PPARγ agonists delay age‐associated metabolic disease and extend longevity

Xu, Lingyan; Ma, Xinran; Verma, N. K.; Périè, Luce; Pendse, Jay; Shamloo, Sama; Josephson, Anne Marie; Wang, Dongmei; Qiu, Jin; Guo, Mingwei; Ping, Xiaodan; Allen, Michele D.; Noguchi, Audrey; Springer, Danielle; Shen, Fei; Liu, Caizhi; Zhang, Shiwei; Li, Lingyu; Jin, Li; Xiao, Junjie; Lu, Jian; Du, Zhen‐Yu; Luo, Jian; Alemán, José O.; Leucht, Philipp; Mueller, Elisabetta

doi:10.1111/acel.13267

Cited by 36 publications

(19 citation statements)

References 47 publications

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“…Our results showed that the protective effect of LXA4 was reversed by GW9662, indicating that LXA4 exerts its renal protection by binding to PPAR-g. As the main function of PPAR during the inflammatory reaction is to promote the inactivation of NF-kB (23), and NF-kB signaling was also implicated in cellular senescence via the ROS-NF-kB-p53 pathway (33), we further determined the expression of the NF-kB-p53-p21 senescent pathway in the kidney sections and found that the pathway was activated in the CLP model, and the changes were reversed by the PPAR-g antagonist GW9662. These results are consistent with a recent study showing that PPAR-g agonists delays cellular senescence and age-associated metabolic disease (34). All the results indicate that LXA4 exerts its anti-senescence and antiinflammatory effects via the PPAR-g/NF-kB pathway.…”

Section: Discussionsupporting

confidence: 93%

Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence

et al. 2021

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Acute kidney injury (AKI) occurs in half of patients with septic shock, resulting in unacceptably high mortality. However, effective preventive treatments are still lacking. We hypothesized that pretreatment with lipoxin A4 (LXA4), known to promote inflammation resolution, may attenuate septic AKI via blocking crosstalk between inflammation and cellular senescence. In this study, rats developed AKI following cecal ligation and puncture (CLP), as evidenced by a dynamic increase in serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and pathological injury, accompanied by increased levels of inflammation (IL-6, TNF-α, and HMGB1) and tubular cell senescence. While, on the one hand, inhibition of senescence with rapamycin restored renal function and attenuated septic inflammatory response, on the other hand, LXA4 administration inhibited renal inflammation and tubular epithelial cell senescence after CLP. Ultimately, pretreatment with LXA4 significantly restored renal function and increased the survival rate of rats after CLP. Furthermore, LXA4 inhibited NF-κB-mediated inflammatory response and the p53/p21 senescence pathway in vivo and in vitro. However, the effect was reversed by PPAR-γ siRNA and antagonist. These results indicated that LXA4 exerted its renoprotective effects by blocking the crosstalk between inflammation and premature senescence in a PPAR-γ-dependent manner. Our findings also suggested that premature senescence plays a critical role in septic AKI and that inhibition of the crosstalk between inflammation and premature senescence may represent a new and major mechanism through which LXA4 attenuates septic AKI.

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Section: Discussionsupporting

confidence: 93%

Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence

et al. 2021

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“…Many studies have provided reliable clinical evidence, suggesting that insulin resistance is a major cardiovascular risk factor independent of other risk factors in CVDs in older adults in community populations and patients with type I and type II diabetes ( 79 ). In patients with ischemic stroke, insulin resistance is independently associated with poor functional prognosis after acute ischemic stroke ( 80 , 81 ). Skeletal muscle is the leading site of glucose uptake, deposition, and actin secretion, which protect insulin resistance.…”

Section: The Pathogenesis Of Sarcopenia and Cvdsmentioning

confidence: 99%

Relationship Between Sarcopenia and Cardiovascular Diseases in the Elderly: An Overview

Zhang

et al. 2021

Front. Cardiovasc. Med.

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With the advent of population aging, aging-related diseases have become a challenge for governments worldwide. Sarcopenia has defined as a clinical syndrome associated with age-related loss such as skeletal muscle mass, strength, function, and physical performance. It is commonly seen in elderly patients with chronic diseases. Changes in lean mass are common critical determinants in the pathophysiology and progression of cardiovascular diseases (CVDs). Sarcopenia may be one of the most important causes of poor physical function and decreased cardiopulmonary function in elderly patients with CVDs. Sarcopenia may induce CVDs through common pathogenic pathways such as malnutrition, physical inactivity, insulin resistance, inflammation; these mechanisms interact. In this study, we aimed to investigate the relationship between sarcopenia and CVDs in the elderly. Further research is urgently needed to understand better the relationship, pathophysiology, clinical presentation, diagnostic criteria, and mechanisms of sarcopenia and CVDs, which may shed light on potential interventions to improve clinical outcomes and provide greater insight into the disorders above.

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“…Transient receptor potential vanilloid 1 (TRPV1), which is also a target of anandamide, has been recently implicated in the expression of LTP at hippocampal CA1 region [ 24 ]. Thus, we evaluated if TRPV1 antagonism with a specific drug (AMG9810) might reverse the beneficial effect on synaptic plasticity observed in 5xFAD FAAH-null mice.…”

Section: Resultsmentioning

confidence: 99%

Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer's disease

Ruiz‐Pérez

Esteban

Marqués

et al. 2021

J Neuroinflammation

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Background The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. Methods In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse− model. Results We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3–CA1 synapse, both basal synaptic transmission and long-term potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron–glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH−/− animals. Conclusion In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer’s disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the disease.

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PPARγ agonists delay age‐associated metabolic disease and extend longevity

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 36 publications

References 47 publications

Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence

Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence

Relationship Between Sarcopenia and Cardiovascular Diseases in the Elderly: An Overview

Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer's disease

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