Open Access | Editorial
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Oxidative stress in aging: stayin’ alive?
* Corresponding author: Yuji Ikeno
Mailing address: Barshop Institute for Longevity and Aging
Studies, The University of Texas Health Science Center at San
Antonio, 15355 Lambda Drive, San Antonio, TX 78245-3207,
USA.
E-mail: ikeno@uthscsa.edu
Received: 11 June 2020 / Accepted: 14 June 2020
DOI: 10.31491/APT.2020.06.015
Abstract
There is still ongoing controversy about the oxidative stress theory of aging, particularly in mammals, after a significant number of studies have been conducted to test this theory. Results generated from the studies strongly indicate that accumulation of oxidative damage alone does not play a significant role as an underlying mechanism of aging, which calls into question that significant modifications to the theory are required to understand the relationship between oxidative stress and aging. To examine the exact role of oxidative stress in aging and age-related diseases, our laboratory has been conducting studies with unique animal models: 1) mice overexpressing or down-regulating thioredoxin (Trx) in the cytosol (Trx1) or in mitochondria (Trx2); and 2) rats overexpressing Cu/Zn superoxide dismutase (SOD). Results generated from these studies strongly indicate that: 1) changes in oxidative stress and redox state could play more important roles in age-related pathological changes, e.g., cancer and metabolic disorders; 2) redox regulation of signaling pathways could play more important roles in aging than accumulation of oxidative damages; 3) the potential benefit of changes in oxidative stress and redox state could be organ/tissue specific; 4) the roles of oxidative stress could vary in different stages of life (i.e., young versus old); and 5) synergetic effects of changes in oxidative stress in multiple cellular compartments may be required to have a significant impact on aging. Therefore, the studies with more careful approach would uncover the exact roles and pathophysiological consequences of oxidative stress during aging.
Keywords
Oxidative stress, aging, age-related diseases, cancer, obesity, healthspan
The free radical theory of aging, originally proposed by
Dr. Denham Harman in the 1950s and later modified as
the oxidative stress theory of aging, has been extensively
studied over the past 60 years. There is substantial evidence that strongly supports this theory: 1) the levels of
oxidative damage to macromolecules increase with age; 2)
extended lifespan in various animal models is correlated
to reduced oxidative damage and/or increased resistance
to oxidative stress. In the 1990s, the effects of oxidative
stress on lifespan were examined using mice that genetically altered various components of the antioxidant defense system to directly test the oxidative stress theory
of aging. In theory, the increased resistance to oxidative stress by the overexpression of major antioxidant enzymes
increases the lifespan of mice, while reduced resistance
to oxidative stress by the down-regulation of major antioxidant enzymes shortens the lifespan of mice. However,
the overexpression of major antioxidant enzymes did not
extend lifespan except in MCAT mice, which overexpressed catalase in mitochondria; and the down-regulation
of major antioxidant enzymes did not shorten lifespan in
mice, except in Cu/ZnSOD-null mice. Thus, a majority of
the data from mice with genetically altered levels of major
antioxidant enzymes do not support the oxidative stress
theory of aging, which seriously calls into question the exact roles of oxidative damage/stress on the aging process
in mammals.
Our laboratory has been conducting research to test the
exact roles of oxidative stress in aging and age-related diseases using unique animal models: 1) mice overexpressing
or down-regulating thioredoxin (Trx) in the cytosol (Trx1)
or in mitochondria (Trx2); and 2) rats overexpressing Cu/
ZnSOD. We chose to examine the effects of Trx in aging because of its unique characteristics: Trx has ability
to attenuate the level of oxidative stress and alter redoxsensitive signaling pathways. Thus, Trx could have more diverse effects on pathophysiology during aging other
than altering the accumulation of oxidative damages. We
also conducted an aging study with Cu/ZnSOD rats to test
the possible species differences, i.e., mouse vs. rats.
The studies with Trx1 and Trx2 transgenic and knockout
mice revealed that: 1) either Trx1 or Trx2 overexpression
showed a slight extension of lifespan mainly in the earlier
part of life with a slight acceleration of cancer development in the later part of life; 2) synergetic overexpression
of Trx1 and Trx2 shortened lifespan with enhanced cancer
development and changes in signaling pathways involved
in tumor growth, which was contrary to initial expectations; and 3) the ongoing study with mice down-regulating both Trx1 and Trx2 demonstrates a slight extension
(9-10%) of lifespan in both males and females. The Cu/
ZnSOD rats study showed that Cu/ZnSOD overexpression
in Sprague-Dawley (SD) rats extends lifespan while Cu/
ZnSOD transgenic mice and F344 rats showed no changes
in lifespan. Interestingly, the life-extension of Cu/ZnSOD
transgenic SD rats is associated with: 1) reduced age-related cancer; 2) attenuated kidney pathology; 3) enhanced
insulin sensitivity; and 4) reduced senescence-associated
beta-galactosidase positive cells in adipose tissues. These
unexpected, but very intriguing observations strongly suggest: 1) changes in oxidative stress and redox state could
play more important roles in age-related pathological
changes, e.g., cancer and metabolic disorders, than aging
per se; 2) redox regulation of signaling pathways could
play more important roles in aging than accumulation of
oxidative damages; 3) the potential benefit of changes
in oxidative stress and redox state could be organ/tissue
specific; 4) the roles of oxidative stress could vary in different stages of life (i.e., young vs. old); and 5) synergetic
effects of changes in oxidative stress in multiple cellular
compartments, e.g., cytosol and mitochondria, may be required to have a significant impact on aging in mammals.
We believe that oxidative stress plays important roles in
aging in multiple ways. The detailed analyses of the roles
of oxidative stress/cellular redox state in healthspan, agerelated diseases, organ specific functional changes, and
different stages of life, will allow us to have a clearer
picture and lead to a major paradigm shift of the oxidative
stress theory of aging.