Geroscience: Linking Aging to Chronic Disease

Kennedy, Brian K.; Berger, Shelley L.; Brunet, Anne; Campisi, Judith; Cuervo, Ana María; Epel, Elissa S.; Franceschi, Claudio; Lithgow, Gordon J.; Morimoto, Richard I.; Pessin, Jeffrey E.; Rando, Thomas A.; Richardson, Arlan; Schadt, Eric E.; Wyss‐Coray, Tony; Sierra, Felipe

doi:10.1016/j.cell.2014.10.039

Cited by 1,976 publications

(1,595 citation statements)

References 15 publications

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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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Aging is one of the greatest risk factors for many diseases, and it ultimately restricts the lifespan of organisms by increasing the probability of death (Dillin, Gottschling & Nystrom, 2014; Guarente, Ruvkun & Amasino, 1998; Kennedy et al., 2014; Kenyon, 2005; Niccoli & Partridge, 2012). Since the discovery and characterization of the first long‐lived mutants in Caenorhabditis elegans and Saccharomyces cerevisiae more than two decades ago (Kaeberlein, McVey & Guarente, 1999; Kenyon, Chang, Gensch, Rudner & Tabtiang, 1993; Morris, Tissenbaum & Ruvkun, 1996; Ogg et al., 1997; Wang et al., 1993), the concept that aging is a malleable biological process has been well embraced (Finch & Ruvkun, 2001; Gems & Partridge, 2013; Kennedy, 2008; Kenyon, 2005, 2010).…”

Section: Research Organisms For Agingmentioning

confidence: 99%

The African turquoise killifish: A research organism to study vertebrate aging and diapause

Brunet²

2018

Aging Cell

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SummaryThe African turquoise killifish has recently gained significant traction as a new research organism in the aging field. Our understanding of aging has strongly benefited from canonical research organisms—yeast, C. elegans, Drosophila, zebrafish, and mice. Many characteristics that are essential to understand aging—for example, the adaptive immune system or the hypothalamo‐pituitary axis—are only present in vertebrates (zebrafish and mice). However, zebrafish and mice live more than 3 years and their relatively long lifespans are not compatible with high‐throughput studies. Therefore, the turquoise killifish, a vertebrate with a naturally compressed lifespan of only 4–6 months, fills an essential gap to understand aging. With a recently developed genomic and genetic toolkit, the turquoise killifish not only provides practical advantages for lifespan and longitudinal experiments, but also allows more systematic characterizations of the interplay between genetics and environment during vertebrate aging. Interestingly, the turquoise killifish can also enter a long‐term dormant state during development called diapause. Killifish embryos in diapause already have some organs and tissues, and they can last in this state for years, exhibiting exceptional resistance to stress and to damages due to the passage of time. Understanding the diapause state could give new insights into strategies to prevent the damage caused by aging and to better preserve organs, tissues, and cells. Thus, the African turquoise killifish brings two interesting aspects to the aging field—a compressed lifespan and a long‐term resistant diapause state, both of which should spark new discoveries in the field.

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“…This view is now changed. As the intrinsic biological mechanism of aging is slowly revealed, there is hope that interventions that slow aging and prevent or delay the onset of chronic disease and functional impairments can be discovered (Kennedy et al., 2014; Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013). …”

Section: Introductionmentioning

confidence: 99%

Plasma proteomic signature of age in healthy humans

Tanaka¹,

Biancotto²,

Moaddel³

et al. 2018

Aging Cell

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396

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To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22–93 years old, who were disease‐ and treatment‐free and had no physical and cognitive impairment. Using a p ≤ 3.83 × 10−5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 ± 0.001, p = 7.49 × 10−56). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort.

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Geroscience: Linking Aging to Chronic Disease

Cited by 1,976 publications

References 15 publications

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

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

The African turquoise killifish: A research organism to study vertebrate aging and diapause

Plasma proteomic signature of age in healthy humans

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