Sir2 links chromatin silencing, metabolism, and aging.

By L. Guarente. Genes & Development, 2000

722 citations recorded by the source corpus.

Aging is manifested by a progressive decline in vitality over time leading to death. Studies in budding yeast allow aging to be followed in individual pedigrees of cells, that is, those of mother cells, consequent to many rounds of cell division (Mortimer and Johnston 1959). These studies have led to the general conclusion that the silencing protein Sir2 is a limiting component of longevity; deletions of SIR2 shorten life span and an extra copy of this gene increases life span (Kaeberlein et al. 1999). Recent studies have spurred interest in Sir2 as a candidate longevity factor in a broad spectrum of eukaryotic organisms. SIR2 gene homologs have been found in a very wide range of organisms ranging from bacteria to humans (Brachmann et al. 1995). Moreover, a biochemical activity of Sir2 likely responsible for chromatin silencing, nicotinamide–adenine dinucleotide (NAD)-dependent histone deacetylase, has recently been discovered and shown to be broadly conserved (Imai et al. 2000). In this review, I will briefly discuss silencing as it pertains to SIR2 and its relationship to aging. I will then trace the studies that led to the discovery of the NADdependent histone deacetylase. I will next speculate how the regulation of Sir2 by NAD could represent the link between caloric intake and the pace of aging, which is widely observed in many organisms (Weindruch et al. 1986). Finally, I will present a speculative model of how a gradual disruption in chromatin silencing may occur and how such a change may cause aging.

Subfields: Geriatrics and Gerontology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d4e960a1f74f0cb20ae6482edae0af7c71920b53

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In Geriatrics and Gerontology

1. L. Guarente
2. Johan Auwerx
3. C. Cantó
4. M. Haigis
5. R. Houtkooper
6. D. Sinclair
7. F. Picard
8. M. McBurney

In Molecular Biology

1. L. Guarente
2. W. Gu
3. S. Baylin
4. Peter A. Jones
5. C. Brooks
6. M. Haigis
7. Johan Auwerx
8. R. Houtkooper

Citations in the corpus

• Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. (2003, background): “Transgenic mice harboring an aminoterminal p53 deletion mutant exhibit an early aging phenotype [80], and Sir2a is involved in gene silencing and extension of life span in yeast and Caenorhabditis elegans [81].”
• The nucleosome: from genomic organization to genomic regulation. (2004, background): “(D) The bromodomain of Gcn5 in complex with the H4 tail (blue) with acetyllysine 16 (orange) (Owen et al., 2000). aspects of gene regulation and cellular metabolism binding by bromodomain is characterized by weak affinity, but the binding affinity dramatically increases when(Guarente, 2000).”
• Calorie restriction--the SIR2 connection. (2005, background): “The unusual enzymatic activity of Sir2 suggested that this protein e tsenses the metabolic state of cells and sets the life span accordingly (Guarente, 2000).”
• Mammalian SIRT1 represses forkhead transcription factors. (2004, background): “This metabolicColumbia University shift upregulates the Sir2p deacetylase by increasing1150 St. Nicholas Avenue the NAD/NADH ratio (Guarente, 2000; Lin et al., 2004).”
• The epigenomics of cancer. (2007, background): “In addition, through mechanisms including deacetylation of the histone residue, H4K16, the yeast SIRT1 ortholog, Sir2, is an important participant in gene silencing (Guarente, 2000; Kimura et al., 2002; Suka et al., 2002).”
• Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase (2004, background): “In yeast, the SIR2 gene is involved in the regulation of transcriptional silencing, DNA damage responses, and is required for lengthening of lifespan following caloric restriction in yeast (Guarente, 2000; Lin et al, 2002).”