Free Radical Biomedicine: Principles, Clinical ... - Bentham Science

234 Free Radical Biomedicine: Principles, Clinical Correlations, and Methodologies Y. Robert Li
3. ANIMAL STUDIES
In line with a causative role of oxidative stress in cellular senescence, animal studies also provide
substantial evidence supporting an important role of oxidative stress in aging process. Commonly used
animal models in aging studies include invertebrates (e.g., Caenorhabditis elegans, Drosophila
melanogaster) and small mammals (e.g., mice). The gold standard for determining whether aging is altered
is lifespan. Outlined below are the major experimental findings in this area.
3.1. Increased Oxidative Damage and Decreased Antioxidant Defenses during Aging
Substantial correlative studies demonstrate that increased levels of oxidative damage to cellular
constituents, including proteins, lipids, and nucleic acids, and decreased antioxidant defenses occur during
aging. Mitochondria isolated from old animals release more ROS than those from young counterparts.
Comparative biology studies show that in general the production of mitochondrial ROS is correlated
inversely with the lifespan of the animal species [13]. Although these correlative and comparative biology
studies do not establish a cause-and-effect relationship between oxidative stress and aging, the findings are
consistent with the free radical theory of aging.
3.2. Extension of Lifespan by Antioxidants
3.2.1. Exogenous Antioxidants
Different from the correlative and comparative biology studies, interventional studies using antioxidants
provide much more compelling evidence for a causative role of oxidative stress in aging. A number of
structurally-unrelated compounds with antioxidant properties, including glutathione precursors, dietary
polyphenols, antioxidant enzyme mimetics, spin traps, and antioxidant nanomaterials are shown to prolong
lifespan in various animal species. For example, treatment of mice with a carboxyfullerene superoxide
dismutase mimetic is found to not only reduce age-associated oxidative stress and mitochondrial free
radical production, but also improve cognition and significantly extends lifespan [14]. Carboxyfullerene is
a derivative of the nanomaterial fullerene. Other antioxidant nanomaterials, including cerium oxide and
platinium nanoparticles have also been demonstrated to prolong the lifespan of the invertebrate animals,
including Drosophila melanogaster and Caenorhabditis elegans [15, 16]. More recently, 4,4’diaminodiphenysulfone,
a human drug capable of inducing endogenous antioxidants, is shown to augment
the antioxidative stress capacity of Caenorhabditis elegans, improve mitochondrial function, and increase
the longevity of the organism [17].
3.2.2. Endogenous Antioxidants
In line with the lifespan-extending effects of exogenous antioxidants described above, targeted
overexpression of catalase in mitochondria results in extension of lifespan in mice [18]. These mice also
exhibit decreased oxidative stress, attenuated mitochondrial deletion, and delayed development of cardiac
pathology and cataract. Cardiac-specific overexpression of catalase in mice also prolongs lifespan and
attenuates aging-associated cardiomyocyte contractile dysfunction and protein damage [19]. These findings
suggest that catalase may be a longevity-determining enzyme [20] (Fig. 11.2). In addition to catalase,
cardiac overexpression of another antioxidant protein, metallothionein in mice has been shown to blunt
aging-associated superoxide production and oxidative damage, and increase the lifespan by 14% [21], an
extension comparable to that associated with overexpression of catalase in mitochondria [18]. In
Drosophila melanogaster, overexpression of Cu,Zn superoxide dismutase (Cu,ZnSOD) and catalase or
methionine sulfoxide reductase reduces oxidative stress and increases the longevity of the flies [22-24].
Recently, evidence also suggests a potential involvement of the antioxidant gene regulator, Nrf2 and related
Cap’n’collar transcription factors in protecting against senescence and promoting longevity [25-29] (Fig.
11.3). Collectively, the above experimental data point to the effectiveness of antioxidants in blunting agingassociated
oxidative stress and in extending lifespan in animal models.