![Telomere caps](https://upload.wikimedia.org/wikipedia/commons/4/4a/Telomere_caps.gif)
A telomere (; ) is a region of repetitive
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
sequences associated with specialized proteins at the ends of linear
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
s. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature most commonly found in
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s. In most, if not all species possessing them, they protect the terminal regions of
chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
systems from mistaking the very ends of the DNA strand for a
double-strand break
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
.
Discovery
In the early 1970s, Soviet theorist
Alexei 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
Leonard Hayflick (born 20 May 1928) is a Professor of Anatomy at the UCSF School of Medicine, and was Professor of Medical Microbiology at Stanford University School of Medicine. He is a past president of the Gerontological Society of America and ...
's idea of limited
somatic cell
A somatic cell (from Ancient Greek σῶμα ''sôma'', meaning "body"), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Such cells compo ...
division, Olovnikov suggested that DNA sequences are lost every time a cell replicates until the loss reaches a critical level, at which point cell division ends.
In 1975–1977,
Elizabeth Blackburn
Elizabeth Helen Blackburn, (born 26 November 1948) is an Australian-American Nobel laureate who is the former president of the Salk Institute for Biological Studies. Previously she was a biological researcher at the University of California, ...
, working as a postdoctoral fellow at
Yale University
Yale University is a private research university in New Haven, Connecticut. Established in 1701 as the Collegiate School, it is the third-oldest institution of higher education in the United States and among the most prestigious in the wo ...
with
Joseph G. Gall, discovered the unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends.
Blackburn,
Carol Greider, and
Jack Szostak
Jack William Szostak (born November 9, 1952) is a Canadian American biologist of Polish British descent, Nobel Prize laureate, university professor at the University of Chicago, former Professor of Genetics at Harvard Medical School, and Alexan ...
were awarded the
2009 Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
for the discovery of how chromosomes are protected by telomeres and the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
telomerase
Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...
.
In 1983,
Barbara McClintock, an American
cytogeneticist
Cytogenetics is essentially a branch of genetics, but is also a part of cell biology/cytology (a subdivision of human anatomy), that is concerned with how the chromosomes relate to cell behaviour, particularly to their behaviour during mitosis a ...
and the first woman to receive an unshared
Nobel Prize
The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
in Physiology or Medicine, received the Nobel Prize for observing that the chromosomes lacking end parts became "sticky" and hypothesized the existence of a special structure at the chromosome tip that would maintain chromosome stability.
Structure and function
End replication problem
![Dnareplication](https://upload.wikimedia.org/wikipedia/commons/9/92/Dnareplication.svg)
During DNA replication,
DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
cannot replicate the sequences present at the
3' ends of 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
Primer may refer to:
Arts, entertainment, and media Films
* ''Primer'' (film), a 2004 feature film written and directed by Shane Carruth
* ''Primer'' (video), a documentary about the funk band Living Colour
Literature
* Primer (textbook), a t ...
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 the primer (made of
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
) 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 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 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 pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s per
cell division
Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
.
If coding sequences are degraded in this process, potentially vital genetic code would be lost. Telomeres are non-coding, repetitive sequences located at 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
prokaryote
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
s, relying on circular chromosomes, accordingly do not possess telomeres. A small fraction of
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
l chromosomes (such as those in ''
Streptomyces'', ''
Agrobacterium
''Agrobacterium'' is a genus of Gram-negative bacteria established by H. J. Conn that uses horizontal gene transfer to cause tumors in plants. '' Agrobacterium tumefaciens'' is the most commonly studied species in this genus. ''Agrobacterium'' i ...
'', and ''
Borrelia
''Borrelia'' is a genus of bacteria of the spirochete phylum. Several species cause Lyme disease, also called Lyme borreliosis, a zoonotic, vector-borne disease transmitted by ticks. Other species of ''Borrelia'' cause relapsing fever, and are t ...
''), however, are linear and possess telomeres, which are very different from those of the eukaryotic chromosomes in structure and function. The known structures of bacterial telomeres take the form of
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
bound to the ends of linear chromosomes, or hairpin loops of single-stranded DNA at the ends of the linear chromosomes.
Telomere ends and shelterin
![Telosome](https://upload.wikimedia.org/wikipedia/commons/2/26/Telosome.png)
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 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
The TRF1 is a 155mm French towed howitzer produced by Nexter (ex Giat Industries) and used by the French Army.
The TRF1 was showcased in 1979 at the Eurosatory arms trade show, as a replacement for Armée de Terre's BF-50. Giat produced it fro ...
,
TRF2,
TIN2,
POT1
Protection of telomeres protein 1 is a protein that in humans is encoded by the ''POT1'' gene.
Function
This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein func ...
