Our society is characterized by a progressive phenomenon of population ageing, with a high prevalence of chronic and degenerative diseases and an increasing level of disability1,2,3. World-wide the average life of man is approaching 80 years, while the Maximum Life Span, which is species-specific, is approximately 120 years, twice the maximum age of the chimpanzee, the animal most closely correlated with man from a genetic point of view (only 0.6% genomic differences).
Everyone at birth receives a patrimony of resources which form a functional reserve and will be used during a lifetime: as demonstrated in many studies, this reserve is genetically programmed. Every man is subjected to an astronomical clock that beats its time in seconds, minutes, hours, but this clock is subordinate to a biological clock that, for every individual, begins to run after conception and differentiates time in development and successive impoverishment of the initial patrimony, not only of the organism, but also of its organs, tissues and cells, each and every one of them having a different biological age. The speed of the biological clock depends on the interaction between genetic patrimony and environment. An unfavourable interaction will lead to a premature death, while an optimal interaction will lead to natural death at 120 years. In this context we can define ageing as a complex cascade of processes which lead to the progressive reduction of the functional reserve of the entire organism, of the single organs and apparatuses. Longevity is obtained when ageing proceeds gradually, that is when the rate of reduction of the functional reserve is not too fast, avoiding the collapse of a function involving the entire organism4. Ageing processes, increasing the vulnerability of the old and the loss of adaptability, are the substrata for environmental factors: if we are not to waste our genetic patrimony we can make it so that our genes are expressed to the maximum of their potential diminishing the aggression of external risk factors. Excluding pathogenic noxae, external factors commonly considered capable of modifying the expression of the genetic program are: eating habits, smoking and drinking habits, physical activity and psychic factors.
2. Genes and Ageing
Thanks to the genome map sequenced by the Human Genome Project, a data bank will soon be available to facilitate the location and the study of those genes involved in the development and in the manifestation of the character of man, that is of normal (physiological) characters, of rare (variant) and of anomalous (pathological) characters. The somatic differences that can be observed between persons (phenotypic differences) are basically in relation to two genetic events that confer the so-called “genetic variability”: rare mutations, which are present in the population with a frequency <1%, and common mutations, which are present in the population with a frequency >1%, these last also called polymorphisms. Each and every one of us contains in his genoma both rare mutations and polymorphisms. While mutations, more recent from an evolutionistic point of view, are rare genetic variations responsible for important phenotypic changes as happens in “mendelian” diseases, the polymorphisms, much older from an evolutionistic point of view, are common genetic variations responsible for minor phenotypic changes (for example different blood types), which often mediate the interaction with the environmental factors. Polymorphisms are the genetic variations most often involved as risk factors in complex diseases. They are moreover involved in the phenomenon of ageing. For example the fact that there is a great variability in lifespan between healthy subjects of the same race living in the same geographic area, is due to the presence of polymorphisms, which can be defined as minor differences of the genetic equipment of everybody5,6.
Improvements in our genetic acquaintances will enable us to classify the genotype of all diseases and to find new metabolic ways involved in their pathogenesis. Knowing the genotype, the physician is enabled to prescribe a therapy aimed at the cause and not at physical characteristics. Moreover, understanding how common pathogenetic mechanisms can be involved in different diseases, a therapy developed for a single disease could be used in order to cure other diseases. One of the most interesting applications of knowing the genomic sequences is represented by pharmacogenomics. In a certain population, some persons are complete responders to a therapy, others are only modest or marginal responders, some are non-responders and some persons express adverse reactions. The variability of the clinical response to a particular drug is not only due to the physiological mechanisms of the drug and environmental factors, but above all to the genetic constitution of the single subject, which is responsible for more than 85% of the total variability, according to some authors. The genetic profile of an individual determines in fact the characteristics of the target of the drug as well as of the proteins involved in the process of its absorption and metabolism. The variation of a nucleotide of a single gene can result in a different structure and function of a certain protein and therefore in a modification of the metabolic pathway of the drug. Subjects with a particular genotype can be unable to metabolize a particular drug and may therefore present a greater risk of adverse reactions or interactions with other drugs, while other genes are in a position to determine a faster metabolization of some drugs, consequently reducing their efficacy.
Vincenzo Marigliano: Department of Sciences on Ageing, University of Rome ‘La Sapienza’.
1 Cicconetti, P., Riolo, N., Ettorre E. and Marigliano, V. (2003): “Evoluzione demografica: invecchiamento e fragilità”, Rec Prog. Med 2003, 94; 7-8: 309-313.
2 Marigliano, V. (2002): “Demografia dell’Invecchiamento”, in V. Marigliano, Argomenti di Geriatria, Ed. CESI, Roma.
3 Marigliano, V. et al. (2007):: “Invecchiamento e longevità”, Manuale Breve di Geriatria, Casa Editrice Universo.
5 Pilotto, A., Seripa, D., Dalla Piccola, B. et al. (2007): “La genetica in geriatria: da fattore di rischio alla farmacogenetica”, Geriatria; Suppl. XIX, Vol. 1.
6 Jazwinski, M. J. S. (1996): “Longevity, Genes, and Aging”, Science, Vol 273, 5 July.
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Tags: cronic diseases, Genes and aging, predictive medicine