Autophagy: Renovation of Cells and Tissues

Mizushima, Noboru; Komatsu, Masaaki

doi:10.1016/j.cell.2011.10.026

Cited by 5,251 publications

(4,330 citation statements)

References 134 publications

(187 reference statements)

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“…Recent studies have demonstrated that the anti‐aging effect of autophagy is related to its cell‐autonomous functions, which avoids accumulation of toxic proteins (e.g., misfolded or aggregated proteins) and organelles (e.g., damaged mitochondria) and inhibits cell death (Mizushima & Komatsu, 2011; Rubinsztein et al., 2011). Furthermore, autophagy may also mediate anti‐aging effect by cell‐nonautonomous effects, including the clearance of intracellular pathogens, the reduction in inflammatory cytokine secretion, and the improvement of neuroendocrine circuits function (Mizushima & Komatsu, 2011; Rubinsztein et al., 2011). We demonstrated that young plasma could restore autophagy activity in aged livers.…”

Section: Discussionmentioning

confidence: 99%

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

et al. 2017

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SummaryRecent studies showing the therapeutic effect of young blood on aging‐associated deterioration of organs point to young blood as the solution for clinical problems related to old age. Given that defective autophagy has been implicated in aging and aging‐associated organ injuries, this study was designed to determine the effect of young blood on aging‐induced alterations in hepatic function and underlying mechanisms, with a focus on autophagy. Aged rats (22 months) were treated with pooled plasma (1 ml, intravenously) collected from young (3 months) or aged rats three times per week for 4 weeks, and 3‐methyladenine or wortmannin was used to inhibit young blood‐induced autophagy. Aging was associated with elevated levels of alanine transaminase and aspartate aminotransferase, lipofuscin accumulation, steatosis, fibrosis, and defective liver regeneration after partial hepatectomy, which were significantly attenuated by young plasma injections. Young plasma could also restore aging‐impaired autophagy activity. Inhibition of the young plasma‐restored autophagic activity abrogated the beneficial effect of young plasma against hepatic injury with aging. In vitro, young serum could protect old hepatocytes from senescence, and the antisenescence effect of young serum was abrogated by 3‐methyladenine, wortmannin, or small interfering RNA to autophagy‐related protein 7. Collectively, our data indicate that young plasma could ameliorate age‐dependent alterations in hepatic function partially via the restoration of autophagy.

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Section: Discussionmentioning

confidence: 99%

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

et al. 2017

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“…Macroautophagy is a proteolytic process whereby organelles and cellular proteins are encapsulated and delivered to lysosomes (Mizushima & Komatsu, 2011). This form of autophagy takes place in three phases: induction, autophagosome formation, and degradation.…”

Section: Introductionmentioning

confidence: 99%

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

et al. 2015

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SummaryGaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer‐amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL‐1β and IL‐6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase‐1, led to the maturation of IL‐1β in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small‐molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL‐1β secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65‐NF‐kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL‐1β. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets.

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“…Autophagy is an intracellular process used to recycle cytoplasmic components through lysosomal degradation to support cell homoeostasis 25. Research in various model organisms has found that autophagy is a vital mediator of the ageing process 26, 27.…”

Section: Discussionmentioning

confidence: 99%

Spermidine promotes nucleus pulposus autophagy as a protective mechanism against apoptosis and ameliorates disc degeneration

Zheng

Wang

Chen

et al. 2018

J Cellular Molecular Medi

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Spermidine has therapeutic effects in many diseases including as heart diastolic function, myopathic defects and neurodegenerative disorders via autophagy activation. Autophagy has been found to mitigate cell apoptosis in intervertebral disc degeneration (IDD). Accordingly, we theorize that spermidine may have beneficial effects on IDD via autophagy stimulation. In this study, spermidine's effect on IDD was evaluated in tert‐butyl hydroperoxide (TBHP)‐treated nucleus pulposus cells of SD rats in vitro as well as in a puncture‐induced rat IDD model. We found that autophagy was actuated by spermidine in nucleus pulposus cells. In addition, spermidine treatment weakened the apoptotic effects of TBHP in nucleus pulposus cells. Spermidine increased the expression of anabolic proteins including Collagen‐II and aggrecan and decreased the expression of catabolic proteins including MMP13 and Adamts‐5. Additionally, autophagy blockade using 3‐MA reversed the beneficial impact of spermidine against nucleus pulposus cell apoptosis. Autophagy was thus important for spermidine's therapeutic effect on IDD. Spermidine‐treated rats had an accentuated T2‐weighted signal and a diminished histological degenerative grade than vehicle‐treated rats, showing that spermidine inhibited intervertebral disc degeneration in vivo. Thus, spermidine protects nucleus pulposus cells against apoptosis through autophagy activation and improves disc, which may be beneficial for the treatment of IDD.

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Autophagy: Renovation of Cells and Tissues

Cited by 5,251 publications

References 134 publications

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

Spermidine promotes nucleus pulposus autophagy as a protective mechanism against apoptosis and ameliorates disc degeneration

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