81nematodes (Vellai et al. 2003 ), fruit flies (Kapahi et al. 2004 ), and mice (Selman
et al. 2009 ). By inactivating mTOR, RAP can extend mouse lifespan (Harrison
et al. 2009 ). However, it has been demonstrated that NO can prolong life expec-
tancy through upregulating mTOR activity (Pervin et al. 2007 ). Similarly,
branched-chain amino acids can promote the survival of middle-aged mice by
activating mTOR partly through enhancing NO generation (D’Antona et al. 2010 ).
Furthermore, it remains unclear which aspects of the mTOR signaling pathway
contribute to the aging or aging-delaying process because mTOR controls the
multifaced aspects of cell physiology, including ribosome biogenesis, translation,
autophagy, and proliferation (Wullschleger et al. 2006 ).
A well-documented association of aging with telomeres suggests a possi-
ble correlation of lifespan extension with chromosome protection. Since the the-
ory depicting metabolic suppression mitigates DNA damage was suggested in
the last decade (Koubova and Guarente 2003 ), a novel model of CR-conferred
DNA protection seems commonly accepted. According to this model, starva-
tion can alleviate DNA damage and confer a tissue-protective phenotype through
repressing the cellular metabolism and activating the mitochondrial functional-
ity (Longo and Fontana 2010 ). Most recently, CR is shown to maintain/elongate
telomeres and synergize with telomerase for extending mouse longevity (Vera
et al. 2013 ). Although CR-triggered NO is believed to relevant to longevity, it
remains unsolved whether NO also maintains/elongates the length of telomeres.
Interestingly, it has documented that CAT inactivation or H 2 O 2 induction can
extend yeast lifespan (Mesquita et al. 2010 ). These questionable issues encourage
us to explore a plausible relationship between NO and H 2 O 2 during aging, and
decipher how can NO and H 2 O 2 exert their antiaging effects.
How can CR cause mitochondrial uncoupling is an open question, and why
CR-mediated mitochondrial uncoupling enables lifespan extension is yet to be
elucidated. Furthermore, it is indefinable for the mechanistic explanation of CR-
exerted effects on longevity by current theories because enhanced respiratory
activity is apparently conflicted with limited food supply during CR. It is also
confusing for the concept of mitochondrial biogenesis or mitochondrial activa-
tion. Additionally, autophagy is likely a result rather than a cause for CR-extended
lifespan, and the molecular event involving the interaction between SIRT1 and res-
veratrol as well as between mTOR and RAP needs further verification.
6.2 ART Extends Yeast Lifespan via NO Signaling
6.2.1 Purposes and Significance
Because NO is known to reversibly bind to the prosthetic heme moiety of COX
(Mason et al. 2006 ), we proposed that CR-triggered NO may interact with COX
to result in mitochondrial uncoupling and respiratory enhancement. To verify this
preposition, we chose ART that alkylates hemoproteins (Zhang and Gerhard 2009 )
6.1 An Overview on Aging and Antiaging