80 6 ART for Antiaging
cGMP for activating NOS and producing NO, through which mitochondrial bio-
genesis is evoked and lifespan extended (Nisoli et al. 2004 ; Nisoli and Carruba
2006 ). As supporting evidence, the NO donor S-nitrosoglutathione confers yeast
an extended lifespan (Li et al. 2011 ). Nevertheless, NOS homologs have not been
identified in yeast although NO is always detected in budding yeast (Saccharomyces
cerevisiae) (Lewinska et al. 2011 ) and fission yeast (Schizosaccharomyces pombe)
(Kig and Temizkan 2009 ). However, it is believed that mitochondrial COX might be
responsible for NO production from nitrite reduction (Castello et al. 2006 ).
CR-enhanced mitochondrial biogenesis seems an acceptable conclusion for
lifespan extension because it has been reported that an incremental respiratory
activity corresponds an extended lifespan in cells and animals (Lanza and Nair
2010 ). Accompanying with longevity, augmented respiration occurs in yeast, fruit
flies, mice, and rats (Lin et al. 2002 ; Civitarese et al. 2007 ). However, a recent
report has argued that a life-long CR only preserves mitochondrial functions other
than enhances mitochondrial biogenesis (Lanza et al. 2012 ). Other new findings
have also questioned if CR really elicits mitochondrial biogenesis (Hancock et al.
2011 ; Miller et al. 2012 ).
To decipher such a discrepancy, we suggested here that a respiratory burst
might occur only in the early phase of CR (a short-term or acute CR), whereas
a respiratory delay might kept in the late phase of CR (a long-term or chronic
CR). In consistence with this deduction, a systemic research has revealed that
mitochondrial translation and O 2 consumption are enhanced only during the log-
arithmic and early postdiauxic growth stage in yeast cultures (Pan et al. 2011 ).
An “uncoupling to survival” hypothesis suggests that CR could increase the res-
piratory capacity through mitochondrial uncoupling (Brand 2000 ). Indeed, several
uncoupling strategies do lead to lifespan extension in model organisms includ-
ing yeast (Barros et al. 2004 ), nematodes (Lemire et al. 2009 ), and fruit flies
(Humpherey et al. 2009 ). A low dose of DNP, a mitochondrial uncoupler, allows
lifespan extension in mice (Cerqueira et al. 2011 ).
An alternative conclusion has been drawn that CR leads to the oxidized nico-
tinamide adenine dinucleotide (NAD+)-dependent deacetylase Sirtuin 1 (SIRT1)-
dependent autophagy in human cells in vitro and in nematodes in vivo (Morselli
et al. 2010 ). However, it has been debated about a correlation of autophagy with
longevity because autophagy is unlikely sufficient to extend lifespan although CR-
induced antiaging effects might be linked to autophagy (Hansen et al. 2008 ). For
instance, RAP inhibits polyglutamine aggregation independently of autophagy by
reducing protein synthesis is essential for longevity (King et al. 2008 ), and transla-
tion inhibition alone is sufficient to extend lifespan (Hands et al. 2009 ). Currently,
an implication of SIRT1 in CR-induced lifespan extension in nematodes and
fruit flies are being questioning (Blagosklonny 2010 ; Burnett et al. 2011 ), but the
SIRT1 activator resveratrol can induce the beneficial metabolic changes in obese
persons by mimicking CR’s effects (Timmers et al. 2011 ).
An evolutionarily conserved protein kinase, mTOR, is being extensively inves-
tigated in regard to its antiaging effects. The activation of mTOR homologs lim-
iting the extension of lifespan has been filed in yeast (Pan and Shadel 2009 ),