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Cellular senescence contributes to inflammatory kidney disease via the secretion of inflammatory and profibrotic factors. Protease-activating receptor 2 (PAR2) is a key regulator of inflammation in kidney diseases. However, the relationship between PAR2 and cellular senescence in kidney disease has not yet been described. In this study, we found that PAR2-mediated metabolic changes in renal tubular epithelial cells induced cellular senescence and increased inflammatory responses. Using an aging and renal injury model, PAR2 expression was shown to be associated with cellular senescence. Under in vitro conditions in NRK52E cells, PAR2 activation induces tubular epithelial cell senescence and senescent cells showed defective fatty acid oxidation (FAO). Cpt1α inhibition showed similar senescent phenotype in the cells, implicating the important role of defective FAO in senescence. Finally, we subjected mice lacking PAR2 to aging and renal injury. PAR2-deficient kidneys are protected from adenine- and cisplatin-induced renal fibrosis and injury, respectively, by reducing senescence and inflammation. Moreover, kidneys lacking PAR2 exhibited reduced numbers of senescent cells and inflammation during aging. These findings offer fresh insights into the mechanisms underlying renal senescence and indicate that targeting PAR2 or FAO may be a promising therapeutic approach for managing kidney injury., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

β-Hydroxybutyrate (HB) is a ketone body used as an energy source that has shown anti-inflammatory effects similar to calorie restriction (CR); Here, PGC-1α, an abundantly expressed co-factor in the kidney, was reported to interact with both FoxO1 and NF-κB although the definitive interactive mechanism has not yet been reported. In this study, we investigated whether renal aging-related inflammation is modulated by HB. We compared aged rats administered with HB to calorie restricted rats and examined the modulation of FoxO1 and the NF-κB pathway through interactions with PGC-1α. We found that in aged rats treated with HB, pro-inflammatory signaling changes were reversed and showed effects comparable to CR. As FoxO1 and its target genes catalase/MnSOD were upregulated by HB treatment and PGC-1α selectively interacted with FoxO1, not with NF-κB, and ameliorated the renal inflammatory response. These findings were further confirmed using FoxO1 overexpression and siRNA transfection in vitro . Our findings suggest that HB suppressed aging-related inflammation as a CR mimetic by enabling the co-activation and selective interaction between FoxO1 and PGC-1α. This study demonstrates the potential therapeutic role of HB as a CR mimetic, which ameliorates inflammation by a novel mechanism where FoxO1 outcompetes NF-κB by interacting with PGC-1α in aging kidneys.

Age-related dysregulated inflammation plays an essential role as a major risk factor underlying the pathophysiological aging process. To better understand how inflammatory processes are related to aging at the molecular level, we sequenced the transcriptome of young and aged rat kidney using RNA-Seq to detect known genes, novel genes, and alternative splicing events that are differentially expressed. By comparing young (6 months of age) and old (25 months of age) rats, we detected 722 up-regulated genes and 111 down-regulated genes. In the aged rats, we found 32 novel genes and 107 alternatively spliced genes. Notably, 6.6% of the up-regulated genes were related to inflammation (P < 2.2 × 10-16, Fisher exact t-test); 15.6% were novel genes with functional protein domains (P = 1.4 × 10-5); and 6.5% were genes showing alternative splicing events (P = 3.3 × 10-4). Based on the results of pathway analysis, we detected the involvement of inflammation-related pathways such as cytokines (P = 4.4 × 10-16), which were found up-regulated in the aged rats. Furthermore, an up-regulated inflammatory gene analysis identified the involvement of transcription factors, such as STAT4, EGR1, and FOSL1, which regulate cancer as well as inflammation in aging processes. Thus, RNA changes in these pathways support their involvement in the pro-inflammatory status during aging. We propose that whole RNA-Seq is a useful tool to identify novel genes and alternative splicing events by documenting broadly implicated inflammation-related genes involved in aging processes., Competing Interests: The authors have no potential conflict of interest to declare.

