Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis.

Abstract

Cell death plays a pivotal role in the body to maintain homeostasis during aging. Studies have shown that damaged cells, which must be removed from the body, accumulate during aging. Decay of the capacity and/or control of cell death during aging is widely considered to be involved in some age-dependent diseases. We investigated the accumulation of protein carbonyls and the role of cell death induced by hydrogen peroxide in human fibroblasts from individuals of various ages (17-80 years). The results showed that levels of oxidatively modified proteins increased with age, not only in whole-cell lysates but also in mitochondrial fractions, and this change correlates with a decline in the intracellular ATP level. Exposure of fibroblasts to hydrogen peroxide led to cell death by apoptosis and necrosis. Younger (<60 years old) cells were more resistant to necrosis induced by hydrogen peroxide than were older cells (>60 years old), which contained lower levels of free ATP than did younger cells. Treatment of cells of all ages with inhibitors of ATP synthesis (oligomycin, 2,4-dinitrophenol, or 2-deoxyglucose) made them more susceptible to cell death but also led to a switch in the death mode from apoptosis to necrosis. Furthermore, hydrogen peroxide treatment led to a greater accumulation of several inflammatory cytokines (IL-6, IL-7, IL-16, and IL-17) and increased necrosis in older cells. These results suggest that age-related decline in the ATP level reduces the capacity to induce apoptosis and promotes necrotic inflammation. This switch may trigger a number of age-dependent disorders.

• Authors: Noriyuki Miyoshi, Hammou Oubrahim, P Boon Chock, Earl R Stadtman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 6 Pg. 1727-31 (Feb 07 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16443681 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Cytokines
• Adenosine Triphosphate
• Hydrogen Peroxide
• JNK Mitogen-Activated Protein Kinases

Topics

• Adenosine Triphosphate (metabolism)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Aging (physiology)
• Apoptosis (drug effects)
• Cells, Cultured
• Cytokines (metabolism)
• Fibroblasts
• Humans
• Hydrogen Peroxide (pharmacology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Middle Aged
• Necrosis
• Oxidation-Reduction (drug effects)
• Phosphorylation (drug effects)