The Effects of Metformin on Age-Related Changes in the Liver Sinusoidal Endothelial Cell

Hunt, Nicholas J.; Lockwood, Glen P.; Kang, Sun Woo; Pulpitel, Tamara; Clark, Ximonie; Mao, Hong; McCourt, Peter; Cooney, Gregory J.; Couteur, Frank H Le; Couteur, David G. Le; Cogger, Victoria C.

doi:10.1093/gerona/glz153

Cited by 35 publications

(50 citation statements)

References 41 publications

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“…AGING fenestrations) or chronic caloric restriction over a lifetime reversed the age-related loss of fenestrations [62]. In a similar manner, metformin, which acts on the AMPK nutrient-sensing pathway [55,63], increased fenestration porosity in old mice and improved insulin sensitivity [53]. Finally, there have been reports that resveratrol, which acts on the sirtuin-mediated nutrientsensing pathway [64], increases fenestrations in a Werner Syndrome mouse, which is a model for premature aging [65].…”

Section: Delaying Lsec Senescencementioning

confidence: 94%

“…Age-induced pseudocapillarization is a sequential process, starting with defenestration at a relatively young age and progressing towards LSEC thickening and fibrosis later in life ( Figure 1) [30]. In turn, finding approaches to reverse defenestration and pseudocapillarization have being actively and successfully pursued in several laboratories as a strategy to ameliorate some age-related diseases [52][53][54][55].…”

Section: Agingmentioning

confidence: 99%

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LSEC model of aging

Grosse

Bulavin

2020

Aging

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The accumulation of senescent cells has been shown detrimental in many contexts [1-5]. In turn, the analysis of senescence in vascular endothelial cells is one of the main directions in the field of vascular aging as it plays a key role in the initiation, progression, and advancement of cardio-vascular diseases [3, 6-9]. While attenuating senescence has already been shown to ameliorate several pathological conditions, more recent work suggested that elimination of senescent cells could be advantageous for health and lifespan [4, 10-12]. Removing certain senescent cells that can be robustly replaced without conferring changes on organ structure or function is clearly beneficial. However, accumulating data suggest that there are functionally important senescent cell types that might not be efficiently replaced under physiological conditions, especially in old organisms. For example, age-induced senescence has been recently described in hypothalamic stem cells [13], while we found a significant build-up of senescence in liver sinusoid endothelial cells (LSECs). LSECs are fenestrated endothelial cells that line the hepatic sinusoids. These cells have several important physiological roles, including facilitating the bi-directional transfer of substrates between the blood and hepatocytes, endocytosing circulating proteins, regulating immunotolerance, and maintaining sinusoidal microenvironment [14-24]. LSECs are the main cell type responsible for clearing blood-borne macromolecular waste [14-16], including most viruses [17-19] and lipopolysaccharides (LPS) [20, 21]. Furthermore, LSECs are responsible for the selective uptake of high-density lipoprotein [20, 22], in this way governing cardiovascular risk and all-cause mortality [23, 24]. Among the many toxins that are removed by LSECs, oxidized low density lipoprotein (oxLDL) [25, 26] is of specific interest as a major atherogenic substance [27-29]. Other toxic agents endocytosed by LSECs include Advanced Glycation End products (AGEs)heterogenous metabolic byproducts formed by non-enzymatic irreversible protein glycosylation/glycoxidation and that are resistant to proteolysis [30-32]. The accumulation of AGEs in tissues is harmful, observed in several pathological conditions [33-35], and thought to result from chronic hyperglycemia and increased oxidative and carbonyl stress [36-38]. The removal of both oxLDL and AGEs, however, is an inefficient process and their build up, as seen in several pathological conditions or after a www.aging-us.com

