Aging-related expression of membrane transporters in rat – AGEMETAR

Duration: 1 Oct 2014-31 Mar 2019

ABSTRACT
Aging is a physiological process characterized by a gradual decline in physical fitness and other functional capabilities. The mechanisms of aging and possible actions of slowing down or ameliorating aging-related processes are poorly understood. In humans, one of the characteristics of old age is polypharmacy, which elevates risks of drug-drug interactions and drug-induced adverse reactions and organ toxicity, such as hepatotoxicity and nephrotoxicity. These reactions may partially result from diminished drug metabolism and/or mainly from impaired activity/expression of various membrane transporters that are responsible for drug excretion in liver and kidneys. These both mechanisms have been poorly studied in senescent organs. Here we promote a hypothesis that the aging-induced oxidative stress, known to downregulate the activity/expression of the aging suppressor gene (Klotho) and to shorten the length of telomeres, also diminishes the activity/expression of various membrane transporters in liver and kidneys, and that these changes can be ameliorated by treating animals with antioxidants resveratrol and melatonin. The extent and the intensity of aging-related changes, and the beneficial effects of antioxidants may be sex-related. To test this hypothesis, we propose various biochemical and cell- and molecular-biological studies of aging parameters and aging-dependent expression of various membrane transporters in the mammalian liver and kidneys using a rat model of experimental aging. Possible aging-related decline in the expression of these transporters may explain a higher incidence (women > man) of drug interactions and toxicity in old people. The studies will define the underlying cellular mechanisms that contribute to generation of the aging-related pathophysiological conditions in the liver and kidneys, and will indicate possible ways of their amelioration. Positive results may point to remedies to be used for improving the health of elderly people.

PROJECT LEADERS:

• Ivan Sabolić, MD, PhD; Head of  Molecular Toxicology Unit
• Davorka Breljak, PhD; Head of Molecular Toxicology Unit (from 1 Oct 2015)

Animal Breeding Unit: Vedran Micek, DVM, PhD student

Analytical Toxicology and Mineral Metabolism Unit: Jasna Jurasović, chemist, PhD; Tatjana Orct, chemist, PhD

Toxicology Unit: Maja Peraica, MD, PhD; Dubravka Rašić, biologist and chemist, PhD; Ivana Novak Jovanović, food technologist, PhD

Mutagenesis Unit: Goran Gajski, molecular biologist, PhD; Marko Gerić, experimental biologist, PhD student

Laboratory for Molecular and Cellular Biology (IRB): Ivica Rubelj, molecular biologist, PhD; Lucija Nanić, molecular biologist, PhD student