An antisteatosis response regulated by oleic acid through lipid droplet-mediated ERAD enhancement.

Although excessive lipid accumulation is a hallmark of obesity-related pathologies, some lipids are beneficial. Oleic acid (OA), the most abundant monounsaturated fatty acid (FA), promotes health and longevity. Here, we show that OA benefits by activating the endoplasmic reticulum (ER)-resident transcription factor SKN-1A (Nrf1/NFE2L1) in a lipid homeostasis response.

Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.

Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5.

Agephagy - Adapting Autophagy for Health During Aging.

Autophagy is a major cellular recycling process that delivers cellular material and entire organelles to lysosomes for degradation, in a selective or non-selective manner. This process is essential for the maintenance of cellular energy levels, components, and metabolites, as well as the elimination of cellular molecular damage, thereby playing an important role in numerous cellular activities. An important function of autophagy is to enable survival under starvation conditions and other stresses.

A triple drug combination targeting components of the nutrient-sensing network maximizes longevity.

Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging.

Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling.

The groundbreaking discovery that lower levels of insulin/IGF-1 signaling (IIS) can induce lifespan extension was reported 24 years ago in the nematode Caenorhabditis elegans. In this organism, mutations in the insulin/IGF-1 receptor gene daf-2 or other genes in this pathway can double lifespan. Subsequent work has revealed that reduced IIS (rIIS) extends lifespan across diverse species, possibly including humans.

The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease.

Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in the gene. There is an established association between mutations and Parkinson's disease (PD), and indeed mutations are now considered to be the greatest genetic risk factor for PD. Impaired lysosomal-autophagic degradation of cellular proteins, including α-synuclein (α-syn), is implicated in the pathogenesis of PD, and there is increasing evidence for this also in GD and -PD.

Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease.

Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer's disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects.

Metformin: Restraining Nucleocytoplasmic Shuttling to Fight Cancer and Aging.

In this issue of Cell, Wu et al. employed C. elegans and human cell experiments to identify a pathway through which metformin increases lifespan and inhibits growth.

A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin.

Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD.

Mitochondrial dysfunction and defects in lipid homeostasis as therapeutic targets in neurodegeneration with brain iron accumulation.

The PLA2G6 gene encodes a group VIA calcium independent phospholipase A2 (iPLA2β), which hydrolyses glycerophospholipids to release fatty acids and lysophospholipids. Mutations in PLA2G6 are associated with a number of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), infantile neuroaxonal dystrophy (INAD), and dystonia parkinsonism, collectively known as PLA2G6-associated neurodegeneration (PLAN). Recently Kinghorn et al.

Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis.

The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life.

Genetics and pharmacology of longevity: the road to therapeutics for healthy aging.

Aging can be defined as the progressive decline in tissue and organismal function and the ability to respond to stress that occurs in association with homeostatic failure and the accumulation of molecular damage. Aging is the biggest risk factor for human disease and results in a wide range of aging pathologies. Although we do not completely understand the underlying molecular basis that drives the aging process, we have gained exceptional insights into the plasticity of life span and healthspan from the use of model organisms such as the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster.

Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction.

The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism.

[Molecular gerontology: towards healthy aging].

For many years aging research was confined to statistics, psychology, and socioeconomic aspects of old age. However, today the study of aging is one of the most attractive and prosperous fields in biology. This change followed on from observations that single gene mutations can modulate the aging process, demonstrating the dynamic and plastic nature of the pathways involved.

From white to brown fat through the PGC-1α-dependent myokine irisin: implications for diabetes and obesity.

Summary and comment on a recent paper entitled ‘A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis’ (Boström et al., 2012).

Parkin' control: regulation of PGC-1α through PARIS in Parkinson's disease.

Summary and comment on a recent paper entitled ‘PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease’ (Shin et al., 2011).

[Depression and diabetes: from epidemiology to neurobiology].

Introduction: Worldwide, diabetes mellitus and depression are among the most prevalent diseases in their respective fields, metabolism and psychiatry. However, there is evidence that patients with diabetes are at increased risk of developing depression, although a bidirectional relationship might also exist.

Aim: To present a comprehensive review of the clinical, epidemiological, psychosocial, emotional, and neurobiological basis of the relation between diabetes and depression.

[Alzheimer's disease and methylenetetrahydrofolate reductase gene polymorphisms: a potential nutrigenomic approach for Mexico].

The establishment of medical genomics in Mexico offers the possibility to study in a more comprehensive manner the etiological factors of different diseases, providing a global view of the interaction between the genome and the environment. Nutrition is recognized as a significant determinant in several diseases, yet its interaction with polymorphisms, and in general with the genome, has not been properly addressed Mexico has a high prevalence of polymorphisms of the methylenetetrahydrofolate reductase gene, and in both clinical and basic studies this has been associated with an increased susceptibility of developing Alzheimer's disease. We propose a potential nutrigenomic approach for the study of Alzheimer disease in Mexico.

[Nutritional genomics: an approach to the genome-environment interaction].

Nutritional genomics forms part of the genomic sciences and addresses the interaction between genes and the human diet, its influence on metabolism and subsequent susceptibility to develop common diseases. It encompasses both nutrigenomics, which explores the effects of nutrients on the genome, proteome and metabolome; and nutrigenetics, that explores the effects of genetic variations on the diet/disease interaction. A number of mechanisms drive the gene/diet interaction: elements in the diet can act as links for transcription factor receptors and after intermediary concentrations, thereby modifying chromatin and impacting genetic regulation; affect signal pathways, regulating phosphorylation of tyrosine in receptors; decrease signaling through the inositol pathway; and act through epigenetic mechanisms, silencing DNA fragments by methylation of cytosine.