Regulation of Yeast Chronological Life Span by TORC1 via Adaptive Mitochondrial ROS Signaling

Abstract

Summary Here we show that yeast strains with reduced target of rapamycin (TOR) signaling have greater overall mitochondrial electron transport chain activity during growth that is efficiently coupled to ATP production. This metabolic alteration increases mitochondrial membrane potential and superoxide production that we propose supplies an adaptive signal during growth that extends chronological life span (CLS). In strong support of this concept, uncoupling respiration during growth or over-expressing mitochondrial manganese superoxide dismutase significantly curtails CLS extension in tor1Δ strains, and treatment of wild-type strains with either rapamycin (to inhibit TORC1) or menadione (to generate mitochondrial ROS) during growth is sufficient to extend CLS. Finally, extension of CLS by reduced TORC1/Sch9p-mitochondrial signaling occurs independently of Rim15p and is not a function of changes in media acidification/composition. Considering the conservation of TOR-pathway effects on life span, mitochondrial ROS signaling may be an important mechanism of longevity regulation in higher organisms.

Artemisinin mimics calorie restriction to extend yeast lifespan via a dual-phase mode: a conclusion drawn from global transcriptome profiling

“…Therefore, it seems that MAPK may not be activated due to ROS deprival although the correlation of ROS levels with MAPK activity and MAPK gene expression is yet to be identified in yeast. On the other hand, it is accepted that protein kinases are implicated in yeast longevity [19,29,39,40], we actually observed the significant upregulation of Tor1 in PME yeast cells, which is as same as the case described in fission yeast [41]. It is unclear, however, whether the upregulation of Tor1 is due to the inhibition of Tor1p per se upon exposure of yeast cells to CR, ART, or H 2 O 2 .…”

“…From the observation that the increases in mitochondrial translation and oxygen consumption are manifested during logarithmic and early postdiauxic growth stages in yeast [19], we proposed here a hypothesis of "dual-phase responses", which annotates the active reactions of yeast upon CR by the first phase of "mitochondrial enhancement" (ME), or a respiratory burst phase, and the second phase of "post-mitochondrial enhancement" (PME), or a respiratory decay phase. While ME occurs only in the early CR phase (short-term or acute CR), PME maintains in the late CR phase (life-long or chronic CR).…”

Extension of Saccharomyces paradoxus Chronological Lifespan by Retrotransposons in Certain Media Conditions Is Associated with Changes in Reactive Oxygen Species

“…Functional mitochondria are required for increased CLS of yeast tor1Δ mutants (Bonawitz et al 2007). These mutants exhibit elevated mitochondrial membrane potential and mitochondrial superoxide during active growth, but reduced mitochondrial membrane potential, superoxide, and ROS detected by DHR in early stationary phase (Pan et al 2011). Overexpression of the mitochondrial superoxide dismutase, SOD2, prevents lifespan extension in tor1Δ mutants.…”

“…Changes in mitochondrial function and ROS levels during active growth that lead to decreased ROS levels during early stationary phase underlie yeast CLS extension due to deletion of the TOR1 gene (Bonawitz et al 2007;Pan et al 2011). TOR genes in diverse organisms encode kinases responsive to nutrient conditions and growth signaling that regulate processes such as translation, ribosome biogenesis, and autophagy to influence cell growth, metabolism, and aging (Bjedov and Partridge 2011).…”

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

“…Lifespan is also extended in response to elevated ROS levels when C. elegans is fed the glucose analog 2-deoxyglucose (4). Likewise, ROS is part of the mechanism by which TOR inhibition extends lifespan in yeast (5), and acute inhibition of the daf-2 insulin/insulin-like growth factor 1 (IGF-1) receptor extends life in C. elegans (6). ROS also plays an important role in the extension of lifespan caused by a mild inhibition of respiration in worms and flies (2,3,7).…”