03 February 2006

Telomeres and Telomerase -- Masters of Destiny?

This bio.com newsfeature discusses fascinating research by scientists from Brown University.
Human cells replicate anywhere from 60 to 90 times before senescence sets in, a phenomenon scientists believe is a safeguard against disease. While senescent cells still function, they don't behave the way young cells do - and are associated with skin wrinkles, delayed wound healing, weakened immune system response and age-related diseases such as cancer.

... Veterinarians took small skin samples from the monkeys' forearms. Scientists in the Sedivy lab tested the connective tissue for the presence of six biomarkers, or biological "red flags," that signal cellular aging. For replicative senescence, the most important biomarker is telomere dysfunction-induced foci, or TIFs. Presence of these structures signals that the protective chromosome caps called telomeres have dwindled enough to halt cell division.

Scientists painstakingly counted the cells with aging biomarkers. What they found: The number of senescent cells increased exponentially with age. TIF-positive cells made up about 4 percent of the connective tissue cell population in 5-year-olds. In 30-year-olds, that number rose as high as 20 percent.

..."This research confirms that telomeres are important in aging," he said. "But we've only scratched the surface. Now that we've come up with the tools and methods for further TIF research, I am eager to see if the same patterns play out in other tissue."

Brown post-doctoral research fellow Utz Herbig is the lead author of the article. Brown undergraduate Mark Ferreira rounds out the Brown research team. Laura Condel and Dee Carey from the Southwest Foundation for Biomedical Research also contributed.

The National Institute on Aging funded the work.

Source: Brown University

Another report from Bio.com is this industry analysis of telomerase activators from Geron Corp. Geron's telomerase activators should find good use in treatment of HIV disease, and of malignancies.
During the progression of HIV disease, certain immune cells called CD8+ cytotoxic T-cells undergo accelerated replicative senescence (cellular aging), and lose their ability to proliferate and kill HIV-infected CD4+ T-cells. Previous work by Dr. Effros and colleagues demonstrated that introducing the telomerase gene into CD8+ cells from HIV/AIDS donors increased their proliferative capacity, their ability to produce IFN(gamma), and their ability to inhibit viral replication and kill HIV-infected T-cells. Dr. Effros demonstrated that the small molecule telomerase activators TAT0001 (GRN951) and TAT0002 (GRN665) improved the proliferative response of T-cells and increased IFN(gamma) production. The new data presented at the Gordon Conference showed that HIV-specific CD8+ cells pre-treated with either TAT0001 or TAT0002 had enhanced ability to inhibit viral replication when co-cultured with HIV-infected CD4+ cells.

"The new work conducted by Dr. Effros confirms and extends her earlier studies with TAT0001 and TAT0002, showing that our drug candidates enhance multiple functions of the cytotoxic T-cells that keep HIV in check," stated Calvin B. Harley, Ph.D., Geron's chief scientific officer. "These data, our ongoing safety studies and other product development activities are leading us to a novel pharmacologic approach for the treatment of HIV/AIDS."

Geron is active in all phasis of telomerase and telomerase inhibitor research. The company also is doing much work in stem cell research.

Telomeres are nucleic acid sequences at the end of chromosomes. Telomeres shorten with each cell division, up to the "Hayflick limit" of cell divisions.
At that point, cells resist the stimuli to divide.

Here is a research report from bio.com discussing possible use of telomere treatments for cancer.

Some scientist speculate that telomeres may be at the root of many species extinctions.

This is very dangerous territory, and must be covered with all meticulous thoroughness. Geron has been following a productive trail for many years now. It is a good company to follow, as well as its competitors.

Update: Here is a link to a story from medicineworld.org
Chromosome ends, or telomeres, are repetitive stretches of DNA that protect chromosomes in much the same way as plastic tips on shoelaces prevent the fabric from fraying. Each time a cell divides, its chromosome ends get a little shorter, and eventually the cell can no longer divide because its critical genetic information is exposed. In stem cells, however, a protein called telomerase normally maintains the telomeres' length, allowing the cells to divide indefinitely.

Now, the Hopkins scientists report that mice engineered to have just half the normal amount of telomerase can't maintain their stem cells' chromosome ends, showing that a little telomerase isn't enough. In these "half-telomerase" mice, their telomeres shortened over time, bringing an early demise to stem cells that replenish the blood supply, immune system and intestine, the scientists report. Moreover, offspring of these mice bred to have normal levels of telomerase still exhibited early loss of stem cells, the scientists report in the Dec. 16 issue of Cell.

...Because sperm and egg arise from stem cells, too, their telomeres gradually shorten, and each successive generation starts out with chromosomes whose telomeres are even shorter than their parents, the scientists report. The failure of telomerase to lengthen these telomeres explains why successive generations develop the physical symptoms of the disease at younger ages than their parents or grandparents, say the researchers.

"Normal levels of telomerase didn't lengthen short telomeres in our mice, so the longer the telomeres are to start with, the longer transplanted stem cells will be able to divide and the more likely the transplant is to succeed," explains Greider.

To engineer the half-telomerase mice, Ling-Yang Hao, then a graduate student, knocked out one copy of the telomerase gene in non-laboratory mice, whose telomere length is similar to humans'. (Typical laboratory mice have very long telomeres.).

He then bred these half-telomerase mice to one another and the team studied offspring that also carried just one telomerase copy. (Because one copy of each gene is inherited from each parent, only 50 percent of the offspring would be expected to end up with only one telomerase copy; 25 percent would have no telomerase gene, and 25 percent would have two copies of the telomerase gene.).

By the fifth generation, mice had severely shortened telomeres and exhibited failure of organs that have high turnover of their cells -- the bone marrow and intestine among them.

"We thought there might be some relationship between telomerase, telomere length and the survival of stem cells, but it was really exciting to see it," says Greider.

...The scientists are now mating these short-telomere mice with mice with regular-length telomeres to see whether telomere length goes back up. They're also studying the affected stem cells to find out exactly how critically short telomeres are affecting their survival.
The scientists were funded by the National Institutes of Health and the Johns Hopkins Institute for Cell Engineering. Authors on the paper are Hao, Armanios, Greider, Margaret Strong, Baktiar Karim, David Felser and David Huso, all of Johns Hopkins School of Medicine. Karim and Huso are with the Department of Comparative Medicine.


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