STUDY DESIGN: Experimental in vivo and in vitro study of intervertebral disc (IVD) degeneration and the mechanism exploration. OBJECTIVE: This report aims to verify the expression of Sirt1 in IVD degeneration of different grades and explore its potential mechanism in human nucleus pulposus cells. SUMMARY OF BACKGROUND DATA: Silent mating type information regulator 2 homolog 1 (Sirt1) has draw immense attention because of its influence on a variety of aging-related diseases. The present study is a continuation and complement of our former in vivo study of Sirt1 and its role in puncture-induced rodent disc degeneration model. METHODS: Sirt1 protein expression level and histological morphology were evaluated in the discs of different degeneration levels, which is graded according to the Pfirrmann grading scale. Then the mRNA and protein expression levels of type II collagen, MMP-13, ADAMTS-5, p21, p16, cell proliferation, and apoptosis ratio were tested in vitro nucleus pulposus cells that expressed different levels of Sirt1 by reverse transcription polymerase chain reaction, western blot analysis, CCK-8 assay, and flow cytometry analysis. RESULTS: Sirt1 protein expression level decreased in the discs of high Pfirrmann grade and the score of histological morphology of human intervertebral disc is consistent with the Pfirrmann grade. Besides, when resveratrol activated Sirt1, nucleus pulposus cells proliferation increased while the cell apoptosis ratio decreased; the expression of type II collagen increased while MMP-13, ADAMTS-5 decreased. It showed the opposite results when the cells were transfected by Sirt1 siRNA. In addition, the expression of both p21 and p16 decreased when Sirt1 was activated. CONCLUSION: Sirt1 is a protective mediator in IVD degeneration and the expression of Sirt1 decreases in degenerative disc. Activation of Sirt1 works on suppressing cellular senescence, promoting cell proliferation, and restraining the apoptosis of nucleus pulposus cells. LEVEL OF EVIDENCE: N/A.