2 Sirtuins: A Universal Link between NAD, Metabolism, and Aging

Nature is an endless combination and repetition of a very few laws. She hums the old well-known air through innumerable variations. Ralph Waldo Emerson Essay I History , Essays: First Series, 1841 For the past several years, Sir2 family proteins, now called “sirtuins,” have been emerging as an evolutionarily conserved, critical regulator for aging and longevity in diverse model organisms, providing a novel paradigm to the field of aging research. The SIR2 gene was originally identified by Klar et al. (1979) as one of the genes that regulate the a and α mating types of budding yeast, Saccharomyces cerevisiae . Subsequent studies have demonstrated that Sir2 has a critical role in the regulation of transcriptional silencing at mating-type loci, telomeres, and ribosomal DNA (rDNA) repeats (Guarente 1999). At mating-type loci and telomeres, the Sir complex that includes Sir2 and the other two Sir proteins, Sir3 and Sir4, forms polymerized, closed chromatin structure, namely, heterochromatin, and silences reporter genes inserted into these genomic loci (Rine and Herskowitz 1987; Gottschling et al. 1990). At rDNA repeats, Sir2 is included in another complex named RENT ( re gulator of n ucleolar silencing and t elophase exit), along with Net1, Cdc14, and other proteins, and is involved in silencing transcription of pol II reporter genes inserted into rDNA repeats (Bryk et al. 1997; Smith and Boeke 1997; Straight et al. 1999). Sir2-mediated rDNA silencing is also important for suppression of homologous recombination within this highly repetitive rDNA region (Gottlieb and Esposito 1989). Silencing requires specific lysines in the amino-terminal tails...