Still Living Better through Chemistry: An Update on Caloric Restriction and Caloric Restriction Mimetics as Tools to Promote Health and Lifespan.

Caloric restriction (CR), the reduction of caloric intake without inducing malnutrition, is the most reproducible method of extending health and lifespan across numerous organisms, including humans. However, with nearly one-third of the world's population overweight, it is obvious that caloric restriction approaches are difficult for individuals to achieve. Therefore, identifying compounds that mimic CR is desirable to promote longer, healthier lifespans without the rigors of restricting diet. Many compounds, such as rapamycin (and its derivatives), metformin, or other naturally occurring products in our diets (nutraceuticals), induce CR-like states in laboratory models. An alternative to CR is the removal of specific elements (such as individual amino acids) from the diet. Despite our increasing knowledge of the multitude of CR approaches and CR mimetics, the extent to which these strategies overlap mechanistically remains unclear. Here we provide an update of CR and CR mimetic research, summarizing mechanisms by which these strategies influence genome function required to treat age-related pathologies and identify the molecular fountain of youth.

Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function.

Hearts utilize fatty acids as a primary source of energy. The sources of those lipids include free fatty acids and lipoprotein triglycerides. Deletion of the primary triglyceride-hydrolyzing enzyme lipoprotein lipase (LPL) leads to cardiac dysfunction. Whether heart LPL-knockout (hLPL0) mice are compromised due a deficiency in energetic substrates is unknown. To test whether alternative sources of energy will prevent cardiac dysfunction in hLPL0 mice, two different models were used to supply nonlipid energy. 1) hLPL0 mice were crossed with mice transgenically expressing GLUT1 in cardiomyocytes to increase glucose uptake into the heart; this cross-corrected cardiac dysfunction, reduced cardiac hypertrophy, and increased myocardial ATP. 2) Mice were randomly assigned to a sedentary or training group (swimming) at 3 mo of age, which leads to increased skeletal muscle production of lactate. hLPL0 mice had greater expression of the lactate transporter monocarboxylate transporter-1 (MCT-1) and increased cardiac lactate uptake. Compared with hearts from sedentary hLPL0 mice, hearts from trained hLPL0 mice had adaptive hypertrophy and improved cardiac function. We conclude that defective energy intake and not the reduced uptake of fat-soluble vitamins or cholesterol is responsible for cardiac dysfunction in hLPL0 mice. In addition, our studies suggest that adaptations in cardiac metabolism contribute to the beneficial effects of exercise on the myocardium of patients with heart failure.

Functional Analysis of an Acyltransferase-Like Domain from Polyunsaturated Fatty Acid Synthase in Thraustochytrium.

Biosynthesis of very long chain polyunsaturated fatty acids (VLCPUFA) such as docosahexaenoic acid (DHA, 22:6-4,7,10,13,16,19) and docosapentaenoic acid (DPA, 22:5-4,7,10,13,16) in protist Thraustochytrium is catalyzed by a polyunsaturated fatty acids (PUFA) synthase comprising three large subunits, each with multiple catalytic domains. This study used complementation test, in vitro assays, and functional expression to characterize an acyltransferase (AT)-like domain in Subunit-B of a PUFA synthase from Thraustochytrium. Complementation test in Escherichia coli showed that the AT-like domain could not restore the growth phenotype of a temperature-sensitive mutant (∆fabDts) defective in malonyl-CoA:ACP transacylase activity. In vitro assays showed that the AT-like domain possessed thioesterase activity towards a few acyl-CoAs tested where docosahexaenoyl-CoA (DHA-CoA) was the preferred substrate. Expression of this domain in an E. coli mutant (∆fadD) defective in acyl-CoA synthetase activity resulted in the increased accumulation of free fatty acids. Site-directed mutagenesis showed that the substitution of two putative active site residues, serine at 96 (S96) and histidine at 220 (H220), in the AT-like domain significantly reduced its activity towards DHA-CoA and accumulation of free fatty acids in the ∆fadD mutant. These results indicate that the AT-like domain of the PUFA synthase does not function as a malonyl-CoA:ACP transacylase, rather it functions as a thioesterase. It might catalyze the last step of the VLCPUFA biosynthesis by releasing freshly synthesized VLCPUFAs attached to ACP domains of the PUFA synthase in Thraustochytrium.

Haskap Berry Phenolic Subclasses Differentially Impact Cellular Stress Sensing in Primary and Immortalized Dermal Fibroblasts.

It is generally accepted that dietary phenolics from fruits are of significant importance to human health. Unfortunately, there is minimal published data on how differences in phenolic structure(s) impact biological pathways at cellular and molecular levels. We observed that haskap berry extracts isolated with ethanol:formic acid:water or phenolic subclass fractions separated using different concentrations of ethanol (40% and 100%) impacted cell growth in a positive manner. All fractions and extracts significantly increased population doubling times. All extracts and fractions reduced intracellular free radicals; however, there were differences in these effects, indicating different abilities to scavenge free radicals. The extracts and fractions also exhibited differing impacts on transcripts encoding the antioxidant enzymes (CAT, SOD1, GPX1, GSS and HMOX1) and the phosphorylation state of nuclear factor-κB (NF-κB). We further observed that extracts and fractions containing different phenolic structures had divergent impacts on the mammalian target of rapamycin (mTOR) and sirtuin 1 (SIRT1). siRNA-mediated knockdown of SIRT1 transcripts demonstrated that this enzyme is key to eliciting haskap phenolic(s) impact on cells. We postulate that phenolic synergism is of significant importance when evaluating their dietary impact.

