Aging is a highly complex biological process resulting in the progressive loss of ability of organs and cells to maintain biochemical function, eventually leading to age associated diseases and death.

Arising from the inability to meet the environmental demands for continued existence, many theories have been proposed as the molecular basis of the Aging process, such as, genetic programming, perturbation of the neuroendocrine and immune systems, molecular instability, free radical damage, protein glycosylations etc.  However, one of the obvious and readily recognized outcomes of the Aging process is the progressive decrease in the bioenergetic capacity of individuals with age.  Thus it might be said that one plays their best squash to 30 years, tennis to 40 years, golf to 50 years, bowls to 60 years and so on.

We at the Centre for Molecular Biology and Medicine have in recent years published a series of milestone papers suggesting the why, and the how, by which this decline in bioenergy function occurs.  Further they have suggested an amelioration treatment for the re-energization of cells/tissues/organs of animals and human subjects, thereby potentially attenuating the severity of some age associated diseases and most importantly with potential to improve human well being and life style.

At the turn of the century, life expectancy was barely 50 years and infectious diseases such as pneumonia, influenza and tuberculosis were the major killers.  At the close of the century, life expectancy in advanced societies is about 80 years, the present day challenges are the systemic diseases associated with advancing years such as heart, vascular, diabetes, stroke etc.  The onset of these conditions begins to be observed at about 50 years of age.

Cellular Biology...

The source of the energy that we use for all of our activities is the food we eat.   But the energy in this food must be converted into a form that is accessible to the biological machinery that makes up our cells and hence our organs.   To do this, the nutrients are broken down within cells into simpler substances and the energy extracted is stored in one of a number of so-called ‘high energy’ compounds.   The most important of these is known as ATP, this compound is the universal energy fuel of all living organisms.   The main sites within the cell at which this energy generation takes place are called mitochondria.

Mitochondria are membranous structures found in all cells of higher organisms and are referred to as the power houses of cells.  The major bioenergy generating system (also known as the oxidative phosphorylation system) of higher organisms is located in the mitochondria of the cells.  This system is comprised of a series of compounds linked together in a chain of increasing order of electrochemical potential, embedded in the mitochondrial membrane.  Basically, in this process, hydrogen extracted from our food is fed, into one end of an electrochemical chain and is then passed along the chain in a series of alternating oxidation and reduction steps (redox chain) to combine finally with oxygen to form water.  Essentially all the oxygen inhaled by higher organisms ends up as water, oxygen is referred to as a redox sink.  This process of producing water generates large amounts of energy whereby the membrane becomes like a battery, positively charged on one side, negatively charged on the other.  This membrane potential can then be directly used as energy, or the energy can be fed off at three sites to make the substance ATP.  ATP is the universal energy fuel of all living organisms.  Energy capacity of biological systems can be measured as ATP formed or membrane potential generated.  Figure 1 outlines the nature of the mitochondrial oxidative phosphorylation system which is comprised of five enzyme complexes I - V.  Except for complex II all complexes are dependent upon mitochondrial gene products for function.  The first step in energy generation begins with NADH the major coenzyme of oxidative metabolism being oxidized by donating H (H⁺ + e_¯) to the so-called electron transport chain.  The (H⁺ + e_¯) passed along the chain with carriers alternatively being reduced then oxidized finally for the (H⁺ + e_¯) to react with oxygen to form water.  At the levels of complexes I, III, IV, ATP is formed by interaction with complex V.

Figure 1: (Click to Enlarge)

One of the most important compounds in the mitochondrial oxidative phosphorylation system is coenzyme Q10.  It functions in the chain between complexes I, II and III and plays a particularly important role in energy generation, as it shuttles within the mitochondrial membrane.  Coenzyme Q10 is also unique in the energy chain as it is a relatively simple molecule and can be manipulated compared with the protein components of the energy chain.  Coenzyme Q10, chemically is a benzoquinone and it, or derivatives of it (coenzyme Q10 analogues) occur in all living cells and are key components of the bioenergy generating systems of all cells.  Quinones are redox compounds, that is they can undergo cyclic oxidation and reduction (donate and accept hydrogen and its components, H⁺ + e_¯), Quinones can also function as anti-oxidants (oxygen radical scavengers).

