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, b-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.

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 supra-reactive 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.

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 (CoQH₂).³ Instead, treating a tropical marine bacterium to UVA radiation significantly enhanced the antioxidant (ubiquinol) form of coenzyme Q,⁵ presumably by up-regulating 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.

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 age-related 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 often-concurrent development of degenerative disease in human aging.