di
Anna Giulia Cattaneo.
Department of Biotechnology and Life Sciences, University of Insubria, via J-H Dunant, 3, Varese, Italy.

The definition of aging in healthy humans is a field of interest not only for geriatrics studies, but for forensic medicine, demographic and economic sciences too. In spite of its speculative importance, we can only roughly approximate this definition. Difficulties raise from different perspectives.

The aging process behaves like an evolution-driven process, strictly linked to the reproductive potential of species. To the evolutionary pressure, several other poorly predictable factors, like chance, environmental risks and insults, are to be added in the equation.
In humans this event lacks adequate experimental models. To define live-long processes, we need models belonging to species whose natural life span is shorter enough to be studied in more than one generation during the professional live of one generation of scientists. Not only, to infer data having statistical significance in humans, the observation should be carried out in populations large enough to reach statistical meanings. Such a model does not seem to exist.

The modern experimental biology recognizes and recommends many useful models defined as "alternative". This term is addressed to models not involving mammals, but restricted to established cell lineages, living tissues or organs maintained or even grown in vitro, monocellular organisms like yeasts, the fruitfly and other invertebrate well adapted to laboratory conditions. Among vertebrates, several alternative models well characterized for in vivo studies include the Xenopus sp, and some fish, like D.rerio.
None of these models, however, shows the requisites for an exhaustive study of human aging. In our species this process is too complex to be reproduced in vitro, a condition adequate to study simple aspects of aging, not its main mechanisms, nor to describe the phenomenon in its complexity. In healthy humans the aging process is limited to the late live, when the reproductive process is exhausted. Species whose reproduction potential is evenly distributed along the period of life, like yeasts and other monocellular prokaryotes adapted to laboratory conditions, appear therefore to be poorly adequate. Further restriction are bound to the absence, in invertebrates, of complex structures, like lungs or cardio-vascular system. Finally, the energetic cost for maintaining homeothermy must be kept in mind. Keeping together all these considerations, an acceptable model of human aging should be searched between mammals usually bred in laboratory, mainly rodents. In this manner, the choice is restricted also to species who age at the end of their reproductive life. The observations will necessarily be limited to fewer individuals that expected in population studies, and this limitation is the price of a more accurate model. And however, the model still lacks accuracy, because the aging events differs in humans and in rodents.

A second difficulty rises from the absence of sure markers of senescence, and especially by the complete lack of specific gene linked to the process of senescence, or "gerontogenes", a term used by Rattan (FASEB J, 1995, 9:284-286). Processes determining an irreversible aging are mainly linked to oxidative damage of cell structures: aging starts when the aggressions overcomes the maintenance and repair systems of the organism. While many genes have been identified, whose function is linked to these aging mechanisms, none of them has evolved to cause accumulation of molecular damage or to determinate the life span.

Being the senescence, at least apparently, more linked to this epigenetic modifications than to the genome itself, a powerful tool to approaching this question could be the metabonomics. The term refers to the comprehensive study of set of parameters representative of entire metabolic pathways depicted simultaneously. This methods is newly accessible by the development of experimental procedures linked to the recording of magnetic resonance spectra, applied to the molecular content of blood, urine and other biological specimens. Every spectrum can be resolved in relation to the main peaks, corresponding to different metabolites. The overall procedure is minimally invasive, rapid, powerful and highly reproducible. While at the present limited to research, the method is very promising in many complex field, like the assessment of life span and aging in humans. Its standardization is in progress and advancement are rapidly achieved, the cost is progressively reducing. The major limitation is, at the present, represented by the low number of technicians trained for the interpretation of results, requiring basis of advanced statistics.

If metabolism is at the basis of the human aging process, a specific marker should eventually be found with the development of this powerful descriptive means, and samples of population large enough to sustain a robust statistical analysis should be obtained at reasonable time and cost. Finally, a distinctive profile of healthy aging process should be differentiated from other correlated causes of illness and death.