A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans

Hansen, Malene; Chandra, Abha; Mitic, Laura L.; Onken, Brian; Driscoll, Monica; Kenyon, Cynthia

doi:10.1371/journal.pgen.0040024

Cited by 680 publications

(707 citation statements)

References 69 publications

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“…Dauer formation is associated with increased autophagy and requires autophagy genes APG1, APG7, APG8, and AUT10 (Melendez et al ., 2003). Accordingly, increased autophagy is essential for lifespan extension in dietary restriction conditions or TOR inhibition in C. elegans (Hansen et al ., 2008). But, whereas DAF‐2 mutants require both autophagy and the transcription factor DAF‐16/FoxO to promote longevity, autophagy takes place in the absence of DAF‐16/FoxO.…”

Section: Animal Modelsmentioning

confidence: 99%

“…But, whereas DAF‐2 mutants require both autophagy and the transcription factor DAF‐16/FoxO to promote longevity, autophagy takes place in the absence of DAF‐16/FoxO. This may suggest that autophagy provides raw material for new macromolecular synthesis that requires the action of DAF‐16/FoxO, recycling this material into cell‐protective longevity proteins (Hansen et al ., 2008). In Salmonella ‐infected worms, inactivation of the autophagy pathway was shown to increase bacterial intracellular replication, reducing animal lifespan, culminating in an apoptotic‐independent death (Jia et al ., 2009).…”

Section: Animal Modelsmentioning

confidence: 99%

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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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Section: Animal Modelsmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

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

2015

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“…Although free radicals have been correlated with senescence, in both mice and worms, there is increasing evidence that they may not be the causative agent (Doonan et al 2008;Ran et al 2007;Van Raamsdonk and Hekimi 2009;Van Remmen et al 2003;Yen et al 2009). The target of rapamycin pathway, which may also link DR and insulin/IGF signaling, regulates autophagy, and this is important for both DR and insulin/IGF mediated longevity (Hansen et al 2008;Kaeberlein et al 2005;Kapahi et al 2004;Melendez et al 2003).…”

Section: Gompertz Analysismentioning

confidence: 99%

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

Yen

Mobbs

2009

AGE

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Cold temperature, dietary restriction, reduced insulin/insulin-like growth factor signaling, and mutations in mitochondrial genes have all been shown to extend the lifespan of Caenorhabditis elegans (Kenyon et al., Nature 366:461-464, 1993; Klass, Mech Ageing Dev 6:413-429, 1977; Lakowski and Hekimi, Science 272:1010-1013. Additionally, all of them extend the lifespan of mice (Bluher et al., Science 299:572-574, 2003; Conti et al., Science 314:825-828, 2006; Holzenberger et al., Nature 421:182-187, 2003; Liu et al., Genes Dev 19:2424-2434 Weindruch and Walford, Science 215:1415-1418, 1982. The mechanism by which these treatments extend lifespan is currently unknown, but our study uses an epistatic approach to show that these four manipulations are mainly additive in terms of lifespan. Classical interpretation of this data suggests that these manipulations are independent of each other. However, using a Gompertz mortality rate analysis, the maximum mortality rate doubling time can be achieved through the use of only dietary restriction and cold temperature, suggesting that the mechanisms by which cold temperature and caloric restriction extend lifespan are the only independent mechanisms.

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“…Autophagy in particular can degrade damaged proteins, protein aggregates, and damaged organelles that accumulate during aging and in age-related pathologies (Mizushima et al 2008) and is elicited by ageextending interventions and in long-lived mutants (Hansen et al 2008;Tóth et al 2008;Wang and Miller 2012;Alvers et al 2009). …”

mentioning

confidence: 99%

“…Indeed, autophagic degradation declines with age (Cuervo 2008), and dietary restriction (DR) prevents this age-related decline in rat liver (Del Roso et al 2003). In addition, autophagy is required for chronological lifespan extension in yeast (Alvers et al 2009), and for the longevity response to DR and reduced TOR and insulin signaling in C. elegans, even though its induction alone is not sufficient to extend lifespan (Hansen et al 2008). Inhibiting autophagy triggers premature cellular senescence in human fibroblasts (Kang et al 2011), but it is also required for the senescence transition in response to oncogenic signaling (Young et al 2009), suggesting that autophagy could have pleiotropic effects.…”

mentioning

confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

124

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans

Cited by 680 publications

References 69 publications

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

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

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

p62/SQSTM1 at the interface of aging, autophagy, and disease

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