Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in , encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling.

Dietary Protein, Metabolism, and Aging.

Dietary restriction (DR), a moderate reduction in food intake, improves health during aging and extends life span across multiple species. Specific nutrients, rather than overall calories, mediate the effects of DR, with protein and specific amino acids (AAs) playing a key role. Modulations of single dietary AAs affect traits including growth, reproduction, physiology, health, and longevity in animals.

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.

Inactivation of class II PI3K-C2α induces leptin resistance, age-dependent insulin resistance and obesity in male mice.

Aims/hypothesis: While the class I phosphoinositide 3-kinases (PI3Ks) are well-documented positive regulators of metabolism, the involvement of class II PI3K isoforms (PI3K-C2α, -C2β and -C2γ) in metabolic regulation is just emerging. Organismal inactivation of PI3K-C2β increases insulin signalling and sensitivity, whereas PI3K-C2γ inactivation has a negative metabolic impact. In contrast, the role of PI3K-C2α in organismal metabolism remains unexplored.

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.

The aging-disease false dichotomy: understanding senescence as pathology.

From a biological perspective aging (senescence) appears to be a form of complex disease syndrome, though this is not the traditional view. This essay aims to foster a realistic understanding of aging by scrutinizing ideas old and new. The conceptual division between aging-related diseases and an underlying, non-pathological aging process underpins various erroneous traditional ideas about aging.

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.

QuantiFly: Robust Trainable Software for Automated Drosophila Egg Counting.

We report the development and testing of software called QuantiFly: an automated tool to quantify Drosophila egg laying. Many laboratories count Drosophila eggs as a marker of fitness. The existing method requires laboratory researchers to count eggs manually while looking down a microscope.

Promoting health and longevity through diet: from model organisms to humans.

Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles.

Comparison of the mammalian insulin signalling pathway to invertebrates in the context of FOXO-mediated ageing.

Motivation: A large number of experimental studies on ageing focus on the effects of genetic perturbations of the insulin/insulin-like growth factor signalling pathway (IIS) on lifespan. Short-lived invertebrate laboratory model organisms are extensively used to quickly identify ageing-related genes and pathways. It is important to extrapolate this knowledge to longer lived mammalian organisms, such as mouse and eventually human, where such analyses are difficult or impossible to perform.

Dietary restriction extends lifespan in wild-derived populations of Drosophila melanogaster.

Dietary restriction (DR) can result in lifespan-extension and improved function and health during ageing. Although the impact of DR on lifespan and health has been established in a variety of organisms, most DR experiments are carried out on laboratory strains that have often undergone adaptation to laboratory conditions. The effect of DR on animals recently derived from wild populations is rarely assessed.

Long-term p110α PI3K inactivation exerts a beneficial effect on metabolism.

The insulin/insulin-like growth factor-1 signalling (IIS) pathway regulates cellular and organismal metabolism and controls the rate of aging. Gain-of-function mutations in p110α, the principal mammalian IIS-responsive isoform of PI 3-kinase (PI3K), promote cancer. In contrast, loss-of-function mutations in p110α impair insulin signalling and cause insulin resistance, inducing a pre-diabetic state.

Genetics of longevity in model organisms: debates and paradigm shifts.

Discovering the biological basis of aging is one of the greatest remaining challenges for science. Work on the biology of aging has discovered a range of interventions and pathways that control aging rate. A picture is emerging of a signaling network that is sensitive to nutritional status and that controls growth, stress resistance, and aging.

Alternative Perspectives on Aging in Caenorhabditis elegans: Reactive Oxygen Species or Hyperfunction?

Significance: The biological mechanisms at the heart of the aging process are a long-standing mystery. An influential theory has it that aging is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair, and turnover) protect against aging and increase lifespan.

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).

Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila.

Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C.

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).

Treating aging: progress toward dietary restriction mimetics.

During the last decade, biogerontologists have labored to understand the biological basis of the aging process by studying the genes and signaling pathways that regulate it. But the last year has seen a breakthrough in a different direction: toward treatments that might slow aging by mimicking the effects of dietary restriction.

Stress-response hormesis and aging: "that which does not kill us makes us stronger".

Hormesis refers to the beneficial effects of a treatment that at a higher intensity is harmful. In one form of hormesis, sublethal exposure to stressors induces a response that results in stress resistance. The principle of stress-response hormesis is increasingly finding application in studies of aging, where hormetic increases in life span have been seen in several animal models.