The orexigenic hormone acyl-ghrelin increases adult hippocampal neurogenesis and enhances pattern separation

The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies1,2. Its mammalian homologue, SIRT1, appears to have evolved complex systemic roles in cardiac function, DNA repair, and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 plays a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, while its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of CREB expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the down-regulated expression of CREB and BDNF, thereby impairing synaptic plasticity. These findings demonstrate a novel role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signaling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of CNS disorders.

To evaluate any association between obesity in middle age, measured by body mass index and skinfold thickness, and risk of dementia later in life. Analysis of prospective data from a multiethnic population based cohort. Kaiser Permanente Northern California Medical Group, a healthcare delivery organisation. 10,276 men and women who underwent detailed health evaluations from 1964 to 1973 when they were aged 40-45 and who were still members of the health plan in 1994. Diagnosis of dementia from January 1994 to April 2003. Time to diagnosis was analysed with Cox proportional hazard models adjusted for age, sex, race, education, smoking, alcohol use, marital status, diabetes, hypertension, hyperlipidaemia, stroke, and ischaemic heart disease. Dementia was diagnosed in 713 (6.9%) participants. Obese people (body mass index > or = 30) had a 74% increased risk of dementia (hazard ratio 1.74, 95% confidence interval 1.34 to 2.26), while overweight people (body mass index 25.0-29.9) had a 35% greater risk of dementia (1.35, 1.14 to 1.60) compared with those of normal weight (body mass index 18.6-24.9). Compared with those in the lowest fifth, men and women in the highest fifth of the distribution of subscapular or tricep skinfold thickness had a 72% and 59% greater risk of dementia, respectively (1.72, 1.36 to 2.18, and 1.59, 1.24 to 2.04). Obesity in middle age increases the risk of future dementia independently of comorbid conditions.

Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.