Physiological tissue-specific and age-related reduction of mouse TDP-43 levels is regulated by epigenetic modifications.

The cellular level of TDP-43 (also known as TARDBP) is tightly regulated; increases or decreases in TDP-43 have deleterious effects in cells. The predominant mechanism responsible for the regulation of the level of TDP-43 is an autoregulatory negative feedback loop. In this study, we identified an in vivo cause-effect relationship between Tardbp gene promoter methylation and specific histone modification and the TDP-43 level in tissues of mice at two different ages. Furthermore, epigenetic control was observed in mouse and human cultured cell lines. In amyotrophic lateral sclerosis, the formation of TDP-43-containing brain inclusions removes functional protein from the system. This phenomenon is continuous but compensated by newly synthesized protein. The balance between sequestration and new synthesis might become critical with ageing, if accompanied by an epigenetic modification-regulated decrease in newly synthesized TDP-43. Sequestration by aggregates would then decrease the amount of functional TDP-43 to a level lower than those needed by the cell and thereby trigger the onset of symptoms.

Sirtuins and resveratrol-derived compounds: a model for understanding the beneficial effects of the Mediterranean diet.

The beneficial effects of the Mediterranean diet (MD) had been first observed about 50 years ago. Consumption of fresh vegetables and fruits, cereals, red wine, nuts, legumes, etc. has been regarded as the primary factor for protection from many human pathologies by the Mediterranean diet. Subsequently, this was attributed to the presence of polyphenols and their derivatives that, by exerting an anti-inflammatory and anti-oxidative effect, can be involved in the prevention of many diseases. Clinical trials, observational studies and meta-analysis have demonstrated an antiageing effect of MD accompanied by a reduced risk of age-related pathologies, such as cardiovascular, metabolic and neurodegenerative diseases, as well as cancer. The scientific explanation of such beneficial effects was limited to the reduction of the oxidative stress by compounds present in the MD. However, recently, this view is changing thanks to new studies aimed to uncover the molecular mechanism(s) activated by components of this diet. In particular, a new class of proteins called sirtuins have gained the attention of the scientific community because of their antiageing effects, their ability to protect from cardiovascular, metabolic, neurodegenerative diseases, cancer and to extend lifespan in lower organisms as well as in mammals. Interestingly, resveratrol a polyphenol present in grapes, nuts and berries has been shown to activate sirtuins and such activation is able to explain most of the beneficial effects of the MD. In this review, we will highlight the importance of MD with particular attention to the possible molecular pathways that have been shown to be influenced by it. We will describe the state of the art leading to demonstrate the important role of sirtuins as principal intracellular mediators of the beneficial effects of the MD. Finally, we will also introduce how Mediterranean diet may influence microbioma composition and stem cells function.