ASRM - Chromosome Ends: Why We Care About Them?
Telomeres are DNA sequences that cap the ends of each of our chromosomes. These sequences comprise of short codes of DNA nucleotides, specifically AGGGTT in humans, repeated many times over lasting thousands of digits. They serve to protect the integrity of our genetic material against damage. Over time, injury may occur to cause breakage and thus shortening of the telomeres. This DNA end breakage is healed by the action of a protein called telomerase that diligently adds back new DNA repeats to increase telomere length.
Telomere length and telomerase activity are thought to contribute to the process of human aging. Notably in cancer cells, telomerase becomes overactive and continues to replenish telomeres, thus promoting cellular immortality. Inhibiting telomerase activity in cancer cells can stop cell division over several generations. Rare genetic mutations in telomerase in humans can lead to limited life span. Large epidemiologic data have shown that telomere maintenance is associated with normal human aging and diseases of old age. For example, short telomeres are found in people with cardiovascular diseases, stroke, vascular dementia, obesity, osteoporosis, diabetes, and certain cancers. Longer telomere length is associated with having more years of healthy life in the elderly population. Telomerase function and telomere maintenance are not purely influenced by ones genetics. Many non-genetic factors such as psychological stress, nutritional status, and behavioral factors can modify telomere maintenance, and thus affecting overall health.
Although not much research has been done in the direction of reproductive health, Dr. Blackburn presented some interesting preliminary data on the association between telomere maintenance and ovarian aging. In epidemiologic studies, telomere length has been associated with reproductive outcomes such as incidences of recurrent miscarriages and pregnancies with Down syndrome. While telomere length in peripheral blood cells does not appear to correlate with ovarian reserve using anti-mullerian hormone (AMH) as a surrogate marker, telomere length in eggs is associated. Women with long telomeres in their eggs have higher levels of AMH than women with short egg telomeres. Furthermore, women who produce higher numbers of eggs during IVF have longer egg telomeres compared to women with poor IVF response.
Irreversible ovarian aging is perhaps one of the most challenging problems in reproductive medicine. We do not yet fully understand the mechanism by which the inevitable decline of eggs in our ovaries occurs, and so far there is no stopping our natural biologic clock. Our current best defense is freezing eggs at a younger age for future use. Perhaps telomere maintenance plays an important role in protecting the health of eggs from DNA damaging injuries that accumulate during the time span from birth to the end of our reproductive years. If so, then identifying influential factors that can modify telomere lengths and telomerase activity may prove to be invaluable in the prevention and treatment of diminished ovarian reserve.
Paraphrasing Dr. Szostak, who shared the 2009 Nobel prize with Dr. Blackburn for the discovery of telomerase, the ends may just be the beginning.
- Liyun Li, M.D.