2 1 Background
In recent years, we revealed that ART can mimic CR to extend yeast lifespan
and compromise mouse telomere shortening by targeting the mitochondrial res-
piratory chains. Although NOS is absent in yeast, an alternative hemoprotein COX
in mitochondria was observed to produce NO (Wang and Zeng 2014 ). In a simi-
lar pattern with NO, ART enables transient mitochondrial dysfunction through
binding to COX, and subsequently plays a longevity-promoting role in yeast
(Wang et al. 2015a). Like NO, ART can compromise telomere shortening by tar-
geting COX and evoking antioxidative responses in mouse skeletal muscle cells.
Interestingly, the NO donor sodium nitroprusside (SNP), the NO precursor l-argi-
nine (ARG), and the oxidant H 2 O 2 , in certain concentrations, can also exhibit the
CR-like effect in telomere maintenance (Wang et al. 2015b).
It would be considered a huge breakthrough to elucidate the conjugation
of ART with COX functionally resembling the interaction of NO with COX.
The NO-COX interaction during CR is a prerequisite to trigger antioxidative
responses, protect DNA from oxidative damage, compromise telomere shorten-
ing, and delay progressive aging. In such a context, the NO-COX interaction is
eligible as a promising target for antiaging drug discovery, from which the func-
tional mimetics of CR are expected to emerge or to be developed. Being equally
important, validation of ART conjugation to NOS might help to decipher why
ART is effective in dealing with so many inflammatory diseases. ART can pre-
vent inflammation-triggered NO burst through inhibiting NOS, by which ART
attenuates hypoxia, angiogenesis, hyperplasia, and inflammatory infiltration
in the synovial tissue. Therefore, a priority of coping with autoimmune dis-
eases should be better by eradicating infectious pathogens rather than inhibiting
inflammation per se.
The discovery of interactions between ART and COX/NOS should pave a path
toward penetration into unknown mechanisms involved in the NO’s beneficial or
harmful effects. From this clue, aging and aging-associated diseases would be no
longer tractable and irreversible. It remains, however, an open question regarding
whether the powerful oxidant peroxynitrite (ONOO−) that is derived from NO
and superoxide anion (O 2 −) would cause carcinogenesis, and it is also unclear if
ONOO− is an initiator of the neurodegenerative diseases via putative protein nitra-
tion. The future achievements in this exciting research area should increase our
knowledge about aging-related processes, which might eventually facilitate a clini-
cal solution to malignant tumors/cancer, insulin-resistant diabetes, cardiovascular
diseases, autoimmune diseases, and neurodegenerative diseases.
1.1 A Brief Story About Discovery on the Pleiotropic Use of ART.
Although the mechanism by which ART kills the malarial parasite remains incon-
clusive, it is gradually evident that ART can preferentially conjugate the heme
moiety of hemoproteins among multiple malarial targets. The covalent conjugation