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1.
Front Aging ; 22021 Sep.
Article in English | MEDLINE | ID: mdl-35340273

ABSTRACT

As the most energetically expensive cellular process, translation must be finely tuned to environmental conditions. Dietary restriction attenuates signaling through the nutrient sensing mTOR pathway, which reduces translation and redirects resources to preserve the soma. These responses are associated with increased lifespan but also anabolic impairment, phenotypes also observed when translation is genetically suppressed. Here, we restricted translation downstream of mTOR separately in major tissues in C. elegans to better understand their roles in systemic adaptation and whether consequences to anabolic impairment were separable from positive effects on lifespan. Lowering translation in neurons, hypodermis, or germline tissue led to increased lifespan under well-fed conditions and improved survival upon withdrawal of food, indicating that these are key tissues coordinating enhanced survival when protein synthesis is reduced. Surprisingly, lowering translation in body muscle during development shortened lifespan while accelerating and increasing reproduction, a reversal of phenotypic trade-offs associated with systemic translation suppression. Suppressing mTORC1 selectively in body muscle also increased reproduction while slowing motility during development. In nature, this may be indicative of reduced energy expenditure related to foraging, acting as a "GO!" signal for reproduction. Together, results indicate that low translation in different tissues helps direct distinct systemic adaptations and suggest that unknown endocrine signals mediate these responses. Furthermore, mTOR or translation inhibitory therapeutics that target specific tissues may achieve desired interventions to aging without loss of whole-body anabolism.

2.
J Gerontol A Biol Sci Med Sci ; 72(4): 473-480, 2017 Apr 01.
Article in English | MEDLINE | ID: mdl-28158466

ABSTRACT

Genetic changes resulting in increased life span are often positively associated with enhanced stress resistance and somatic maintenance. A recent study found that certain long-lived Caenorhabditis elegans mutants spent a decreased proportion of total life in a healthy state compared with controls, raising concerns about how the relationship between health and longevity is assessed. We evaluated seven markers of health and two health-span models for their suitability in assessing age-associated health in invertebrates using C elegans strains not expected to outperform wild-type animals. Additionally, we used an empirical method to determine the transition point into failing health based on the greatest rate of change with age for each marker. As expected, animals with mutations causing sickness or accelerated aging had reduced health span when compared chronologically to wild-type animals. Physiological health span, the proportion of total life spent healthy, was reduced for locomotion markers in chronically ill mutants, but, surprisingly, was extended for thermotolerance. In contrast, all short-lived mutants had reduced "quality-of-life" in another model recently employed for assessing invertebrate health. Results suggest that the interpretation of physiological health span is not straightforward, possibly because it factors out time and thus does not account for the added cost of extrinsic forces on longer-lived strains.


Subject(s)
Caenorhabditis elegans/physiology , Longevity/physiology , Aging/genetics , Aging/physiology , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Feeding Behavior/physiology , Fertility , Fluorescence , Genotype , Locomotion , Longevity/genetics , Muscle Contraction/physiology , Mutation , Oxidative Stress , Pharyngeal Muscles/physiology , Stress, Physiological , Thermotolerance
3.
Aging Cell ; 15(6): 1027-1038, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27538368

ABSTRACT

Although certain methods of lowering and/or altering mRNA translation are associated with increased lifespan, the mechanisms underlying this effect remain largely unknown. We previously showed that the increased lifespan conferred by reducing expression of eukaryotic translation initiation factor 4G (eIF4G/IFG-1) enhances survival under starvation conditions while shifting protein expression toward factors involved with maintaining ER-dependent protein and lipid balance. In this study, we investigated changes in ER homeostasis and found that lower eIF4G/IFG-1 increased survival under conditions of ER stress. Enhanced survival required the ER stress sensor gene ire-1 and the ER calcium ATPase gene sca-1 and corresponded with increased translation of chaperones that mediate the ER unfolded protein response (UPRER ). Surprisingly, the heat-shock transcription factor gene hsf-1 was also required for enhanced survival, despite having little or no influence on the ability of wild-type animals to survive ER stress. The requirement for hsf-1 led us to re-evaluate the role of eIF4G/IFG-1 on thermotolerance. Results show that lowering expression of this translation factor enhanced thermotolerance, but only after prolonged attenuation, the timing of which corresponded to increased transcription of heat-shock factor transcriptional targets. Results indicate that restricting overall translation through eIF4G/IFG-1 enhances ER and cytoplasmic proteostasis through a mechanism that relies heavily on hsf-1.

