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

Abstract

Calorie restriction (CR) promotes longevity among distinct organisms from yeast to mammals. Although CR-prolonged lifespan is believed to associate with enhanced respiratory activity, it is apparently controversial for accelerated energy consumption regardless of insufficient nutrient intake. In reconciling the contradiction of less food supply versus much metabolite dispense, we revealed a CR-based mode of dual-phase responses that encompass a phase of mitochondrial enhancement (ME) and a phase of post-mitochondrial enhancement (PME), which can be distinguished by the expression patterns and activity dynamics of mitochondrial signatures. ME is characterized by global antioxidative activation, and PME is denoted by systemic metabolic modulation. CR-mediated aging-delaying effects are replicated by artesunate, a semi-synthetic derivative of the antimalarial artemisinin that can alkylate heme-containing proteins, suggesting artesunate-heme conjugation functionally resembles nitric oxide-heme interaction. A correlation of artesunate-heme conjugation with cytochrome c oxidase activation has been established from adduct formation and activity alteration. Exogenous hydrogen peroxide also mimics CR to trigger antioxidant responses, affect signaling cascades, and alter respiratory rhythms, implying hydrogen peroxide is engaged in lifespan extension. Conclusively, artesunate mimics CR-triggered nitric oxide and hydrogen peroxide to induce antioxidative networks for scavenging reactive oxygen species and mitigating oxidative stress, thereby directing metabolic conversion from anabolism to catabolism, maintaining essential metabolic functionality, and extending life expectancy in yeast.calorie restriction, nitric oxide, artesunate, hydrogen peroxide, longevity, Saccharomyces cerevisiae Citation:Wang DT, Wu M, Li SM, Gao Q, Zeng QP. Artemisinin mimics calorie restriction to extend yeast lifespan via a dual-phase mode: a conclusion drawn from global transcriptome profiling. Sci China Life Sci, 2015, 58: 451 -465,

Insulin Does Not AugmentIn VitroTumor Growth Under A Hyperglycemia-Mimicking Milieu And In A Calorie Restriction-Resembling Manner

“…On the other hand, we noticed decrease in ROS and reduction in apoptosis of GH3 cells grown in a high-glucose medium supplemented with insulin, which was also observed in CR [32]. In our previous work, CR in yeast and mice was also found to diminish ROS burst, compromise telomere shortening, and promote lifespan extension [33,34]. It is well-known that resveratrol is an activator of SIRT, metformin is an activator of AMPK, and CR activates AMPK, SIRT1, and PGC-1α [35,36].…”

Artemisinin: A Panacea Eligible for Unrestrictive Use?

“…Two years ago, artemisinin was elucidated to bind to the heme-containing cytochrome c anchored on the mitochondrial respiratory chain complexes in mice, which increases the levels of adenosine monophosphate (AMP) and the oxidized form of nicotinamide adenine dinucleotide (NAD), but decreases those of adenosine triphosphate (ATP) and the reduced form of NAD (NADH). The ultimate outcome is that AMP-activated protein kinase (AMPK), silent information regulator 2 type 1 (SIRT1), and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) are activated, thereby promoting mitochondrial biogenesis, maintaining telomere integrity, and extending lifespan in yeast and mice ( Wang et al, 2015a , b ).…”

“…As a pluripotent drug with increasing clinical value in anti-malarial, anti-tumor, and anti-inflammatory roles, artemisinin seems to be an elixir with metformin- and resveratrol-like effects on human health because they behave as the activators of AMPK and/or SIRT1 in yeast and mice ( Wang et al, 2015a , b ). The most recently revealed pharmaceutical roles and selective signaling mechanisms of artemisinin were outlined in Figure 1 .…”

Peer Review #2 of "Artemisinin mimics calorie restriction to trigger mitochondrial biogenesis and compromise telomere shortening in mice (v0.1)"

“…The discrepancy of findings that CR-mediated lifespan extension with or without mitochondrial biogenesis may be resulted from the earlier or later stages, in other words, an acute short-term CR or a chronic long-term CR. We have suggested a mechanistic model of dual-phase responses to CR exposure in yeast, in which the phase of mitochondrial enhancement within hours is a respiratory burst phase, and the phase of post-mitochondrial enhancement within days and months is a respiratory decay phase [32]. It is reasonable that respiratory burst may be attributed to mitochondrial biogenesis, whereas respiratory decay should not be accompanied with mitochondrial biogenesis.…”