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Review
. 2003 Sep;67(3):376-99, table of contents.
doi: 10.1128/MMBR.67.3.376-399.2003.

Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatin

Kevin J Bitterman  1 , Oliver Medvedik, David A Sinclair
Affiliations
Review

Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatin

Kevin J Bitterman et al. Microbiol Mol Biol Rev. 2003 Sep.

Abstract

When it was first proposed that the budding yeast Saccharomyces cerevisiae might serve as a model for human aging in 1959, the suggestion was met with considerable skepticism. Although yeast had proved a valuable model for understanding basic cellular processes in humans, it was difficult to accept that such a simple unicellular organism could provide information about human aging, one of the most complex of biological phenomena. While it is true that causes of aging are likely to be multifarious, there is a growing realization that all eukaryotes possess surprisingly conserved longevity pathways that govern the pace of aging. This realization has come, in part, from studies of S. cerevisiae, which has emerged as a highly informative and respected model for the study of life span regulation. Genomic instability has been identified as a major cause of aging, and over a dozen longevity genes have now been identified that suppress it. Here we present the key discoveries in the yeast-aging field, regarding both the replicative and chronological measures of life span in this organism. We discuss the implications of these findings not only for mammalian longevity but also for other key aspects of cell biology, including cell survival, the relationship between chromatin structure and genome stability, and the effect of internal and external environments on cellular defense pathways. We focus on the regulation of replicative life span, since recent findings have shed considerable light on the mechanisms controlling this process. We also present the specific methods used to study aging and longevity regulation in S. cerevisiae.

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Figures

FIG. 1.
FIG. 1.
Yeast cell division and bud scar formation. (A) The budding of each daughter cell leaves a ring-shaped deposit, termed the bud scar, on the cell wall of the mother cell. These chitin-containing rings, formed at the neck of buds, can be stained with calcofluor, a fluorescent dye. The exact number of times an individual mother cell has undergone division can thus be determined by counting the number of bud scars present. (B) An aged yeast nucleus has an enlarged and fragmented nucleolus (arrows), unlike the nucleoli of two young cells in the upper left corner.
FIG. 2.
FIG. 2.
Instability of repeated DNA as a cause of replicative aging in S. cerevisiae. The yeast rDNA locus is the most highly repetitive locus in the organism, consisting of ∼150 tandem 9.1-kb repeats. These repeats are stabilized, in part, by the NAD+-dependent HDAC Sir2. The initiating event is the generation of an ERC by homologous recombination between repeats within the rDNA array on chromosome XII. ERCs have a high probability of replicating and are segregated almost exclusively to the mother cell. They accumulate exponentially in mother cells, resulting in fragmented nucleoli, cessation of cell division, and cellular senescence. Stabilization of the rDNA locus or inhibition of ERC replication extends the life span. Daughters from very old mothers inherit ERCs due to the breakdown in the asymmetry of inheritance, explaining why daughters of old mothers are prematurely old. Ectopic release of an ERC in a young cell accelerates aging. Overexpression of SIR2 or deletion of FOB1 (encoding a replication fork block protein specific to the rDNA) reduces rDNA recombination and ERC formation, and the life span is extended by 30 to 50%. Reprinted from reference with permission.
FIG. 3.
FIG. 3.
Conserved longevity-regulatory pathways in S. cerevisiae, C. elegans, and possibly humans. There are two ways to study longevity in S. cerevisiae: replicative (mitotic) life span and chronological (nonmitotic) life span. Both these approaches have identified yeast genes with functional homologues in a conserved insulin-like signaling longevity pathway. These include SIR2, which encodes an NAD+-dependent deacetylase, RAS, which encodes a GTP-binding protein, and SCH9, which encodes a serine/threonine kinase. These findings are consistent with the idea that longevity regulation is highly adaptive and that components of a primordial pathway have been conserved in a diverse range of species.
FIG. 4.
FIG. 4.
Crystal structure of the Sir2 deacetylase. (A) Ribbon diagram of Sir2-Af1 complexed with NAD+ (PDB 1ICI based on the structure of Min et al. [141]). The NAD+ molecule and zinc atom are in green. Putative catalytic site B residue His116 is shown as stick model in dark blue. Conserved site C residues Ser24, Asn99, and Asp101 are shown in pink. Gly185, which is located in site A and which is perfectly conserved in all Sir2 family members, is shown in light blue. (B) Surface representation of Sir2-Af1. Blue and red patches show surface electrostatic potential distribution for positively and negatively charged residues, respectively. Amino acid residues 30 to 47 are shown as a ribbon diagram for better visualization of the NAD+-binding pocket. This pocket is spatially divided into three regions, termed sites A, B, and C, which contact different portions of the NAD+ molecule (141). An acetyllysine substrate is proposed to come in close proximity to site B by inserting into a tunnel within the indicated substrate-binding cleft (9). The inhibitor nicotinamide is proposed to bind in the C site (16). Models were generated using Web Lab Viewer Lite software.
FIG. 5.
FIG. 5.
Pathways for NAD+ and nicotinamide metabolism in S. cerevisiae. In yeast, NAD+ can be recycled from nicotinamide via the NAD+ salvage pathway or synthesized de novo from tryptophan. Nicotinamide generated by Sir2 is converted into nicotinic acid by the nicotinamidase Pnc1 and subsequently into NaMN by Npt1. Nicotinic acid may also enter the pathway exogenously. The formation of desamido-NAD+ (NaAD) is catalyzed by one of two adenylyltransferases encoded by NMA1 and NMA2, and the subsequent formation of NAD+ by the NAD+ synthetase Qns1. Trptophan taken up from the medium is converted into quinolinic acid by Bna1 to Bna5. A quinolinic acid phosphoribosyltransferase, encoded by BNA6/QPT1, catalyzes the subsequent conversion to NaMN, which feeds into the salvage pathway.
FIG. 6.
FIG. 6.
Model for the regulation of Sir2 activity and life span by nicotinamide. Disparate environmental stimuli including calorie restriction, heat, and osmotic stress serve as inputs to a common pathway of longevity. Cells coordinate a response to these inputs by inducing the transcription of PNC1, which encodes an enzyme that converts nicotinamide to nicotinic acid, thereby alleviating the inhibition of Sir2 and promoting longevity.
FIG. 7.
FIG. 7.
Glucose-sensing and signaling pathways of S. cerevisiae. Proteins indicated by bold type have been shown via genetic analyses to extend the replicative life span when either deleted or mutated. Glucose in the environment is first sensed by either of two complementary receptor families, the Hxt hexose transporters or the G-protein-coupled receptor, Gpr1. Glucose-mediated signals arising from these receptors cause Cdc25 to catalyze the formation of GTP-bound Ras1-Ras2, which then binds to and regulates the adenylate cyclase complex. Cyr1 (Cdc35) within the complex then generates cAMP, which in turn activates PKA, consisting of subunits Tpk1, Tpk2, and Tpk3. PKA inhibits Msn2 and Msn4, two factors required for the expression of heat shock proteins and superoxide dismutases, which are important for regulating the chronological life span. Further downstream, both pathways also converge on the Snf1 serine/threonine kinase complex, which is responsible for derepressing genes that are turned off during growth at relatively high glucose concentrations. The activity of the Snf1 complex is modified by the Glc7-Hex2 complex and also perhaps by a proposed kinase(s) that may be responsive to intracellular ATP and AMP levels. The Snf1 complex inhibits the Mig1-Ssn6-Tup1 repressor complex, required for shutting off the transcription of genes needed for respiration, and activates Sip4, which turns on the transcription of genes required for gluconeogenesis under conditions of low glucose concentrations.
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