Mitochondria...

It has long been understood that energy production in the cells of the body is controlled by the action of mitochondria.  There are numerous mitochondria in each cell.  The mitochondria are distinct membranous structures which, contain a small (37) special set of genes encoded in mitochondrial DNA which are concerned ONLY with the production of cellular energy.  The very small number of mitochondrial genes contrast with the 100,000 or more genes (DNA) in the chromosomes of the nucleus which specify all other cellular functions.  Molecular changes to the DNA (mutations) produce faulty or non-functional genes; consequently a mitochondrial DNA mutation will deleteriously affect the mitochondrion’s energy capacity by altering the properties of one of its redox components.  Figure 1 represents a combination of the mitochondrial DNA and the oxidative phosphorylation system.  Mitochondrial DNA occurs as a closed circle and the genes which contribute to the oxidative phosphorylation system are colour coded to show where their products function in the system.  The three sites of formation of ATP are also shown.  A mutation in the mitochondrial DNA has the potential to render the whole oxidative phosphorylation chain non-functional by disrupting the flow of (H⁺ + e_¯) along the chain.  It is analogous to breaking a link in a metal chain.

Discovery -  A Therapy for Aspects of Aging

A major discovery by Centre scientists has been that mitochondrial DNA mutations occur in all individuals and that there is a progressive accumulation of these mutations with age with a consequential decrease in bioenergy capacity of cells/tissues/organs.  At a low incidence level in the young there are no deleterious effects due to the multiple numbers of mitochondria which occur in cells.  However, over the years the number of mitochondria with mutations progressively increases to the point of affecting cells and crucial organ function.  The effects are progressive; at first the effects will be totally sub clinical, but increasingly they become more severe until eventually the mitochondrial energy production decline results in a bioenergy capacity decrease affecting heart, brain, muscle etc. function.  These effects may still be sub-clinical but will impinge on well-being and life style.  If and when the bioenergy decrease becomes sufficiently severe overt disease will result.

Centre scientists have shown that the mitochondrial oxidative phosphorylation system can be manipulated to produce more energy when supplemented with coenzyme Q10.  This is a significant discovery with potentially wide ranging medical implications.  Centre scientists refer to it as ‘redox therapy’.  Other redox compounds are being investigated by Centre scientists in animal experiments.

Re-Energization improved function of rat hearts...

Centre scientists have demonstrated striking benefits are obtained by treating old rats with coenzyme Q10 (see Figure 2). Young and old rats were treated with coenzyme Q10 or placebo vehicle for a period then the capacity of animals’ hearts to work following aerobic stress pacing, was assessed.  As expected the heart performance of the old animals was inferior to that of the young animals but the hearts of the coenzyme Q10 treated old animals was similar to that of the young animals!

Recovery of Work Performance...

The hearts of young (6 months) and old (35 months) rats were treated either with coenzyme Q10 or placebo vehicle.  The hearts of the animals were subjected to an aerobic pacing stress, rested briefly, then aerobically stressed again.  The function of the hearts is measured as a percentage recovery of initial work capacity following a short rest.  The hearts of the old animals supplemented with coenzyme Q10 function in this test as well as young animals!

Research Program...

The continuing work of our aging project research teams is directed towards a number of closely linked ends.  A primary objective is to deepen our understanding of the process which leads to degeneration of the cellular energy system.  An important part of this investigation is determining the mechanism by which coenzyme Q10 acts to ameliorate the bioenergy decline.

A major objective is the development of a bioenergy status diagnostic.  This diagnostic is being developed to establish a bioenergy well-being/health deficit risk assessment, according to an individual’s age.  In the future, diagnosis of a bioenergy deficit would lead to a simple therapy with a potential attendant improvement in life style.  This work is generously supported by a grant from ATTORI.

Work on the Aging project is the joint responsibility of four research groups acting in concert.  The activities of the four groups are described in the following sections.