Environmental biochemistry
and photobiology
Marine Biotechnology for
Anti-Aging Research
Dunlap WC 1, Fujisawa A 2 and Yamamoto Y 2
1.
Marine Biotechnology, Australian Institute of Marine Science
2. Dept. of Chemistry and Biotechnology, University of Tokyo
Perspective: Human Health and Oxidative Damage
The ultimate Holy Grail of medicine would be to slow or reverse the processes of
aging. While aging is predisposed by genetic factors, it is becoming increasingly
clear that biogenic oxidants (AKA, "free radicals" or "reactive oxygen species")
progress the aging process by causing an accumulation of oxidative damage to
living cells and tissues. In the well-accepted Free Radical Theory of Aging1 this
accumulation of oxidative damage is largely responsible for the general decline
of health we experience with age. Protection against oxidative damage includes
the elaboration of water-soluble reductants (glutathione, ascorbate, urate) in the
cytosol, lipid-soluble antioxidants (ubiquinol, tocopherols, -carotene) residing in
cellular membranes, and the antioxidant enzymes, superoxide dismutase,
catalase, ascorbate peroxidase, glutathione peroxidase and glutathione
reductase. Despite this impressive array of defences, unrepaired (or misrepaired)
cellular damage accumulates, and this progression is notable by the aging of our
appearance.
Dr. Walt Dunlap and the High
Performance Liquid
Chromatograph (HPLC) at the
Australian Institute of Marine
Science facility at Cape
Ferguson.
Biogenic production of free radicals occurs mostly during normal
processes of cellular metabolism in the conversion of dietary fuel to
useable energy across a series of electron couples in the electron transport
chain that drives ATP synthesis. A by-product of energy metabolism is the
uncoupling of electrons in the transport chain (located in the mitochondria
of higher organisms) to generate superoxide, via activation of molecular
oxygen, leading to the production of hydrogen peroxide and the suprareactive hydroxyl radical. Such reactive oxygen species (ROS) are highly
damaging to DNA, proteins and membrane lipids causing cellular
impairment. In the normal condition of aging, antioxidant functions
decline to further accelerate the aging process, and this exacerbates the
progression of age-related degenerative diseases.
Preventing the formation of reactive oxidants in metabolic electron
transport presents a clear strategy for reducing cellular oxidative stress.
The first stage (Complex I) of electron transport is critical to conserving
mitochondrial energy. In this metabolic step, coenzyme Q is the electron
and proton carrier within the mitochondrial membrane. Additional to
electron transport, coenzyme Q resides in all cellular membranes where
the reduced form (ubiquinol) also functions as a powerful lipid-phase
antioxidant,2 and its reductive capacity is coupled to recycling the
antioxidant activity of vitamin E.3 Regulating molecular processes to
sustain adequate levels of CoQ in its reduced state is thus vital for cellular
management of oxidative stress.
Regulation of NAD(P)H: Quinone Oxidoreductase Activity in Marine
Bacteria
Recycling of coenzyme Q from ubiquinone (inactive) to ubiquinol (redox active) is
affected by the enzyme NAD(P)H:quinone oxidoreductase (NQR). In cellular
systems where NQR activity is constitutively homeostatic, metabolic stress is
indicated by an oxidative shift in the cellular coenzyme Q (ubiquinol/ubiquinone)
ratio.4 Accordingly, It was expected that photooxidative stressing of marine
bacteria would increase the oxidative consumption rate of ubiquinol (CoQH 2).3
Instead, treating a tropical marine bacterium to UVA radiation significantly
enhanced the antioxidant (ubiquinol) form of coenzyme Q, 5 presumably by upregulating NQR activity to compensate for the applied stress. 6 Our finding of CoQ
redox regulation by marine bacteria is a novel adaptive response, although an
analogous behaviour was observed for human blood mononuclear cells to
increase NQR activity 3-fold on exposure to UVB radiation.7 The profound
magnitude of evolutionary divergence in these cells suggests a tightly conserved
function in molecular response to photooxidative stress.
Changes in %CoQH2 on UV exposure of a bacterium isolated
mid-summer from the surface mucus of a shallow-water coral
from the Great Barrier Reef.