,
TPP1, and
RAP1
Rap1 (Ras-proximate-1 or Ras-related protein 1) is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction. There are two isoforms of the Rap1 protein, each encoded by ...
.
In many species, the sequence repeats are enriched in
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
, e.g. TTAGGG in
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s,
which allows the formation of
G-quadruplex
In molecular biology, G-quadruplex Nucleic acid secondary structure, secondary structures (G4) are formed in nucleic acids by sequences that are rich in guanine. They are helical in shape and contain guanine tetrads that can form from one, two o ...
es, 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
ciliate
The ciliates are a group of alveolates characterized by the presence of hair-like organelles called cilia, which are identical in structure to flagellum, eukaryotic flagella, but are in general shorter and present in much larger numbers, with a ...
s (that possess telomere repeats similar to those found in
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s) to form such G-quadruplexes that accommodate it, rather than 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.
Telomerase
![Synthesis of chromosome ends by telomerase](https://upload.wikimedia.org/wikipedia/commons/5/56/Synthesis_of_chromosome_ends_by_telomerase.svg)
Many organisms have an 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 is active only in
germ cell
Germ or germs may refer to:
Science
* Germ (microorganism), an informal word for a pathogen
* Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually
* Germ layer, a primary layer of cells that forms during emb ...
s, some types of
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s such as
embryonic stem cells
Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist ...
, and certain
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...
s. Telomerase can be reactivated and telomeres reset back to an embryonic state by
somatic cell nuclear transfer
In genetics and developmental biology, somatic cell nuclear transfer (SCNT) is a laboratory strategy for creating a viable embryo from a body cell and an egg cell. The technique consists of taking an enucleated oocyte (egg cell) and implanting a ...
. The steady shortening of telomeres with each replication in somatic (body) cells may have a role in
senescence
Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...
and in the prevention of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. This is because 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.
Length
Telomere length varies greatly between species, from approximately 300
base pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s in yeast to many kilobases in humans, and usually is composed of arrays of
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
-rich, six- to eight-base-pair-long repeats. Eukaryotic telomeres normally terminate with
3′ single-stranded-DNA overhang, which 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 protein
Telomere-binding proteins (also known as TERF, TRBF, TRF) function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 ( TERF2). Tel ...
s. At the very end of the T-loop, 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.
Shortening
Oxidative damage
Apart from the end replication problem,
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
studies have shown that telomeres accumulate damage due to
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
and that oxidative stress-mediated DNA damage has a major influence on telomere shortening
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
. There is a multitude of ways in which oxidative stress, mediated by
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(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, 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.
Association with aging
Telomere shortening is associated with aging, mortality, and aging-related diseases. Based upon comparison between individuals of different ages, telomere length is negatively associated with the number of cell divisions in germ and tumor cells. This leads to the link between age and telomere length, as one might expect, the older an individual is the more times their cells have replicated their genome and divided. In contrast to humans, mice have been demonstrated to have significantly longer telomeres. This could demonstrate how the effects of telomere shortening might have a different or no effect on other eukaryotes, as the older mice had no significant difference in telomere length than younger mice.
Furthermore, the role and importance of telomeres appears to have varying degrees of importance among model organisms. Common model organisms such as mice, S. cerevisiae, and C. elegans, were able to withstand the knockdown of telomerase with little effect for multiple generations. Despite the resiliency of these eukaryotes, a decrease in telomerase function in humans resulted in multiple threatening complications after only a few generations.
This carries implications on the importance of preserving telomeres in human health.
The age of a father plays a role in the length of a child's telomeres, which has evolutionary implications. Although
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
telomeres shorten with age, sperm telomeres lengthen with age. Shorter telomeres are theorized to impose lower energy costs (due to less replication) but also have immune system-related and other aging- and disease-related costs, so the effect of paternal age on telomere length might be an adaptation to increase the chances that the child will be fit for the environment they're born into. Telomerase is normally triggered by cancer cells, however in some cases, cancer cells use a mechanism called alternative telomere lengthening to retain telomeres.
Potential effect of psychological stress
Meta-analyses
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
found that increased perceived
psychological stress
In psychology, stress is a feeling of emotional strain and pressure. Stress is a type of psychological pain. Small amounts of stress may be beneficial, as it can improve athletic performance, motivation and reaction to the environment. Exces ...
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 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.
Lengthening
![Hayflick Limit (1)](https://upload.wikimedia.org/wikipedia/commons/7/72/Hayflick_Limit_%281%29.svg)
The phenomenon of limited cellular division was first observed by
Leonard Hayflick
Leonard Hayflick (born 20 May 1928) is a Professor of Anatomy at the UCSF School of Medicine, and was Professor of Medical Microbiology at Stanford University School of Medicine. He is a past president of the Gerontological Society of America and ...
, and is now referred to as the
Hayflick limit.
