Target Health Blog

Telomeres and Longevity

January 20, 2020

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Quiz
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As mentioned in What's New, Target Health LLC wishes you a Happy Lunar New Year filled with Health, Wealth, Happiness and Longevity.

Speaking of longevity, you can measure your telomeres to determine your longevity. Read on?

Human chromosomes (grey) capped by telomeres (white)
Photo credit: by U.S. Department of Energy Human Genome Program -
http://science.nasa.gov/media/medialibrary/2006/03/16/22mar_telomeres_resources/caps.gif, Public Domain, Wikipedia Commons


Telomeres are critical for maintaining genomic integrity and may be factors for age-related 1) ___. Laboratory studies show that telomere dysfunction or shortening is commonly acquired during the process of aging and tumor development. Short telomeres can lead to genomic instability, chromosome loss and the formation of non-reciprocal translocations; and telomeres in tumor cells and their precursor lesions are significantly shorter than surrounding normal tissue.

A telomere is a region of repetitive nucleotide sequences at each end of a 2) ___, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos “end“ and mer?s “part“. In humans, average telomere length declines from about 11 kilobases at birth to fewer than 4 kilobases in old 3) ___, with the average rate of decline being greater in men than in women. During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened (this is because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand). The telomeres are disposable buffers at the ends of chromosomes which are truncated during cell division; their presence protects the 4) ___ before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of shelterin proteins, as well as by the RNA that telomeric DNA encodes (TERRA).

Over time, due to each cell division, the telomere ends become shorter. They are replenished by an enzyme, telomerase reverse transcriptase.

Editor's note: Two helpful definitions, if you've forgotten your high school biology:

A prokaryote is a unicellular organism that lacks a membrane-bound nucleus, mitochondria, or any other membrane-bound organelle

Eukaryotes are organisms whose cells have a nucleus enclosed within membranes, unlike prokaryotes (Bacteria and Archaea), which have no membrane-bound organelles

Telomeres are repetitive nucleotide sequences located at the termini of linear chromosomes of most eukaryotic organisms. Most prokaryotes, having circular chromosomes rather than linear, do not have telomeres. Telomeres compensate for incomplete semi-conservative DNA replication at chromosomal ends. While replicating DNA, the eukaryotic DNA replication enzymes (the DNA polymerase protein complex) cannot replicate the sequences present at the ends of the chromosomes (or more precisely the chromatid fibers). Hence, these sequences and the information they carry may get lost. This is the reason telomeres are so important in context of successful cell division: They “cap“ the end-sequences and themselves get lost in the process of DNA replication. But the cell has an enzyme called telomerase, which carries out the task of adding repetitive nucleotide sequences to the ends of the DNA. Telomerase “replenishes“ the telomere “cap.“ In most multicellular eukaryotic organisms, telomerase is active only in germ cells, some types of stem 5) ___ 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 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 shortening in humans can induce replicative senescence, which blocks cell division. This mechanism appears to prevent genomic instability and development of cancer in human aged cells by limiting the number of cell divisions. However, shortened telomeres impair immune function that might also increase cancer susceptibility. If telomeres become too short, they have the potential to unfold from their presumed closed structure. The cell may detect this uncapping as DNA damage and then either stop growing, enter cellular old age (senescence), or begin programmed cell self-destruction (apoptosis) depending on the cell's genetic background. Uncapped telomeres also result in chromosomal fusions. Since this damage cannot be repaired in normal somatic cells, the cell may even go into apoptosis. Many aging-related diseases are linked to shortened 6) ___. Organs deteriorate as more and more of their cells die off or enter cellular senescence. 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. Recent meta-analyses suggest 1.4 to 3.0 fold increased risk of cancer for those with the shortest vs. longest telomeres. However, the increase in risk varies by age, sex, tumor type, and differences in lifestyle factors.

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 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 is well-recognized as capable of immortalizing human somatic cells. It is becoming apparent that reversing shortening of telomeres through temporary activation of telomerase may be a potent means to slow aging. The reason that this would extend human life is because it would extend the Hayflick limit. Three routes have been proposed to reverse telomere shortening: drugs, gene therapy, or metabolic suppression, so-called, torpor/hibernation. So far these ideas have not been proven in humans, but it has been demonstrated that telomere shortening is reversed in hibernation and aging is slowed and that hibernation prolongs life-span. It has also been demonstrated that telomere extension has successfully reversed some signs of aging in laboratory mice and the nematode worm species Caenorhabditis elegans. It has been hypothesized that longer telomeres and especially telomerase activation might cause increased cancer. However, longer telomeres might also protect against cancer, because short telomeres are associated with cancer. It has also been suggested that longer telomeres might cause increased energy consumption. Techniques to extend telomeres could be useful for 7) ___ engineering, because they might permit healthy, noncancerous mammalian cells to be cultured in amounts large enough to be engineering materials for biomedical repairs.

In vitro studies have shown that telomeres are highly susceptible to oxidative 8) ___. There is evidence that oxidative stress-mediated DNA damage is an important determinant of telomere shortening. Telomere shortening due to free radicals explains the difference between the estimated loss per division because of the end-replication problem (c. 20 bp) and actual telomere shortening rates (50-100 bp), and has a greater absolute impact on telomere length than shortening caused by the end-replication problem. Population-based studies have also 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 9) ___, 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.

Telomere shortening is associated with aging, mortality and aging-related diseases. Normal aging is associated with telomere shortening in both humans and mice, and studies on genetically modified animal models suggest causal links between telomere erosion and aging. However, it is not known whether short telomeres are just a sign of cellular age or actually contribute to the aging process themselves. Telomeres shorten with age and progressive telomere shortening leads to senescence and/or apoptosis. Shorter telomeres have also been implicated in genomic instability and oncogenesis. Older people with shorter telomeres have three and eight times increased risk to die from heart and infectious diseases, respectively. Rate of telomere shortening is therefore critical to an individual's health and pace of aging. Smoking, exposure to pollution, a lack of physical activity, obesity, stress, and an unhealthy diet increase oxidative burden and the rate of telomere shortening. To preserve telomeres and reduce cancer risk and pace of aging, it is worth considering, to eat less; include antioxidants, fiber, soy protein and healthy fats (derived from avocados, fish, and nuts) in our diet; and stay lean, active, healthy, and stress-free through regular exercise and meditation. Foods such as fatty 10) ___ (good fat) tuna, salmon, herring, mackerel, halibut, anchovies, cat-fish, grouper, flounder, flax seeds, chia seeds, sesame seeds, kiwi, black raspberries, lingonberry, green tea, broccoli, sprouts, red grapes, tomatoes, olive fruit, and other vitamin C-rich and E-rich foods are a good source of antioxidants. These combined with a Mediterranean type of diet containing fruits, and whole grains would help protect telomeres.

Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370421/; Wikipedia.com

ANSWERS: 1) diseases; 2) chromosome; 3) age; 4) genes; 5) cells; 6) telomeres; 7) tissue; 8) stress; 9) carotene; 10) fish

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