The integrity of the genetic information contained within our chromosomes is carefully preserved by ingenious systems: breaks in the DNA sequence are rapidly repaired by enzymes and chromosome ends are protected by nucleotide caps known as telomeres.
Though telomeres help keep the chromosomes from unraveling, their end portions do not replicate with each mitotic division. Left to their own devices, telomeres would soon shorten and disappear. Fortunately, there is a compensatory enzyme, telomerase, which solves this problem by adding specific DNA repeats to the end of the telomere region, thereby extending cell life. “In normal cells, telomerase helps protect telomeres,” said Elizabeth Blackburn, the Morris Herzstein professor of biology and physiology at the University of California, San Francisco, in her Leaders in Biomedicine lecture at HMS on May 6. “But in cancer cells, telomerase is bad news since it is cancer promoting. A high fraction of human cancers have hyperactive telomerase, which makes sense since a characteristic of cancer cells is that they keep on dividing—they are immortalized cells.” One strategy for fighting cancer might be to inhibit telomerase activity. Blackburn and colleagues have done just that, with surprising results. They found that telomerase-deprived cancer cells showed rapid cellular and genetic changes including changes in morphology, glucose metabolism, and gene-expression profiles even before any effect on telomere length was seen. Furthermore, when they knocked down telomerase in cancer cells in mice, though the cells continued to proliferate, they were significantly less metastatic. Blackburn therefore suggests that telomerase may have other functions besides elongating telomeric DNA. While excessive telomerase activity in cancer cells is bad for health, increased telomerase activity in normal cells is actually an indicator of longevity, Blackburn said. Long-term studies in humans have shown strong correlations between telomere length and telomerase levels, and disease risk and incidence. But it is not yet clear what causes what—do shorter telomeres make a person more prone to disease? Or do environmental factors and disease wear telomeres down? Results from a clinical study presented by Blackburn indicated a possible case for the latter. She described her collaborative research showing that chronic stress, long known to have a negative impact on health, is strongly associated with lower telomerase activity. Their studies investigating chronic stress in women showed that there is an inverse relationship between perceived stress and its duration, and shorter telomeres and lower telomerase activity in white blood cells. Their studies also linked low telomerase activity to increased risk of cardiovascular disease. Blackburn explained that increased vulnerability to disease including cancer is one of many aspects of aging, but it remains unclear how much is governed by our genes and how much is determined by other factors. “Interestingly, studies that have looked at increased disease susceptibility in aging have shown that telomere maintenance is playing a role,” said Blackburn. “For the first time, we’ve started to find implications that telomeres are influenced not only by genetic factors but also by nongenetic factors.” Discoveries such as these indicate that telomerase may be an attractive therapeutic candidate for anticancer strategies as well as for other diseases related to aging.
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