Stress Relief For Aging Cells

Everyday deep inside your cells, reruns of an I Love Lucy episode are constantly replayed.

Lucy and Ethel get jobs wrapping chocolate bon-bons. At first, the conveyor belt carrying the chocolates moves slowly, and Lucy and Ethel easily manage to wrap each one in paper. But then the conveyor belt speeds up and comical chaos ensues. The two can’t keep up and they start eating the chocolates, their cheeks bulging with bon-bons, until they finally stash dozens under their hats.

Cells churn out proteins in a similar fashion. Most of the time, the conveyor belt moves slowly and proteins are manufactured, folded, and shipped with no problems. But sometimes the cell increases production, and just like Lucy and Ethel, the cell’s assembly line – the endoplasmic reticulum (ER) – becomes stressed and starts making mistakes.

Cells can call in temporary workers to help relieve the stress, but one – called CHOP – can overstay its welcome. If CHOP remains for more than a few days, the cell will die.

“This scenario often happens as we age,” says Ira Tabas, MD, PhD, an atherosclerosis researcher in the Department of Medicine. “Our cells become faced with chronic ER stress, and prolonged exposure to CHOP is recognized as a major factor in a wide variety of chronic diseases associated with aging, including atherosclerosis, Alzheimer's disease, and diabetes.”

Now Dr. Tabas and his colleagues have discovered how some cells turn off CHOP, which may be lead to new therapies to treat these diseases. The work, carried out by Connie Woo, PhD, a postdoctoral fellow in Dr. Tabas’ lab, appears in the Dec. 2009 issue of Nature Cell Biology.

Until now, researchers had believed that CHOP could only be turned off if the whole beneficial stress response was turned off as well. And conversely, if the stress response was on, CHOP was present.

But one cell presented a paradox. “Immune cells are under immense ER stress because they make tons of antibodies and other defensive proteins for several days,” Dr. Tabas says. “That’s long enough for CHOP to kill those cells, but the paradox is that the cells don’t die. It had to evolve that way or else we would all die of infection before we had the chance to pass on our genes.”

When Dr. Tabas and his colleagues looked in activated immune cells to explain how the cells stay alive, they found that CHOP is turned off by a family of receptors that detect bacteria and viruses, but the rest of the ER stress response still worked.

“It’s like the immune cells recognize the bug, realize this is going to take a few days, and then turn off CHOP but leave the rest of the ER stress pathway functioning normally,” Dr. Tabas says.

Infections with bacteria and viruses may seem far removed from vascular disease, but Dr. Tabas hopes the information gleaned from the infected cells could one day turn into a treatment for atherosclerosis. Dead cells inside atherosclerotic plaques often lead to blood clots and heart attacks. CHOP kills these cells, so turning off CHOP – but keeping the rest of the ER stress response intact – may keep the cells alive and prevent heart attacks. A similar strategy may work for other diseases in which excess CHOP does damage, like neurodegenerative diseases and diabetes.

“The idea to selectively turn off CHOP in these scenarios has long been recognized as a desirable goal among researchers working on these diseases – we just didn't know how to do it,” Dr. Tabas say. “Perhaps we can trick the cells into using nature's own beautiful strategy – originally designed to keep immune cells alive during infection – to accomplish this goal."

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CHOP, Connie Woo, ER, Ira Tabas, Nature Cell Biology