Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation

Bharath, Leena P.; Agrawal, Manju; McCambridge, Grace; Nicholas, Dequina; Hastürk, Hatice; Liu, Jing; Jiang, Kai; Li, Rui; Guo, Zhenheng; Deeney, Jude T.; Apovian, Caroline M.; Snyder‐Cappione, Jennifer; Hawk, Gregory S.; Fleeman, Rebecca M.; Pihl, Riley; Thompson, Katherine; Belkina, Anna C.; Cui, Licong; Proctor, Elizabeth A.; Kern, Philip A.; Nikolajczyk, Barbara S.

doi:10.1016/j.cmet.2020.04.015

Cited by 397 publications

(305 citation statements)

References 91 publications

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“…Systemic inflammation is similarly associated with aging – often referred to as ‘inflammaging’ ( López-Otín et al, 2013 ), and this contributes to aging-related decline, as evidenced for example by the observation that inhibition of pro-inflammatory NF-κB signaling can reduce aging phenotypes ( Tilstra et al, 2012 ). Interestingly, recent research demonstrated that T cells may contribute to age-related inflammation and its metabolic complications, such as hyperglycemia ( Bharath et al, 2020 ; Desdín-Micó et al, 2020 ; Lee et al, 2019 ), and engineered T cells can prevent pathology by clearing senescent cells ( Amor et al, 2020 ). However, here we will focus on the inverse relationship: how do systemic changes associated with aging impact T cell responses, particularly in the context of cancer?…”

Section: Introductionmentioning

confidence: 99%

The effects of age and systemic metabolism on anti-tumor T cell responses

Drijvers

Sharpe

Haigis

2020

eLife

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Average age and obesity prevalence are increasing globally. Both aging and obesity are characterized by profound systemic metabolic and immunologic changes and are cancer risk factors. The mechanisms linking age and body weight to cancer are incompletely understood, but recent studies have provided evidence that the anti-tumor immune response is reduced in both conditions, while responsiveness to immune checkpoint blockade, a form of cancer immunotherapy, is paradoxically intact. Dietary restriction, which promotes health and lifespan, may enhance cancer immunity. These findings illustrate that the systemic context can impact anti-tumor immunity and immunotherapy responsiveness. Here, we review the current knowledge of how age and systemic metabolic state affect the anti-tumor immune response, with an emphasis on CD8+ T cells, which are key players in anti-tumor immunity. A better understanding of the underlying mechanisms may lead to novel therapies enhancing anti-tumor immunity in the context of aging or metabolic dysfunction.

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Section: Introductionmentioning

confidence: 99%

The effects of age and systemic metabolism on anti-tumor T cell responses

Drijvers

Sharpe

Haigis

2020

eLife

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“…However, it remains unclear the potential mechanism of preadmission metformin usage associated with lower mortality in AKI patients with diabetes. Metformin could improve autophagy and mitochondrial function in diabetes [26]and decrease in ammation by down-regulate proin ammatory cytokines, such as IL-6 and TNF-α [27,28]. Besides, metformin may have a potential role in antimicrobial therapy.…”

Section: Discussionmentioning

confidence: 99%

Association of Preadmission Metformin Exposure and Outcomes in Acute Kidney Injury Patients with Type 2 Diabetes in Intensive Care Unit: a Cohort Study

Zheng¹,

Wen²,

Chen³

et al. 2020

Preprint

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Background: Acute kidney injury (AKI) occurred in more than half of ICU patients. The effective prevention and therapies strategy of AKI remains limited. This study is to assess AKI mortality among diabetes patients with or without preadmission prescriptions for metformin. Methods: We included AKI patients with type 2 diabetes in Medical Information Mart for Intensive Care (MIMIC)-III database. 30-day mortality, neutrophil-to-lymphocyte ratio, and length of stay (LOS) in the hospital were compared between those with and without preoperative prescriptions. The statistical approaches included multivariate regression, propensity score analysis and an inverse probability‑weighting model to ensure the robustness of our findings. Results: In total, 4328 AKI patients with type 2 diabetes (998 in preadmission metformin usage group and 3330 in no preadmission metformin usage) were included in the analysis. The overall 30-day mortality was 14.2% (613/4328). There was 15.7% (523/3330) and 9.0% (90/998) of 30-day mortality in no preadmission metformin usage and preadmission metformin usage group, respectively. In the main analysis, preadmission metformin usage was associated with a 37% lower of 30-day mortality (HR=0.63,95% CI:0.50-0.80, p<0.0001) in inverse probability‑weighting model. Conclusions: This cohort study suggested that preadmission metformin usage may be associated with reduced risk-adjusted mortality in AKI patients with type 2 diabetes. Further randomized controlled trials are needed.

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“…Research linking the role of autophagy's impact on cellular and organismal lifespan as well as cellular nutrient and stress-sensing pathways has burgeoned in the last decade. This research has identified a growing list of pharmacological agents as well as diet and dietary compounds that lead to increased autophagy function and clearance of excess cellular protein [156][157][158][159][160][161][162][163][164][165][166][167].…”

Section: Manipulating For Lamina Protein Clearancementioning

confidence: 99%

“…Furthermore, activation of SIRT1 results in deacetylation of nuclear LC3, enabling relocalization of LC3 to the cytoplasm from the nucleus and promoting autophagy and potentially formation of nucleophagy-associated vesicles. Although there is debate surrounding target specificity of many compounds that target nutrient/energy sensing pathways, there is strong evidence linking increased AMPK and SIRT1 function with compounds such as metformin [158,159,162,[175][176][177] and resveratrol [160,[178][179][180][181][182][183], respectively to increased health and lifespan. The benefits of these compounds is likely through increased autophagy and indicates the potential therapeutic use of these compounds (or similar molecules with higher target specificity) to promote protein accumulation clearance from the lamina.…”

Section: Manipulating For Lamina Protein Clearancementioning

confidence: 99%

The Nuclear Lamina: Protein Accumulation and Disease

et al. 2020

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Cellular health is reliant on proteostasis—the maintenance of protein levels regulated through multiple pathways modulating protein synthesis, degradation and clearance. Loss of proteostasis results in serious disease and is associated with aging. One proteinaceous structure underlying the nuclear envelope—the nuclear lamina—coordinates essential processes including DNA repair, genome organization and epigenetic and transcriptional regulation. Loss of proteostasis within the nuclear lamina results in the accumulation of proteins, disrupting these essential functions, either via direct interactions of protein aggregates within the lamina or by altering systems that maintain lamina structure. Here we discuss the links between proteostasis and disease of the nuclear lamina, as well as how manipulating specific proteostatic pathways involved in protein clearance could improve cellular health and prevent/reverse disease.

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Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation

Cited by 397 publications

References 91 publications

The effects of age and systemic metabolism on anti-tumor T cell responses

The effects of age and systemic metabolism on anti-tumor T cell responses

Association of Preadmission Metformin Exposure and Outcomes in Acute Kidney Injury Patients with Type 2 Diabetes in Intensive Care Unit: a Cohort Study

The Nuclear Lamina: Protein Accumulation and Disease

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