7 Prospective
proteins. Gene mutations and chromosome instability are implicated in tumorigen-
esis and carcinogenesis, while protein modifications may interfere with enzymatic
functions and signal transduction due to denatured proteins/enzymes. So ROS and
RNS are most likely among the etiological initiators of many disorders and syn-
dromes, including aging and aging-related diseases (Bondy and Maiese 2010 ).
Cumulative evidence has shown that ROS, RNS, and their interactions are
seemingly implicated in the pathogenesis of inflammatory diseases. For example,
high-level NO-driven hypoxia induces angiogenesis, hyperplasia, and inflamma-
tory infiltration in the synovial tissue during progression to RA (Bao et al. 2012 ;
Wu et al. 2012 ); NO-derived ONOO− mediates nitrosylation/nitration of pro-
teins as a possible etiological initiator of protein misfolding-related diseases; and
NO-derived ONOO− initiates DNA damage and gene mutation with an implica-
tion in the origin of CSC. The following prospects would share with peers the
most recent achievements on ONOO−’s pathogenic potentials and suggest further
endeavors to be pursued in the future.
7.1 Nitrosylation/Nitration in the Active Center
of Aging-Related Disorders? of Proteins: A Universal Initiator
of Aging-Related Disorders?
Autophagy, or autophagocytosis, is a lysosomal clearance process that recycles
cellular components and reallocates nutritional intermediates to ensure homeosta-
sis between anabolism and catabolism within living cells. In response to diverse
environmental signals such as growth factors, amino acids, energy currency, and
starvation, autophagy is actively implicated in many physiological and patho-
logical aspects. While aging is often associated with the reduced autophagy,
longevity is attributed to the controlled autophagy in animals and mammalian
cells. Knockdown of the autophagy inhibitor p53 can induce the degeneration
seen in aging animals. Autophagy triggers lifespan extension, whereas impaired
autophagy is often accompanied with the loss of longevity-promoting effects con-
ferred by resveratrol, RAP, and CR (Rubinsztein et al. 2011 ). Perhaps the most
primordial function of autophagy is adaptation to nutrient deprivation, but new
evidence also reveals the autophagy’s crucial roles in immunity and inflamma-
tion, thereby protecting from infectious, autoimmune, and inflammatory diseases
(Levine et al. 2011 ).
In mammals, autophagy is dually tuned by SIRT1 and mTORC1. While SIRT1
knock in induces autophagy, SIRT1 knockout or knockdown prevents the induc-
tion of autophagy by resveratrol and nutrient deprivation in human cells (Morselli
et al. 2010 ). Autophagy is negatively regulated by mTORC1, which can be inhib-
ited by RAP or starvation. Under glucose starvation, AMPK promotes autophagy
by directly activating the mammalian autophagy-initiating kinase Ulk1 through
the phosphorylation of serine 317 and serine 777. Under nutrient sufficiency, high
mTOR activity prevents Ulk1 activation by the phosphorylation of Ulk1 at serine