Unfolded Protein Response

Publication Title: 
PLoS genetics

Cells respond to accumulation of misfolded proteins in the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR) signaling pathway. The UPR restores ER homeostasis by degrading misfolded proteins, inhibiting translation, and increasing expression of chaperones that enhance ER protein folding capacity. Although ER stress and protein aggregation have been implicated in aging, the role of UPR signaling in regulating lifespan remains unknown. Here we show that deletion of several UPR target genes significantly increases replicative lifespan in yeast.

Author(s): 
Labunskyy, Vyacheslav M.
Gerashchenko, Maxim V.
Delaney, Joe R.
Kaya, Alaattin
Kennedy, Brian K.
Kaeberlein, Matt
Gladyshev, Vadim N.
Publication Title: 
PLoS biology

An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats-met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues.

Author(s): 
Bayat, Vafa
Thiffault, Isabelle
Jaiswal, Manish
TÈtreault, Martine
Donti, Taraka
Sasarman, Florin
Bernard, GeneviËve
Demers-Lamarche, Julie
Dicaire, Marie-JosÈe
Mathieu, Jean
Vanasse, Michel
Bouchard, Jean-Pierre
Rioux, Marie-France
Lourenco, Charles M.
Li, Zhihong
Haueter, Claire
Shoubridge, Eric A.
Graham, Brett H.
Brais, Bernard
Bellen, Hugo J.
Publication Title: 
Biochimica Et Biophysica Acta

Hyperglycemia is a hallmark of diabetes that is associated with diabetic complications and a reduction of lifespan. Using the mev-1 mutant of the nematode Caenorhabditis elegans we here tried to identify molecular mechanisms underlying the lifespan reducing effects of glucose. The lowest glucose concentration tested (10mM) caused a significant lifespan reduction at 37∞C and was used to assess effects on mitochondrial efficiency, formation of protein carbonyls and levels of methylglyoxal, a precursor of advanced glycation end products (AGEs).

Author(s): 
Fitzenberger, Elena
Boll, Michael
Wenzel, Uwe
Publication Title: 
Cell Cycle (Georgetown, Tex.)

Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR.

Author(s): 
Menendez, Javier A.
Joven, Jorge
AragonËs, Gerard
BarrajÛn-Catal·n, Enrique
Beltr·n-DebÛn, Ra˙l
Borr·s-Linares, Isabel
Camps, Jordi
Corominas-Faja, Bruna
CufÌ, SÌlvia
Fern·ndez-Arroyo, Salvador
Garcia-Heredia, Anabel
Hern·ndez-Aguilera, Anna
Herranz-LÛpez, MarÌa
JimÈnez-S·nchez, Cecilia
LÛpez-Bonet, Eugeni
Lozano-S·nchez, Jes˙s
Luciano-Mateo, Fedra
Martin-Castillo, BegoÒa
Martin-Paredero, Vicente
PÈrez-S·nchez, Almudena
Oliveras-Ferraros, Cristina
Riera-Borrull, Marta
RodrÌguez-Gallego, Esther
Quirantes-PinÈ, Rosa
Rull, Anna
Tom·s-Menor, Laura
Vazquez-Martin, Alejandro
Alonso-Villaverde, Carlos
Micol, Vicente
Segura-Carretero, Antonio
Publication Title: 
PLoS genetics

Cells respond to accumulation of misfolded proteins in the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR) signaling pathway. The UPR restores ER homeostasis by degrading misfolded proteins, inhibiting translation, and increasing expression of chaperones that enhance ER protein folding capacity. Although ER stress and protein aggregation have been implicated in aging, the role of UPR signaling in regulating lifespan remains unknown. Here we show that deletion of several UPR target genes significantly increases replicative lifespan in yeast.

Author(s): 
Labunskyy, Vyacheslav M.
Gerashchenko, Maxim V.
Delaney, Joe R.
Kaya, Alaattin
Kennedy, Brian K.
Kaeberlein, Matt
Gladyshev, Vadim N.
Publication Title: 
Cell

The hexosamine biosynthetic pathway (HBP) generates metabolites for protein N- and O-glycosylation. Wang et al. and Denzel et al. report a hitherto unknown link between the HBP and stress in the endoplasmic reticulum. These studies establish the HBP as a critical component of the cellular machinery of protein homeostasis.

