Associations have been reported between plasma Cu and Zn levels and the incidence of the most important age-related diseases. Previously proposed methods of using plasma Cu/Zn as a predictor of all-cause mortality have been derived from populations in which old and very old subjects were underrepresented. The purpose of this paper is to estimate the usefulness of plasma Cu/Zn as a sensitive biomarker of harmful inflammatory or nutritional changes in the elderly and its incremental prognostic utility as a predictor of all-cause mortality in a functionally independent elderly Italian cohort. The association between plasma Cu/Zn and inflammatory (CRP, ESR, IL-6) or nutritional (albumin, BMI) markers was studied in 498 elderly subjects. Blood samples were taken from 164 healthy 20- to 60-year-old volunteer controls. A 3.5 years prospective follow-up study of mortality by age-related diseases was performed in n = 218 over 70-year-olds. Plasma Cu/Zn ratio was associated with all the inflammatory markers studied, as well as with serum albumin, and predicted 3.5 years mortality in subjects over 70. Plasma Cu/Zn was higher in women than men and increased with advancing age. Subjects with stable cardiovascular disease (CVD) displayed higher plasma Cu/Zn than those without, due mainly to increased plasma Cu. However, most of the age-related changes of Cu/Zn resulted from a progressive decline of plasma Zn. Cu/Zn ratio may be considered an important clinical inflammatory-nutritional biomarker as well as a significant predictor of all-cause mortality in over 70-year-olds.

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Vascular complications, including ischaemic cardiomyopathy, are the major causes of death in old diabetic patients. Chronic inflammation due to high IL-6 production occurs in type 2 diabetes (NIDDM) and atherosclerosis. High levels of IL-6 are associated with hyperglycaemia, dyslipidemia and provoke insulin resistance. In ageing and inflammation, IL-6 affects Metallothionein (MT) homeostasis, which in turn is involved in zinc turnover. Zinc deficiency is an usual event in ageing, inflammation, type 2 diabetes and atherosclerosis. No genetic study exists on MT polymorphisms in NIDDM-atherosclerotic patients. The aim of the present study is to screen a single nucleotide polymorphism in the promoter region of the MT2A gene in relation to inflammation (IL-6) and plasma zinc in NIDDM-atherosclerotic patients. The -209 A/G MT2A polymorphism is associated with chronic inflammation (higher plasma levels of IL-6), hyperglycaemia, enhanced HbA1c and more marked zinc deficiency in AA than AG genotype carrying patients. Analysing patients and controls subdivided in AA and AG genotypes, significant interactions existed between disease status and genotypes for glucose and zinc. AA patients are more at risk of developing NIDDM in association with atherosclerosis (p=0.0015 odds ratio=2.617) and its complications, such as ischaemic cardiomyopathy (p=0.0050 odds ratio=12.6). In conclusion, high levels of IL-6 unmask the phenotypes (higher insulin resistance and zinc deficiency) in relation to the genotypes with subsequent risk of developing ischaemic cardiomyopathy in NIDDM-atherosclerotic patients carrying AA genotype. Hence, the novel -209A/G MT2A polymorphism may be a further useful tool for the prevention, diagnosis and therapy of these combined pathologies in the elderly.

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