Title

SIRT1 Markedly Extends Replicative Lifespan if the NAD+ Salvage Pathway Is Enhanced

Document Type

Article

Publication Date

9-17-2009

Journal

FEBS Letters

Volume

583

Issue

18

First Page

3081

Last Page

3085

URL with Digital Object Identifier

10.1016/j.febslet.2009.08.031

Abstract

Sir2 mediates lifespan extension in lower eukaryotes but whether its mammalian homolog, sirtuin 1, silent mating type information regulation 2 homolog (SIRT1), is a longevity protein is controversial. We stably introduced the SIRT1 gene into human vascular smooth muscle cells (SMCs) and observed minimal extension of replicative lifespan. However, SIRT1 activity was found to be exquisitely dependent on nicotinamide phosphoribosyltransferase (Nampt) activity. Moreover, overexpression of Nampt converted SIRT1-overexpressing SMCs to senescence-resistant cells together with heightened SIRT1 activity, suppressed p21, and strikingly lengthened replicative lifespan. Thus, SIRT1 can markedly postpone SMC senescence, but this requires overcoming an otherwise vulnerable nicotinamide adenine dinucleotide salvage reaction in aging SMCs.