We previously observed an accumulation of gangliosides coincident with development of cell senescence, and demonstrated lysosomal permeabilization in human umbilical vein endothelial cells (HUVEC) exposed to glycated collagen I (GC). Therefore we investigated if the lysosome-dependent, caspase-independent or type 2 programmed cell death, autophagy is involved in development of premature senescence of endothelial cells. The cleaved microtubule-associated protein-1 light chain 3 (LC3), a marker of autophagosome formation, was overexpressed within 24h of GC treatment, but by 4-5 days was nearly undetectable. Early induction of autophagosomes was associated with their fusion with lysosomes, a phenomenon, which later became subverted. Autophagic cell death, can be triggered by the products of damaged plasma membrane, sphingolipids and ceramide. We observed a clustering of membrane rafts shortly after exposure to GC and later after 24 hours an internalization, accompanied by an increased acid sphingomyelinase activity and accumulation of ceramide. Pharmacological inhibition of autophagy prevented development of premature senescence, but lead to the enhanced rate of apoptosis in HUVEC exposed to GC. Pharmacological induction of autophagy resulted in reciprocal changes. These observations appear to represent a mechanistic molecular cascade whereby advanced glycation end products (AGEs) like GC induce sphingomyelinase activity, accumulation of ceramide, clustering and later internalization of lipid rafts.