Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

Tugsan Tezil; Manish Chamoli; Che-Ping Ng; Roman P Simon; Victoria J Butler; Manfred Jung; Julie Andersen; Aimee W Kao; Eric Verdin

doi:10.1038/s41514-019-0037-7

Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

NPJ Aging Mech Dis. 2019 Oct 2:5:7. doi: 10.1038/s41514-019-0037-7. eCollection 2019.

Authors

Tugsan Tezil¹, Manish Chamoli¹, Che-Ping Ng¹, Roman P Simon², Victoria J Butler³, Manfred Jung², Julie Andersen¹, Aimee W Kao³, Eric Verdin¹

Affiliations

¹ 1Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400 USA.
² 2Institute of Pharmaceutical Sciences, University of Freiburg, Albertstrasse 25, Freiburg, 79104 Germany.
³ 3Department of Neurology, University of California, San Francisco, CA 94143 USA.

Abstract

Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a target of NDGA and provide mechanistic insight into its role in longevity.

Keywords: Autophagy; Epigenetics.

Abstract

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