Age-dependent increases in apoptosis/necrosis ratios in human lymphocytes exposed to oxidative stress.

Unlike apoptosis, mechanisms leading to necrosis are less well understood. Moreover, changes in necrosis as a function of age have not been studied in human lymphocytes. H(2)O(2)-induced death of peripheral lymphocytes (56 healthy donors, 24-95 years) was evaluated by flow cytometry and propidium iodide staining, caspase activation, DNA laddering, and electron microscopy. H(2)O(2)-induced stress was associated with high levels of necrosis in young individuals (≤30 years), whereas progressively enhanced apoptotic death was observed in older donors, without changes in overall lymphocyte survival. Thus, apoptosis/necrosis ratios were inverted in young versus elderly (≥65 years) donors. Death was not accompanied by increased caspase activity and, accordingly, unaffected by caspase inhibition; however, it was almost completely prevented by poly ADP ribose polymerase inhibition. In summary, aging was associated with changes in the apoptosis/necrosis ratios, rather than susceptibility per se to H(2)O(2)-induced death, which was caspase independent but poly ADP ribose polymerase dependent. Understanding this switch in death modes may aid in understanding age-related disorders.