Protective effect of calorie restriction on age-induced fibrosis

Starting from research by McCay et al., several studies have demonstrated that controlled calorie restriction (CR) exerts an anti-ageing effect in different organisms, from invertebrates to mammals. Observational studies suggest that CR also has beneficial effects on human longevity. However, the anti-aging mechanisms of CR are still not clearly understood. One mechanism might be protection against the age-associated increase of oxidative stress and consequent cellular damage. In parallel, a role of oxidative stress in fibrosis induction and progression has been demonstrated in many human diseases, such as pneumoconiosis, interstitial pulmonary fibrosis, cystic fibrosis, cirrhosis, neurodegenerative diseases and atherosclerosis. In fibrosis, fibroblasts or fibroblast-like cells are activated by various cytokines, among which transforming growth factor beta1 (TGFbeta1) is prominent, to proliferate and produce high levels of extracellular matrix and collagen. High TGFbeta1 levels have been found in human diseases of different organs all characterized by excessive ECM deposition and marked fibrosis (cirrhosis, chronic hepatitis, glomerulonephritis, diabetic nephropathy, atherosclerosis, sclerodermia, pulmonary fibrosis). Fibrosis is also a constant distinctive feature in tissue aging. TGFbeta1 exerts its multiple biological activities through interaction with type I and type II receptors. Signaling to the nucleus is principally through cytoplasmic proteins of the Smad family, but in various cell types TGFbeta1 also activates mitogen activated protein kinase (MAPK) pathways, i.e. extracellular regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38, leading to collagen type I synthesis through activation of the transcription factor activator protein 1 (AP-1). In this context, it is of interest to study the possible protective effect of CR against the onset of fibrosis in the frame of tissue and soma aging. In this connection, our group has shown that, with aging, there is an increase of oxidative stress in rat aorta, with a progressive hoarding of biologically-active end-products, in particular 4-hydroxy-2,3-nonenal (HNE). Moreover, the increase of oxidative stress with aging is accompanied by increased fibrosis in terms of TGFbeta1 and collagen levels. CR protects against both phenomena. With regard to possible protective mechanisms of CR against fibrosclerosis, we believe they may be closely connected to the reduction of oxidative stress: by decreasing HNE levels in older rat aortae, CR significantly decreases JNK and p38 activity. Since JNK is central for AP-1 activation, by negatively modulating JNK, CR also prevents AP-1 activation and consequently down-regulates transcription of AP-1-dependent genes, including TGFbeta1, vimentin and collagen. The possibility of controlling the fibrogenesis process by modifying dietary habits opens new nutritional horizons in the prevention and treatment of several pathological processes characterized by excessive fibrosis. However, since it seems difficult to transpose animal CR model as such to man, interest in natural and/or pharmacological CR mimetic molecules is increasing.