Author(s): 
Vincenz, Lisa
Hartl, F. Ulrich
Publication Title: 
Nature

The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage. Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of oncogenic mutations that increase the risk of leukaemogenesis.

Author(s): 
van Galen, Peter
Kreso, Antonija
Mbong, Nathan
Kent, David G.
Fitzmaurice, Timothy
Chambers, Joseph E.
Xie, Stephanie
Laurenti, Elisa
Hermans, Karin
Eppert, Kolja
Marciniak, Stefan J.
Goodall, Jane C.
Green, Anthony R.
Wouters, Bradly G.
Wienholds, Erno
Dick, John E.
Publication Title: 
Cell Cycle (Georgetown, Tex.)

Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR.

Author(s): 
Menendez, Javier A.
Joven, Jorge
AragonËs, Gerard
BarrajÛn-Catal·n, Enrique
Beltr·n-DebÛn, Ra˙l
Borr·s-Linares, Isabel
Camps, Jordi
Corominas-Faja, Bruna
CufÌ, SÌlvia
Fern·ndez-Arroyo, Salvador
Garcia-Heredia, Anabel
Hern·ndez-Aguilera, Anna
Herranz-LÛpez, MarÌa
JimÈnez-S·nchez, Cecilia
LÛpez-Bonet, Eugeni
Lozano-S·nchez, Jes˙s
Luciano-Mateo, Fedra
Martin-Castillo, BegoÒa
Martin-Paredero, Vicente
PÈrez-S·nchez, Almudena
Oliveras-Ferraros, Cristina
Riera-Borrull, Marta
RodrÌguez-Gallego, Esther
Quirantes-PinÈ, Rosa
Rull, Anna
Tom·s-Menor, Laura
Vazquez-Martin, Alejandro
Alonso-Villaverde, Carlos
Micol, Vicente
Segura-Carretero, Antonio
Publication Title: 
Aging Cell

Dietary restriction (DR) increases lifespan and attenuates age-related phenotypes in many organisms; however, the effect of DR on longevity of individuals in genetically heterogeneous populations is not well characterized. Here, we describe a large-scale effort to define molecular mechanisms that underlie genotype-specific responses to DR. The effect of DR on lifespan was determined for 166 single gene deletion strains in Saccharomyces cerevisiae. Resulting changes in mean lifespan ranged from a reduction of 79% to an increase of 103%.

Author(s): 
Schleit, Jennifer
Johnson, Simon C.
Bennett, Christopher F.
Simko, Marissa
Trongtham, Natalie
Castanza, Anthony
Hsieh, Edward J.
Moller, Richard M.
Wasko, Brian M.
Delaney, Joe R.
Sutphin, George L.
Carr, Daniel
Murakami, Christopher J.
Tocchi, Autumn
Xian, Bo
Chen, Weiyang
Yu, Tao
Goswami, Sarani
Higgins, Sean
Holmberg, Mollie
Jeong, Ki-Soo
Kim, Jin R.
Klum, Shannon
Liao, Eric
Lin, Michael S.
Lo, Winston
Miller, Hillary
Olsen, Brady
Peng, Zhao J.
Pollard, Tom
Pradeep, Prarthana
Pruett, Dillon
Rai, Dilreet
Ros, Vanessa
Singh, Minnie
Spector, Benjamin L.
Vander Wende, Helen
An, Elroy H.
Fletcher, Marissa
Jelic, Monika
Rabinovitch, Peter S.
MacCoss, Michael J.
Han, Jing-Dong J.
Kennedy, Brian K.
Kaeberlein, Matt
Publication Title: 
Experimental Cell Research

The ceramide synthase (CerS) enzymes are key regulators of ceramide homeostasis. CerS1 is central to regulating C18 ceramide which has been shown to be important in cancer and the response to chemotherapeutic drugs. Previous work indicated that some drugs induced a novel and specific translocation of CerS1 from the endoplasmic reticulum to the Golgi apparatus. We now show that diverse stresses such as UV light, DTT, as well as drugs with different mechanisms of action induce CerS1 translocation.

Author(s): 
Sridevi, Priya
Alexander, Hannah
Laviad, Elad L.
Min, Junxia
Mesika, Adi
Hannink, Mark
Futerman, Anthony H.
Alexander, Stephen

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