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Contributed to understanding of stress-responsive pathways, protection of the proteome, metabolism, and lifespan. Studied heat shock response (HSR) and the role of molecular chaperones in biology and disease. Cloned the human Hsp70 gene, characterized the human HSR, the mechanisms of stress-inducible transcriptional control, and biochemical properties of human Hsp70 in protein-folding homeostasis and stress signaling. Cloned vertebrate heat-shock transcription factors (Hsf) and elucidated the Hsf tissue-specific and stress responsive pathways. Studied Hsf1, providing an understanding of activation mechanisms and the roles of molecular chaperones on the HSR. Demonstrated application of his work to aging by showing that Hsf1 is essential for lifespan enhancement by the insulin-signaling pathway, and integrated into metabolism via the regulatory role by the NAD-dependent sirtuin, SIRT1. Showed that aggregation-prone proteins cause other metastable proteins to subsequently misfold, thus amplifying the collapse of proteostasis. Showed that the stress factors Daf-16 and Hsf1 can reverse this damage by enhancing expression of chaperones and other arms of the proteostasis network to restore organismal stress resilience.