Autophagy maintains stemness by preventing senescence

García‐Prat, Laura; Martínez-Vicente, Marta; Perdiguero, Eusebio; Ortet, Laura; Rodríguez-Ubreva, Javier; Rebollo, Elena; Ruiz-Bonilla,; Gutarra, Susana; Ballestar, Esteban; Al, Serrano; Sandri, Marco; Muñoz‐Cánoves, Pura

doi:10.1038/nature16187

Cited by 1,126 publications

(925 citation statements)

References 52 publications

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“…The insulin growth factor 1 (Igf‐1) and its receptor (Igf‐1r; Kenyon, 2005; Longo & Finch, 2003; Milman, Huffman, & Barzilai, 2016), as well as the stemness potential of stem cells (Garcia‐Prat et al, 2016; Garcia‐Prat, Sousa‐Victor, & Munoz‐Canoves, 2017), represent already established age‐associated pathways. To determine whether they were mechanistically involved—at least in part—in the AT‐1 sTg phenotype, we analyzed whole tissue activation of Igf‐1r signaling (Supporting Information Figure S4a,b); we also treated cultured MEF with Igf‐1 (Supporting Information Figure S4c,d).…”

Section: Resultsmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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The membrane transporter AT‐1/SLC33A1 translocates cytosolic acetyl‐CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT‐1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT‐1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT‐1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a‐Fam134b‐LC3β and Atg9a‐Sec62‐LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of AT‐1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl‐CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl‐CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol‐to‐ER flux of acetyl‐CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl‐CoA‐dependent homeostatic mechanisms linked to metabolism and inflammation.

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Section: Resultsmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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“…In human fibroblasts, autophagy regulates ROS‐induced senescence by p21 in a p38 MAPKα‐dependent manner (Luo et al., 2011). Also autophagy has been proven to be a crucial stem cell fate regulator via regulating ROS and DNA damage markers associated with p16INK4a and pS6 induction (Garcia‐Prat et al., 2016). Thus, the complex molecular network needs to be further explored.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have indicated that autophagy is required for maintaining the stemness and differentiation capacity of stem cells. It has been reported that basal autophagy is a crucial mechanism in the maintenance of the young state of satellite cells, and failure of autophagy causes cell senescence characterized by declines in number and function of satellite cells (Garcia‐Prat et al., 2016). Autophagy can protect BMMSCs from oxidative stress (Song, Song, & Tong, 2014), which indicates that autophagy plays a protective role in cell aging.…”

Section: Introductionmentioning

confidence: 99%

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

et al. 2017

Aging Cell

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SummaryBone marrow‐derived mesenchymal stem cells (BMMSCs) exhibit degenerative changes, including imbalanced differentiation and reduced proliferation during aging, that contribute to age‐related bone loss. We demonstrate here that autophagy is significantly reduced in aged BMMSCs compared with young BMMSCs. The autophagy inhibitor 3‐methyladenine (3‐MA) could turn young BMMSCs into a relatively aged state by reducing their osteogenic differentiation and proliferation capacity and enhancing their adipogenic differentiation capacity. Accordingly, the autophagy activator rapamycin could restore the biological properties of aged BMMSCs by increasing osteogenic differentiation and proliferation capacity and decreasing adipogenic differentiation capacity. Possible underlying mechanisms were explored, and the analysis revealed that autophagy could affect reactive oxygen species and p53 levels, thus regulating biological properties of BMMSCs. In an in vivo study, we found that activation of autophagy restored bone loss in aged mice. In conclusion, our results suggest that autophagy plays a pivotal role in the aging of BMMSCs, and activation of autophagy could partially reverse this aging and may represent a potential therapeutic avenue to clinically treat age‐related bone loss.

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“…The general agreement that failure of the proteostasis network with age contributes to aging (Chang et al., 2017; Cuervo, 2008; Garcia‐Prat et al., 2016; Madeo et al., 2015; Rubinsztein et al., 2011) has called considerable recent attention to autophagy as one of the main components of this network. Despite growing evidence of autophagy dysfunction with age and of the beneficial effects of activating this pathway in experimental models of age‐related disorders (reviewed in (Cuervo, 2008; Rubinsztein et al., 2011; Madeo et al., 2015)), the molecular basis behind autophagic failure in aging requires clarification.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy contributes to maintain cellular and tissue homeostasis by assuring protein and organelle quality control (Kaushik & Cuervo, 2015). A growing number of reports have linked malfunctioning of autophagy with aging, highlighting the role of autophagy as an anti‐aging cellular mechanism (Chang, Kumsta, Hellman, Adams & Hansen, 2017; Cuervo, 2008; Garcia‐Prat et al., 2016; Madeo, Zimmermann, Maiuri & Kroemer, 2015; Rubinsztein, Marino & Kroemer, 2011). Furthermore, genetic inhibition of this degradative process recapitulates features associated with aging and age‐related diseases (Hara et al., 1997; Komatsu et al., 2006, 2007; Menzies et al., 2017).…”

Section: Introductionmentioning

confidence: 99%

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

et al. 2018

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SummaryInability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule‐based minus‐end‐directed motor proteins, the well‐characterized dynein, and the less‐studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti‐aging purposes.

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Autophagy maintains stemness by preventing senescence

Cited by 1,126 publications

References 52 publications

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

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