Time filter

Source Type

Pani G.,University Cattolica Medical School
Seminars in Cell and Developmental Biology | Year: 2015

Dietary restriction (DR, in the form of reduced calorie intake or alternate fasting with overall normal energy supply) elicits cell protective responses in nearly all tissues and organs including brain, and extends lifespan in a fashion that is conserved from the simplest model organisms to mammals and non-human primates. Importantly, studies on DR promise to reveal novel strategies to prolong healthspan and prevent age-related disorders in human beings. The present review focuses on the neuroprotective actions of DR as demonstrated by accumulating experimental and encouraging albeit still limited clinical and epidemiological data. Following an overview of the most relevant evidence for the benefit of DR on neurodegenerative disorders and brain aging and damage in animals and human beings, the article will address the major mechanisms currently believed to participate in these effects, at a tissue (antiinflammation, enhanced adult neurogenesis and neuronal plasticity) and cellular (autophagy and mitochondrial biogenesis) level. Then it will "zoom-in" on the molecular circuitries (AMPK/mTOR, Sirtuins, CREB/Sirt1) whereby neuronal cells perceive the reduced availability of nutrients and translate this information into protective adaptive responses. As a further development of this aspect, the emerging connection between cell metabolism and chromatin remodeling will be analyzed, together with its relevance for our understanding of how food intake affects neuronal gene expression and brain health. © 2015 Elsevier Ltd. Source

Pani G.,University Cattolica Medical School
Aging | Year: 2010

Both Reactive Oxygen Species (ROS) and hyperactivation of the nutrient-sensing mTOR/S6 kinase cascade have been linked to aging and age-related diseases as well as to the anti-aging effect of calorie restriction. Recent findings that the pro-aging and pro-oxidant molecule p66shc contributes to S6K activation by nutrients and promotes insulin resistance and diabetes in mice may provide an answer to the "ROS or TOR?" dilemma. © Pani. Source

Fusco S.,University Cattolica Medical School | Fusco S.,San Raffaele Scientific Institute | Leone L.,University Cattolica Medical School | Barbati S.A.,University Cattolica Medical School | And 9 more authors.
Cell Reports | Year: 2016

Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis. Using a combination of in vitro and in vivo studies, Fusco et al. find that excess glucose impairs the self-renewal capacity of neural stem cells through a molecular circuit that involves the transcription factor CREB and Sirtuin 1. The authors suggest that this circuitry may link nutrient excess with neurodegeneration and brain aging. © 2016 The Authors. Source

Ranieri S.C.,University Cattolica Medical School | Fusco S.,University Cattolica Medical School | Panieri E.,University Cattolica Medical School | Labate V.,University Cattolica Medical School | And 8 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes. Source

Discover hidden collaborations