ReviewThe paradoxical role of thioredoxin on oxidative stress and aging
Section snippets
Oxidative stress and aging
The free radical or oxidative stress theory of aging is one of the most popular theories in aging research and has been extensively studied over the past several decades. One consistent line of evidence supporting this theory is the large amount of data that has shown an age-related increase in oxidative damage in various cellular molecules (including lipids, proteins, and DNA) in organisms ranging from invertebrates to humans [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. Another strong
Transgenic mice overexpressing thioredoxin in the cytosol (Trx1)
Thioredoxin (Trx) was first recognized in the early 1960s as the major reductant for a variety of enzymes. Two forms have been identified in humans, one cytosolic (Trx1) [56] and one mitochondrial (Trx2) [57]. A major role of Trx is to donate a hydrogen atom to enzymes involved in reductive reactions [e.g., ribonucleotide reductase, which reduces ribonucleotides to deoxyribonucleotides for DNA synthesis; peroxiredoxin (Prx), which reduces peroxides [58], [59], [60]; and methionine sulfoxide
Transgenic mice overexpressing thioredoxin in mitochondria (Trx2)
As mentioned above, Schriner et al. [52] reported that overexpression of catalase in mitochondria (mCAT mice) significantly extended lifespan and reduced the incidence of some cancers in mice. These data strongly suggest that protection of mitochondria from oxidative stress could provide benefits on pathophysiology during aging. In fact, overexpressing Trx in mitochondria (Trx2) could show more significant effects on oxidative stress and longevity than increasing expression of cytosolic Trx1.
Survival studies with mice down-regulating Trx1 or Trx2
When testing the effects of reduced levels of thioredoxin in the cytosol or mitochondria on aging, we expected to observe the reverse effects, i.e., these mice might have a shorter lifespan due to reduced resistance to oxidative stress or impaired mitochondrial function, while age-related cancer development may be attenuated. To examine the effects of down-regulation of Trx in the cytosol or mitochondria on aging, we conducted survival studies with Trx1KO and Trx2KO mice. For these studies, we
Combined effects of up-regulating or down-regulating Trx1 and Trx2
Although overexpression or down-regulation of Trx1 or Trx2 alone showed several very interesting cellular and physiological changes, the impact on survival was somewhat disappointing. Overexpression of Trx in either the cytosol or mitochondria provided an extension of lifespan only in the early part of life, and maximum lifespan was not extended. On the other hand, down-regulation of Trx in either the cytosol or mitochondria showed some changes in pathophysiology, e.g., a slightly reduced
Effects of thioredoxin on oxidative stress and aging
After conducting survival studies using various mouse models up- or down-regulating Trx, our laboratory made several interesting observations regarding the role of thioredoxin on aging: (1) overexpression of Trx1 [Tg(act-TRX1)+/0 and Trx1Tg mice] or Trx2 (Trx2Tg mice) alone showed benefits only in the early part of life; (2) down-regulation of Trx1(Trx1KO mice) or Trx2 (Trx2KO mice) alone showed no effect on lifespan; (3) combined overexpression of Trx1 and Trx2 (Trx1Tg × Trx2Tg mice) resulted in
Conclusions
In spite of many endeavors over the past several decades to prove one of the most popular theories in aging research, the free radical or oxidative stress theory of aging, the results generated from our lab and others have raised more questions than answers about the theory and seriously challenged the role of oxidative damage/stress in the aging process in mammals. The results generated from our lab (Trx1Tg, Trx2Tg, Trx1KO, Trx2KO, Trx1Tg × Trx2Tg, and Trx1KO × Trx2KO mice) and others (e.g. mCAT
Acknowledgments
We would like to dedicate this article to Dr. Denham Harman, who revolutionized aging research with his Free Radical Theory of Aging. Though recent studies have challenged aspects of the theory, it has survived and evolved to include new findings. New avenues of research continue to advance and mold his theory, and his contributions to aging research will live on forever.
This research was supported by the VA Merit Review Grant 1 I01BX001023 from the Biomedical Laboratory Research & Development
References (89)
Free Radical Biol. Med.
(1994)- et al.
Mutat. Res.
(1995) - et al.
J. Biol. Chem.
(1987) Exp. Gerontol.
(1988)- et al.
Free Radical Biol. Med.
(1994) - et al.
Exp. Gerontol.
(1981) - et al.
Mech. Ageing Dev.
(1983) - et al.
J. Nutr.
(1990) - et al.
J. Nutr.
(1983) - et al.
Biochem. Biophys. Res. Commun.
(1987)
Mech. Ageing Dev.
Arch. Gerontol. Geriatr.
Mech. Ageing Dev.
Free Radical Biol Med.
Mech. Ageing Dev.
Arch. Biochem. Biophys.
Arch. Gerontol. Geriatr.
Mech. Ageing Dev.
Free Radical Biol. Med.
Exp. Gerontol.
Arch. Biochem. Biophys.
Mech. Ageing Dev.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Diabetes Res. Clin. Pract.
Methods Enzymol.
J. Biol. Chem.
Mech. Ageing Dev.
Methods Enzymol.
Free Radical Biol. Med.
Am. J. Pathol.
Dev. Biol.
Free Radical Biol. Med.
Biochem. Biophys. Acta
Immunol. Lett.
Science
Nat. Genet.
Ann. N.Y. Acad. Sci.
Science
Nucleic Acid Res.
FASEB J.
Mech. Ageing Dev.
Proc. Natl. Acad. Sci. U.S.A.
Cited by (54)
Mesothelioma Biomarkers: Discovery in Search of Validation
2020, Thoracic Surgery ClinicsPolyphenols and their potential role in preventing skeletal muscle atrophy
2020, Nutrition ResearchCitation Excerpt :Oxidative stress, characterized by increased reactive oxygen species (ROS) production and impairment of antioxidant defense systems, can be considered a major trigger of imbalance between protein synthesis and degradation leading to muscle atrophy [16-19], as found in the pathogenesis of chronic and degenerative disorders [20-25]. In skeletal muscle, high levels of ROS promote proteolytic process activation [26-31] as well as mitochondria dysfunction with impairment of mitochondria membrane functions and a reduction in mitochondria biogenesis [32, 33]. ROS is reported in various atrophic conditions [34, 35], myopathies [36, 37], and muscular dystrophies [38-40].
Oxidative stress and sarcopenia
2020, Aging: Oxidative Stress and Dietary AntioxidantsFunctions of thioredoxin1 in brain development and in response to environmental chemicals in zebrafish embryos
2019, Toxicology LettersCitation Excerpt :Thioredoxin1 is a stress-inducible protein, and is a scavenger of reactive oxygen species (ROS) (Nakamura et al., 1997; Mitsui et al., 1992; Das and Das, 2000). Overexpression of Thioredoxin1 provides protection against oxidative stress, and causes changes in redox-sensitive signaling (Cunningham et al., 2015). For example, overexpression of Thioredoxin1 suppresses toxicity induced by H2O2 and the herbicide paraquat in cultured cells (Byun et al., 2005).
Brain region-specific effects of long-term caloric restriction on redox balance of the aging rat
2019, Mechanisms of Ageing and Development
- 1
Indicates equal contribution by authors.