102 6 ART for Antiaging
After treatment by CR mimetics for 6 h, we determined an elevated ATP level
in mouse skeletal muscles, which is followed by/accompanied with an elevation
of serum NO levels. Importantly, all CR mimetics-treated samples were found to
display a typical characteristic denoting mitochondrial biogenesis: the large num-
bers and multiple layers of mitochondria are distributed along the fibrous mus-
cle tissues. In contrast, a nontreated sample shows only one-layer mitochondrial
distribution (Wang et al. 2015b). So we can draw a preliminary conclusion that
incremented mitochondrial functions might be originated from mitochondrial
biogenesis, which should be preceded by a putative process of mitochondrial
uncoupling. However, we are currently unable to ensure whether mitochondrial
signatures are highly expressed after transient respiratory dysfunction.
It is worthy of indicating that ART was found to simulate the lifespan-prolong-
ing effect of CR in the present work. In this regard, two possibilities for ART-
mediated effects may exist: one is a direct effect, and another is an indirect effect.
To exert a direct role, ART may bind the heme moiety of COX. To act indirectly,
ART may firstly conjugate the NOS’s heme, and secondly induce NOS overex-
pression, NO production, and NO-COX interaction. However, we are unable
to exclude these two possibilities at the moment because we have not yet distin-
guished ART-NOS from ART-COX structurally. Nevertheless, we actually detected
the upregulation of eNOS and COX4 followed by the increases of eNOS and COX
activities after injecting ART into mouse skeletal muscles, suggesting that ART
may simultaneously target eNOS and COX, thereby inhibiting their activities, and
subsequently induce their expression in a feedback manner.
The present study is mainly focused on the engagement of AMPK and SIRT1 in
mitochondrial biogenesis through PGC-1α although we detected the overexpres-
sion of p-mTORSer2448 induced by CR mimetics. The implication of AMPK and
other protein kinases in metabolic modulations via mTOR signaling is of much
importance (Shaw 2009 ). So our future work would be focused on identifying
whether there is also an mTOR-specific mode for metabolic alterations in response
to CR, from which we might reconcile the apparent controversial of enhanced res-
piration leading to extended lifespan.
In summary, we have revealed, for the first time, a mechanistic detail of telomere
maintenance mediated by CR and mimetics. We have also provided a direct message
supporting the debating hormesis hypothesis by validating CR mimetics’ beneficial
roles on DNA protection. Therefore, our study should shed light on the discovery of
new targets and development of new drugs for antiaging and toward longevity.
6.3.4 Conclusions
We report here that three-types of NO generators, ART as a NO inducer, SNP as
a NO donor, and ARG as a NO precursor, can mimic CR to enable the compro-
mise of mouse telomere shortening by eliciting antioxidant responses and induc-
ing mitochondria-targeted and SIRT3-activated Mn-SOD, followed by the global