Anti-aging: A little stress may keep cells youthful

The aging-related protein SIRT1 regulates heat shock response, a mechanism cells use to combat stress

A lot of stress can turn your hair gray, but a little stress can actually delay aging. A protein tied to protecting cells from stress also helps slow aging, a new study finds. The research, published February 20 in Science, identifies a key regulator of a mechanism cells use to prevent protein damage from stress.

Exposure to heat, cold or heavy metals can damage proteins and unravel them from their usual conformations — trauma that can cause cell death. But cells have a damage-limiting mechanism called the heat shock response to combat these and other stresses. As part of the heat shock response, special protein repair molecules patch up the damaged proteins and refold them correctly, preventing death and extending the life of the cell.

Molecular biologist Sandy Westerheide of Northwestern University in Evanston, Ill., and her colleagues found that the heat shock response in human cell lines is regulated by Sirtuin 1, or SIRT1, an aging-related protein. It’s the first evidence linking SIRT1 to the protein-protecting heat shock response.

“This is a very interesting and insightful study,” comments Raul Mostoslavsky, a cell biologist at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston. “We knew that Sirtuin 1 had many roles in longevity. It’s remarkable that it also affects heat shock response.”

The study focused on individual cells, but for whole organisms the finding could shed light on a link between stress and life span. “A little bit of stress can actually prolong life,” says molecular biologist Richard Morimoto of Northwestern, a study coauthor. Mild stress activates the heat shock response but does not harm the cells, he adds.

One mild stress that can activate the heat-shock response is a calorie-restricted diet, which has been shown to extend the life of all species tested so far, including mice and dogs. Calorie-restricted diets increase the levels of Sirtuin 1, or SIRT1, an aging-related protein.

“Now we know that these diets could prolong life through heat shock factor 1,” says Westerheide.

Heat shock factor 1 is a key component of the heat shock response. When a cell is under stress, heat shock factor 1 latches on to DNA and steps up production of the protein repair molecules. But the cell can’t exist in a state of emergency all the time. After the protein repair molecules become abundant, the damage-limiting mechanism shuts itself down. A chemical called an acetyl group is added to the heat shock factor 1, making it “fall off” the DNA strand, says Westerheide.

But sometimes the process gets shut down before all the damage is repaired.

Researchers already knew that SIRT1 protects cells from aging through several different stress-busting pathways. But in this report, Westerheide and her colleagues show that SIRT1 can also remove the acetyl groups from heat shock factor 1, allowing it to stay on the DNA and to keep producing the protein repair molecules.

As an organism ages, the amount of SIRT1 decreases as the cells age, so heat shock response is reduced. Consequently, older cells are less able to cope with damage caused by stress, the researchers report.

One day, SIRT1 could be used to activate the heat shock response on demand, the researchers speculate. “This could help us to age in a more healthy way,” Westerheide says. Heat shock response could also help repair the damaged brain proteins that cause neurodegenerative diseases such as Alzheimer’s and Huntington’s disease, she says.

But using SIRT1 to keep cells in a defensive state could have negative consequences. It would also help cancer cells combat stress and thrive, the researchers note. “It’s a fine balance,’ Westerheide says.

Researchers still need to prove that heat shock factor 1 and SIRT1 function together to protect the cells of whole organisms, not just the cell lines that the team tested. “It’s not yet clear if this will be relevant to whole organisms, but I’m hopeful that it will be,” Mostoslavsky says.

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