Aging-dependent Manner Research Articles

Acetylcholine deficit causes dysfunctional inhibitory control in an aging-dependent manner

Inhibitory control is a key executive function that limits unnecessary thoughts and actions, enabling an organism to appropriately execute goal-driven behaviors. The efficiency of this inhibitory capacity declines with normal aging or in neurodegenerative dementias similar to memory or other cognitive functions. Acetylcholine signaling is crucial for executive function and also diminishes with aging. Acetylcholine’s contribution to the aging- or dementia-related decline in inhibitory control, however, remains elusive. We addressed this in Drosophila using a Go/No-Go task that measures inhibition capacity. Here, we report that inhibition capacity declines with aging in wild-type flies, which is mitigated by lessening acetylcholine breakdown and augmented by reducing acetylcholine biosynthesis. We identified the mushroom body (MB) γ neurons as a chief neural site for acetylcholine’s contribution to the aging-associated inhibitory control deficit. In addition, we found that the MB output neurons MBON-γ2α’1 having dendrites at the MB γ2 and α’1 lobes and axons projecting to the superior medial protocerebrum and the crepine is critical for sustained movement suppression per se. This study reveals, for the first time, the central role of acetylcholine in the aging-associated loss of inhibitory control and provides a framework for further mechanistic studies.

Deficiencies of <i>Homer2</i> and <i>Homer3</i> accelerate aging-dependent bone loss in mice

Homer proteins are scaffold proteins that regulate calcium (Ca2+) signaling by modulating the activity of multiple Ca2+ signaling proteins. In our previous report, Homer2 and Homer3 regulated NFATc1 function through its interaction with calcineurin, which then acted to regulate receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis and bone metabolism. However, to date, the role of Homers in osteoclastogenesis remains unknown. In this study, we investigated the roles of Homer2 and Homer3 in aging-dependent bone remodeling. Deletion of Homer2 /Homer3 (Homer2/3 DKO) markedly decreased the bone density of the femur. The decrease in bone density was not seen in mice with Homer2 (Homer2−/−) and Homer3 (Homer3−/−) deletion. Moreover, RANKL treatment of bone marrow-derived monocytes/macrophages in Homer2/3 DKO mice significantly increased the formation of multinucleated cells and resorption areas. Finally, Homer2/3 DKO mice decreased bone density in an aging-dependent manner. These findings suggest a novel potent mode of bone homeostasis regulation through osteoclasts differentiation during aging by Homer proteins, specifically Homer2 and Homer3.

High fat diet significantly changed the global gene expression profile involved in hepatic drug metabolism and pharmacokinetic system in mice

BackgroundHigh fat diet impact transcription of hepatic genes responsible for drug metabolism and pharmacokinetics. Until now, researches just focused on a couple specific genes without a global profile showing. Age-dependent manner was also not noted well. This study aims to investigate the high fat diet effect on transcriptome of drug metabolism and pharmacokinetic system in mouse livers and show the age-dependent evidence.MethodsC57BL/6 male mice were used in this experiment. High fat diet was used to treat mice for 16 and 38 weeks. Serum total cholesterol, low density lipoprotein cholesterol, aspartate transaminase, and alanine transaminaselevels were measured. Meanwhile, Histology, RNA-Seq, RT-PCR analysis and fourteen major hepatic bile acids quantification were performed for the liver tissues. Data was mined at levels of genes, drug metabolism and pharmacokinetic sysem, and genome wide.ResultsTreatment with high fat diet for 38 weeks significantly increased levels of serum lipids as well as aspartate transaminase, and alanine transaminase. Meanwhile, lipid accumulation in livers was observed. At week 38 of the experiment, the profile of 612 genes involved in drug metabolism and pharmacokinetics was significantly changed, indicated by a heatmap visulization and a principal component analysis. In total 210 genes were significantly regulated. Cyp3a11, Cyp4a10, and Cyp4a14 were down-regulated by 10–35 folds, while these three genes also were highly expressed in the liver. High fat diet regulated 11% of genome-wide gene while 30% of genes involved in the hepatic drug metabolism and pharmacokinetic system. Genes, including Adh4, Aldh1b1, Cyp3a11, Cyp4a10, Cyp8b1, Fmo2, Gsta3, Nat8f1, Slc22a7, Slco1a4, Sult5a1, and Ugt1a9, were regulated by high fat diet as an aging-dependent manner. Bile acids homeostasis, in which many genes related to metabolism and transportation were enriched, was also changed by high fat diet with an aging-dependet manner. Expression of genes in drug metabolism and disposition system significantly correlated to serum lipid profiles, and frequently correlated with each other.ConclusionsHigh fat diet changed the global transcription profile of hepatic drug metabolism and pharmacokinetic system with a age-dependent manner.

Erasure of striatal chondroitin sulfate proteoglycan-associated extracellular matrix rescues aging-dependent decline of motor learning.

