Cuervo A M, Dice J F
Department of Physiology Tufts University School of Medicine, Boston, USA.
Front Biosci. 1998 Jan 1;3:d25-43. doi: 10.2741/a264.
One of the common features of cells from senescent tissues is the accumulation of abnormal proteins. Several hypotheses have been proposed to explain the origin of those abnormal proteins. A defect in proteolytic systems usually responsible for the elimination of altered proteins from the cells could clearly contribute to such accumulation. Here we describe the effect of age on the major proteolytic systems within cells: the ubiquitin-proteasome pathway, the calcium-activated calpain pathways, and multiple lysosomal pathways. Our group has contributed to the characterization of a selective pathway of degradation of cytosolic proteins in lysosomes that is activated under conditions of nutrient deprivation. In this lysosomal pathway of proteolysis proteins are transported through the lysosomal membrane assisted by cytosolic and lysosomal molecular chaperones and a receptor protein in the lysosomal membrane. The activity of this pathway significantly decreases with age, and this decrease might account for the cytosolic accumulation of aberrant substrate proteins in senescent cells. The cellular consequences of the decline of this lysosomal pathway together with possible methods to restore the reduced function are also addressed in this review.
衰老组织细胞的一个共同特征是异常蛋白质的积累。人们提出了几种假说来解释这些异常蛋白质的来源。通常负责从细胞中清除改变的蛋白质的蛋白水解系统中的缺陷显然可能导致这种积累。在这里，我们描述了年龄对细胞内主要蛋白水解系统的影响：泛素-蛋白酶体途径、钙激活的钙蛋白酶途径和多个溶酶体途径。我们小组对溶酶体中细胞质蛋白降解的选择性途径的特征进行了研究，该途径在营养剥夺条件下被激活。在这种溶酶体蛋白水解途径中，蛋白质在细胞质和溶酶体分子伴侣以及溶酶体膜中的一种受体蛋白的协助下穿过溶酶体膜。随着年龄的增长，该途径的活性显著降低，这种降低可能是衰老细胞中异常底物蛋白在细胞质中积累的原因。本综述还讨论了这种溶酶体途径下降的细胞后果以及恢复功能降低的可能方法。