Aging is associated with increased vulnerability to inflammatory challenge. However, the effects of altered inflammatory response on the metabolic status of tissues or organs are not well documented. In this study, we present evidence demonstrating that lipopolysaccharide (LPS)-induced upregulation of the inflammasome/IL-1β pathway is accompanied with an increased inflammatory response and abnormal lipid accumulation in livers of aged rats. To monitor the effects of aging on LPS-induced inflammation, we administered LPS (2 mg kg(-1) ) to young (6-month old) and aged (24-month old) rats and found abnormal lipid metabolism in only aged rats with increased lipid accumulation in the liver. This lipid accumulation in the liver was due to the dysregulation of PPARα and SREBP1c. We also observed severe liver inflammation in aged rats as indicated by increased ALT levels in serum and increased Kupffer cells in the liver. Importantly, among many inflammation-associated factors, the aged rat liver showed chronically increased IL-1β production. Increased levels of IL-1β were caused by the upregulation of caspase-1 activity and inflammasome activation. In vitro studies with HepG2 cells demonstrated that treatment with IL-1β significantly induced lipid accumulation in hepatocytes through the regulation of PPARα and SREBP1c. In summary, we demonstrated that LPS-induced liver inflammation and lipid accumulation were associated with a chronically overactive inflammasome/IL-1β pathway in aged rat livers. Based on the present findings, we propose a mechanism of aging-associated progression of steatohepatitis induced by endotoxin, delineating a pathogenic role of the inflammasome/IL-1β pathway involved in lipid accumulation in the liver., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Chronic inflammation is a major risk factor underlying aging and the associated diseases of aging; of particular interest is insulin resistance during aging. Chronic inflammation impairs normal lipid accumulation, adipose tissue function, mitochondrial function, and causes endoplasmic reticulum (ER) stress, which lead to insulin resistance. However, some studies show that insulin resistance itself amplifies chronic inflammation. The activity of the insulin-dependent Akt signaling pathway is highlighted because of its decrease in insulin-sensitive organs, like liver and muscle, which may underlie insulin resistance and hyperinsulinemia, and its increased levels in non-metabolic organs, such as kidney and aorta. In that the prevalence of obesity has increased substantially for all age groups in recent years, our review summarizes the data showing the involvement of chronic inflammation in obesity-induced insulin resistance, which perpetuates reciprocal interactions between the chronic inflammatory process and increased adiposity, thereby accelerating the aging process.

Mitochondrial adenine nucleotide translocator (ANT) plays important roles in the regulation of mitochondrial permeability transition and cell bioenergetics. The mouse has three ANT isoforms (1, 2 and 4) showing tissue-specific expression patterns. Although ANT1 is known to have a pro-apoptotic property, the specific functions of ANT2 have not been well determined. In the present study, ANT2 expression was significantly lower in the aged rat liver and in a liver fibrosis model. To explore the protective role of ANT2 in the liver, we established a hepa1c1c7 cell line overexpressing ANT2. Overexpression of ANT2 caused hepa1c1c7 cells to be more resistant to oxidative stress, and mitochondrial membrane potential (MMP, ∆Ψm) was relatively intact in ANT2-overexpressing cells under oxidative stress. In addition, ANT2 was found to increase ATP production by influencing mitochondrial bioenergetics. These results imply that the hepatoprotective effect of ANT2 is due to the stabilization of MMP and enhanced ATP production, and thus, maintaining ANT2 levels in the liver might be important to enhance resistance to aging and oxidative stress., (© 2012 Informa UK, Ltd.)

Peptidylarginine deiminases (PADs) are a group of posttranslational modification enzymes that citrullinate (deiminate) protein arginine residues in a Ca(2+)-dependent manner. Enzymatic citrullination abolishes positive charges of native protein molecules, inevitably causing significant alterations in their structure and functions. Among the five isoforms of PADs, PAD2 and PAD4 are proved occupants of the central nervous system (CNS), and especially PAD2 is a main PAD enzyme expressed in the CNS. We previously reported that abnormal protein citrullination by PAD2 has been closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and prion disease. Protein citrullination in these patients is thought to play a role during the initiation and/or progression of disease. However, the contribution of changes in PAD2 levels, and consequent citrullination, during developmental and aging processes remained unclear. Therefore, we used quantitative real-time RT-PCR, Western blot analysis, and immunohistochemical methods to measure PAD2 expression and localization in the brain during those processes. PAD2 mRNA expression was detected in the brains of mice as early as embryonic day 15, and its expression in cerebral cortex, hippocampus, and cerebellum increased significantly as the animals aged from 3 to 30 months old. No citrullinated proteins were detected during that period. Moreover, we found here, for the first time, that PAD2 localized specifically in the neuronal cells of the cerebral cortex and Purkinje cells of the cerebellum. These findings indicate that, despite PAD2's normally inactive status, it becomes active and citrullinates cellular proteins, but only when the intracellular Ca(2+) balance is upset during neurodegenerative changes.

Although systems biology is a perfect framework for investigating system-level declines during aging, only a few reports have focused on a comprehensive understanding of system-level changes in the context of aging systems. The present study aimed to understand the most sensitive biological systems affected during aging and to reveal the systems underlying the crosstalk between aging and the ability of calorie restriction (CR) to effectively slow-down aging. We collected and analyzed 478 aging- and 586 CR-related mouse genes. For the given genes, the biological systems that are significantly related to aging and CR were examined according to three aspects. First, a global characterization by Gene Ontology (GO) was performed, where we found that the transcriptome (a set of genes) for both aging and CR were strongly related in the immune response, lipid metabolism, and cell adhesion functions. Second, the transcriptional modularity found in aging and CR was evaluated by identifying possible functional modules, sets of genes that show consistent expression patterns. Our analyses using the given functional modules, revealed systemic interactions among various biological processes, as exemplified by the negative relation shown between lipid metabolism and the immune response at the system level. Third, transcriptional regulatory systems were predicted for both the aging and CR transcriptomes. Here, we suggest a systems biology framework to further understand the most important systems as they age.

