How Aging Cells Retire: Loss Of Protection At Tips Of Chromosomes May Explain Why Elderly Cells Cease To Divide

Now, in the March 29 issue of Science, Rockefeller University researchers propose how these molecular clocks may ultimately count down the final days of a cell's reproductive life.

"Our work suggests that an old cell stops replicating when its telomeres are too short to function, not when they are completely gone," says Titia de Lange, Ph.D., head of the Laboratory of Cell Biology and Genetics and principal investigator of the study. Other authors include first author Jan Karlseder, Ph.D., a postdoctoral fellow at Rockefeller, and Agata Smogorzewska, a student in the Tri-Institutional M.D.-Ph.D. Program of Rockefeller, Weill Medical College of Cornell University and Sloan-Kettering Institute.

Most cells in our body can duplicate themselves only a limited number of times before they retire, or enter senescence - the last stage of their life when they can no longer reproduce. Telomeres, which are located on the ends of each chromosome in the cell's nucleus, shorten in length with each cell division, thereby ticking away the days until an aging cell finally retires.

Two years ago, de Lange, in collaboration with Jack Griffith, Ph.D., at the University of North Carolina, showed that telomeres don't stick out as previously believed but form closed loops, called "t-loops." They proposed that t-loops act to "cap" or protect chromosome ends.

But just how shrinking telomeres trigger an aging cell to retire has puzzled scientists until now.

According to the Rockefeller researchers, a cell ceases to divide when its telomeres become too short to protect the ends of chromosomes - and not when they completely run out, as many scientists previously believed.

"Perhaps the short telomeres in old cells are no longer able to form these protective loops, and it is the opened telomeres that trigger senescence," says Karlseder.

If scientists can figure out what triggers a cell to enter senescence, they might be able to delay this process for the treatment of diseases in which a cell ages too fast, such as dyskeratosis congenita, Bloom and Werner syndromes. The findings also may lead to new strategies for regenerating cells that are lost in degenerative diseases.

Conversely, it may one day be possible to destroy the immortal cells of cancer - which have figured out a way to keep their telomeres long - by manipulating them into an early retirement.

"Aging and cancer are flip sides of the same coin," says Karlseder. "The trick for scientists is to be able to influence one without adversely affecting the other."

Previously, many scientists believed that an aging cell entered senescence when its shrinking telomeres disappeared. But, in the new study, the Rockefeller scientists show that a protein called TRF2 can allow old cells to continue to replicate even when their telomeres are very short.

"TRF2 helps critically short telomeres function better and this, in turn, allows these cells to live just as long as cells with longer telomeres," says Karlseder. "This is significant because it means that a change in the protected status of telomeres, and not their complete loss, is what triggers senescence."

Since the 1970s, scientists have known that the ends of every chromosome in a cell contain identical regions of DNA repeats that make up the telomeres. But, it wasn't until recently that scientists realized that these fragile chromosomal ends hold secrets to aging and cancer. This insight arose from the finding that an enzyme called telomerase elongates the telomeres of both reproductive cells and cancer cells and, as a result, extends the life span of these cells.

In the current study, the scientists add another chapter to this story. Initially, they found that human cells made to overproduce TRF2, a protein they first identified in 1997, exhibited an increase in the rate at which their telomeres shortened. While normal cells lose their telomeric DNA at a rate of 100 units per cell division, cells overproducing TRF2 exhibited a rate of up to 180 units per cell division.

But these same cells entered senescence when their telomeres were shorter than normal, thereby compensating for the increased rate of shortening. Moreover, in some cases, these cells lived longer than normal cells.

They also showed that TRF2 protected these critically short telomeres from chromosome damage, such as chromosome end fusions and breaks.

Together, the results suggest that TRF2, by protecting short telomeres, allows cells overproducing TRF2 to have longer life spans. Furthermore, the researchers speculate that TRF2 is stimulating the ability of telomeres to form loops - and that the loss of these protective structures is what triggers cells to enter senescence.

"Our model suggests that old human cells have telomeres that can't form t-loops, and this is something we are now trying to test," says Karlseder.

The research was supported by grants from the Ellison Medical Foundation, the National Institutes of Health, the Human Frontiers in Sciences Program, a Charles H. Revson Fellowship and the Rockefeller/Weill Cornell/Sloan-Kettering M.D.-Ph.D. Program.

John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of which are on campus. Rockefeller University scientists have received this award for two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in Physiology or Medicine. At present, 33 faculty are elected members of the U.S. National Academy of Sciences. Celebrating its Centennial anniversary in 2001, Rockefeller - the nation's first biomedical research center - continues to lead the field in both scientific inquiry and the development of tomorrow's scientists.