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Ticking of Cellular Clock Reverberates Throughout the Landscape of Aging

Telomeres

Telomeres, shown here in red and green at chromosome ends, keep track of the number of times a cell has divided.

Like cats, human cells have a finite number of lives. Once they divide a certain number of times, they change shape, slow their pace, and eventually stop dividing—a phenomenon called "cellular senescence." Biologists know that a cellular clock, composed of structures at the chromosome end known as telomeres, records how many "lives" a cell has expended. Until recently, however, they had not yet defined how the clock's ticking signals the approach of cellular oblivion.

In a study published in Nature Structural and Molecular Biology, a team led by Jan Karlseder reports that as cells count down to senescence and telomeres wear down, their DNA undergoes massive changes in how it is packaged—changes that likely trigger what we call "aging."

"Prior to this study we knew that telomeres get shorter and shorter as a cell divides and that when they reach a critical length, cells stop dividing or die," said Karlseder. "Something must translate the local signal at chromosome ends into a huge signal felt throughout the nucleus. But there was a big gap in between."

Karlseder and his group began to close that gap by comparing levels of proteins called histones in young cells—cells that had divided 30 times—with "late middle-aged" cells, which had divided 75 times and were on the downward slide to senescence, which occurs at 85 divisions. Histone proteins bind linear DNA strands and compress them into nuclear complexes, collectively referred to as chromatin.

To their surprise, Karlseder's team found that aging cells simply made less histone protein than young cells do. "These proteins are required throughout the genome, and therefore any event that disrupts this production line affects the stability of the entire genome," explains postdoctoral fellow Roddy O'Sullivan, the study's lead author.

The team then undertook exhaustive "time-lapse" comparisons of histones in young versus aging cells and confirmed that marked differences in the abundance and variety of histones were evident at every step as cells moved through cell division.

Comparisons of histone patterns in cells taken from human subjects—a nine- versus 92-year-old—dramatically mirrored the histone trends seen in cell lines. "These key experiments suggest that what we observe in cultured cells in a laboratory setting actually occurs and is relevant to aging in a population," says Karlseder.