Senescence maker protein 30 (SMP30) is decreased in an androgen-independent manner in kidney and liver with age. However, regulation of SMP30 expression in the brain has not been examined in aging and neurodegenerative diseases. To investigate SMP30 expression in the brain, we utilized aging and kainate (KA)-induced neurodegenerative disease models. Interestingly, expression of SMP30 was unlikely to decrease in the aged brain, but total levels of SMP30 protein were increased at 4 weeks after KA injury. Increased glial fibrillary acidic protein (GFAP) with elevated SMP30 expression was observed at the same time post-KA, indicating that regulation of SMP30 expression in the brain may be associated with astrocytosis. We confirmed that KA induced GFAP expression with increased SMP30 in rat astrocyte cells. Moreover, we found that ERK1/2 activation was involved in the up-regulation of SMP30 in astrocytes. Our results suggest that elevated SMP30 in activated astrocytes plays an important supportive role after brain damage., (2009 Wiley-Liss, Inc.)

To investigate effects of aging on adhesion molecules (AMs), the present study assessed the expressions of aortic P-selectin and vascular adhesion molecule-1 (VCAM-1) in young (6-month-old) and old (24-month-old) Fischer 344 rats fed ad libitum (AL) or calorie-restricted diets. Results showed increased levels of aortic P-selectin and VCAM-1 in the old AL rats, causing excessive leukocyte infiltration as indicated by enhanced myeloperoxidase level. These elevations were parallel to increased oxidative stress including lipid peroxides during aging. Then involvement of redox-sensitive transcription factor nuclear factor-kappaB was analyzed, and greater activation of nuclear factor-kappaB-inducing kinase (NIK)/IkappaB kinase (IKK)/Inhibitor of kappaB (IkappaB) pathway in aorta from old AL rats was found. Further, in cultured endothelial cells challenged by various oxidative stimuli, the induced redox imbalance triggered overexpression and promoter activities of P-selectin and VCAM-1. Our study documented that aortic upregulated AMs with age are closely related to activation of NIK/IKK/IkappaB/nuclear factor-kappaB pathway brought on by oxidative stress.

Myeloperoxidase (MPO), a heme protein existing in neutrophil and monocyte, is implicated in various stages of inflammatory conditions with the production of a variety of potent oxidants. To investigate the extent of the involvement of MPO in aging, we measured MPO activities in kidney of rats at different ages maintained with an ad libitum (AL) or a calorie restriction (CR) dietary regimen. Results showed that the MPO activities increased during aging in AL rats, but were significantly attenuated by CR. This result was consistent with altered protein level of MPO during aging. In addition, we were able to detect dityrosine that is a stable end MPO-oxidation product. The amount of dityrosine increased in old AL, but not in old CR rats. To examine the source responsible for increased MPO activity during aging for leukocyte recruitment and infiltration, the levels of vascular cell adhesion molecule (VCAM-1) protein were measured. The level of VCAM-1 showed age-dependent increase in AL rats, which was correlated with higher activity of MPO in old AL rats. Furthermore, we have found that LPS-induced inflammation increased the activity and protein levels of MPO, and VCAM-1 expression in young rat kidneys. These findings suggest that increased MPO activity with aging may related to increased recruitment of inflammatory cells, contributing to protein oxidation accumulation in the aging process. We propose that age-related alterations of MPO, dityrosine, and VCAM were modulated by CR through its anti-inflammatory action.

Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease., (Copyright 2002 Elsevier Science Inc.)

