Manipulation of a Nuclear NAD+ Salvage Pathway Delays Aging without Altering Steady-state NAD+ Levels*

By Rozalyn M. Anderson, Kevin J. Bitterman, Jason G. Wood, Oliver Medvedik, H. Cohen, Stephen S. Lin, J. Manchester, Jeffrey I. Gordon, D. Sinclair. Journal of Biological Chemistry, 2002

222 citations recorded by the source corpus.

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 SIR2provide 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, andNMA2, increase telomeric and rDNA silencing, implying that multiple steps affect the rate of the pathway. AlthoughSIR2-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.

Subfields: Aging, Geriatrics and Gerontology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8589755fd3d57f5ee7e4aaa434f7a2c64d017991

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

1. L. Guarente
2. D. Sinclair
3. M. Haigis
4. F. Picard
5. Joseph A. Baur
6. Su-Ju Lin
7. A. Sauve
8. E. Ford

In Geriatrics and Gerontology

1. L. Guarente
2. D. Sinclair
3. M. Haigis
4. F. Picard
5. Joseph A. Baur
6. Su-Ju Lin
7. E. Ford
8. A. Sauve

In Molecular Biology

1. L. Guarente
2. D. Sinclair
3. M. Haigis
4. F. Picard
5. Su-Ju Lin
6. E. Ford
7. W. Kraus
8. Laura Bordone

Citations in the corpus

• Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. (2007, background): “In yeast, the first step is catalyzed by Pnc1 and in mammals by the NAM phosphoribosyltransferase Nampt, also known as PBEF or visfatin (Fukuhara et al., 2004; Rongvaux et al., 2002; Samal et al., 1994).”
• Calorie restriction extends yeast life span by lowering the level of NADH. (2004, background): “It has been shown that cells lacking the NPT1 gene (encoding nicotinic acid phosphoribosyl transferase in the NAD salvage pathway) exhibit a 40% to 60% decrease in NAD levels (Smith et al. 2000; Anderson et al. 2002).”
• Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae (2003, background): “Because Sir2 protein levels do not increase in response to calorie restrictio”
• Calorie restriction--the SIR2 connection. (2005, background): “The above model for activation of Sir2p by CR in yeast, however, has been challenged by the findings of Anderson et al. (2002) that the NAD salvage pathway plays a key role in CR (Figure 2).”
• PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes (2017, background): “More broadly, a number of studies have shown that modulation of cellular NAD+ levels can regulate the catalytic activities of sirtuins (Anderson et al. 2002, 2003; Araki et al. 2004; Revollo et al. 2004); presumably, similar mechanisms can regulate the catalytic activities of PARPs as well.”