Cognitive decline is a feature of aging. Accumulating evidence suggests that the brain extracellular matrix (ECM) is involved in the process of aging-dependent cognitive impairment and neurodegeneration by regulating synaptic neurotransmission and affecting neuroplasticity. Age-related changes in brain structure and cognition are not uniform across the whole brain. Being one of the most vulnerable brain regions to aging-dependent alterations, striatum is integral to several central nervous system functions, such as motor, cognition, and affective control. However, the striatal ECM is largely understudied. We first describe 2 major types of chondroitin sulfate proteoglycan (CSPG)-associated ECM in striatum: perineuronal nets and diffusive ECM. Both types of ECM accumulate in an aging-dependent manner. The accumulation of CSPG-associated ECM correlates with aging-dependent decline in striatum-related cognitive functions, including motor learning and working memory. Enzymatic depletion of CSPG-associated ECM in aged mice via chondroitinase ABC significantly improves motor learning, suggesting that changes in neural ECM CSPGs regulate striatal plasticity. Our study provides a greater understanding of the role of neural ECM underlying striatal plasticity, which is an important precursor to design appropriate therapeutic strategies for normal and pathologic aging.

Aging-dependent expression of synapse-related proteins in the mouse brain.

A synapse is a cell adhesion structure that permits a neuron to pass a chemical or electrical signal to another neuron. They connect neurons and form neural networks that are essential for brain functions, such as learning and memory. At a chemical synapse, the presynapse and the postsynapse are connected by cell adhesion molecules. The presynapse contains synaptic vesicles and their release machinery, whereas the postsynapse contains postsynaptic densities and receptors for the neurotransmitters. Many proteins constituting a synapse have been identified, but their life-span expression profiles remain elusive. Here, we investigated the expression levels of representative synapse-related proteins by Western blot using the extranuclear supernatant fraction of the brains of mice at various ages. These proteins were classified into seven groups depending on their expression profiles during the embryonic stage, those from postnatal day 6 (P6) to P30, and those after P90. The expression levels of the majority of the proteins were gradually increased from the embryonic stage and then decreased at P14 or P30. After P90, the expression levels were not markedly changed or, in some proteins, increased. These results indicate that the expression levels of the synapse-related proteins are regulated orderly in an aging-dependent manner.

P38\u03b1 MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner

Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α−/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.

Aging and/or tissue-specific regulation of patchoulol and pogostone in two Pogostemon cablin (Blanco) Benth. cultivars.

In Pogostemon cablin (Blanco) Benth. essential oil, patchoulol and pogostone are the two major bioactive phytochemicals while their in vivo biosynthesis remains largely unknown. In this study, seven genes of the plastidic methylerythritol 4-phosphate pathway (MEP) and three genes of the cytoplasmic mevalonate pathway (MVA) in two cultivars, HN and YN, were isolated. Gene expression and phytochemical profiles across leaves and stems at different developmental stages of the two cultivars were evaluated using quantitative reverse-transcription polymerase chain reaction and gas chromatography-mass spectrometry, respectively. Hierarchical analysis showed that the expression of MVA- and MEP-related genes was clustered similarly in the two cultivars. Phytochemical assay revealed that the contents of patchoulol in leaves and pogostone in stems were regulated in an aging-dependent manner. Pogostone was only detected in stems but not in leaves of the two cultivars. The Pearson correlation analysis suggested that several genes were presumably involved in the biosynthesis of patchoulol and pogostone. In the YN cultivar, the 1-deoxy-d-xylulose-5-phosphate reductoisomerase and isopentenyl pyrophosphate isomerase 2 genes, and 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase were positively responsible for patchoulol and pogostone biosynthesis, respectively. In the HN cultivar, 3-hydroxy-3-methylglutaryl-coenzyme A reductase and mevalonate diphosphate decarboxylase, and mevalonate kinase expression were positively associated with pogostone and patchoulol biosynthesis, respectively. The genes identified in this study are good candidates for the enhancement of patchoulol content in the leaves or pogostone content in the stems of P. cablin. Taken together, our results lay a solid foundation for better understanding of the mechanism underlying patchoulol and pogostone biosynthesis, which in turn may help to improve their content in P. cablin.

Profiling aged artisanal Cheddar cheese using secondary electrospray ionization mass spectrometry.

A number of direct injection mass spectrometry methods that can sample foods nondestructively and without sample preparation are being developed with applications ranging from the rapid assessment of food safety to the verification of protected designations of origin. In this pilot study, secondary electrospray ionization mass spectrometry (SESI-MS) in positive- and negative-ion modes was used to collect volatile fingerprints of artisanal Cheddar cheeses aged for one to three years. SESI-MS fingerprints were found to change in an aging-dependent manner and can be used to descriptively and predictively categorize Cheddars by their aging period, identify volatile components that increase or decrease with aging, and robustly discriminate individual batches of artisanal cheese. From these results, it was concluded that SESI-MS volatile fingerprinting could be used by artisanal food producers to characterize their products during production and aging, providing useful data to help them maximize the value of each batch.

