Genetcis

G e N e t i c S , t e c H N o l o G Y , A N D S o c i e t Y 289

G e n e t i c s , t e c h n o l o G y , a n d s o c i e t y

telomeres: the Key to immortality?

Humans, like all multicellular organisms, grow old and die. As we age, our immune systems become less efficient, wound healing is impaired, and tissues lose re- silience. It has always been a mystery why we go through these age-related declines and why each species has a characteris- tic finite life span. Why do we grow old? Can we reverse this march to mortality? Some recent discoveries suggest that the answers to these questions may lie at the ends of our chromosomes.

The study of human aging begins with a study of human cells growing in culture dishes. Like the organisms from which the cells are taken, cells in culture have a fi- nite life span. This replicative senescence was first noted by Leonard Hayflick in the 1960s. He reported that normal hu- man fibroblasts lose their ability to grow and divide after about 50 cell divisions. These senescent cells remain metaboli- cally active but can no longer prolifer- ate. Eventually, they die. Although we don’t know whether cellular senescence directly causes organismal aging, the evi- dence is suggestive. For example, cells de- rived from young people undergo more divisions than those from older people; cells from short-lived species stop grow- ing after fewer divisions than those from longer-lived species; and cells from pa- tients with premature aging syndromes undergo fewer divisions than those from normal patients.

Another characteristic of aging cells involves their telomeres. In most mam- malian somatic cells, telomeres become shorter with each DNA replication be- cause DNA polymerase cannot synthe- size new DNA at the ends of each parent strand. However, as discussed in detail in this chapter, cells that undergo extensive proliferation, like embryonic cells, germ cells, and adult stem cells, maintain their telomere length by using telomerase—a re- markable RNA-containing enzyme that adds telomeric DNA sequences onto the ends of linear chromosomes. However, most somatic cells in adult organisms do not proliferate and do not contain active telomerase.

Could we gain perpetual youth and vi- tality by increasing our telomere lengths? Studies suggest that it may be possible to reverse senescence by artificially increas- ing the amount of telomerase in our cells. When investigators introduced cloned telomerase genes into normal human cells in culture, telomeres lengthened, and the cells continued to grow past their typical senescence point. These studies suggest that some of the atrophy of tis- sues that accompanies old age could be reversed by activating telomerase genes. However, before we use telomerase to achieve immortality, we need to consider a potential serious side effect: cancer.

Although normal cells shorten their telomeres and undergo senescence after a specific number of cell divisions, can- cer cells do not. More than 80 percent of human tumor cells contain telomerase activity, maintain telomeres, and achieve immortality. Those that do not contain active telomerase use a less well under- stood mechanism known as ALT (for “al- ternative lengthening of telomeres”).

These observations have motivated scientists to devise new cancer therapies based on the idea that agents that inhibit telomerase might destroy cancer cells by allowing telomeres to shorten, thereby forcing the cells into senescence. Because most normal human cells do not express telomerase, such a therapy might target tumor cells and be less toxic than most current anticancer drugs. Many such anti- telomerase drugs are currently under de- velopment, and some are in clinical trials.

Will a deeper understanding of telo- meres allow us to both arrest cancers and reverse the descent into old age? Time will tell.

Your Turn

Take time, individually or in groups, to answer the following questions. Investigate the references and links to help you understand some of the re- search on telomeres, aging, and cancer.

1. How might our knowledge about telomeres and telomerase be applied to anti-aging strategies? Are

such strategies or therapies being developed?

Sources of information can be obtained by us- ing the PubMed Web site (http://www.ncbi. nlm.nih.gov/sites/ entrez?db=pubmed).

2. One anti-telomerase drug, called GRN163L, is being developed by Geron Corporation as a treatment for cancer. How does GRN163L work? What is the current status of GRN163L clinical trials? What are some possible side effects for anti- telomerase drugs?

Read about this drug and its clinical tri- als on the Geron Web site at http://www. geron.com. Search on PubMed for scientific papers dealing with GRN163L’s anticancer effects.

3. People suffering from chronic stress appear to have more health prob- lems and to age prematurely. Is there any evidence that chronic stress, poor health, and telomere length are linked? How might stress affect telo- mere length or vice versa?

Some recent papers suggest how these phe- nomena may be linked. One such paper is Epel, E. S., et al. 2004. Accelerated telomere shortening in response to life stress. Proc. Natl. Acad. Sci. USA 101(49): 17312– 17315.

4. In 2006, the Lasker Award for Ba- sic Medical Research was awarded to Drs. Elizabeth Blackburn, Carol Greider, and Jack Szostak, who subse- quently were awarded the 2009 Nobel Prize in Physiology or Medicine. How did the intersections of people, ideas, and good fortune lead to their discov- ery of telomerase and its role in aging and cancer? What is the future for this research?

Listen to interviews with these scientists, in which they tell their stories about their research and where they see the field going, at http://www.laskerfoundation. org/ 2006videoawards.

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