The Plasticity of Aging: Insights from Long-Lived Mutants

Kenyon, Cynthia

doi:10.1016/j.cell.2005.02.002

Cited by 1,217 publications

(1,077 citation statements)

References 135 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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“…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

125

104

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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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“…Among these hallmarks, the “deregulated nutrient sensing” was the first to be described to influence aging in animals, through the insulin and IGF‐1 signaling pathway (IIS) (Kenyon, 2005). IGF‐1 is produced by several cells types (mainly hepatocytes) in response to GH release from the anterior pituitary.…”

Section: Introductionmentioning

confidence: 99%

“…Dietary restriction is a well‐known environmental signal shown to expand lifespan in eukaryote species, from yeast to primates (Colman et al ., 2009; Fontana et al ., 2010; Mattison et al ., 2012). The “longevity response” to dietary restriction is regulated by several nutrient‐sensing pathways: the kinase TOR, AMP kinase, sirtuins, and the IIS (Kenyon, 2005). …”

Section: Introductionmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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The Plasticity of Aging: Insights from Long-Lived Mutants

Cited by 1,217 publications

References 135 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

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

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

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