Significant discoveries were subsequently made by a group of scientists organized at
Geron Corporation
Geron Corporation is a biotechnology company located in Foster City, California, Foster City, California, which specializes in developing and commercializing therapeutic products for cancer that inhibit telomerase.
Company information
Geron, ba ...
by Geron's founder
Michael D. West
Michael D. West (born in Niles, Michigan on 28 April 1953) is an American biogerontologist, and a pioneer in stem cells, cellular aging and telomerase. He is the founder and CEO of AgeX Therapeutics,
a startup focused on the field of experime ...
, 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
Science is a systematic endeavor that builds and organizes knowledge in the form of testable explanations and predictions about the universe.
Science may be as old as the human species, and some of the earliest archeological evidence for ...
'' to be capable of extending cell lifespan, and now is well-recognized as capable of immortalizing human somatic cells.
Two studies on long-lived
seabird
Seabirds (also known as marine birds) are birds that are adapted to life within the marine environment. While seabirds vary greatly in lifestyle, behaviour and physiology, they often exhibit striking convergent evolution, as the same enviro ...
s demonstrate that the role of telomeres is far from being understood. In 2003, scientists observed that the telomeres of
Leach's storm-petrel
Leach's storm petrel or Leach's petrel (''Hydrobates leucorhous'') is a small seabird of the tubenose order. It is named after the British zoologist William Elford Leach. The scientific name is derived from Ancient Greek. ''Hydrobates'' is from ...
(''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 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.
Sequences
Known, up-to-date telomere
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
sequences are listed i
Telomerase Databasewebsite.
Research on disease risk
Telomeres are critical for maintaining genomic integrity and may be factors for age-related diseases. Laboratory studies show that telomere dysfunction or shortening is commonly acquired due the process of cellular aging and tumor development. The function of telomeres is widely accepted as a buffer against tumor growth, to protect chromosome structure, and prevent the loss of vital genetic information during replication. While telomeres keep the growth and division of somatic cells in check, this can inadvertently select for rapidly dividing cells that have suffered telomere damage. As other cells divide as they are supposed to, the abnormal cells divide much quicker, outcompeting the undamaged cells, while acquiring more DNA damage that could further increase their ability to grow.
This results in tumor formation.
Certain lifestyle factors have been shown to prematurely shorten telomere length. Smoking is negatively correlated to telomere length. The average human loses roughly 25-27 base pairs per year due to telomere shortening. A study of telomere length in white blood cells of chronic smokers revealed an additional 5 base pairs lost per year. Obesity is another factor that contributes to accelerated telomere shortening. It is well established that obesity causes increased oxidative stress. Ultimately, this increased oxidative damage can impair DNA and, consequently, reduce telomere length. Furthermore, dietary intake and physical activity decrease the rate of telomere shortening. An increase in consumption of antioxidants such as omega-3 fatty acids, vitamins E, C, and beta-carotene can reduce oxidative stress on DNA. Women with diets consisting of a high intake of these antioxidants revealed longer telomere length and a decreased risk in breast cancer. In relation to obesity, exercise promotes metabolization of fat and detrimental waste products, as well as increases the activity of telomerase. . Moreover, physical activity decreases the expression of proteins associated with apoptosis (p53 and p16) in mice populations, which indicates reduced levels of oxidative stress and thereby telomere shortening.
Observational studies have found shortened telomeres in many types of experimental cancers. In addition, people with cancer have been found to possess shorter leukocyte telomeres than healthy controls. In 2011, meta-analyses suggested 1.4 to 3.0 fold increased risk of cancer for those with the shortest vs. longest telomeres.
Telomeres also exist as a possible drug target. While telomeres serve a vital function in humans, telomerase activity is generally low in most somatic cells and tissues. This provides a unique avenue for targeting eukaryotic pathogens. There are many parasitic strains of eukaryotes such as protozoans and infectious yeast that heavily rely upon telomerase activity to monitor their genome. Since normal telomerase activity in most human cells is low, targeting parasitic telomerase function might be a successful short-term treatment against pathogenic eukaryotes, without causing harm to the host.
Measurement
Several techniques are currently employed to assess average telomere length in eukaryotic cells. One method is the Terminal Restriction Fragment (TRF) southern blot. 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 the length of telomere from
whole genome sequencing
Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a s ...
(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
Flow-FISH (fluorescent in-situ hybridization) is a cytogenetic technique to quantify the copy number of RNA or specific repetitive elements in genomic DNA of whole cell populations via the combination of flow cytometry with cytogenetic fluoresc ...
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
Elizabeth Helen Blackburn, (born 26 November 1948) is an Australian-American Nobel laureate who is the former president of the Salk Institute for Biological Studies. Previously she was a biological researcher at the University of California, ...
, who was co-founder of one company, promoted the clinical utility of telomere length measures.
