Everything wears out. In humans, wearing out translatesinto aging. As cells in the body undergo senescence _aging _ their pattern of gene expression changes.Scientists have long been looking for changes in geneexpression that are characteristic of all aging cells toidentify a specific biomarker for cell senescence. Nowthey may have some clues.

A paper published in the current issue of the Proceedingsof the National Academy of Sciences (PNAS), datedSept. 26, 1995, describes the development of a biomarkerthat measures cell senescence both in culture and in vivo.

The article titled, "A biomarker that identifies senescenthuman cells in culture and in aging skin in vivo," waswritten as a result of work done in senior author JudithCampisi's lab at Lawrence Berkeley Laboratory at theUniversity of California. Maarten Linskens, of GeronCorp., in Menlo Park, Calif., and collaborators fromseveral universities also contributed to the work reported.

Normal cultured cells invariably arrest their growth aftera finite number of divisions. This process of cellsenescence is believed to be the underlying cause of agingand also a tumor-suppressive mechanism. However, therole that cell senescence plays in organismal aging is notwell-understood because senescent cells cannot be readilydistinguished from non-dividing or terminallydifferentiated cells in intact tissues.

Campisi and collaborators have shown that beta-galactosidase, histochemically detectable at pH 6, isexpressed in culture by senescent fibroblasts and skincells, called keratinocytes, but not in non-dividingfibroblasts and terminally differentiated keratinocytes.This enzyme activity also was absent in immortal cells,but was induced by genetic manipulations that reversedimmortality in these cells.

After demonstrating these correlations in culture, theyextended their work to skin cells isolated directly fromhuman donors of varying ages. They found an age-dependent increase in beta-galactosidase expression. Thisincrease was measured in dermal fibroblasts andepidermal keratinocytes.

Calvin Harley, vice president of research at Geron, toldBioWorld Today that, "While cell aging is a well-established process in cultured cells, it is not well-documented as occurring in vivo. In fact, it is stillsomewhat controversial." Harley continued, "This workwas able to confirm that cell senescence does occur invivo."

According to Harley, Geron has followed up this work bygenerating a catalogue of gene expression changes infibroblasts, both in culture and in vivo, and correlatedthem with aging. "We have been able to establish thatsenescence occurs in vivo in cell types other than thosereported on in the PNAS paper," said Harley. "It doesappear to be a generalized phenomenon that occurs in allcell types in vivo."

"The ability to detect the presence of senescent cells inaging tissue is an important step in Geron's program todetermine a common link between age-related diseases,"said Harley.

The Next Step? Treating Age-Related Diseases

"With this new ability to study senescent cells, we canmove forward more rapidly in our research and drugdiscovery efforts focused on understanding and treatingdisease-causing changes associated with cellular aging,"he said. "Geron has a novel scientific platform that thecompany wants to capitalize on to screen for potentialdrugs that can reverse cell senescence."

Karl Riabowol, a molecular biologist at the University ofCalgary, Canada, who works on cell aging, told BioWorldToday that, "Good biomarkers are very important inmeasuring a biological process or effect, cell agingincluded.

"There are other correlates of cell aging, such astelomerase activity and the shortening of chromosomaltelomeres in normal cells, but they are not as easilymeasured." Riabowol pointed out that, "Using thecommon assay for beta-galactosidase provides a veryhandy way of looking at cell aging."

Riabowol explained that it is unknown why beta-galactosidase expression is a good biomarker, but itslinkage to cell aging is very tight.

"Lots of enzymes are altered," he said, "both in terms ofsecretion and activity, in aging cells. Also, cellulararchitecture is very different in older cells."

Riabowol concluded that, "Maybe the expression of thisenzyme is altered by these changes. Whatever theultimate biological explanation, this assay appears to bethe easiest and best one for detecting cell senescence." n

-- Chester A. Bisbee Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.