension Prize and Laureate Diploma from

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3844-815: Was the author of the book, How and Why We Age , published in August 1994 by Ballantine Books , New York City and available since 1996 as a paperback. This book has been translated into nine languages and is published in Brazil , the Czech Republic , Germany , Hungary , Israel , Japan , Poland , Russia , and Spain . It was a selection of the Book of the Month Club and has sold over 50,000 copies worldwide. Hayflick and his associates have vehemently condemned "anti-aging medicine" and criticized organizations such as

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