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Randomized controlled trial of metformin and dietary restriction to prevent age-related morbid events in people with metabolic syndrome

Objective

Age–related chronic diseases (ArCD) are complex non-linear processes that depends on a large number of interconnected genetic and metabolic pathways which should be tackled with a many faceted preventive strategy. Calorie-dense diet and sedentary lifestyle are responsible of the growing prevalence of metabolic syndrome (MetS), which, together with tobacco, is the major preventable cause of ArCD, mediated by the increased availability of insulin, growth factors, and inflammatory cytokines. In animals, calorie restriction (CR) is the most potent dietary intervention for preventing ArCD and prolonging life. In humans, we and others have shown that a sustainable CR, resulting in decreased prevalence of MetS, can be obtained through a comprehensive change in dietary habits, reducing animal food and refined carbohydrates, and increasing whole grain cereal products, legumes and vegetables, according to the Mediterranean and macrobiotic diet principles. Metformin (MET), an antidiabetic drug associated with decreased cancer incidence, activates the same gene pathways activated by CR, including AMPK/TSC, which reduces energy consuming processes, and cell proliferation (through the inhibition of mTOR). We propose a placebo controlled randomised trial to test whether treatment with MET, with or without associated CR, reduces the incidence of major chronic diseases, such as cancer, myocardial infarction, stroke, and diabetes. We estimated that randomizing 2,000 women and men aged 55-74 at high risk of developing ArCD because of MetS, shall provide over 90% power (at alpha = 0.05) to detect a significant 25 to 33% reduction of ArCD incidence in 5 years. In a subsample of the cohort we shall study the genetic and epigenetic mechanisms of the preventive action of metformin and CR.

Field of science

  • /medical and health sciences/basic medicine/neurology/stroke
  • /natural sciences/biological sciences/biochemistry/biomolecules/carbohydrates
  • /medical and health sciences/clinical medicine/endocrinology/diabetes
  • /agricultural sciences/agriculture, forestry, and fisheries/agriculture/horticulture/root crop
  • /medical and health sciences/clinical medicine/oncology/cancer

Call for proposal

ERC-2012-ADG_20120314
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Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI
Address
Via Venezian 1
20133 Milan
Italy
Activity type
Research Organisations
EU contribution
€ 2 499 999,60
Principal investigator
Franco Berrino (Dr.)
Administrative Contact
Antonio Cannarozzo (Dr.)

Beneficiaries (1)

FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI
Italy
EU contribution
€ 2 499 999,60
Address
Via Venezian 1
20133 Milan
Activity type
Research Organisations
Principal investigator
Franco Berrino (Dr.)
Administrative Contact
Antonio Cannarozzo (Dr.)