Review
The paradoxical role of thioredoxin on oxidative stress and aging

https://doi.org/10.1016/j.abb.2015.02.025Get rights and content

Highlights

  • Oxidative stress could have different impacts at different stages of life.

  • Redox-sensitive signaling could play more important roles than oxidative damage.

  • Oxidative stress plays different roles in aging in different cellular compartments.

Abstract

In spite of intensive study, there is still controversy about the free radical or oxidative stress theory of aging, particularly in mammals. Our laboratory has conducted the first detailed studies on the role of thioredoxin (Trx) in the cytosol (Trx1) and in mitochondria (Trx2) on oxidative stress and aging using unique mouse models either overexpressing or down-regulating Trx1 or Trx2. The results generated from our lab and others indicate that: (1) oxidative stress and subsequent changes in signaling pathways could have different pathophysiological impacts at different stages of life; (2) changes in redox-sensitive signaling controlled by levels of oxidative stress and redox state could play more important roles in pathophysiology than accumulation of oxidative damage; (3) changes in oxidative stress and redox state in different cellular compartments (cytosol, mitochondria, or nucleus) could play different roles in pathophysiology during aging, and their combined effects show more impact on aging than changes in either oxidative stress or redox state alone; and (4) the roles of oxidative stress and redox state could have different pathophysiological consequences in different organs/tissues/cells or pathophysiological conditions.

To critically test the role of oxidative stress on aging and investigate changes in redox-sensitive signaling pathways, further study is required.

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

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