93A correlation of enhanced respiration by potent antioxidation as one of the
mechanisms of longevity is established in yeast, nematodes, and mice. A grow-
ing body of literature has indicated that mitochondrial ROS can act as a media-
tor exerting adaptive/hormetic effects on yeast lifespan (Agarwal et al. 2005 ;
Kharade et al. 2005 ; Piper et al. 2006 ). A recent study has also shown that CR
elevates H 2 O 2 levels in an early stationary phase, and induces SOD activity to help
extending lifespan (Mesquita et al. 2010 ; Schulz et al. 2007 ). Our results showing
that H 2 O 2 can mimic CR to extend yeast lifespan provides support to the putative
mechanism. Supporting evidence also comes from a recent work indicating that
a mitochondrial superoxide signal triggers an increased longevity in nematodes
(Yang and Hekimi 2010 ).
Nevertheless, how antioxidative responses delay aging is still largely unknown.
We found that CR-exposed yeast cells exhibit no remarkable induction of Sod2
genes but significant activation of Sod2-encoded Mn-SOD in PME. In this aspect,
a recent report provides a possible explanation: the activation of Mn-SOD needs
SIRT3 for deacetylating two critical lysine residues (Qiu et al. 2010 ), suggesting
that CR may modulate Mn-SOD activity post-translationally. Additionally, ART
and H 2 O 2 mimic CR in fully different ways from previously described CR mimics.
While RAP acts as an inhibitor of mTORC1 (Harrison et al. 2009 ), and resveratrol
serves as an activator of SIRT1 (Borra et al. 2005 ) or as an inhibitor of cAMP
phosphodiesterases (Park et al. 2012 ), ART and H 2 O 2 do behave like mitochon-
drial uncouplers such as DNP (Cerqueira et al. 2011 ).
We proposed here a mechanistic model of CR-triggered NO and ART-driven
lifespan extension by dual-phase responses (Fig. 6.2). In the ME phase, mRNA
and protein synthesis are increased, respiration is enhanced by accelerated mito-
chondrial biogenesis. In the PME phase, mRNA and protein synthesis are
decreased, respiration is decayed by suppressed mitochondrial biogenesis.
Fig. 6.2 A putative signaling pathway responsible for yeast lifespan extension involved in the
mode of dual-phase responses. The red arrows indicate a promotion role (positive control), the
green arrows indicate a repression role (negative control), and the yellow arrows represent the
direction of electron transport along the mitochondrial respiratory chain. The up arrow (↑) within
a frame shows an elevation level, and the down arrow (↓) within a frame shows a decline level.
AMP adenosine monophosphate; ART artemisinin; CAT catalase; COX cytochrome c oxidase;
CR calorie restriction; ME mitochondrial enhancement; NAD+ oxidized nicotinamide dinucleo-
tide; NO nitric oxide; PME postmitochondrial enhancement; ROS reactive oxygen species; SOD
superoxide dismutase
6.2 ART Extends Yeast Lifespan via NO Signaling