Wasting Away: Stress response keeps aging cells from fattening up (Fat cell formation)
Authors: Strauss Evelyn 
Published: August 2003

BOSTON
--Many people battle fat for years, only to find at the end of their lives that they're losing it in all the wrong places. Sunken eyes, inability to control body temperature, and susceptibility to infection plague elderly people as their fat pads shrink. New work, presented 16 February at the AAAS meeting here, fills in some molecular steppingstones that mark the path to a decrease in fat cell formation.

As people age, they lose fat where it should be--under the skin, for instance--and gain it where it shouldn't be--in tissues such as bone marrow and muscle. This redistribution occurs in part because precursor cells destined to store fat lose their bearings. Over the past several years, scientists have established that two key proteins--whose concentrations decline with age--activate a set of genes required for precursor cells to mature into fat cells. Replacing the regulator proteins restores precursor cells to their destinies, indicating that the genes are still able to guide maturation if prompted. Researchers are therefore trying to figure out what regulates the regulators.

James Kirkland, a cell biologist at Boston University, has been picking his way upstream of the regulators. CUG triplet repeat binding protein (CUGBP) cranks up production of another protein that in turn blocks output of both regulators. Kirkland reported at the meeting that precursor fat cells from old rats produce more CUGBP than do similar cells from young rats. Swelling CUGBP concentrations in older animals probably contribute to the decline in the two key regulators, he says.

Going back one more step, Kirkland's team examined a protein called TNFα, which is produced in response to stress, accumulates in fat tissues with age, and thwarts production of the two maturation regulators--but the molecular underpinnings of these events have been unclear. Now Kirkland's team has found that treating precursor fat cells with TNFα causes their CUGBP concentrations to double. Other cellular events might similarly stunt precursor cells' maturation. When the researchers stimulated production of reactive oxygen species--destructive molecules implicated in aging--in cultured fat precursor cells from young rats, CUGBP concentrations shot up.

Together, Kirkland says, the results suggest that cellular events associated with aging activate stress pathways, which operate through a string of regulator proteins to stem fat cell formation. The emerging molecular details might provide the basis for future therapies, he says: "In fat tissue, there might be points where you can intervene." Success at restoring specialized functions to old fat cells might provide a model for rejuvenating other tissues, he adds.

Kirkland's approach is unusual, says Huber Warner, associate director for the Biology of Aging Program at the National Institute on Aging in Bethesda, Maryland: "He's looking at a phenomenon we're all familiar with--the changes in amounts and location of fat--but he's kind of alone in investigating the molecular basis for it."

--Evelyn Strauss