95cellular aging of somatic cells, especially in blood white cells. A longer telomere
may reflect less DNA damage and more chromosome integrity. Because CR can
prolong lifespan among eukaryotes, we are interested in whether CR would elon-
gate telomere lengths in mice. We believed that this investigation should be ben-
eficial to eventually elucidate aging-involved and longevity-related mechanisms in
mammals and humans as well.
According to the findings that CR activates eNOS (Cerqueira et al. 2011 ) and
NO binds to COX (Mason et al. 2006 ), we proposed that CR-triggered NO may
interact with COX to initiate mitochondrial uncoupling/biogenesis and induce
antioxidative responses, thereby alleviating oxidative stress, attenuating DNA
damage, and eventually mitigating telomere attrition. To provide evidence support-
ing this proposition, we injected mouse skeletal muscles individually with a kind
of NO generators, including the NO inducer ART that inhibits NOS activity and
induces NOS expression in a feedback manner (Zeng and Zhang 2011 ), the NO
donor SNP that releases NO in vivo, or the NO precursor ARG that generates NO
through NOS catalysis. In the present study, all NO generators were called as CR
mimetics because they can partially mimic CR’s effects. We intended to disclose
the implication of NO derived from CR mimetics in telomere maintenance/elonga-
tion, and reveal a possible correlation of mitochondrial biogenesis with telomere
maintenance.
6.3.2 Results and Analysis
6.3.2.1 CR Mimetics-Accelerated Antioxidative Responses
for Attenuation of Oxidative Stress
Upon competitive occupation within the heme-localized cavity of COX (Mason
et al. 2006 ), NO should block the transport of electrons along the respiratory
chain, trigger the burst of ROS, and induce the corresponding responses from the
ROS-scavenging networks. To reveal the effect of NO on the elicitation of antioxi-
dative responses, we evaluated the activities of major antioxidants after injection
of ART, SNP, and ARG separately into mouse skeletal muscles. At the same time,
we compared their antioxidant activities with those in mice exposed to CR. As one
of the most common types of ROS, H 2 O 2 was also included in the comparison.
Consequently, all tested mouse samples exhibit the simultaneous activation of
two types of antioxidant enzymes, SOD and CAT, and one type of the antioxidant
peptide GSH in a time-dependent manner. Interestingly, ARG confers the highest
activities of SOD, CAT, and GSH (Wang et al. 2014 ). These results indicated that
CR mimetics can activate antioxidative responses by synchronously activating the
high-molecular-weight antioxidant enzymes and low-molecular-weight antioxi-
dant peptides, which can be repeated by CR per se and exogenous H 2 O 2.
Except for activation of total superoxide-scavenging enzymes including Cu/Zn-
SOD and Mn-SOD, CR and mimetics also specifically activates Mn-SOD and its
6.3 ART as a NO Mimetic Compromises Mouse Telomere Shortening