Functional recovery of senescent cells through restoration of receptor-mediated endocytosis

The functional deterioration of an organism with age causes the major problem of maintaining the quality of life at old age. Degenerative changes in the organism may to some extent reflect alterations that can be observed in cells during in vitro replicative senescence. At the cellular level, the receptor-mediated endocytosis in the membrane might be emphasized as a responsible mechanism for functional decay, since the endocytosis is in charge of many important biological phenomena: nutrient uptake, growth factor sensitivity, immune response, protection from environment and pathogen uptake, etc. We found that two major endocytotic pathways, i.e. clathrin-mediated and caveolae-dependent endocytosis, are down regulated in senescent cells. For the down regulation of the clathrin dependent receptor-mediated endocytosis, the reduction of amphiphysin-1 was found responsible, which was confirmed by Western blot analysis, dominant negative mutant transfection and restoration of gene activity by microinjection. With respect to the hypo-responsiveness of senescent cells to growth factors, the upregulation of caveolins has been suggested to be a causal factor. The overexpression of caveolins caused senescent-like changes in epidermal growth factor (EGF) response of the young cells, while down regulation of caveolins by use of antisense-oligonucleotides restored the EGF response in old cells, suggesting that caveolin system would be one of the major mechanisms responsible for decreased responses to growth factors in the senescent cells. Based on these results, it can be suggested that the functional deterioration of the senescent cells may be explained in terms of the down regulation of receptor mediated endocytosis, at least in part, and that the restoration of endocytosis apparatus either with amphiphysin supplementation or with reduction of caveolins might lead to functional recovery of the senescent cells. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.