Macroautophagy/autophagy is a central mechanism by which cells maintain integrity and homeostasis, and endotoxin-induced autophagy plays important roles in innate immunity. Although TLR4 stimulation mediated by lipopolysaccharide (LPS) also upregulates autophagy in hepatocytes and liver, its physiological role remains elusive. The objective of this study was to determine the role of LPS-induced autophagy in the regulation of liver lipid metabolism. LPS treatment (5 mg/kg) increased autophagy, as detected by LC3 conversion and transmission electron microscopy (TEM) analysis in C57BL6 mouse livers. AC2F hepatocytes also showed increased autophagic flux after LPS treatment (1 μg/ml). To investigate the role of LPS-induced autophagy further, liver lipid metabolism changes in LPS-treated mice and fasted controls were compared. Interestingly, LPS-treated mice showed less lipid accumulation in liver than fasted mice despite increased fatty acid uptake and lipid synthesis-associated genes. In vitro analysis using AC2F hepatocytes demonstrated LPS-induced autophagy influenced the degradation of lipid droplets. Inhibition of LPS-induced autophagy using bafilomycin A1orAtg7knockdown significantly increased lipid accumulation in AC2F hepatocytes. In addition, pretreatment with chloroquine aggravated LPS-induced lipid accumulation and inflammation in C57BL6 mouse livers. The physiological importance of autophagy was verified in LPS-treated young and aged rats. Autophagic response was diminished in LPS-treated aged rats and lipid metabolism was impaired during sepsis, indicating autophagy response is important for regulating lipid metabolism after endotoxin challenge. Our findings demonstrate endotoxin-induced autophagy is important for the regulation of lipid metabolism, and suggest that autophagy helps maintain lipid metabolism homeostasis during sepsis. [ABSTRACT FROM PUBLISHER]

Social work curriculum that offers an optimistic perspective on aging has the potential to help social work students go on to practice in a nondiscriminatory way with older adults. This study introduces social work students to the productive aging concept, an optimistic view to social potential in later life, in lecture format and assesses postlecture changes in their perceptions of older adults. Seventy-two students (16 BSW; 56 MSW) were recruited from a large university in the southeast United States to participate in a lecture on productive aging. A one-group pretest–posttest design was used, and a paired samplesttest (n= 72) was used to analyze changes in social work students’ perceptions toward older adults. Negative attitudes toward older adults decreased and positive attitudes toward older adults increased among students following their participation in the lecture on productive aging. This finding suggests the productive aging concept may favorably influence student perceptions of older adults. Future research should aim to investigate ways in which these changes in perception at the college level can translate and self-sustain in social work practice for social work students postgraduation. [ABSTRACT FROM PUBLISHER]

Aging is associated with increased vulnerability to inflammatory challenge. However, the effects of altered inflammatory response on the metabolic status of tissues or organs are not well documented. In this study, we present evidence demonstrating that lipopolysaccharide ( LPS)-induced upregulation of the inflammasome/ IL-1β pathway is accompanied with an increased inflammatory response and abnormal lipid accumulation in livers of aged rats. To monitor the effects of aging on LPS-induced inflammation, we administered LPS (2 mg kg−1) to young (6-month old) and aged (24-month old) rats and found abnormal lipid metabolism in only aged rats with increased lipid accumulation in the liver. This lipid accumulation in the liver was due to the dysregulation of PPARα and SREBP1c. We also observed severe liver inflammation in aged rats as indicated by increased ALT levels in serum and increased Kupffer cells in the liver. Importantly, among many inflammation-associated factors, the aged rat liver showed chronically increased IL-1β production. Increased levels of IL-1β were caused by the upregulation of caspase-1 activity and inflammasome activation. In vitro studies with HepG2 cells demonstrated that treatment with IL-1β significantly induced lipid accumulation in hepatocytes through the regulation of PPARα and SREBP1c. In summary, we demonstrated that LPS-induced liver inflammation and lipid accumulation were associated with a chronically overactive inflammasome/ IL-1β pathway in aged rat livers. Based on the present findings, we propose a mechanism of aging-associated progression of steatohepatitis induced by endotoxin, delineating a pathogenic role of the inflammasome/ IL-1β pathway involved in lipid accumulation in the liver. [ABSTRACT FROM AUTHOR]

Abstract: Senescence marker protein 30 (SMP30) was recently identified as gluconolactonase, which is involved in vitamin C (VC) biosynthesis. Therefore, the antioxidant property of SMP30 is thought to be mediated by its gluconolactonase function. However, pathologic effects of SMP30 deficiency independent of VC biosynthesis have not been studied in models of neurodegenerative diseases. In the present study, we evaluated the effect of SMP30 deficiency on Parkinson’s disease (PD) in SMP30 knockout (KO) mice. Wild type and SMP30 KO mice supplemented with VC were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results showed that MPTP-induced dopaminergic neuronal loss and motor function impairment were more significant in the SMP30 KO mice. Reactive oxygen species generation and microglia activation were higher in MPTP-treated SMP30 KO mice. However, SMP30 deficiency mitigated MPTP-induced astrocyte activation and glia-derived neurotrophic factor production. Cultures of astrocytes recovered from wild type and SMP30 KO mice revealed that SMP30 deficiency abolished 1-methyl-4-phenyl-pyridinium-induced astroglial activation by blocking the extracellular signal-regulated kinase pathway. Taken together, our findings demonstrate for the first time that SMP30 deficiency increases the severity of PD and suggest a beneficial role of SMP30 in protective astrocyte activation in response to neurodegeneration. The present study shows that modulation of astrocytic SMP30 can be a promising target for treating PD. [Copyright &y& Elsevier]