101to increase longevity in nematodes by triggering the response to ROS (Yang and
Hekimi 2010 ). Moreover, H 2 O 2 -induced antioxidative capacity was proven to
extend yeast lifespan (Mesquita et al. 2010 ). Our findings have validated that CR
and mimetics can induce SOD, CAT, and GSH for effective ROS scavenging.
In particular, our findings revealing the synchronous induction of mitochondrial
Mn-SOD and SIRT3 by CR and mimetics are in consistence with a recent report
describing that CR dramatically reduces oxidative stress by inducting SIRT3-
activated Mn-SOD (Qiu et al. 2010 ).
According to previous work done by others, BRCA1 and BRCA2 are
believed to interact with RAD51 during repairing DNA double-strand breaks
(Boulton 2006 ; Badie et al. 2010 ). BRCA1 is recruited to the telomere in a
RAD50-dependent manner and may regulate telomere length and stability,
in part through its presence at the telomere (Ballal et al. 2009 ). BRCA1 and
BARD1 also constitute a heterodimeric RING finger complex with ubiquitin
ligase (E3) activity (Hashizume et al. 2001 ). Therefore, it seemed that ROS-
mediated DNA damage is repaired by BARD1, BRCA1, BRCA2, RAD50, and
RAD51. We noticed that CR and mimetics can lead to the global downregulation
of almost all examined Ubi genes including DNA repair genes, hence implying a
less extent of DNA damage. Because BRCA1 is involved in DNA repair (Starita
and Parvin 2003 ), we are confident to conclude that the dramatic downregulation
of DNA repair genes implies that extensive DNA repair is unnecessary because
of scarce DNA damage.
Telomeres are recently shown to be a favored target of persistent DNA damage
in aging and stress-induced senescence (Hewitt et al. 2012 ). Downregulation of
DNA repair genes is an important hint indicating attenuated DNA damage due to
potent ROS scavenging from inducible antioxidant networks. Indeed, the longer
telomeres were detected among treatments, in which ARG that leads to the long-
est telomeres may be implicated in human health beneficial (Gad 2010 ). Whether
longer telomeres are due to compromised telomere shortening or enhanced tel-
omere extension is unclear although CR is shown to synergize with telomerase
in extending mouse telomeres (Vera et al. 2013 ). Our data verified that both Tert
mRNA and TERT are downregulated in similar with BRCA1, and addressed that
longer telomeres are attributed to less DNA damage, leading to mitigated telomere
shortening.
From above results, we may draw the following conclusion as that CR-
triggered NO can enhance the respiratory capacity, as described in yeast (Barros
et al. 2004 ), nematodes (Lemire et al. 2009 ), fruit flies (Humpherey et al. 2009 ),
and mice (Cerqueira et al. 2011 ). The accelerated respiration is attributed to NO
signaling, which initiates augmented ROS burst, enhanced antioxidative responses,
mitigated DNA damage, and downregulated DNA repair genes, finally leading
to the compromise of telomere shortening. Interestingly, we have noticed a dual-
phase mode of respiratory modulation in budding yeast, i.e., a phase of respiratory
burst during acute CR followed by a phase of respiratory decay during chronic CR
(Wang et al. 2015a). We should examine if such a dual-phase mode of respiratory
modulation exists in mice exposed to long-term CR.
6.3 ART as a NO Mimetic Compromises Mouse Telomere Shortening