Scheme indicating up-regulation of NAD(P)H: quinone oxidoreductase activity to
increase cellular %CoQH2 on exposure of a marine bacterium to UVA radiation.
Changes in NAD(P)H: quinone oxidoreductase activity on UV
exposure of a marine bacterium isolated from the surface mucus
of a shallow-water coral from the Great Barrier Reef.
Biomedical Application of CoQ regulation in Anti-Aging Medicine
Metabolic oxidative stress has been implicated, directly or indirectly, in a variety
of pathological disorders and chronic degenerative processes including the
development of cancer, atherosclerosis, inflammation, neurodegenerative
disorders (i.e., Alzheimer’s and Parkinson’s diseases), cataracts, retinal
degeneration, reperfusion injury (stroke), diabetes (type 2), immune suppression,
and dermal aging. Anti-aging medicine, a therapeutic extension of preventative
health, is predicted to become the preeminent mode of healthcare in the 21st
century.8 Marine biotechnology offers to meet this challenge in biomedical
research innovation. Early marine life having evolved to establish an oxygenic
environment uniquely offers a lateral view to examine adaptive processes of
biogenic and environmental stress management, particularly necessary in early
development of aerobic metabolism.
In human physiology, coenzyme Q is well defined as a critical component of
metabolic energy production necessary for health and to sustain life-style
activities. In regulating energy production, NAD(P)H:quinone oxidoreductase is
vital for recycling of CoQ in mitochondrial electron transport and also functions to
provide adequate reduced CoQ for effective antioxidant protection. Given that
inhibition of cellular NQR enhances free radical damage9 and that aging and agerelated degenerative diseases may progress from a diminished capacity to
maintain adequate antioxidant levels of CoQH2,10 the UV-signalling pathway
discovered in marine bacteria may serve as a powerful cellular model to probe
regulation of human NQR activity for amelioration of age-deficient CoQ balance.
We hypothesise that finding a molecular mimic to regulate NQR activity11 may
offer a therapeutic strategy to retard the progressive debilitation and the oftenconcurrent development of degenerative disease in human aging.
References
1. Beckman KB and Ames BN (1998). The free radical theory of aging
matures. Physiol. Rev. 78: 547-581.
2. Stocker R, Bowry VW and Frie B (1991). Ubiquinol-10 protects low
density lipoprotein more efficiently against lipid peroxidation than does 
-tocopherol. Proc. Natl. Acad. Sci. U.S.A. 88: 1646-1650.
3. Kagen VE, Arroyo A, Tyurin VA, Tyurina YY, Villalba JM, Nava P (1998).
Plasma membrane NADH-coenzyme Q reductase generates
semiquinone radicals and recycles vitamine E homologue in a
superoxide-dependent reaction. FEBS Lett. 428: 43-6.
4. Yamamoto Y and Yamashita S (2000). Redox status of plasma
coenzyme Q as an indicator of oxidative stress. In: Coenzyme Q:
Molecular Mechanisms in Health and Disease. Kagen VE and Quin PJ
(eds), CRC Press, Boca Raton, Florida, p 261-268.
5. Søballe B and Poole RK (2000). Ubiquinone limits oxidative stress in
Escherichia coli. Microbiology 146: 787-796.
6. Dunlap WC, Fujisawa A and Yamamoto Y (submitted). CoQ redox
balance in marine bacteria exposed to UVA Radiation: apparent upregulation of NAD(P)H:quinone oxidoreductase activity. Redox Report.
7. American Academy of Anti-Aging Medicine. http://www.worldhealth.net.
8. Beyer RE, Segura-Agillar JE, Di Bernard S, Cavazzoni M, Fato R,
Fiorentini D, Galli MC, Setti M, Landi L and Lenaz G (1996). The role of
DT-diaphorase in the maintenance of the reduced antioxidant form of
coenzyme Q in membrane systems. Proc Natl Acad Sci USA 93: 25282532.
9. Ernster L and Dallner G (1995). Biochemical, physiological and medical
aspects of ubiquinone function. Biochim Biophys Acta 1271: 195-204.
10. Jaiswal AK (2000). Regulation of genes encoding NAD(P)H: quinone
oxidoreductases. Free Radic Biol Med 29: 254-262.
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