With mounting evidence that senescence is a cancer countermeasure, Lowe and his team wondered if senescence played a part in another disorder: liver disease. Previously, researchers had noticed senescent cells in diseased livers, and Lowe wondered whether they were harmful or beneficial.

Hepatitis infection, alcohol abuse, and fatty liver disease can bring on cirrhosis, a permanent scarring that undermines the liver's normal function. A buildup of connective tissue, known as fibrosis, presages cirrhosis. When a liver is damaged, particular liver cells called stellate cells churn out extracellular matrix, the protein structure that forms fibrous tissue. If the cause of liver damage disappears, the stellate cells help other cells grow, repair, and replenish the liver. But a chronic drinking problem or untreated infection puts a liver under constant stress. Under these conditions, fibrosis spreads, cirrhosis sets in, and, ultimately, the liver fails.

Lowe's recent studies suggest that senescence helps put a damper on fibrosis. His team injected mice with an agent that damaged their livers, spurring fibrosis. In the animals' livers, senescent stellate cells peppered fibrotic regions, the team reported in August 2008 in Cell. In animals that can't undergo cellular senescence because they lack p53, fibrosis was more pervasive. Lowe posits that senescence hampers fibrosis by preventing stellate cells from growing too heartily and manufacturing a flood of extracellular matrix.

Fibrosis is part of the normal response to repair an injury, and unless a liver suffers continuous insults, fibrosis eventually dissipates. Lowe also found that senescence not only prevents fibrosis, it also helps clear fibrosis once it starts. In normal animals, fibrosis subsided and eventually disappeared once the liver-damaging injections stopped. But in animals without p53—and therefore deficient in senescence—fibrosis persisted.

Researchers have known for a while that senescent cells exude sets of molecules that deplete extracellular matrix. His findings suggest one possible reason for this behavior. “It fits nicely with this puzzling gene expression pattern that's been around for some time,” he says.

Lowe adds that cirrhosis puts patients at increased risk for liver cancer, and he's trying to understand why, in light of the new findings. Opposing Green's IGFBP7 finding, previous studies have found that senescent cells produce molecules that spur cancer, rather than prevent it. Senescence might be built to cope with an immediate insult, says Lowe, even if, over the long haul, quieting cells creates havoc. The body “can't stop everything,” says Lowe.

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