From Longevity Wiki

A telomere is a region of repetitive nucleotide sequences at the end of linear DNA chromosomes. Together with associated proteins, telomeres protect the terminal regions of chromosomal DNA from degradation and ensure the integrity of chromosomes. Telomere dysfunction has been described as one of the molecular hallmarks of ageing.


In the 1930s Barbara McClintock and Herman Muller inferred the existence of unique structures at the end of chromosomes in corn and fruit fly.[1][2] They hypothesised that these structures were essential for chromosome stability and prevention of chromosome fusions. The name “telomere” was coined - from the Greek telos meaning “end” and meros meaning “part". In 1978 Elizabeth Blackburn sequenced telomeric DNA of a protozoan Tetrahymena thermophila and revealed it is composed of tandem repeats of hexanucleotide sequences. [3] In 1982, together with Jack Szostak, she experimentally confirmed the protective role of telomeres. [4] In 1985 Blackburn and Carol Greider discovered a novel enzyme, telomerase, capable of extending telomere length. [5] Blackburn, Szostak and Greider were awarded a Nobel Prize in Physiology or Medicine in 2009 “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”.[6]

Telomere function and structure

Telomeres are DNA fragments that cap the ends of linear chromosomes and protect them from erosion and end-to-end fusions.[7] The terminal ends of linear chromosomes cannot be fully replicated, and as a result telomeres shorten at each mitotic cycle. As telomeres reach a critical length, they cannot longer fully maintain their protective functions, which triggers a DNA damage response and arrests cell proliferation.[8] As DNA breaks in telomeres are irreparable, cell senescence can be triggered even when telomere lenght is not critically short. [9]

Telomeric DNA is made of tandem repeats of nucleotide sequences, and does not code for proteins. Sequence of telomeres is well-conserved among humans and other vertebrates and consists of “TTAGGG” repeats.[10][11] As opposed to the sequence, telomere length varies widely among and within species, within an organism, and even between chromosomes.[11] In humans, telomere length has been shown to vary between 5 and 15 thousand base pairs.[12] The telomere is cloaked in a specialised six-protein complex, called shelterin, which ensures protection of chromosome ends and distinguishes telomeres from sites of DNA damage.[13]


Telomerase is an enzyme that elongates telomeres. It consists of an RNA subunit (TERC) and a protein subunit, telomerase reverse transcriptase (TERT). TERT is able to bind the end part of the chromosome’s telomeric sequence and synthesise new telomeric repeats using TERC as a template. Telomerase is abundantly present in germ cells, stem cells and most cancer cells. Differentiated (non-dividing) cells show modest or undetectable expression levels of telomerase. [14]

Telomeres in aging and age-related diseases

Telomere dysfunction has been described as one of the 9 Hallmarks of Aging, as shortening ("attrition") of telomeres in general progresses with age in all proliferating tissues.[15][16]

The rate of telomere attrition changes throughout the lifetime, and is much faster in the first two years of life than during later life.[17] On average, telomere length in human leukocytes was found to shorten by 30-35 base pairs per year, reaching about 6 thousand base pairs in people over 60 years old.[18] Telomeric length of 5 thousand base pairs has been suggested to be a "telomeric brink" denoting a high risk of imminent death.[19] Although most people do not reach the telomeric brink in their lifetime, further extension of human longevity might be increasingly constrained by telomere length.

Accelerated telomere shortening and dysfunction has been linked to several age-related diseases, such as chronic obstructive pulmonary disease, metabolic syndrome, liver cirrhosis, atherosclerosis, osteoporosis, chronic kidney disease.[20] However, associations between telomere length and age-dependent conditions are often inconsistent and the molecular understanding of these associations is still lacking.[16] There is currently insufficient clinical evidence to use telomere length or shortening rate as biomarkers for human aging, but research in this area is ongoing.[21]

Telomeres and telomerase in cancer and other diseases

Increased levels of telomerase have been found in the vast majority of human cancers, whereas mutations decreasing telomerase function cause a range of genetic disorders, such as dyskeratosis congenita, idiopathic pulmonary fibrosis and bone marrow failure.[22] Longer telomere lenghts have been associated with higher risk of melanoma, lung cancer, prostate cancer, and chronic lymphocytic leukemia. [19]

Telomeres and telomerase in anti-aging therapies

Age-reversing telomerase mRNA therapeutics

A dogma arose in the 1990s that telomerase causes cancer. This is wrong and set back the field by decades. The reality is that permanent telomerase supports cancer, whereas healthy stem cells frequently turn on telomerase transiently throughout our lives to stave off the devastating effects of short telomeres.[23] A single dose of telomerase mRNA delivered in vivo using lipid nanoparticles reverses years of telomere shortening in hours.[24]


Mice engineered with much longer telomeres than those of the natural species showed improved mitochondrial function, improved metabolic parameters, decreased cancer, and increased longevity (12.75% increase in median longevity). [25][26] Due to concerns related to the association between telomerase expression and cancer, this was an important finding that suggests that telomere length per se does not increase cancer risk in mice.[25]

Gene therapies delivering telomerase gene have been studied in mice. In a 2012 study by Bernardes de Jesus and colleagues, treatment of adult and old mice with a single injection of an adeno-associated virus expressing mouse TERT had beneficial effects on health, fitness, and longevity.[27] Mice treated at 1 year of age had an increase of median lifespan of 24%, while mice treated at 2 years of age had a lifespan increase of 13%.

In a 2022 study by Jaijyan and colleagues, monthly treatment of mice with a cytomegalovirus vector expressing mouse TERT extended median lifespan by 41.4%.[28][29] Both intranasal and injectable preparations of the vector were tested, and performed equally well in delivering gene therapy to multiple organs, without increasing cancer or unwanted side effects. The sample size was small, with a total of 16 mice across the 2 delivery groups. However, the extent of lifespan extension was striking and requires further testing, such as in different mice strains and with larger sample sizes. The observed extension of lifespan also suggests that telomerase may actually decrease cancer risk, consistent with a younger phenotype by influencing aging.[25][28]


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