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Scientists at Joslin Diabetes Center have identified a keymechanism of action for the TOR (target of rapamycin) proteinkinase, a critical regulator of cell growth which plays a majorrole in illness and aging. This finding not only illuminates thephysiology of aging but could lead to new treatments to increaselifespan and control age-related conditions, such as cancer , type 2 diabetes , and neurodegeneration. Over the past decade, studies have shown that inhibiting TORactivity, which promotes cell growth by regulating proteinsynthesis, increases lifespan in a variety of species includingflies and mice; in recent years research has focused on uncoveringthe precise mechanisms underlying this effect. The Joslin study,published in the May 2 issue of Cell Metabolism, reports that TOR has a direct impact on two master gene regulatorproteins - SKN-1 and DAF-16 - which control genes that protectagainst environmental, metabolic and proteotoxic stress . The TOR kinase acts in two signaling pathways, TORC1 and TORC2.When TORC1 is inhibited, SKN-1 and DAF-16 are mobilized, leading toactivation of protective genes that increase stress resistance andlongevity. This new finding was demonstrated in experiments with C. elegans , a microscopic worm used as a model organism, but activation ofprotective genes was also observed in mice. Most findings in C. elegans have turned out to be applicable to mice and humans. "We uncovered a critical mechanism in the relationship between TORand aging and disease. There is a homeostatic relationship betweenprotein synthesis and stress defenses: when protein synthesis isreduced, stress defenses increase," says lead author T. KeithBlackwell, MD, PhD, co-head of the Joslin Islet Cell & RegenerativeBiology Section and Professor of Pathology at Harvard MedicalSchool. The Blackwell lab studies the aging process and how it isinfluenced by insulin and other metabolic regulatory mechanisms. TOR activity, which is essential for early development but can leadto age-related decline, is implicated in a variety of chronicdiseases, including diabetes, cardiovascular disease, cancer andneurodegenerative disorders, such as Alzheimer's and Parkinson's disease . In diabetes, TOR has both positive and negative effects: Itpromotes beta cell growth and insulin production but inappropriateTORC1 activity leads to insulin resistance and beta cell demise, aswell as fat accumulation. At the same time, insufficient TORC2activity can lead to insulin resistance. The new results on TOR and SKN-1 suggest that SKN-1 might have apositive effects in Type 2 diabetes: "Turning on this pathway couldbe important in defending against the effects of high glucose, andpromoting beta cell health" says Blackwell. In the study, TOR activity was inhibited by genetic interferenceand the TOR-inhibitor rapamycin, a naturally occurring compoundwhich is used as an immunosuppressant in organ transplants, and hasbeen shown to increase lifespan in mice. Using rapamycin or relateddrugs to treat diseases affected by TOR has been a subject ofintense interest among scientists and clinicians. The study foundthat rapamycin inhibits both TORC1 and TORC2, which will interestscientists investigating rapamycin as a pharmaceutical. "We need toincrease understanding of rapamycin and its effects on TOR activityto determine how targeting TOR or processes it controls can helptreat diseases that involve TOR and derangement of metabolism. Wealso need to look at therapies that work on TORC1 and TORC2independently," said Blackwell. However, one caveat with TORinhibition is that the kinase plays such a central role in thebasic physiology of growing and dividing cells. The new resultssuggest that in some situations we might want to bypass TOR itself,and directly harness beneficial processes that are controlled bySKN-1 or DAF-16. Future research will focus on gaining a deeper understanding of howTOR acts on beneficial defense pathways and affects aging anddisease. "In science, we are always looking for ways to interferewith mechanisms that promote aging and disease in ways that arebeneficial to people," says Blackwell. Additional References Citations. The e-commerce company in China offers quality products such as Open Die Forging Press Manufacturer , Mechanical Power Presses, and more. For more , please visit Hydraulic Press Machine today!
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