Role of neutral sphingomyelinases in aging and inflammation

Aging is characterized by changes in the organism’s immune functions and stress response, which in the elderly leads to increased incidence of complications and mortality following inflammatory stress. Alterations in the neuro-endocrine axes and overall decline in the immune system play an essential role in this process. Overwhelming evidence however suggests that many cellular cytokine signaling pathways are also affected, thus underscoring the idea that both, ‘‘cellular’’ and ‘‘systemic’’ changes contribute to aging. IL-1β for example, induces more potent cellular responses in hepatocytes isolated from aged animals then in hepatocytes from young rats. This phenomenon is referred to as IL-1β hyperresponsiveness and is linked to abnormal regulation of various acute phase proteins during aging. Evidence has consistently indicated that activation of neutral sphingomyelinase and the resulting accumulation of ceramide mediate cellular responses to LPS, IL-1β, and TNFα in young animals. More recent studies identified the cytokine-inducible neutral sphingomyelinase with NSMase2 (smpd3) that is localized in the plasma membrane and mediates cellular responses to IL-1β and TNFα. Intriguingly, constitutive up-regulation of NSMase2 occurs in aging and it underlies the hepatic IL-1β hyperresponsiveness. The increased activity of NSMases2 in aging is caused by a substantial decline in hepatic GSH content linking thereby oxidative stress to the onset of pro-inflammatory state in liver. NSMase2 apparently follows a pattern of regulation consisting with ‘‘developmental-aging’’ continuum, since in animal models of delayed aging, like calorie-restricted animals, the aging-associated changes in NSMase activity and function are reversed.