Loss of outer retinal neurons and circuitry alterations in the DBA/2J mouse.

The DBA/2J mouse line develops essential iris atrophy, pigment dispersion, and glaucomatous age-related changes, including an increase of IOP, optic nerve atrophy, and retinal ganglion cell (RGC) death. The aim of this study was to evaluate possible morphological changes in the outer retina of the DBA/2J mouse concomitant with disease progression and aging, based on the reduction of both the a- and b-waves and photopic flicker ERGs in this mouse line. Vertically sectioned DBA/2J mice retinas were evaluated at 3, 8, and 16 months of age using photoreceptor, horizontal, and bipolar cell markers. Sixteen-month-old C57BL/6 mice retinas were used as controls. The DBA/2J mice had outer retinal degeneration at all ages, with the most severe degeneration in the oldest retinas. At 3 months of age, the number of photoreceptor cells and the thickness of the OPL were reduced. In addition, there was a loss of horizontal and ON-bipolar cell processes. At 8 months of age, RGC degeneration occurred in patches, and in the outer retina overlying these patches, cone morphology was impaired with a reduction in size as well as loss of outer segments and growth of horizontal and bipolar cell processes into the outer nuclear layer. At 16 months of age, connectivity between photoreceptors and horizontal and bipolar cell processes overlying these patches was lost. Retinal degeneration in DBA/2J mice includes photoreceptor death, loss of bipolar and horizontal cell processes, and loss of synaptic contacts in an aging-dependent manner.

On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis

Major vault protein (MVP), the main component of vault complex, is overexpressed in many multidrug-resistant cancer cell lines, suggesting a possible role for MVP in cell signaling and survival. In this study, we have found that MVP is markedly increased in senescent human diploid fibroblasts (HDFs) as well as in aged organs. We examined whether MVP expression might be affected by apoptotic stress in an aging-dependent manner. We treated young and senescent HDFs with apoptosis-inducing agents such as H(2)O(2), staurosporine and thapsigargin, and monitored MVP expression. We found that MVP expression is markedly reduced in young HDFs but not in senescent HDFs, in response to apoptotic stresses. Downregulation of MVP increased the sensitivity of senescent HDFs to apoptosis. Also, the level of antiapoptotic B-cell lymphoma protein-2 (Bcl-2) was significantly reduced and the accumulation of c-Jun increased in MVP knocked-down senescent HDFs. Moreover, treatment of MVP knocked-down senescent HDFs with SP600125, a specific c-Jun NH(2)-terminal kinase (JNK) inhibitor, restored the level of Bcl-2 protein. Taken together, these results suggest that MVP is important in the resistance of senescent HDFs to apoptosis by modulation of Bcl-2 expression by JNK pathway.

Regulations of collagen synthesis by ascorbic acid, transforming growth factor-β and interferon-γ in human dermal fibroblasts cultured in three-dimensional collagen gel are photoaging- and aging-independent

Decreased collagen synthesis and loss of responsiveness to growth factors are well known phenomena in in vivo or in vitro aged cells. Ascorbic acid and some cytokines such as transforming growth factor-β and interferon-γ are important regulators of collagen synthesis. To investigate the responsiveness of fibroblasts with regard to the photoaging and aging process, we examined the effect of ascorbic acid, TGF-β, and IFN-γ on collagen synthesis in dermal fibroblasts from three newborn foreskins (1 day old) and in both exposed and unexposed skin fibroblasts from 4 old individuals (60–76 years old) cultured in monolayer and in collagen gel. We demonstrated that basal levels of collagen synthesis decreased with increasing age. Photoaged fibroblasts in collagen gel showed greater basal collagen synthesis than aged fibroblasts in the same individuals, but similar basal collagen synthesis in monolayer cultures. Even though basal levels of collagen synthesis in collagen gel are downregulated in a photoaging- and aging-dependent manner, collagen synthesis by ascorbic acid in collagen gel, and by TGF-β and IFN-γ in both monolayer culture and collagen gel were regulated in a photoaging- and aging-independent manner. In monolayer culture, however, the responsiveness to ascorbic acid in newborn fibroblasts was greater than in photoaged and aged fibroblasts. Our results suggest that there are differences in collagen synthesis between photoaged and aged cells, depending on culture conditions. Responsiveness to ascorbic acid, TGF-β and IFN-γ related to collagen synthesis in photoaged and aged fibroblasts in collagen gel appears to be the same as in newborn fibroblasts, even though basal levels of collagen synthesis are downregulated in a photoaging- or aging-dependent manner.