The Hallmarks of Aging

López-Otı́n, Carlos; Blasco, Marı́a A.; Partridge, Linda; Serrano, Manuel; Kroemer, Guido

doi:10.1016/j.cell.2013.05.039

Cited by 11,886 publications

(12,047 citation statements)

References 302 publications

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“…An explanation for this discrepancy is that p53 deficiency allows beneficial propagation of damaged cells rescuing certain progeroid traits. However, when cellular damage is extensive and the regenerative capacity of tissues is severely limited, p53 deficiency would become deleterious and accelerate aging (Lopez‐Otin, Blasco, Partridge, Serrano & Kroemer, 2013). Our results are consistent with this model; they indicate that mutations in Ft1 result in a relatively mild genomic damage that triggers DDR‐related checkpoints, which are abolished by mutations in p53 allowing resumption of cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

et al. 2018

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SummaryHuman AKTIP and mouse Ft1 are orthologous ubiquitin E2 variant proteins involved in telomere maintenance and DNA replication. AKTIP also interacts with A‐ and B‐type lamins. These features suggest that Ft1 may be implicated in aging regulatory pathways. Here, we show that cells derived from hypomorph Ft1 mutant (Ft1 kof/kof) mice exhibit telomeric defects and that Ft1 kof/kof animals develop progeroid traits, including impaired growth, skeletal and skin defects, abnormal heart tissue, and sterility. We also demonstrate a genetic interaction between Ft1 and p53. The analysis of mice carrying mutations in both Ft1 and p53 (Ft1 kof/kof ; p53 ko/ko and Ft1 kof/kof ; p53 +/ko) showed that reduction in p53 rescues the progeroid traits of Ft1 mutants, suggesting that they are at least in part caused by a p53‐dependent DNA damage response. Conversely, Ft1 reduction alters lymphomagenesis in p53 mutant mice. These results identify Ft1 as a new player in the aging process and open the way to the analysis of its interactions with other progeria genes using the mouse model.

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Section: Discussionmentioning

confidence: 99%

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

et al. 2018

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“…In fact, the reduced rates of mitophagy observed in KIFC3 depleted cells can explain the abnormal morphology of the mitochondria compartment previously described upon KIFC3 knockdown (Dietrich, Seiler, Essmann & Dodt, 2013). Thus, loss of KIFC3 leads to reduced autophagic activity and perturbed mitochondria morphology/content, two well‐described features of old cells (Kennedy et al., 2014; Lopez‐Otin et al., 2013) .…”

Section: Discussionmentioning

confidence: 99%

“…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). Loss of protein/organelle quality control is a universal hallmark of aging, and malfunctioning of autophagy with age contributes to this gradual accumulation of damaged proteins and dysfunctional organelles (Kaushik & Cuervo, 2015; Kennedy et al., 2014; Lopez‐Otin, Blasco, Partridge, Serrano & Kroemer, 2013). However, the cellular and molecular mechanisms underlying this progressive decline in autophagy during aging remain unknown.…”

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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“…Recently, hallmarks of aging, including cellular senescence and stem cell exhaustion, were identified (Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013), guiding the research on aging and aging intervention strategies. Furthermore, the first clinical trial, Target Aging with Metformin (TAME), was approved to create a paradigm for evaluating pharmacologic approaches to delay aging (Barzilai, Crandall, Kritchevsky, & Espeland, 2016).…”

Section: Introductionmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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SummaryMetformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.

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The Hallmarks of Aging

Cited by 11,886 publications

References 302 publications

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

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

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

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