Aging and uremia: Is there cellular and molecular crossover?

White, William E.; Yaqoob, Muhammad; Harwood, Steven

doi:10.5527/wjn.v4.i1.19

Cited by 35 publications

(20 citation statements)

References 131 publications

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“…Chronic metabolic disease conditions such as diabetes mellitus or chronic kidney disease with uremia accelerate both detrimental clinical phenotypes 14 . This involves mechanisms usually associated with age, such as premature cellular senescence and other cell fates 15 adversely affecting viability, adaptibility, and resistance to stress 10,11,16 .…”

mentioning

confidence: 99%

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Schaub

Gürgen

Maus

et al. 2019

Sci Rep

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Vascular regeneration depends on intact function of progenitors of vascular smooth muscle cells such as pericytes and their circulating counterparts, mesenchymal stromal cells (MSC). Deregulated MSC differentiation and maladaptive cell fate programs associated with age and metabolic diseases may exacerbate arteriosclerosis due to excessive transformation to osteoblast-like calcifying cells. Targeting mTOR, a central controller of differentiation and cell fates, could offer novel therapeutic perspectives. In a cell culture model for osteoblastic differentiation of pluripotent human MSC we found distinct roles for mTORC1 and mTORC2 in the regulation of differentiation towards calcifying osteoblasts via cell fate programs in a temporally-controlled sequence. Activation of mTORC1 with induction of cellular senescence and apoptosis were hallmarks of transition to a calcifying phenotype. Inhibition of mTORC1 with Rapamycin elicited reciprocal activation of mTORC2, enhanced autophagy and recruited anti-apoptotic signals, conferring protection from calcification. Pharmacologic and genetic negative interference with mTORC2 function or autophagy both abolished regenerative programs but induced cellular senescence, apoptosis, and calcification. Overexpression of the mTORC2 constituent rictor revealed that enhanced mTORC2 signaling without altered mTORC1 function was sufficient to inhibit calcification. Studies in mice reproduced the in vitro effects of mTOR modulation with Rapamycin on cell fates in vascular cells in vivo. Amplification of mTORC2 signaling promotes protective cell fates including autophagy to counteract osteoblast differentiation and calcification of MSC, representing a novel mTORC2 function. Regenerative approaches aimed at modulating mTOR network activation patterns hold promise for delaying age-related vascular diseases and treatment of accelerated arteriosclerosis in chronic metabolic conditions.

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mentioning

confidence: 99%

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Schaub

Gürgen

Maus

et al. 2019

Sci Rep

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“…However, there was no significant association between perioperative fluid volume and postoperative complications in this study (data not shown), while blood transfusion was given more frequently in the low eGFR group than the normal group. Third, a number of studies have shown that renal insufficiency is associated with a variety of impaired immune system in humans [30][31][32]. For instance, uremia causes Data are presented as mean ± SD (range) or count (%) CI confidence interval, CRT chemoradiotherapy, eGFR estimated glomerular filtration rate, PDAC pancreatic ductal adenocarcinoma inflammation and reduces immune response, thereby resulting in increased susceptibility to infection.…”

Section: Discussionmentioning

confidence: 99%

Impact of preoperative asymptomatic renal dysfunction on clinical course after pancreatoduodenectomy

Nagai

Sho

Akahori

et al. 2015

J Hepatobiliary Pancreat Sci

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Background Although recent large-scale clinical studies have shown that preoperative renal insufficiency is associated with increased risk of postoperative complications after pancreatoduodenectomy (PD), it is unknown whether asymptomatic renal dysfunction has an impact on postoperative course after PD. Methods Two hundred and fifty-four patients who underwent PD between 2007 and 2013 were enrolled. Renal function was evaluated by the preoperative estimated glomerular filtration rate (eGFR). Patients were divided into two groups according to the cutoff value of 55 of eGFR. Results Thirty-five patients were classified as the low eGFR group, while 219 were classified as the normal group. There were differences between groups in age, comorbidity and pancreatic texture. The incidence of overall postoperative complication, grade B/C pancreatic fistula and severe complication in the low eGFR group was significantly higher than that in the normal group. Multivariate analysis identified low eGFR as an independent risk factor for severe postoperative complications and grade B/C pancreatic fistula after PD. However, there were no differences in mortality and survival between the low and normal eGFR groups. ConclusionsWe have demonstrated for the first time that preoperative asymptomatic renal dysfunction may be a significant risk factor for severe morbidity and clinically relevant pancreatic fistula after PD.

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“…Conversely, in an experimental model of renal failure, inflammation markers were related to increased autophagy in muscle (159). Thus, it is not yet clear whether increased or defective autophagy is a causative factor in uremic inflammation (161).…”

Section: Causes Of Uremic Inflammationmentioning

confidence: 96%

Inflammation and premature aging in advanced chronic kidney disease

Kooman

Dekker

Usvyat

et al. 2017

American Journal of Physiology-Renal Physiology

179

154

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Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed.

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Aging and uremia: Is there cellular and molecular crossover?

Cited by 35 publications

References 131 publications

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

mTORC1 and mTORC2 Differentially Regulate Cell Fate Programs to Coordinate Osteoblastic Differentiation in Mesenchymal Stromal Cells

Impact of preoperative asymptomatic renal dysfunction on clinical course after pancreatoduodenectomy

Inflammation and premature aging in advanced chronic kidney disease

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