In wildlife
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
endotherm
An endotherm (from Greek ἔνδον ''endon'' "within" and θέρμη ''thermē'' "heat") is an organism that maintains its body at a metabolically favorable temperature, largely by the use of heat released by its internal bodily functions inst ...
s, i.e. birds and mammals. They have provided evidence for the inheritance of telomere length; however,
heritability
Heritability is a statistic used in the fields of breeding and genetics that estimates the degree of ''variation'' in a phenotypic trait in a population that is due to genetic variation between individuals in that population. The concept of h ...
estimates vary greatly within and among species. Age and telomere length often negatively correlate in vertebrates, but this decline 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 the exposure to stressors (e.g. pathogen infection, competition, reproductive effort and high activity level) was associated with shorter telomeres across different animal taxa. Telomeres are also a candidate health biomarker for ecotoxicology studies, however, their use still needs further validation as the current literature is taxonomically biased and limited by a reduced number of experimental and longitudinal approaches.
Although ca. 80% of living animals are
ectotherm
An ectotherm (from the Greek () "outside" and () "heat") is an organism in which internal physiological sources of heat are of relatively small or of quite negligible importance in controlling body temperature.Davenport, John. Animal Life ...
s, the knowledge about telomere dynamics in these species is still limited to a few studies in reptiles, fish, and amphibians, whereas invertebrates telomeres have been virtually not explored.
Ectotherm
An ectotherm (from the Greek () "outside" and () "heat") is an organism in which internal physiological sources of heat are of relatively small or of quite negligible importance in controlling body temperature.Davenport, John. Animal Life ...
s are significantly more likely than
endotherm
An endotherm (from Greek ἔνδον ''endon'' "within" and θέρμη ''thermē'' "heat") is an organism that maintains its body at a metabolically favorable temperature, largely by the use of heat released by its internal bodily functions inst ...
s to have variation in somatic telomerase expression. For instance, in many fish, telomerase occurs throughout the body (and associated with this, telomere length is roughly the same across all its tissue). 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
Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...
, and even within smaller taxonomic groups these patterns appear diverse. Due to the different reproductive timelines of some ectotherms, selection on disease is relevant for a much larger fraction of these creatures’ lives than it is for mammals, so early- and late-life telomere length, and their possible links to cancer, seem especially important in these species from a
life history theory
Life history theory is an analytical frameworkVitzthum, V. (2008). Evolutionary models of women's reproductive functioning. ''Annual Review of Anthropology'', ''37'', 53-73 designed to study the diversity of life history strategies used by differen ...
point of view.
Indeed, ectotherms are more sensitive to environmental variation than endotherms and factors such as temperature are known to their growth and maturation rates, thus, ectothermic telomeres are predicted to be greatly affected by climate change.
See also
*
Epigenetic clock
*
Centromere
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers ...
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DNA damage theory of aging
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear ...
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Immortality
Immortality is the concept of eternal life. Some modern species may possess biological immortality.
Some scientists, futurists, and philosophers have theorized about the immortality of the human body, with some suggesting that human immorta ...
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Maximum life span
Maximum life span (or, for humans, maximum reported age at death) is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. The term can also denote an estimate of the m ...
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Rejuvenation (aging)
Rejuvenation is a medical discipline focused on the practical reversal of the aging process.
Rejuvenation is distinct from life extension. Life extension strategies often study the causes of aging and try to oppose those causes in order to slow ...
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Senescence
Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...
, biological aging
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Tankyrase
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Telomere-binding protein
Telomere-binding proteins (also known as TERF, TRBF, TRF) function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 ( TERF2). Tel ...
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G-quartet
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Immortal DNA strand hypothesis
The immortal DNA strand hypothesis was proposed in 1975 by John Cairns as a mechanism for adult stem cells to minimize mutations in their genomes. This hypothesis proposes that instead of segregating their DNA during mitosis in a random manner, ...
Notes
References
External links
Telomeres and Telomerase: The Means to the EndNobel Lecture by
Elizabeth Blackburn
Elizabeth Helen Blackburn, (born 26 November 1948) is an Australian-American Nobel laureate who is the former president of the Salk Institute for Biological Studies. Previously she was a biological researcher at the University of California, ...
, which includes a reference to the impact of stress, and pessimism on telomere length
Telomerase and the Consequences of Telomere DysfunctionNobel Lecture by
Carol GreiderDNA Ends: Just the BeginningNobel Lecture by
Jack Szostak
Jack William Szostak (born November 9, 1952) is a Canadian American biologist of Polish British descent, Nobel Prize laureate, university professor at the University of Chicago, former Professor of Genetics at Harvard Medical School, and Alexan ...
{{Authority control
Chromosomes
Molecular biology
Repetitive DNA sequences
Non-coding DNA