6 1 Background
is widely accepted that lifespan is determined by an individual genetic background
and multiple environmental factors. Regardless of genetic determinations, it is
believed that the natural aging process may be modulated to some extent through
artificial interventions such as CR.
For an environmental impact on lifespan, Harman first proposed a free radical
theory of aging early in the past century (Harman 1956 ), and later it was extended
to be implicated in the structural and functional adaptation of mitochondria to
nutritional stress stimuli (Harman 1972 ). According to Harman’s aging theory,
free radicals are supposed to be responsible for biomolecule damage, which
results in cellular changes and thus organismal aging. One of the main criticisms
to his aging theory is that it only considers the harmful effects of free radicals, but
ignores their beneficial roles (Afanas’ev 2010 ). Nowadays, it is known that ROS in
a sublethal concentration have potentials to induce the antioxidative response and
provide protection from further oxidative stress. This phenomenon has been called
as “hormesis”‚ through which an intrinsic protective potential can be excited by a
traceamount of toxic substance (Kaser 2003 ).
It has been gradually accepted that ROS are “double-edged swords” for living
cells. Whether ROS are harmful or beneficial depends on their relative concentra-
tions. In an extremely high concentration, ROS directly cause cell death, whereas
in a relatively low concentration, they allow cell survival. So there must have a
concentration threshold for ROS exerting a “good” or “bad” effect. Such a con-
centration-dependent ROS threshold is apparently governed by the homeostasis
of cellular oxidation and antioxidation. When the attacking power from oxidants
overwhelms the combating capacity by antioxidants, damage to cells and macro-
molecules must be ensued (Thannickal et al. 2000 ).
Except for ROS, free radicals also include reactive nitrogen species (RNS),
mainly NO, ONOO−, nitric dioxide (NO 2 ), and trinitric dioxide (N 2 O 3 ). In gen-
eral, a lower level of NO promotes cell survival and proliferation, while a higher
level of NO favors cell cycle arrest, apoptosis, and senescence (Thomas et al.
2004 ). Because NO can react with O 2 − to produce ONOO−, it means that more
ROS predispose more RNS in the case of enhanced NO production. As an essen-
tial result, ONOO− must pose oxidative stress-like nitrosative stress to multiple
systems and exert pathogenic effects on subjected organs (Patcher et al. 2007 ). NO
has been shown to increase the mitochondrial levels of O 2 − and H 2 O 2 (Poderoso
et al. 1996 ). We also found that NO and H 2 O 2 can induce superoxide dismutase
(SOD) and catalase (CAT) in yeast (Wang et al. 2015a) as well as in mouse skel-
etal muscle cells (Wang et al. 2015b).
Mitochondria are major subcellular compartments that generate ROS, which
are originated from NO binding to COX. As previously noted, ROS within cells
can be modulated by NO-mediated mitochondrial biogenesis (Nisoli and Carruba
2006 ). NO can thus affect the fate of living cells in either a ROS-independent or
dependent manner. Although an extremely high level of NO plays a pathogenic or
even lethal role, an appropriate level of NO exerts a beneficial and healthy effect.
Such a consideration inspired us suggesting a threshold theory of NO-mediated
disease and health effects.