Telomere Shortening, Aging, and Cancer
- What are Telomeres?
- Function of Telomeres
- Telomere Shortening and Aging
- Telomerase and Stem Cells
- Telomere Lengthening in Cancer
- Telomeres and Other Diseases
Telomeres are sections of DNA that form protective caps at the ends of chromosomes, a bit like the plastic coating found at the tips of shoelaces. Without these protective tips, DNA gets damaged over time and cells eventually fail to function properly. As is the case with all DNA, they are made up of the four nucleic bases, namely:A for adenine, T for thymine, C for cytosine and G for guanine.
Telomeres are chains of DNA consisting of the same short sequence of bases, repeated over and over. In the case of humans, this repeated sequence is TTAGGG on one DNA strand, which pairs with AATCCC on the other DNA strand. The telomere is usually made up of around 3,000 repeated sequences and can contain as many as 15,000 bases.
The three main purposes of telomeres are as follows:
- They help arrange each of the 46 chromosomes present in the nucleus of the cell
- They form a protective cap at the ends of chromosomes
- They ensure correct replication of chromosomes during cell division
Every time a cell divides, chromosomes become shorter. Since the ends of the chromosomes are protected by telomeres, the only part of the chromosome that loses bases (about 25 to 200) is the end of the telomere and the rest of the DNA is left undamaged. Without the telomeres, important parts of the chromosome would be lost every time a cell undergoes DNA replication, which is generally around 50 to 70 times. The stretch of DNA that is essential for life would get shorter with each cell division.
Without telomeres, the ends of chromosomes could start fusing together, which would damage the DNA and cause cell death or malfunction and cancer. Since broken DNA is damaging, cells need to be able to sense and repair this damage. If chromosomes did not have telomeres, they would look like broken DNA and the cell would attempt to repair it unnecessarily. This would also cause cells to stop dividing and then cell death.
Telomeres affect how our cells age. Once they lose a certain number of bases and become too short, the cell can no longer divide and be replicated.
This inactivity or senescence leads to cell death (apoptosis) and the shortening of telomeres is associated with aging, cancer and an increased likelihood of death. Since every organ and tissue in the body is made of cells, telomeres are vital to keeping us alive and healthy.
The shortening of telomeres is associated with all aspects of the aging process and indicates a person’s biological age rather than chronological age.
Scientists first observed the association between telomere shortening and aging almost 40 years ago and today scientist are still busy studying telomeres and the beneficial effects of potentially reversing their shortening as people age.
In younger cells, an enzyme called telomerase prevents telomeres from losing too many bases by adding the TTAGGG repeat back to the ends of chromosomes. However, as a cell repeatedly divides, telomerase becomes less able to keep up with the number of bases that need adding and the telomeres start to shorten as the cell ages.
Telomerase is found in high concentrations in cells that divide rapidly such as germline cells (sperm and eggs) and stem cells, where it maintains telomere length and therefore DNA, following replication. Telomere length is therefore retained or even lengthened in these cells, meaning they do not age. By contrast, telomerase is only present at very low concentrations in somatic cells (the rest of the cells in our body), meaning these cells age and become less functional over time. Telomerase is also present at high concentration in cancer cells, which enables them to stay alive and continue replicating. If telomerase activity could be inhibited in these cells, telomere shortening would eventually stop them dividing successfully and forming tumors.
Evidence suggests that telomere length can be used as an indicator of predicted lifespan. In newborns, white blood cells have telomeres ranging from 8,000 to 13,000 base pairs in length, as compared with 3,000 in adults and only 1,500 in the elderly. After the newborn phase, the number of base pairs tends to decline by approximately 20 to 40 per year. For example, by time a person reaches the age of 40, their telomeres could have lost up to 1,600 base pairs.
However, aging is not the only factor associated with telomere shortening; other factors such as smoking and obesity also affect telomere length.
Stem cells are unspecialized cells capable of differentiating into any type of somatic cell (body cells that are not reproductive cells). They are also capable of self-renewal through cell division to generate more of the same type of stem cell. In some organs such as the bone marrow, they quickly divide to replace damaged tissue, but in other organs such as the heart, they only divide under certain conditions.
As a person ages, the stem cell count decreases and they produce fewer new somatic cells, which causes organs to degenerate.
