Stressed Out: Activation of damage-fighting molecules wanes in old cells (Oxidative stress)
Authors: Davenport R. John 
Published: August 2003

When bombarded with stresses, cells recruit a molecular shield to stave off damage and maintain cellular vitality. Two defense pathways that compose part of the shield languish over the lifetime of rodents and might spark an age-related decline in stress resistance, according to new results. And a well-known life-extending treatment appears to restore the molecular armor.

Cells sustain a continual assault by harmful agents such as reactive oxygen species (ROS), which are thought to contribute to aging (see
"The Two Faces of Oxygen"
). A breakdown in molecular defenses could render older organisms more vulnerable to such threats. This idea is supported by the observation that many life-extending mutations in nematodes, flies, and yeast also enhance stress resistance. Although the general effects of trauma on cells have been well studied, how the molecular mechanics of stress resistance change with age is fuzzy. Results of a new study take a first step toward sharpening this picture. Stressful conditions activate two proteins, named ERK and Akt; each calls other proteins into action. In turn, those molecules switch on genes to help quench ROS and prevent cell death. Ikeyama and colleagues wondered whether the activation of these two molecular wardens diminishes with age.

To find out, the researchers grew kidney cells from young and old rats and treated each with the oxidizing agent hydrogen peroxide. Cells from old animals died in greater numbers and suffered more DNA breakage than did cells from young animals. Further results suggest that ERK and Akt might contribute to the difference: Cells from old animals contained less of the activated forms of the two proteins than did cells from young animals. In addition, when the team used chemical inhibitors to block activation of Akt and ERK, young cells became as sensitive as old cells to hydrogen peroxide. The findings hint that the Akt and ERK pathways founder with age, leading to increased vulnerability to oxidative damage.

The scientists next wondered whether caloric restriction--the only treatment known to extend life-span in mammals--could restore stress resistance to cells. The team took kidney cells from both young and old rats that had been subjected to caloric restriction and again measured both sensitivity to hydrogen peroxide and amount of activated Akt and ERK. Caloric restriction didn't alter cell survival or the amount of activated Akt and ERK in young animals, but the regimen made old cells look young again: Cells from older dieting animals withstood peroxide treatment as well as cells from young animals did, and the cells harbored similar amounts of activated Akt and ERK. Many investigators believe that caloric restriction reduces oxidative stress by minimizing the amount of ROS produced during the conversion of food into energy. But the new results add to growing evidence that caloric restriction might also inflict a mild stress that mobilizes cellular machinery to combat assaults.

Many protein networks in addition to those triggered by Akt and ERK are likely to be involved in stress resistance, and the study provides a starting point for understanding how protective molecular pathways deteriorate with age. It's not yet clear whether an increase in the ability of cells to respond to acute stress translates into a more robust life for the organism, but the new results offer hope that a therapeutic boost to these defenses could restore vitality to aging animals.

--R. John Davenport; suggested by Nick Bishop

S. Ikeyama, G. Kokkonen, S. Shack, X.-T. Wang, N. J. Holbrook, Loss in oxidative stress tolerance with aging linked to reduced extracellular signal-regulated kinase and Akt kinase activities.
FASEB J.
16
, 114-116 (2002).
[Abstract]
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