Aging is a universal process and yet it is a remarkably difficult phenomenon to define. The human body theoretically should be able to regenerate itself indefinitely as it has numerous processes that repair and renew time dependent damage. And yet we age. In the Department of Physiology at Trinity College we are interested in the processes that underlie cellular aging and in ways in which these processes can be delayed.

All organisms fundamentally operate on a cellular level. Cells co-operate and co-ordinate to form tissues and organs. To do this they must produce energy, and it is this process, it is hypothetised, that creates the conditions that "cause" aging.

To respire, a mammalian cell must combine oxygen and glucose and, from this reaction, "energy" is released and stored in a chemical form. However life evolved in an oxygen-free environment over a billion years ago, and it is imperfectly suited to handling the very high energy potential present in molecular oxygen. It is this leakage of semi-reacted but highly energetic oxygen or reactive oxygen species (ROS) from respiration sites within the cell that is hypothesised to cause aging. For these moieties rip through the delicate cellular architecture, distorting and inactivating proteins, damaging DNA and hardening membranes. Over a life time the destruction wrought by these agents overwhelms the cells reparitive capacities. Muscle cells whither, skin cells lose flexibility, and brain cells decline. An organism grows "old".

The cell has evolved an elaborate defence mechanism against these toxic by-products of respiration. This system comprises enzymatic and non-enzymatic components. Both arms function to neutralise the ROS before they can interact and damage cellular components.

In the laboratory of Dr Marina Lynch in the Physiology Department of Trinity College, we have been studying a portion of the brain, the hippocampus, believed to be involved in memory formation. The brain is composed of an entangled tapestry of specialised cells called neurons. These cells are unable to regenerate themselves and appear to be especially sensitive to the constant barrage of ROS. Over time, the capabilities of these neurons erode, and we believe this is due to a parallel decline in the antioxidant defence system of these cells.

The nonenzymatic portion of the defence system, which is comprised mainly of the vitamins C and E, deteriorates significantly in the aged hippocampus. But also, in aged hippocampal neurons, the activity of a key enzyme involved in trapping ROS is paradoxically increased. This over-activity has deleterious consequences. The enzyme, superoxide dismutase (SOD), converts the toxic ROS into another toxic agent, hydrogen peroxide. This molecule can cause cellular damage if it is not instantly removed, and the enzymes that break down this molecule struggle to cope with its overproduction. The resultant combination of SOD over-activity and the decrease in the concentrations of the vitamins C and E is believed to significantly contribute to the "aging" in these neurons.

It is known that a particular peptide released during infection in the brain, interleukin-1ß (IL-1ß), is also present in high concentration in aged hippocampal neurons. We hypothesised that ROS-mediated neuronal damage causes this peptide to be released and that this in turn stimulates the activity of SOD – thus creating a destructive feedback loop. We postulated that, if this cycle could be stopped by artificially boosting the non-enzymatic portion of the defence system and thus limiting the extent of ROS mediated damage, perhaps the hippocampal neuronal injury witnessed in aging could be deferred?

To test this hypothesis, young and aged rats were fed a diet rich in the vitamins C and E to boost their antioxidant defence system. It was found that there was no increase in concentration in IL-1ß in these animals compared to corresponding controls, SOD activity was not increased, and oxidative damage was also significantly decreased. Furthermore, in a key experiment designed to test hippocampal neuronal function, it was found that aged cells from the diet group recovered their responsiveness to a specific electrical stimulus, and the extent of that response was similar to that of hippocampal neurons from young rats.

We have shown that long-term vitamin supplementation can reverse certain age related changes in hippocampal neurons and that time dependent decline in neuronal function in this portion of the brain can be inhibited.

Contact: Eamonn O’Donnell,
Department of Physiology,
Trinity College, Dublin 2;
E-mail: odonneec@mail.tcd.ie