Mild heat stress stimulates 20S proteasome and its 11S activator in human fibroblasts undergoing aging in vitro.

Repeated mild heat shock (RMHS) has been shown to have several beneficial hormetic effects on human skin fibroblast undergoing aging in vitro. Because an age-related decline in proteasome activity is 1 of the reasons for the accumulation of abnormal proteins during aging, we have investigated the effects of RMHS on the 20S proteasome, which is the major proteolytic system involved in the removal of abnormal and oxidatively damaged proteins. Serially passaged human skin fibroblasts exposed to RMHS at 41 degrees C for 60 minutes twice a week had increased 3 proteasomal activities by 40% to 95% in early- and midpassage cultures.

Molecular mechanisms of anti-aging hormetic effects of mild heat stress on human cells.

In a series of experimental studies we have shown that repetitive mild heat stress has anti-aging hormetic effects on growth and various other cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. We have reported the hormetic effects of repeated challenge at the levels of maintenance of stress protein profile; reduction in the accumulation of oxidatively and glycoxidatively damaged proteins; stimulation of the proteasomal activities for the degradation of abnormal proteins; improved cellular resistance to ethanol, hydrogenperoxide, and ultraviolet-B rays; and enhanced levels of various antioxidant enzymes. We are now undertaking a detailed analysis of the signal transduction pathways to determine alterations in the phosphorylation and dephosphorylation states of extracellular signal-related kinase, c-Jun terminal kinase and p38 MAP-kinases as a measure of cellular responsiveness to mild and severe heat stress.

Proteasomal inhibition by alpha-synuclein filaments and oligomers.

A unifying feature of many neurodegenerative disorders is the accumulation of polyubiquitinated protein inclusions in dystrophic neurons, e.g. containing alpha-synuclein, which is suggestive of an insufficient proteasomal activity.

Mild stress-induced stimulation of heat-shock protein synthesis and improved functional ability of human fibroblasts undergoing aging in vitro.

Repeated mild heat-shock (RMHS) treatment has anti-aging hormetic effects on human fibroblasts undergoing aging in vitro. Since heat and various other stresses induce the transcription and translation of heat-shock proteins (Hsp), it was investigated if RMHS treatment affected the basal levels of four major stress proteins Hsp27, 70, 90 and Hsc70. The basal levels of Hsp27, Hsc70, and Hsp70 increased significantly in late passage senescent cells, which is indicative of an adaptive response to cumulative intracellular stress during aging.