4.
J Lipid Res ; 54(3): 581-591, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23288946

ABSTRACT

Plasma membrane disruptions occur in mechanically active tissues such as the epidermis and can lead to cell death if the damage remains unrepaired. Repair occurs through fusion of vesicle patches to the damaged membrane region. The enzyme phospholipase D (PLD) is involved in membrane traffickiing; therefore, the role of PLD in membrane repair was investigated. Generation of membrane disruptions by lifting epidermal keratinocytes from the substratum induced PLD activation, whereas removal of cells from the substratum via trypsinization had no effect. Pretreatment with 1,25-dihydroxyvitamin D3, previously shown to increase PLD1 expression and activity, had no effect on, and a PLD2-selective (but not a PLD1-selective) inhibitor decreased, cell lifting-induced PLD activation, suggesting PLD2 as the isoform activated. PLD2 interacts functionally with the glycerol channel aquaporin-3 (AQP3) to produce phosphatidylglycerol (PG); however, wounding resulted in decreased PG production, suggesting a potential PG deficiency in wounded cells. Cell lifting-induced PLD activation was transient, consistent with a possible role in membrane repair, and PLD inhibitors inhibited membrane resealing upon laser injury. In an in vivo full-thickness mouse skin wound model, PG accelerated wound healing. These results suggest that PLD and the PLD2/AQP3 signaling module may be involved in membrane repair and wound healing.


Subject(s)
Keratinocytes/metabolism , Phospholipase D/metabolism , Animals , Aquaporin 3/metabolism , Calcitriol/pharmacology , Cells, Cultured , Enzyme Activation/drug effects , Female , Male , Mice , Phosphatidylglycerols/metabolism , Wound Healing/drug effects
5.
Nat Commun ; 2: 597, 2011 Dec 20.
Article in English | MEDLINE | ID: mdl-22186893

ABSTRACT

Severe vitamin E deficiency results in lethal myopathy in animal models. Membrane repair is an important myocyte response to plasma membrane disruption injury as when repair fails, myocytes die and muscular dystrophy ensues. Here we show that supplementation of cultured cells with α-tocopherol, the most common form of vitamin E, promotes plasma membrane repair. Conversely, in the absence of α-tocopherol supplementation, exposure of cultured cells to an oxidant challenge strikingly inhibits repair. Comparative measurements reveal that, to promote repair, an anti-oxidant must associate with membranes, as α-tocopherol does, or be capable of α-tocopherol regeneration. Finally, we show that myocytes in intact muscle cannot repair membranes when exposed to an oxidant challenge, but show enhanced repair when supplemented with vitamin E. Our work suggests a novel biological function for vitamin E in promoting myocyte plasma membrane repair. We propose that this function is essential for maintenance of skeletal muscle homeostasis.


Subject(s)
Cell Membrane/drug effects , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/metabolism , Myoblasts/metabolism , Vitamin E Deficiency/blood , Animals , Cell Membrane/physiology , Dose-Response Relationship, Drug , Glucose/adverse effects , HeLa Cells , Homeostasis , Humans , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Microscopy, Fluorescence , Muscle Fibers, Skeletal/drug effects , Muscle, Skeletal/drug effects , Myoblasts/cytology , Myoblasts/drug effects , Oxidative Stress , Wound Healing/drug effects , alpha-Tocopherol/blood , alpha-Tocopherol/pharmacology
6.
Diabetes ; 60(11): 3034-43, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21940783

ABSTRACT

OBJECTIVE: Skeletal muscle myopathy is a common diabetes complication. One possible cause of myopathy is myocyte failure to repair contraction-generated plasma membrane injuries. Here, we test the hypothesis that diabetes induces a repair defect in skeletal muscle myocytes. RESEARCH DESIGN AND METHODS: Myocytes in intact muscle from type 1 (INS2(Akita+/-)) and type 2 (db/db) diabetic mice were injured with a laser and dye uptake imaged confocally to test repair efficiency. Membrane repair defects were also assessed in diabetic mice after downhill running, which induces myocyte plasma membrane disruption injuries in vivo. A cell culture model was used to investigate the role of advanced glycation end products (AGEs) and the receptor for AGE (RAGE) in development of this repair defect. RESULTS: Diabetic myocytes displayed significantly more dye influx after laser injury than controls, indicating a repair deficiency. Downhill running also resulted in a higher level of repair failure in diabetic mice. This repair defect was mimicked in cultured cells by prolonged exposure to high glucose. Inhibition of the formation of AGE eliminated this glucose-induced repair defect. However, a repair defect could be induced, in the absence of high glucose, by enhancing AGE binding to RAGE, or simply by increasing cell exposure to AGE. CONCLUSIONS: Because one consequence of repair failure is rapid cell death (via necrosis), our demonstration that repair fails in diabetes suggests a new mechanism by which myopathy develops in diabetes.


Subject(s)
Cell Membrane/metabolism , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Muscle Fibers, Skeletal/metabolism , Muscular Diseases/metabolism , Animals , Cell Line , Cell Membrane/drug effects , Cell Membrane/radiation effects , Cell Membrane/ultrastructure , Cells, Cultured , Fluorescent Dyes/metabolism , Fluorescent Dyes/toxicity , Glycation End Products, Advanced/adverse effects , Glycation End Products, Advanced/antagonists & inhibitors , Glycation End Products, Advanced/metabolism , Hyperglycemia/metabolism , Lasers/adverse effects , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Motor Activity , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/radiation effects , Muscle Fibers, Skeletal/ultrastructure , Muscular Diseases/pathology , Myoblasts, Skeletal/metabolism , Necrosis , Receptor for Advanced Glycation End Products , Receptors, Immunologic/metabolism
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