DAMAGE: AN ANTIAGEING HYPOTHESIS

L. Re, S. Barocci, L. Rinaldi, C. Vivani, A. Scucimarra and G. Paolucci
Since many years the role of reactive oxygen species (ROS) in the acute and chronic
diseases represented the topic of numerous scientific papers. Indeed, the oxidative
damage to DNA, RNA, protein and cell membranes that physiologically occurs during the
ageing process and the partial protection exerted by the cell defence systems represent
well-known processes. On the other hand, in various pathological conditions the main
problem is related to a rapid increase in the cellular ROS concentration that exceeds the
capacity of the cell to eliminate them. Normally, ROS derived from the oxygen reduction
during the biochemical pathways of the cell energy production systems (Gershman,
Science, 119: 623-626, 1954). In some pathological conditions ROS could increase either
for a primitive defect of the cell defence system or following an overproductions derived
either from the cell death or apoptosis phenomena. Nevertheless, the role of the oxidative
stress in the induction of apoptosis is well known and the oxidation of glutathione
represents an early event in the course of apoptosis. Recent data dealt on the prooxidative
activity of CuZn superoxide dismutase (SOD) and nitroxide SOD-mimics. SOD is
unique in being present in cells and in various experimental systems in a concentration
excess over its substrate. If the enzyme or its mimics are present in the oxidized form,
they may oxidize various cellular or exogenous substrates (Offer et al, FASEB J, 14(9):
1215-23, 2000). The natural defenses against ROS could be classified as exogenous or
endogenous. The first ones, diet dependent, comprise vitamins, E and C, flavonoids and
polyphenols while SOD, glutathione peroxidase, catalases are being considered the main
endogenous species. The first hypothesis of a positive conditioning induced by low ozone
concentrations against the oxidative stress has been recently proposed by Leon Fernandez
et al (Int. Cong. Pharmacol., CPT 2000, Florence, Brit J Clin Pharmaco, July 15-20, 2000).
The theory is based upon the fact the low, non-toxic, ozone doses could raise the efficacy
of the endogenous system by increasing the production or the activity of some antioxidant
enzymes isoforms. Looking at the ischaemic preconditioning in which is scientifically
proved that repetitive brief ischaemia plays an important role in the acquisition of latephase
cardio protection against ischaemia/reperfusion injury in rats (Yamashita et al, Br J
Pharmacol, 131(3): 415-422, 2000), we can speculate that repetitive brief oxidative stress
induced with low ozone doses could ameliorate the cell defences mechanisms against
ROS. The hypothesis is supported by other data reported by Rao and Shaha (Free Radic
Biol Med, Nov 15; 29 (10): 1015-1027, 2000) demonstrating the formation of multiple
isoforms of glutathione S-transferase after the exposure to H2O2. A further evidence of the
protective action induced by low ozone concentrations has been proposed by our group
(Re et al, Gen Pharmacol, 32; 245-250, 1999). Indeed, we proved the reduction of the
intracellular calcium at presynaptic levels after the exposure to low ozone doses. The
cytosolic calcium could be considered as the common final pathway of the cellular
damage, either physiologically or pathologically. A low calcium level represents a further
element in supporting the idea of the oxidative cell damage protection either in the
chronic or in the acute ageing. We think that the use of ozone in the medical field could
represents a useful and safety therapeutic potential in many pathologies actually orphan
of adequate pharmacological treatment and in the prevention of the naturally occurring
ageing.