Stem cells have certain ways of maintaining telomere length in order to prolong their lifespan. These include regulation by telomere binding protein, DNA duplicase and telomerase. Telomerase is the most important regulator of telomere length, offsetting or delaying telomere shortening during cell division to maintain the integrity of the genome. Telomerase is strongly expressed in cells during embryonic development and then less strongly expressed a few weeks following birth, with the exception of stem cells and fast-renewing cells such as platelets and lymphocytes.
In vitro, the main reason stem cell replication, self-renewal and expansion is limited, is the loss of telomerase and the resulting changes in its expression. As the field of tissue engineering advances, researchers are focused on inducing stem cells to differentiate into the various different cell lines, so being able to induce or increase the expression of telomerase is vital to this work.
Cancer is characterized by fast and uncontrolled cell division, which is aided by the fact that telomerase is highly active in cancer cells, restoring and lengthening any telomeres that have become damaged and shortened. The telomerase enables cancer cells to grow quickly and replicate indefinitely by keeping the telomeres long.
Without telomerase, cancer cells would be deactivated, stop dividing and eventually undergo apoptosis. Telomeres and telomerase are therefore of significant interest to researchers wanting to develop new therapies for cancer. Agents that could inhibit telomerase or kill cells that produce the enzyme could potentially inactivate cancer cells and stop their proliferation. However, inhibiting the activity of telomerase could negatively impact on cells that rely on the enzyme such as sperm, ova and immune cells, potentially causing problems with fertility and the immune response to infection.
However, telomerase is only active at very low levels or absent altogether in somatic cells, which should be largely unaffected by such therapies. Researchers hope this would mean cancer patients experiencing less side effects with this type of therapy, compared with the therapies currently available.
The biology of telomeres is particularly important in cancer research, with scientists keen to understand the best way these structures can be used to advance therapies.
At Yale School of Medicine, professor of Laboratory Medicine, Pathology and Molecular Biophysics and Biochemistry, Sandy Chang, is researching the role that telomeres play in aging and how cancer spreads. Chang’s studies have revealed how shelterin proteins bind to telomeres to protect them and that when components of shelterin are mutated or removed, telomeres become unstable, inducing genome changes that could lead to cancer. He has also found that when one particular shelterin protein was deleted in a mouse model, stem cells lost their ability to function properly. Chang thinks that repairing such mutations in affected patients could one day increase survival and delay cancer onset.
Another study by Angela Rizzo from the IRCCS-Regina Elena National Cancer Institute and colleagues has recently looked at the epigenetic changes in telomeric chromatin that alter telomere protection and are linked to tumor formation. The authors believe that characterizing this telomeric epigenome is key to gaining a better understanding of telomere protection and potentially developing new anti-cancer drugs.
The condition dyskeratosis is characterized by the presence of telomeres that become shortened much more quickly than usual. People with dyskeratosis have skin that becomes keratinized prematurely and the condition can resemble premature aging (progeria). These individuals are at an increased risk for life-threatening infections, cancers of the blood, liver cirrhosis, gut disorders and pulmonary fibrosis.
They are also more likely to experience balding and to have grey hair, spots, bone softening, poor wound healing and learning disabilities. This suggest that telomeres play a role in these conditions, which all involve tissues that rapidly divide. Some research also suggests that telomere shortening plays a role in hypertension, type 2 diabetes and Alzheimer’s disease.
One question that scientists ask is whether telomerase could be used to increase survival by restoring the length of telomeres. If human cells could be “immortalized” in this way, scientists may be able to mass produce cells that could be used for transplantation including insulin generating cells to treat diabetes, cartilage tissue for arthritis, muscle cells to treat muscular dystrophy, and skin cells that could be used in wound healing. An endless supply of the cells would also be helpful in drug and gene discovery experiments.
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- Yale Medicine. Telomere Research, 2019. Available at: https://www.yalemedicine.org/conditions/telomere-research/
- Rizzo, A et al. Emerging roles of telomeric chromatin alterations in cancer. Journal of Experimental & Clinical Cancer Research 2019;38:21 Available at: https://doi.org/10.1186/s13046-019-1030-5
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- All Telomere Content
- What are Telomeres?
- Telomere Shortening
- Systemic Telomere Length and Aging
- Telomeres and Cancer
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