L Castello

Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation

The free radical theory of aging is currently one of the most popular. In parallel, many studies have demonstrated the association of fibrosis and increased oxidative stress in the pathogenesis of some chronic human diseases, and fibrosis is often characteristic of aging tissues. One of the few interventions that effectively slow aging is calorie restriction and the protection against the age-associated increase of oxidative stress remains one of the foremost hypotheses to explain this action. As an alternative to traditional calorie restriction, another dietary regimen, termed alternate-day fasting, has also been tested, whose antiaging mechanisms have not been explored so much extensively. We thus studied the effects of alternate-day fasting, started at 2 months of age, on oxidative stress and fibrosis in the heart during aging. In the left ventricle of the heart of elderly (aged 24 months) versus young (aged 6 months) male rats we found a significant increase in oxidative stress paralleled by increased fibrosis. In parallel there was a significant increase in inflammatory cytokine levels and in NF-kB DNA binding activity with advancing age. Alternate-day fasting protected against all these age-related phenomena. These data support the hypothesis that this kind of dietary restriction protects against age-related fibrosis, at least in part by reducing inflammation and oxidative damage, and this protection can thus be considered a factor in the prevention of age-related diseases with sclerotic evolution.

Calorie restriction protects against age-related rat aorta sclerosis

Many theories have been advanced to account for the ageing process, among which the free radical theory deserves much attention. Numerous studies have also shown an association between tissue fibrosis and oxidative stress. Of note, fibrosis may be considered a significant index of tissue ageing. Calorie restriction (CR) has been demonstrated to maintain many physiological processes in a youthful state until a very advanced age. However the anti‐ageing mechanisms of CR are still not fully understood. We thus evaluated the effect of CR on oxidative damage and its relationship with fibrosis during ageing. We found a significant increase of both oxidative stress and fibrosis parameters in the aortae from aged vs. young rats. CR reversed both phenomena. CR also protected against the age‐associated increase of Jun‐N‐terminal kinase and p‐38 activities, involved in TGFβ1 expression and signaling. On the contrary, extracellular regulated kinases did not show any age‐related change. CR similarly reversed the age‐related increase of AP‐1 DNA binding activity and the AP‐1‐dependent increase of vimentin gene expression. In parallel, CR reversed the age‐related morphological alterations of the aorta wall cell composition. These data further support the relationship between oxidative stress and fibrosis in different diseases and during ageing. The protection exerted by CR against fibrosclerosis might be due to a decrease of oxidative stress, with consequent decreased MAPK activity and down‐regulation of AP‐1 activation and of TGFβ1 expression and signaling.

Alternate-day fasting reverses the age-associated hypertrophy phenotype in rat heart by influencing the ERK and PI3K signaling pathways

The age-related increased impedance in large arteries overloads the senescent heart, and the myocardial phenotype is hypertrophic. Together with qualitative changes observed in the senile heart, this can be responsible for impaired diastolic function. A restricted diet providing adequate nutrient intake, e.g. alternate-day fasting (ADF), has been shown to extend life-span and decrease incidence and progression of age-associated diseases in laboratory rodents, and to ameliorate some metabolic markers of aging in rhesus monkeys and humans. This study reports an age-related increase of some biological and morphological hypertrophy markers in the rat heart, together with increased plasma BNP, a well known marker of heart failure. The tissue modifications might likely be related to hyper-activation of two of the signaling pathways associated with myocardial pathological hypertrophy: ERK1/2 and PI3Kγ. Increased ERK1/2 activation might be in part related to the disturbance of STAT3, with a consequent decrease of SOCS3. In this context, the down-modulation of ERK1/2 and PI3Kγ signaling, together with the restoration of STAT3 activity and SOCS3 content, both observed with ADF, might help to reduce pathological hypertrophy stimuli and to rescue an important cardioprotective pathway, possibly opening new preventive and therapeutic perspectives in age-related heart failure.