Calorie restriction slows aging and increases life span in many organisms. In yeast, a mechanistic explanation has been proposed whereby calorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independent pathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of these genetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reported thus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes.
References
[1]
Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Cohen H, et al. (2002) Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. J Biol Chem 277: 18881–18890.
[2]
Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA (2003a) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in . Nature 423: 181–185.
[3]
Anderson RM, Latorre-Esteves M, Neves AR, Lavu S, Medvedik O, et al. (2003b) Yeast life-span extension by calorie restriction is independent of NAD fluctuation. Science 302: 2124–2126.
[4]
Aparicio OM, Billington BL, Gottschling DE (1991) Modifiers of position effect are shared between telomeric and silent mating-type loci in . Cell 66: 1279–1287.
[5]
Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, et al. (2001) Extending the lifespan of long-lived mice. Nature 414: 412.
[6]
Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277: 45099–45107.
[7]
Borghouts C, Benguria A, Wawryn J, Jazwinski SM (2004) Rtg2 protein links metabolism and genome stability in yeast longevity. Genetics 166: 765–777.
[8]
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, et al. (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303: 2011–2015.
[9]
Bryk M, Banerjee M, Murphy M, Knudsen KE, Garfinkel DJ, et al. (1997) Transcriptional silencing of Ty1 elements in the RDN1 locus of yeast. Genes Dev 11: 255–269.
[10]
Defossez PA, Prusty R, Kaeberlein M, Lin SJ, Ferrigno P, et al. (1999) Elimination of replication block protein Fob1 extends the life span of yeast mother cells. Mol Cell 3: 447–455.
[11]
Fabrizio P, Longo VD (2003) The chronological life span of . Aging Cell 2: 73–81.
[12]
Gottlieb S, Esposito RE (1989) A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell 56: 771–776.
[13]
Houthoofd K, Braeckman BP, Johnson TE, Vanfleteren JR (2003) Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in . Exp Gerontol 38: 947–954.
[14]
Imai S, Armstrong CM, Kaeberlein M, Guarente L (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795–800.
[15]
Ivy JM, Klar AJ, Hicks JB (1986) Cloning and characterization of four SIR genes of . Mol Cell Biol 6: 688–702.
[16]
Jiang JC, Jaruga E, Repnevskaya MV, Jazwinski SM (2000) An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J 14: 2135–2137.
[17]
Jiang JC, Wawryn J, Shantha Kumara HM, Jazwinski SM (2002) Distinct roles of processes modulated by histone deacetylases Rpd3p, Hda1p, and Sir2p in life extension by caloric restriction in yeast. Exp Gerontol 37: 1023–1030.
[18]
Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in by two different mechanisms. Genes Dev 13: 2570–2580.
[19]
Kaeberlein M, McVey M, Guarente L (2001) Using yeast to discover the fountain of youth. Sci Aging Knowledge Environ pe1. 2001.
[20]
Kaeberlein M, Andalis AA, Fink GR, Guarente L (2002) High osmolarity extends life span in by a mechanism related to calorie restriction. Mol Cell Biol 22: 8056–8066.
[21]
Kaeberlein M, Andalis AA, Liszt G, Fink GR, Guarente L (2004) SSD1-V confers longevity by a Sir2p-independent mechanism. Genetics 166: 1661–1672.
[22]
Kennedy BK, Austriaco NR, Zhang J, Guarente L (1995) Mutation in the silencing gene SIR4 can delay aging in . Cell 80: 485–496.
[23]
Kirchman PA, Kim S, Lai CY, Jazwinski SM (1999) Interorganelle signaling is a determinant of longevity in . Genetics 152: 179–190.
[24]
Koubova J, Guarente L (2003) How does calorie restriction work? Genes Dev 17: 313–321.
[25]
Lakowski B, Hekimi S (1998) The genetics of caloric restriction in . Proc Natl Acad Sci U S A 95: 13091–13096.
[26]
Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, et al. (2000) The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci U S A 97: 5807–5811.
[27]
Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in . Science 289: 2126–2128.
[28]
Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, et al. (2002) Calorie restriction extends life span by increasing respiration. Nature 418: 344–348.
[29]
Lin SJ, Ford E, Haigis M, Liszt G, Guarente L (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 18: 12–16.
[30]
Lin SS, Manchester JK, Gordon JI (2003) Sip2, an N-myristoylated beta subunit of Snf1 kinase, regulates aging in by affecting cellular histone kinase activity, recombination at rDNA loci, and silencing. J Biol Chem 278: 13390–13397.
[31]
Mortimer RK, Johnston JR (1959) Life span of individual yeast cells. Nature 183: 1751–1752.
[32]
Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, et al. (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell 116: 551–563.
[33]
Rine J, Herskowitz I (1987) Four genes responsible for a position effect on expression from HML and HMR in . Genetics 116: 9–22.
[34]
Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles—A cause of aging in yeast. Cell 91: 1033–1042.
[35]
Smith JS, Boeke JD (1997) An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev 11: 241–254.
[36]
Takeuchi Y, Horiuchi T, Kobayashi T (2003) Transcription-dependent recombination and the role of fork collision in yeast rDNA. Genes Dev 17: 1497–1506.
[37]
Tanner KG, Landry J, Sternglanz R, Denu JM (2000) Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc Natl Acad Sci U S A 97: 14178–14182.
[38]
Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in . Nature 410: 227–230.
[39]
Weindruch RH, Walford RL (1988) The retardation of aging and disease by dietary restriction. Springfield (Illinois): Charles C Thomas. 436 p.
