Reduced thermotolerance in aged cells results from a loss of an hsp72-mediated control of JNK signaling pathway

Aged organisms exhibit a greatly decreased ability to induce the major heat shock protein, Hsp72, in response to stresses, a phenomenon that can also be observed in cell cultures (Heydari AR, Takahashi R, Gutsmann A, You S an d Richardson A (1994) Hsp70 and aging. Experientia 50: 1092-1098). Hsp72 wa s shown to protect cells from a variety of stresses. The protective functio n of Hsp72 has been commonly ascribed to its chaperoning ability. However, recently we showed that Hsp72 protects cells from heat shock by suppression of a stress-kinase JNK, an essential component of the heat-induced apoptot ic pathway (Gabai VL, Merlin AB, Mosser DD, Caron AW, Rits S, Shifrin VI an d Sherman MY (1997) Hsp70 prevents activation of stress kinases. A novel pa thway of cellular thermotolerance. J Biol Chem 272: 18033-18037). Here we d emonstrate that because of the diminished inducibility of Hsp72 in aged cel ls, Hsp72-mediated control of JNK signaling pathway is compromised. This re sults in increased rate of apoptotic cell death following heat shock. We sh ow that forced expression of Hsp72 in aged cells from an adenovirus-based v ector completely suppresses activation of JNK by heat shock and consequentl y protects from heat-induced apoptosis. We also demonstrate for the first t ime that it is possible to restore endogenous expression of Hsp72 in aged c ells. This can be achieved by treatment with the proteasome inhibitor MG132 . Induction of Hsp72 in aged cells under these conditions leads to suppress ion of JNK activation by a heat shock and restoration of thermotolerance ma nifested in a lower rate of apoptosis.