Age-associated decrease in proteasome content and activities in human dermal fibroblasts: restoration of normal level of proteasome subunits reduces aging markers in fibroblasts from elderly persons.

We measured proteasome activities and the levels of proteasome subunits in dermal fibroblasts from individuals aged 20-82 years. Proteasome activities changed with age in a biphasic manner, decreasing significantly up to 50 years of age and showing no significant change between 50 and 78 years of age. Similarly, proteasome activities in replicatively senescent dermal fibroblasts showed a passage-dependent biphasic change. We confirmed that the decreases in proteasome activities were accompanied by the accumulation of oxidized and ubiquitinated proteins. The decline in proteasome activities in aging fibroblasts was associated with a decrease in the expression of proteasome subunits. We found that the restoration of the normal level of proteasome catalytic subunits, using a lentivirus gene-delivery system, decreased the severity of the aging markers in dermal fibroblasts from elderly donors. These findings suggest that proteasome malfunction may contribute to the aging process in human skin and that the maintenance of normal proteasome activities could delay skin aging.