With TOR, Less Is More: A Key Role for the Conserved Nutrient-Sensing TOR Pathway in Aging

Kapahi, Pankaj; Chen, Di; Rogers, Aric N.; Katewa, Subhash D.; Li, Patrick Wai Lun; Thomas, Emma; Kockel, Lutz

doi:10.1016/j.cmet.2010.05.001

Cited by 594 publications

(544 citation statements)

References 130 publications

(206 reference statements)

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“…Based on its potential to induce autophagy in several neurodegenerative disease models, Rapamycin, also known as sirolimus, is being investigated for AD [148][149][150]. Mechanisms of rapamycin action include removal of damaged mitochondria and cells with dysfunctional mitochondria via mammalian target of rapamycin-dependent activation of autophagy [149,150]. Rapamycin extends lifespan in aged mice [148].…”

Section: Apoptosis and Mitophagy As Therapeutic Targetsmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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Section: Apoptosis and Mitophagy As Therapeutic Targetsmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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“…FOXO is a transcription factor playing a pivotal role in adapting metabolism to nutrient conditions and is one of the most evolutionarily ancient downstream effectors of the insulinsignaling pathway (Hay, 2011;Kapahi et al, 2010). Also, in vivo studies indicate that the FOXO-dependent regulation of AMPs is evolutionarily conserved (see also (Becker et al, 2010;Garsin et al, 2003;Troemel et al, 2006)).…”

Section: Nutrition and The Consequences Of Immune Trade-offsmentioning

confidence: 99%

“…FOXO interacts with TOR and AMPK (Hay, 2011). Target of rapamycin (TOR) and AMP-Activated Protein Kinase (AMPK) integrate information on cellular nutritional status by sensing both qualitative and quantitative changes in nutrients, particularly branch-chain amino acids and glucose (Kapahi et al, 2010;Simpson and Raubenheimer, 2009). Disruption of FOXO activity can have different effects on host survival depending on the nature of the infection (Dionne et al, 2006), which probably reflects the fact that infections by different types of pathogens can trigger different immune pathways (Hoffmann and Reichhart, 2002;Hultmark, 2003;Lemaitre et al, 1997).…”

Section: Nutrition and The Consequences Of Immune Trade-offsmentioning

confidence: 99%

Integrating nutrition and immunology: A new frontier

Ponton

Wilson

Holmes

et al. 2013

Journal of Insect Physiology

129

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“…The maintenance of proteostasis requires translational fidelity, molecular chaperones to facilitate protein folding and the efficient detection, repair and, if necessary, replacement of misfolded and/or damaged proteins that might otherwise compromise cellular function. A reduction in protein synthetic burden may preserve proteostasis by limiting the accumulation of misfolded and/or damaged proteins, possibly by increasing translational fidelity, chaperone capacity, and/or proteolytic capacity (Hipkiss, 2007; Kapahi et al ., 2010; Conn & Qian, 2013; Sherman & Qian, 2013). In addition, when global protein synthesis is inhibited, differential translational upregulation of mRNAs encoding proteins involved in somatic maintenance and stress responses has been reported (Yamasaki & Anderson, 2008; Kapahi et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

“…A reduction in protein synthetic burden may preserve proteostasis by limiting the accumulation of misfolded and/or damaged proteins, possibly by increasing translational fidelity, chaperone capacity, and/or proteolytic capacity (Hipkiss, 2007; Kapahi et al ., 2010; Conn & Qian, 2013; Sherman & Qian, 2013). In addition, when global protein synthesis is inhibited, differential translational upregulation of mRNAs encoding proteins involved in somatic maintenance and stress responses has been reported (Yamasaki & Anderson, 2008; Kapahi et al ., 2010). Conversely, a primary reduction in damage to proteins, induction of chaperone synthesis, or a primary increase in proteolytic capacity (i.e., improved editing) could improve proteostasis independently of the absolute rate of protein synthesis in tissues.…”

Section: Introductionmentioning

confidence: 99%

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

et al. 2015

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SummaryCombating the social and economic consequences of a growing elderly population will require the identification of interventions that slow the development of age‐related diseases. Preserved cellular homeostasis and delayed aging have been previously linked to reduced cell proliferation and protein synthesis rates. To determine whether changes in these processes may contribute to or predict delayed aging in mammals, we measured cell proliferation rates and the synthesis and replacement rates (RRs) of over a hundred hepatic proteins in vivo in three different mouse models of extended maximum lifespan (maxLS): Snell Dwarf, calorie‐restricted (CR), and rapamycin (Rapa)‐treated mice. Cell proliferation rates were not consistently reduced across the models. In contrast, reduced hepatic protein RRs (longer half‐lives) were observed in all three models compared to controls. Intriguingly, the degree of mean hepatic protein RR reduction was significantly correlated with the degree of maxLS extension across the models and across different Rapa doses. Absolute rates of hepatic protein synthesis were reduced in Snell Dwarf and CR, but not Rapa‐treated mice. Hepatic chaperone levels were unchanged or reduced and glutathione S‐transferase synthesis was preserved or increased in all three models, suggesting a reduced demand for protein renewal, possibly due to reduced levels of unfolded or damaged proteins. These data demonstrate that maxLS extension in mammals is associated with improved hepatic proteome homeostasis, as reflected by a reduced demand for protein renewal, and that reduced hepatic protein RRs hold promise as an early biomarker and potential target for interventions that delay aging in mammals.

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With TOR, Less Is More: A Key Role for the Conserved Nutrient-Sensing TOR Pathway in Aging

Cited by 594 publications

References 130 publications

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Integrating nutrition and immunology: A new frontier

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

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