Role of acid sphingomyelinase in the age-dependent dysregulation of sphingolipids turnover in the tissues of rats

Abstract

Old age-associated pathologies usually coincide with altered sphingolipid metabolism. In the present article, the role of acid sphingomyelinase (ASMase) in the age-dependent changes of sphingomyelin (SM) and ceramide contents in the tissues has been investigated by means of ASMase inhibitors, imipramine and zoledronic acid. It has been determined that ceramide content and ceramide/SM ratio increased, while SM level decreased in the heart, liver, blood serum and skeletal muscles of 24-month old rats in contrast to 3-month old animals. Injections of imipramine or zoledronic acid to 24-month old rats resulted in significant downregulation of ASMase in the liver and skeletal and heart muscles. The both inhibitors decreased the ceramide content and ceramide/SM ratio and increased the SM content in all tissues studied, except the heart, of old rats to the levels close to those observed in the young animals. Long-term treatment of rats by inhibitors, which have different mechanisms of action on ASMase, exerts the similar, but not equal effects on enzyme activity and SM turnover. In summary, the data above strongly suggest that the age-dependent up-regulation of ASMase plays an important role in the modulation of ceramide and SM contents in rat tissues and that imipramine and zoledronic acid are useful tools for SM turnover manipulation at old age.

Potential therapeutic target for aging and age-related neurodegenerative diseases: the role of acid sphingomyelinase

“…Intriguingly, a recent study noted that ASM activity increased significantly in plasma from older versus younger individuals 45 . Similarly, old rodents also showed high levels of ASM activity in the plasma compared to that of younger animals 45,46 . This aging-associated increase in plasma ASM is probably related to ASM secreted from ECs in the brain or peripheral blood vessels.…”

“…ASM can also be preferentially transported to the outer leaflet of the cell membrane and secreted into the extracellular space during cellular stress and disease 29,30 . Previous studies have reported that the expression and activity of ASM change with age [45][46][47] . Thus, in this section, we review the critical roles of ASM in association with aging-related dysfunctions in physiological processes.…”

The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration

“…Serum levels of selected sphingomyelins correlate with progression from MCI to AD [ 82 ] ↓ S1P/sphingosine ratio in human aging hippocampus (only in females) [ 83 ] ↓ S1P levels in human AD brain hippocampus and inferior temporal cortex; hippocampal changes correlate with Braak stage of neuropathology [ 79 ] ↑ human hippocampal ceramide [ 83 ]. ↑ ceramide/sphingomyelin ratio in the rat serum, liver, heart, and skeletal muscle [ 84 ]. ↑ various human ceramide species [ 85 ].…”

“…↑ various human ceramide species [ 85 ]. ↑ ceramide/sphingomyelin ratio in the rat serum, liver, heart, and skeletal muscle [ 84 ]. Contradictory changes of various ceramides in centenarians [ 80 ] ↑ human brain ceramide levels—including the earliest clinically recognizable AD stage (MCI) [ 77 , 86 – 88 ] ↑ human hippocampal sphingomyelin level [ 83 ].…”

Sphingolipid Metabolism and Signaling in Skeletal Muscle: From Physiology to Physiopathology

“…Thus, this modification ASMase expression could play in important role in changes of SL turnover observed with age (see above). Using various ASMase inhibitors, Babenko et al ( 73 ) demonstrated that downregulation of ASMase reduced skeletal muscle ceramide content and ceramide/SM ratio and increased SM of old rats to the levels close to those observed in young animals. Unfortunately, S1P content had not been assessed in these conditions.…”