Autophagy and ageing: Insights from invertebrate model organisms

Lionaki, Eirini; Markaki, Maria; Tavernarakis, Nektarios

doi:10.1016/j.arr.2012.05.001

Cited by 64 publications

(50 citation statements)

References 227 publications

(284 reference statements)

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“…(C) Fractional volumes of autophagosomes in the RPE of human donor retinas from young, old, early AMD, and late AMD determined from electron micrographs (n D 5 per group), P < 0.05. contrast with other tissues in which autophagic activity has been reported to decrease with age. 35 However, we also show that autophagy capacity appears to be reduced by >25 % in AMD donors compared to age-matched controls.…”

Section: Discussionmentioning

confidence: 89%

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

et al. 2014

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Autophagic dysregulation has been suggested in a broad range of neurodegenerative diseases including agerelated macular degeneration (AMD). To test whether the autophagy pathway plays a critical role to protect retinal pigmented epithelial (RPE) cells against oxidative stress, we exposed ARPE-19 and primary cultured human RPE cells to both acute (3 and 24 h) and chronic (14 d) oxidative stress and monitored autophagy by western blot, PCR, and autophagosome counts in the presence or absence of autophagy modulators. Acute oxidative stress led to a marked increase in autophagy in the RPE, whereas autophagy was reduced under chronic oxidative stress. Upregulation of autophagy by rapamycin decreased oxidative stress-induced generation of reactive oxygen species (ROS), whereas inhibition of autophagy by 3-methyladenine (3-MA) or by knockdown of ATG7 or BECN1 increased ROS generation, exacerbated oxidative stress-induced reduction of mitochondrial activity, reduced cell viability, and increased lipofuscin. Examination of control human donor specimens and mice demonstrated an age-related increase in autophagosome numbers and expression of autophagy proteins. However, autophagy proteins, autophagosomes, and autophagy flux were significantly reduced in tissue from human donor AMD eyes and 2 animal models of AMD. In conclusion, our data confirm that autophagy plays an important role in protection of the RPE against oxidative stress and lipofuscin accumulation and that impairment of autophagy is likely to exacerbate oxidative stress and contribute to the pathogenesis of AMD.

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Section: Discussionmentioning

confidence: 89%

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

et al. 2014

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“…Under conditions of nutrient sufficiency, mTOR phosphorylates and inhibits the autophagy-initiating kinase ULK1 (46). Inactivation of genes involved in autophagy decreases life span in yeast (chronological), C. elegans, and Drosophila, and promotion of autophagy in the fly nervous system extends life span (47)(48)(49). Furthermore, autophagy is required for the extension by rapamycin of yeast chronological life span (47) and for life span extension by CR or genetic inhibition of mTOR signaling in worms (50).…”

Section: Potential Mechanisms Of Life Span Extension By Rapamycinmentioning

confidence: 99%

Rapalogs and mTOR inhibitors as anti-aging therapeutics

Lamming

Ye²,

Sabatini³

et al. 2013

J. Clin. Invest.

469

382

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Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans. This Review discusses the prospects for developing newer, safer anti-aging therapies based on analogs of rapamycin (termed rapalogs) or other approaches targeting mTOR signaling.

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“…Dietary restriction, a reduction in total food intake, has been shown to increase lifespan and reduce fecundity by limiting metabolic rates and the availability of metabolic energy in a wide range of organisms such as yeast, nematodes, flies, and rodents (Masoro, 2005; Mair & Dillin, 2008). Autophagic activity decreases during the course of aging, and genes that control this process are strongly associated with lifespan regulation in flies and worms (Lionaki et al ., 2013). In Drosophila , overexpression of autophagy‐related genes in neurons enhances longevity, while their repression causes neuronal defects and shortening of lifespan (Simonsen et al ., 2008).…”

Section: Discussionmentioning

confidence: 99%

β‐Guanidinopropionic acid extends the lifespan of Drosophila melanogaster via an AMP‐activated protein kinase‐dependent increase in autophagy

Yang

Long

et al. 2015

Aging Cell

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SummaryPrevious studies have demonstrated that AMP‐activated protein kinase (AMPK) controls autophagy through the mammalian target of rapamycin (mTOR) and Unc‐51 like kinase 1 (ULK1/Atg1) signaling, which augments the quality of cellular housekeeping, and that β‐guanidinopropionic acid (β‐GPA), a creatine analog, leads to a chronic activation of AMPK. However, the relationship between β‐GPA and aging remains elusive. In this study, we hypothesized that feeding β‐GPA to adult Drosophila produces the lifespan extension via activation of AMPK‐dependent autophagy. It was found that dietary administration of β‐GPA at a concentration higher than 900 mm induced a significant extension of the lifespan of Drosophila melanogaster in repeated experiments. Furthermore, we found that Atg8 protein, the homolog of microtubule‐associated protein 1A/1B‐light chain 3 (LC3) and a biomarker of autophagy in Drosophila, was significantly upregulated by β‐GPA treatment, indicating that autophagic activity plays a role in the effect of β‐GPA. On the other hand, when the expression of Atg5 protein, an essential protein for autophagy, was reduced by RNA interference (RNAi), the effect of β‐GPA on lifespan extension was abolished. Moreover, we found that AMPK was also involved in this process. β‐GPA treatment significantly elevated the expression of phospho‐T172‐AMPK levels, while inhibition of AMPK by either AMPK‐RNAi or compound C significantly attenuated the expression of autophagy‐related proteins and lifespan extension in Drosophila. Taken together, our results suggest that β‐GPA can induce an extension of the lifespan of Drosophila via AMPK‐Atg1‐autophagy signaling pathway.

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Autophagy and ageing: Insights from invertebrate model organisms

Cited by 64 publications

References 227 publications

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

Rapalogs and mTOR inhibitors as anti-aging therapeutics

β‐Guanidinopropionic acid extends the lifespan of Drosophila melanogaster via an AMP‐activated protein kinase‐dependent increase in autophagy

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