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J. Biol. Chem., Vol. 277, Issue 21, 18881-18890, May 24, 2002
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From the Yeast deprived of nutrients exhibit a marked life
span extension that requires the activity of the
NAD+-dependent histone deacetylase,
Sir2p. Here we show that increased dosage of NPT1, encoding
a nicotinate phosphoribosyltransferase critical for the
NAD+ salvage pathway, increases Sir2-dependent
silencing, stabilizes the rDNA locus, and extends yeast replicative
life span by up to 60%. Both NPT1 and SIR2
provide resistance against heat shock, demonstrating that these genes
act in a more general manner to promote cell survival. We show that
Npt1 and a previously uncharacterized salvage pathway enzyme, Nma2, are
both concentrated in the nucleus, indicating that a significant amount
of NAD+ is regenerated in this organelle. Additional copies
of the salvage pathway genes, PNC1, NMA1, and
NMA2, increase telomeric and rDNA silencing, implying that
multiple steps affect the rate of the pathway. Although
SIR2-dependent processes are enhanced by
additional NPT1, steady-state NAD+ levels and
NAD+/NADH ratios remain unaltered. This finding suggests
that yeast life span extension may be facilitated by an increase in the
availability of NAD+ to Sir2, although not through a simple
increase in steady-state levels. We propose a model in which increased
flux through the NAD+ salvage pathway is responsible for
the Sir2-dependent extension of life span.
Manipulation of a Nuclear NAD+ Salvage Pathway Delays
Aging without Altering Steady-state NAD+ Levels*
§,§,¶,,
,
Department of Pathology, Harvard Medical
School, Boston, Massachusetts 02115 and the ** Department of
Molecular Biology and Pharmacology, Washington University School of
Medicine, St. Louis, Missouri 63110
*
Work was supported in part by The Ellison Foundation, The
American Federation for Aging Research, and The Arminese Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Taplan Fellowship.
¶
Supported by a National Science Foundation scholarship.
Supported by a Leukemia and Lymphoma Society
Special Fellowship. To whom correspondence should be addressed: Dept.
of Pathology, Harvard Medical School, 200 Longwood Ave., Boston, MA
02115. Tel.: 617-432-3931; Fax: 617-432-1313; E-mail:
david_sinclair@hms.harvard.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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