Supporting Information

Files in this Data Supplement:

Linking Budding and Reproductive Lifespan. The budding lifespan is, in effect, a measure of fertility: the number of daughters born to an individual mother. The reproductive lifespan is a measure of time: the number of hours from the birth of a cell to the appearance of its last daughter. The two are linked by taking into account the interval between births. If all cells reproduced at strictly the normal rate of one daughter per 90 min, the two measures of lifespan would be identical. However, the intervals vary between individuals. Demographers are familiar with this situation in human populations and have developed methods for assessing population dynamics based on interbirth intervals and a measure of the probability of moving on from one number of offspring (parity) to the next (the parity progression ratio). This framework can be used to integrate microlevel birth interval analyses into macrolevel studies of fertility and population growth (1). A truly complete picture of lifespan could include this parity-specific dimension as well as the approach we follow in this article.

Molecular Pathways Regulated by Cyr1, Sch9, Msn2, and Mns4. Cyr1 is an adenylate cyclase involved in the cAMP-dependent protein kinase (PKA) pathway (2). The mutation in CYR1 reduces its activity and such reduction has been shown to increase budding lifespan (3, 4). Binding of glucose on the glucose-receptor Gpr1 activates the protein Gpa2, which seems in turn to activate Cyr1, although direct evidence for this latter activation is still lacking. Cyr1 activity is also enhanced by Ras1 and Ras2. Activation of Cyr1 then triggers activation of the PKA pathway by cAMP. The PKA pathway stimulates growth and glycolysis, decreases gluconeogenesis and stress resistance, and reduces budding lifespan (5, 6). Sch9 is a serine threonine kinase that reduces the activity of the PKA pathway, which is not required for the glucose-induced PKA activation by the Ras-Cyr1 pathway but is involved in the nitrogen-induced activation of the fermentable growth medium-induced pathway (7). Sch9 has also been shown to repress Hsp90 (5).

Msn2 and msn4 are transcription factors that control genes the expression of which is governed by the stress response element (STRE). STRE-regulated genes code for enzymes involved in carbon metabolism, transporters, proteases, and proteins acting in stress protection, such as Hsp104, catalase, enzymes of trehalose metabolism, and many others (8). The activation of msn2, msn4, and the STRE-dependent stress response are negatively regulated by the cAMP-PKA metabolic pathway (6, 9, 10).

1. Feeney, G. (1983) Pop. Studies 37, 75-89.

2. Versele, M., Lemaire, K. & Thevelein, J. M. (2001) EMBO Rep. 2, 574-579.

3. Lin, S. J., Defossez, P. A. & Guarente, L. (2000) Science 289, 2126-2128.

4. Fabrizio, P., Pletcher, S. D., Minois, N., Vaupel, J. W. & Longo, V. D. (2004) FEBS Lett. 557, 136-142.

5. Morano, K. A. & Thiele, D. J. (1999) EMBO J. 18, 5953-5962.

6. Thevelein, J. M. & de Winde, J. H. (1999) Mol. Microbiol. 33, 904-918.

7. Crauwels, M., Donaton, M. C. V., Pernambuco, M. B., Winderickx, J., de Winde, J. H. & Thevelein, J. M. (1997) Microbiology 143, 2627-2637.

8. Moskvina, E., Schüller, C., Maurer, C. T. C., Mager, W. H. & Ruis, H. (1998) Yeast 14, 1041-1050.

9. Garreau, H., Hasan, R. N., Renault, G., Estruch, F., Boy-Marcotte, E. & Jacquet, M. (2000) Microbiology 146, 2113-2120.

10. Smith, A., Ward, M. P. & Garrett, S. (1998) EMBO J. 17, 3556-3564.