Molecolar and cellular immunosenescence in human. Paradoxes and perspectives emerging from the study of healty centenarians.

Ageing has been studied extensively1,2. On the contrary, longevity, and particularly human longevity, has been neglected3. Hundreds of theories are available on ageing, indicating that scientists are still far from understanding the biological and cultural basis of this process. To this long list of theories, we have added a new one, based on the consideration that the maintenance of soma integrity is the consequence of a continuous activity of a limited number of cellular defence mechanisms4-6. We have hypothesised that DNA repair, enzymic and non-enzymic antioxidants, production of heat shock and stress proteins, and activity of poly(ADP-ribose)polymerase form a network of interconnected cellular defence mechanisms, whose global efficiency has been set during evolution at different levels in different species and in different individuals of the same species. We have also speculated that apoptosis is a fundamental biological process which can join the list of cellular defence mechanisms, being an ancestral process used to eliminate damaged, mutated, viral-infected or transformed cells7,8. On the whole, the above-mentioned cellular defence mechanisms can be considered as the basic molecular and cellular anti-ageing systems. However, it can be argued that ageing is not simply a cellular mechanism but that it represents the failure of more integrated systems whose purpose is to preserve body integrity. The nervous, the endocrine and the immune systems are all devoted to the maintenance of body homeostasis. Moreover, we and others have argued that these three systems, which evolved together, have to be studied as a whole, and that the more appropriate approach is to consider immunoneuroendocrine cells and organs as part of a unique system devoted to cope with all kinds of internal and external damaging agents 9. In previous papers we have suggested that the immunoneuroendocrine system relies upon the above-mentioned molecular and cellular defence mechanisms for its continuous activity 5. This point of view represents a tentative to combine molecular and cellular with system theories of ageing. It can be predicted that the optimal functioning of this immunoneuroendocrine system is of major importance for survival, ageing and longevity. Accordingly, as far as human longevity is concerned, we hypothesised that people who survived in good conditions for long periods, close to the maximum life span of our species, should be equipped with an optimal immunoneuroendocrine system 5. For this reason, a research project was started some years ago on the biological basis of human longevity, in a selected group of healthy centenarians 6. We will report here some of the data collected in the last few years on the immune system of centenarians. These data are the first part of a broader investigation in which immune and neuroendocrine parameters will be analysed in order to understand some of the molecular and cellular basis of human longevity. A genetic search for longevity assurance genes is also in progress.