Rapamycin extends life- and health span because it slows aging

Blagosklonny, Mikhail V.

doi:10.18632/aging.100591

Cited by 72 publications

(58 citation statements)

References 72 publications

(57 reference statements)

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“…Our study is consistent with previous findings. As a key drug in our experiments, rapamycin is a highly specific inhibitor of mTORC1 and has been used as a clinical immunosuppressant in organ transplantation and as an antiangiogenic agent in clinical trials for treatment of cancers and other vascular diseases [44, 45]. Interestingly, rapamycin has been reported to inhibit tumor angiogenesis through impairment of HIF-1α/VEGF production in some human cancer cell lines [46], which is consistent with our experimental results.…”

Section: Discussionsupporting

confidence: 85%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

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Section: Discussionsupporting

confidence: 85%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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“…However, it is now known that aging can be modulated by genetic pathways and biochemical processes which are evolutionarily conserved (Kenyon, 2010b; Lopez‐Otin et al ., 2013). According to the quasi‐programmed theory, aging is not programmed, but rather a consequence of genetic programs that determine developmental growth early in life (Blagosklonny, 2013a,b). Lopez‐Otin et al .…”

Section: Introductionmentioning

confidence: 99%

Long liveFOXO: unraveling the role ofFOXOproteins 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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“…Rapamycin has also been shown to extend the lifespan of several animal species [148][149][150], and since aging is an obvious risk factor for the development of late-life neurodegenerative diseases, this result has enhanced interest in the use of this drug to fight neurodegenerative diseases. M a n u s c r i p t Other mTOR-dependent compounds are also being used to activate autophagy, some by direct inhibition of mTOR by rapamycin analogs such as CCI-779, RAD001 and AP2373, and others like PP242 and Torin 1 through their ability to inhibit the formation of mTOR complexes [151][152][153][154].…”

Section: Modulation Of Autophagy As a Neuroprotective Therapymentioning

confidence: 99%

Autophagy in neurodegenerative diseases: From pathogenic dysfunction to therapeutic modulation

Martinez-Vicente¹

2015

Seminars in Cell & Developmental Biology

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Rapamycin extends life- and health span because it slows aging

Cited by 72 publications

References 72 publications

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Long liveFOXO: unraveling the role ofFOXOproteins in aging and longevity

Autophagy in neurodegenerative diseases: From pathogenic dysfunction to therapeutic modulation

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