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Section: Delaying Lsec Senescencementioning

confidence: 94%

Section: Agingmentioning

confidence: 99%

LSEC model of aging

Grosse

Bulavin

2020

Aging

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“…In mice treated with metformin for 9 months, enhanced fenestration porosity and frequency were observed, increasing insulin sensitivity in the liver and prolonging lifespan. This is related to the activation of pAMPK, eNOS / cGMP and pMLCK / actin remodeling pathways by metformin [ 97 ]. Furthermore, in middle age mice, long-term metformin treatment improved physical performance and increase insulin sensitivity, thus extending lifespan [ 35 ].…”

Section: Mechanisms Underlying the Anti-ageing Effect Of Metforminmentioning

confidence: 99%

Metformin: A Potential Candidate for Targeting Aging Mechanisms

Hu¹,

Xie²,

Xiao³

et al. 2021

Aging and disease

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Aging is a universal phenomenon in all biological organisms, defined by the loss of reproductive capacity and a progressive decline in fitness. In humans, aging is further associated with an increased incidence of disease conditions. The current aging population has become a primary public burden of the 21 st century. Therefore, to delay the aging process and maintain fitness in the aging population, the discovery of novel antiaging drugs remains an urgent need. In recent years, metformin, a widely used hypoglycemic drug, has attracted growing attention in the field of anti-aging research. Reportedly, numerous studies have indicated that metformin regulates aging-related pathways, possibly delaying the aging process by modulating these pathways. The elucidation of these anti-aging effects may provide insights into the age-retarding potential of metformin. The present review focuses on the predominant molecular mechanisms associated with aging, as well as the anti-aging effects of metformin.

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“…Likewise, MET ameliorates age-related changes in the liver sinusoidal endothelial cell via AMPK and endothelial nitric oxide pathways [13] . Moreover, chronic AMPK activation by MET prevents cardiomyopathy by upregulating autophagy activity in diabetic OVE26 mice [14] .…”

Section: Introductionmentioning

confidence: 99%

Metformin Protects Lens Epithelial Cells Against Senescence in Naturally Aged Model of Mouse

Chen

Wang

et al. 2021

Preprint

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Background: The senescence of lens epithelial cells (LECs) is a major factor of age-related cataract (ARC). ARC results in visual impairment and severe vision loss in elderly. However, the specific mechanism of ARC is not yet clear and there are no effective therapeutic agents to halt the formation of ARC. The current study aimed to further explore the underlying mechanism of formation of ARC and investigate the potential anti-aging effect of metformin (MET) on ARC. Methods: Male C57BL/6 mice were divided into three groups: the young control group (Young, 3 months, n=40), the naturally aged group (Aged, 20months, n=60) and MET group (MET, 20 months, n=60). The young control group (Young, 3 months, n=40) and the naturally aged group (Aged, 20months, n=60) mice received ad libitum standard purified mouse diet and water, while the MET group mice were fed on chows supplied with 0.1% MET for 10 months. The transparency of lens and age-associated proteins P21, P53 were assessed in LECs in three groups. Furthermore, we determined the expressions of AMPK pathway and the effect of MET on AMPK pathway in LECs during the aging process of ARC. Besides, the relationship of autophagy and the senescence of in LECs and the role of MET in the autophagy in in LECs during the aging process of ARC were examined. Results: Our results indicated that age-related inactivation of AMPK pathway and age-related impairment of autophagy might contribute to the senescence of in LECs and occurrence of ARC. Importantly, these results demonstrated that MET effectively alleviated the senescence of in LECs and the formation of ARC probably via inactivation of AMPK pathway and augmentation of autophagy. Conclusion: These findings reveal that MET can be exploited as a potentially useful drug for ARC prevention. Our study will be informative for development of innovative strategies to the clinical treatment of ARC.

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The Effects of Metformin on Age-Related Changes in the Liver Sinusoidal Endothelial Cell

Cited by 35 publications

References 41 publications

LSEC model of aging

LSEC model of aging

Metformin: A Potential Candidate for Targeting Aging Mechanisms

Metformin Protects Lens Epithelial Cells Against Senescence in Naturally Aged Model of Mouse

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