The Nuclear Lamina: Protein Accumulation and Disease.

Cellular health is reliant on proteostasis-the maintenance of protein levels regulated through multiple pathways modulating protein synthesis, degradation and clearance. Loss of proteostasis results in serious disease and is associated with aging. One proteinaceous structure underlying the nuclear envelope-the nuclear lamina-coordinates essential processes including DNA repair, genome organization and epigenetic and transcriptional regulation. Loss of proteostasis within the nuclear lamina results in the accumulation of proteins, disrupting these essential functions, either via direct interactions of protein aggregates within the lamina or by altering systems that maintain lamina structure. Here we discuss the links between proteostasis and disease of the nuclear lamina, as well as how manipulating specific proteostatic pathways involved in protein clearance could improve cellular health and prevent/reverse disease.

Evaluación cefalométrica y electromiográfica de niños y niñas con incompetencia labial y anomalías dentomaxilares / Cephalometric and electromyographic evaluation in children with lip incompetence and dentomaxillary anomalies

Objetivo: Describir las características craneofaciales, dentoalveolares, de tejido blando, vía aérea y el patrón de actividad muscular determinadas a través de los estudios cefalométricos y electromiográficos de individuos incompetentes labiales y con presencia de anomalías dentomaxilares de 7 a 12 años de edad. Materiales y método: Cuarenta y seis participantes con incompetencia labial fueron sometidos a una toma de radiografía lateral de perfil para el análisis cefalométrico. Para el estudio electromiográfico se consideró el patrón de actividad de los músculos Orbicular superior de los labios, orbicular inferior de los labios y temporal anterior en funciones: reposo, fonoarticulación, deglución, máximo apriete labial. Resultados: Se observó clase II esqueletal y molar, retrusión mandibular, biprotrusión incisal, biprotrusión labial, disminución de vía aérea superior. La mayor actividad muscular fue observada en máximo apriete labial. Conclusión: Los niños y niñas con incompetencia labial y anomalías dentomaxilares presentan alteraciones en las características craneofaciales, dentoalveolares, de tejido blando, vía aérea y actividad muscular determinadas a través de los estudios cefalométricos y electromiográficos.

Objective: To describe craniofacial, dentoalveolar, soft issue and airway features, and the muscular activity, determined through a cephalometric and electromyographic study in individuals with lip incompetence and dentomaxillary anomalies aged 7 to 12 years. Methods: Forty-six participants with lip incompetence underwent lateral profile radiography for cephalometric analysis. For the electromyographic study, the activity of the superior orbicularis oris, inferior orbicularis oris and anterior temporalis muscles was considered in the following functions: rest, speaking, swallowing, and reciprocal compression of the lips. Results: Skeletal and molar class II, mandibular retrusion, labial biprotrusion, incisal biprotrusion, and upper airway dysfunction were found. The highest muscular activity was observed in reciprocal compression of the lips. Conclusion: Children with lip incompetence and dentomaxillary anomalies have alterations in the craniofacial, dentoalveolar, soft issue, and airway features, and in the muscular activity , determined through a cephalometric and electromyographic study.

Hydroxyurea-associated squamous dysplasia.

We report 2 cases of squamous dysplasia associated with long-term hydroxyurea therapy. The association between hydroxyurea and multiple aggressive squamous cell carcinomas, Bowen's disease, and multiple actinic keratoses in sun-exposed areas after a variable latency period has been increasingly reported. On reviewing the literature, 17 cases were identified and are reviewed, with emphasis on possible pathogenetic mechanisms of carcinogenicity. Squamous dysplasia, a precursor state to a more aggressive condition of multiple squamous cell carcinomas in photoexposed areas, should be added to the well-known cutaneous toxicities of hydroxyurea therapy.

Development of pemphigus herpetiformis in a patient with psoriasis receiving UV-light treatment.

BACKGROUND: Pemphigus is an autoimmune blistering disease of the skin and mucous membranes. Pemphigus herpetiformis, a rare variant of pemphigus, is characterized by erythematous, vesicular, bullous, or papular lesions in a herpetiform pattern, often associated with pruritus. Clinical cases documenting the development of pemphigus in patients with a history of psoriasis have been reported in the literature. METHODS: We used immunological methods to study a case in which pemphigus herpetiformis occurred in a woman with a history of psoriasis, shortly after a course of ultraviolet B (UVB) therapy. RESULTS: Histopathology revealed a subcorneal blister with prominent neutrophilic infiltration. Immunopathology detected in situ bound and circulating immunoglobulin G (IgG) autoantibodies to epithelial cell surfaces and circulating IgG autoantibodies against desmoglein 1. The patient was also found to have Hashimoto's thyroiditis. CONCLUSIONS: This case illuminates a possible role of UV therapy in the induction of pemphigus herpetiformis through an epitope-spreading mechanism. The patient's autoimmune thyroiditis may also contribute to the predisposition for pemphigus development. The histopathological findings in pemphigus patients with a history of psoriasis may resemble Munro's microabscesses of psoriasis and should therefore alert pathologists and clinicians in considering additional diagnostic methods such as direct and indirect immunofluorescence.