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• W2152578461 abstract "Target of rapamycin (TOR) signaling stimulates cell growth by regulating protein synthesis in response to a variety of stimuli in awiderangeofspeciesandisinhibitedbyrapamycin,anaturallyoccurringantifungalcompoundproducedbybacteriaanddiscoveredonEasterIslandorinthelocalvernacular,RapaNui (rapamycin’snamesake).Recently,rapamycinwasshowntoextendlifespanformice, even when administered late in life, suggesting that inhibiting the mammalian TOR pathway may improve health span forpeople.Energy levels and growth are essential fororganismal survival, yet are inverselyrelated to longevitysince avarietyof inter-ventions that reduce energy levels extendlife span and delay aging (Kenyon, 2005).Most notable are genetic changes thatreduce pro-growth pathways and alsoextend life span across species. Inaddition, caloric restriction (CR) increaseslife span in a wide range of species fromyeast to mammals (Masoro, 2005). Onthebasisoftheseobservations,achemicalintervention that diminishes cell growthpathways or restricts calories may alsoextend life span. Cell growth is an energy-taxing process necessary for cellular pro-liferation. To ensure successful cellgrowth,energyneedsmustbecoordinatedwith energylevelsand afavorableenviron-ment. Thus, RNA transcription and trans-lation must be regulated based on energyand amino acid levels to ensure successfulprotein production. The target of rapamy-cin(TOR)pathway is keyfor this regulation(Tsang et al., 2007; Ma and Blenis, 2009);thus,itisagoodtherapeutictargetforlife-span extension, but administration of TORinhibitors may impart negative sideeffects, particularly if they are adminis-tered early in life at a time when growthis important for fitness. This notion is inaccordance with evolutionary theories ofaging which propose growth is essentialfor early life fitness that enables reproduc-tion but may subsequently lead toage-related decline in health due todiminished selective pressure (Kirkwoodand Austad, 2000).Genetic or agent-induced inhibition ofTOR signaling extends life span in avariety of species that include yeast,nematodes and flies (Kenyon, 2005).Even though inhibiting the TOR pathwayextends life span in numerous species,such evidence has been lacking formammals. However, a study recently pub-lished in Nature provides the longawaited evidence that rapamycin extendslife span in mammals (Harrison et al.,2009). This study is a part of the NationalInstitutes of Aging Interventions TestingProgram (NIA-ITP) that evaluates a varietyof agents on heterogeneous mice atthree test sites. The rationale for usinggenetically heterogeneous mice and threetest sites is to ensure diversity such thata broad spectrum of age-related maladieswill be observed that are not unique toan isogenic strain or a single environment.These heterogeneous mice were gener-ated by crossing four mouse strains suchthat each mouse is genetically unique.These test sites include the JacksonLaboratory, the University of Michiganand the University of Texas HealthScience Center at San Antonio headed bythe principal authors on the paper: DrsDavid E. Harrison, Richard A. Miller andRandy Strong, respectively. In addition,Dr Z. Dave Sharp wasthe sponsor for rapa-mycin. The longer-lived rapamycin-fedmice appeared to have succumbed to thesame life-threatening illnesses at thesame proportion as the control mice,suggesting that rapamycin’s life-extendingproperties were not restricted to alleviat-ing a subset of maladies as would be pre-dicted by the experimental design.Interestingly, rapamycin extended lifespan even when chronic administrationbegan in mice as old as 600 days (equival-entto60yearsinpeople).Thus,rapamycinorothermammalianTOR(mTOR)inhibitorsmay be efficacious for treating age-relatedillnesses in people without early or pro-longed intervention; rapamycin may alsobe used as an aging prophylactic, assum-ing that chronic intervention is not toxic.In order to understand the potentialbeneficialandtoxic effects of chronic rapa-mycin treatment, a complete understand-ing of TOR signaling is necessary. TheTOR signaling pathway is complicatedbeing responsive to a wide range ofstimuli and being interactive with numer-ous molecular mechanisms and cellularprocesses. There are several comprehen-sive reviews that highlight our currentunderstanding of TOR signaling (Reilingand Sabatini, 2006; Tsang et al., 2007;Ma and Blenis, 2009). For its most basicfunction, TOR promotes cell growth by reg-ulating protein synthesis in response togrowth factors, levels of nutrients andamino acids, and various stress conditionsthat include energy levels, hypoxia, DNAdamage, reactive oxygen species andmechanical stress (Figure 1). Thus, TOR" @default.
• W2152578461 created "2016-06-24" @default.
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• W2152578461 date "2009-01-01" @default.
• W2152578461 modified "2023-09-27" @default.
• W2152578461 title "Research Highlight Rapamycin: The Cure for all that Ails" @default.
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