Project summary / objectives

Project summary

A hallmark of cellular ageing is the increase in the oxidatively modified proteins. Oxidative damage in lymphocytes is critical given the importance of the immune system for maintaining good health and for successful ageing.

Some antioxidant micronutrients in the diet, such as zinc, control the development and function of the immune cells, the activity of stress-related proteins [metallothioneins, chaperones, ApoJ, PARP-1, NO, MsrA] and antioxidant enzyme (SOD) and help to maintain genomic integrity and stability, reflecting diet-gene interactions.

During ageing, the intake of zinc decreases due to inadequate diet or/and intestinal malabsorption, contributing to frailty, general disability and increased incidence of age-related degenerative diseases (cancer, infections and atherosclerosis). No focused research has been performed thus far to clarify the intrinsic biochemical mechanisms and the impact of nutrient zinc on the genome during immunosenescence.

The consortium will therefore study the role of zinc in the gene expression and functions of metallothioneins, chaperones, NO, MsrA, ApoJ, telomerase, PARP-1 and DNA-repair as a function of immunosenescence in lymphocytes from old subjects including nonagenarians, as well as in ill old patients affected by age-related diseases and in T-cell clones as in vitro model. Particular attention will be paid to the processing of oxidised proteins by proteasome, which decreases in ageing.

The activity of all proteins herein studied is impaired in ageing and this is directly and indirectly controlled by zinc ion bioavailability (Figure). The zinc deficiency in the elderly will be evaluated through the screening of polymorphic allele frequency of proteins involved in zinc ion metabolism and their relationships to gender. The results will form a rationale for the promotion of healthy ageing through a zinc supplementation.

Project objectives

1) To establish a comprehensive picture of the links between metallothioneins (MTs), chaperones, nitric oxide, telomere length, cell cycle kinetics, ApoJ, PARP-1 activity, signal transduction and DNA repair in lymphocytes from old and nonagenarian subjects, thus providing potential novel biomarkers for immunosenescence and successful ageing, respectively.

A total of about 800 old subjects (age range 65-85 yrs.) belonging to five European geographic areas (Germany, Poland, Greece, Italy, France) will be screened for the genotype of zinc dependent genes, representing the worst possible situation where zinc turnover is lost or badly distributed. In this population, possible reconstitution with zinc supplementation will be carried out.

2) To establish the mechanistic basis of the interrelationships among MTs, chaperones, nitric oxide, telomere length, cell cycle kinetics, ApoJ, PARP-1 activity, signal transduction and DNA repair (see Fig.1). At the same time, the role played by the proteasome system in eliminating harmful related stress proteins whose accumulation within the cytosol is dangerous, will be carefully examined as well as the function of peptide methionine sulfoxide reductases. As a result, those critical steps might be identified where major defects occur.

This would form a rational basis for intervention aimed at retarding the ageing process of the immune system and the development of some age-related diseases (e.g. cancer, infections and atherosclerosis) through the zinc supplementation in genetic zinc deficiency individuals.

The comparison with nonagenarians (about 120) and with ill old patients (about 120) will permit to identify the precise role played by the zinc metabolism in immunosenescence and in healthy ageing, including cognitive performances, between Northern and Southern European countries because the life expectation is longer in these latter due to major zinc content in the Mediterranean diet.