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Calorically restricted rodents also show reduced levels of both activated Ras-GTP and activated ERK[ 66, 68 ] suggesting that signal transduction downstream of Ras is also impaired upon caloric restriction but whether these changes in Ras signal transduction contribute to lifespan extension remains to be determined. Moreover, the Ras-responsive transcription factor, AOP, was required Aopen AOP-320 Network lifespan extension by chico mutation [ Aopen AOP-320 Network ]. During growth, such an interaction is required for maximal PI3K activation [ 72 ]. Thus, the two signaling branches downstream of the insulin receptor are intricately connected.

Ras signaling is activated downstream of the activated insulin receptor. Ras can directly bind to and allosterically activate PI3K. Positive regulatory interactions are indicated by arrows. Negative regulatory interactions are shown as blunt-ended lines.


Each complex contains a different repertoire of protein components and targets different downstream substrates for phosphorylation. Thus, mTORC1 responds to growth factors, energy status, amino acid levels, and cellular stress and is acutely inhibited by rapamycin. Moreover, activation of AMPK is sufficient to extend lifespan across different species [ 80—82 ]. AMPK activity is regulated both positively and negatively by phosphorylation. These include widespread changes in chromatin Aopen AOP-320 Network gene expression, the secretion of pro-inflammatory chemokines and cytokines, growth factors, and proteases, a characteristic feature of senescent cells called the senescence-associated secretory phenotype SASPand the activation of tumor suppression pathways [ 86 ].

Several factors act as triggers to induce cells to senesce including telomere shortening, DNA damage and activation of oncogenic pathways including activation of Ras and chronic stimulation of MAPK signal transduction [ 87 ].

Ras signaling in aging and metabolic regulation - IOS Press

Together, cellular senescence and the Aopen AOP-320 Network are thought to provide an effective safeguard against tumorigenesis by preventing the proliferation of damaged and potentially cancerous cells. Cellular senescence has long been linked to aging and the development of age-related pathologies. Several mechanisms for how senescent cells may promote age-related pathology have been proposed. The accumulation of senescent cells may negatively impact on the regenerative potential of aging tissues by Aopen AOP-320 Network the number of actively dividing cells.

Alternatively, senescent cells may contribute to the disruption of the aging stem cell niche via the SASP [ 86 ]. Importantly, the clearance of senescent cells within a progeroid murine model was able to delay the progression of age-related pathologies but did not reverse their effects [ 90 ]. Oncogenic mutations in Ras that Aopen AOP-320 Network in its hyperactivation can trigger senescence [ 91 ]. In support of this, down-regulation of RasGrf1 in VSELs very small embryonic-like stem cells prevents senescence and age-related depletion of these cells in adult tissues which may contribute to the longevity of RasGrf1 deficient mice [ 58 ].

Interestingly, lifespan extension in these models could not simply be attributed to their protective effects against cancer as cancer-free individuals were still longer-lived. Similarly, mice deficient for RasGrf1 showed decreased cancer incidence but lifespan extension was also observed in cancer-free animals [ 16 ].


Also, pharmacological inhibition of MEK in Drosophila did not prevent hyperplasia of the adult intestinal epithelium [ 17 ], a cancer-like pathology caused by over-proliferation of the intestinal stem cells. Ras signaling may therefore, at least to some extent, influence lifespan independently of its well-established oncogenic functions. One intriguing potential mechanism by which inhibition of Ras signal transduction could promote longevity is through changes in metabolic regulation, particularly fat metabolism. Aging in several animal models is often accompanied by metabolic dysfunction, especially aberrant fat metabolism.

In humans, increased fat deposition, particularly in visceral fat stores, commonly leads to metabolic disease including type 2 diabetes and cardiovascular disease. Surgical removal of visceral fat in rodents extends lifespan and improves several metabolic outcomes with age including insulin sensitivity [ 97 ]. Similarly, long-lived dietary restricted mouse models and mutants with impaired IIS or mTOR Aopen AOP-320 Network are often lean and show improved age-related metabolic profiles [ 98 ]. However, other long-lived mouse mutants, such as the growth hormone deficient mouse, show increased fat mass [ 99 ] suggesting that total lipid levels themselves may not be a key determinant of aging. Instead, age-related deterioration in tissue function may result from lipotoxicity, the ectopic deposition of fat that occurs when the adipocyte fat storage capacity is exceeded or impaired.

Multiple studies have linked activation of ERK to aberrant fat metabolism or accumulation. Mice lacking ERK1 have fewer adipocytes and decreased adiposity compared to their controls [ ].

AOPEN index of parts for sale. Page 1.

Reducing the levels of activated ERK can also provide beneficial outcomes in obesitymodels. Thus, Aopen AOP-320 Network deficient mice were more resistant to obesity when challenged with a high-fat diet [ ]. Similarly, mice exposed to a small molecule inhibitor of MEK not only showed lowered levels of activated ERK but improved metabolic profiles in response to high-fat feeding [ ].

Interestingly, these interactions between ERK activity and metabolism appear to be conserved. An effective strategy for developing new treatments for aging is the repurposing of existing drugs that have already been approved for human use. Such Aopen AOP-320 Network have known mechanisms of action and have been well screened for both safety and toxicity effects. The Ras signaling pathway has been intensively studied in the context of cancer.


Thus, Ras and its downstream signaling effectors have been the focus of extensive screening to identify compounds that inhibit the pathway for use as cancer treatments. Interestingly, one of these small molecule inhibitors, trametinib, which targets Aopen AOP-320 Network MEK kinase with high specificity, extends lifespan in Drosophila [ 17 ] and offers protection against deleterious metabolic effects of both diet- and genetically-induced obesity in mice [ ].

Aopen - Computer Memory Components/Parts Sourcing Streamlined

AOpen AOP drivers are tiny programs that enable your Ethernet Adapter hardware to communicate with your operating system software. Maintaining. Click on the following links for the driver package readme info: /HELP/ This package supports the following driver models:AOpen AOP

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