Ageing: from inflammation to cancer

Leonardi, Giulia C.; Accardi, Giulia; Monastero, Roberto; Nicoletti, Ferdinando; Libra, Massimo

doi:10.1186/s12979-017-0112-5

Cited by 163 publications

(110 citation statements)

References 95 publications

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“…Moreover, because inflammation also contributes to the pathogenesis of other chronic non-CVDs — such as anaemia, cancer, type 2 diabetes, dementia, osteoporosis, sarcopenia, chronic kidney disease, and depression — CVDs in old age often develop in the context of multimorbidity and frailty 3,10,138–143 (Fig. 2).…”

Section: Consequences Of Inflammageing For Cvdmentioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

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Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

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Section: Consequences Of Inflammageing For Cvdmentioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

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“…The dose and time-dependence of radiation exposure can significantly alter the impact of RT on tumor microenvironment by affecting tumor or stromal cell behavior, migration, and treatment response (26,28,29,(83)(84)(85)(86)(87)(88)(89)(90). High-dose irradiation effects include hemorrhage, cognitive decline, neurodegeneration, and premature senescence, which can progress over time (91,92). To identify whether the 20Gy single dose led to aging-like metabolic phenotype or severe neurotoxicity, two aged-mice groups were included (aged (24mo) and aged-obese (24mo)) and their metabolic profiles were compared with 20Gy-IR in C57BL/6 mice cohorts.…”

Section: Discussionmentioning

confidence: 99%

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Gupta

Vučković

Zhang

et al. 2020

Preprint

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AbstractGlioblastoma (GBM) is uniformly fatal with a one year median survival rate, despite the best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified the tumor-promoting effects of prior radiotherapy (RT) on patient-derived intracranial GBM xenografts and characterized the metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24h following 20Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p<0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from the radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (like, modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of the pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1H-NMR revealed significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, TCA intermediates, and increased ATP and GTP. Glutathione and ASC showed highest VIPpred (1.65) in OPLS-DA analysis. Involvement of ASC catabolism was further confirmed by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occuring 2 months vs. 24h following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, as well as elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest that IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

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“…In this sense, analysis of the CD4+/CD8+ dynamics, as a simultaneous marker of allostatic load and premature aging of the immune system has an important prognostic value. Traditionally, in the characterization of immune aging, considerable attention is given to SASP (senescence-associated secretory phenotype), among them an important role is played by soluble factors of the immune system, in particular, inflammatory factors (Wajapeyee et al, 2008;Leonardi et al, 2018;McHugh & Gil, 2018). Their accumulation is a consequence of an imbalance between inflammatory and anti-inflammatory mechanisms, leading to activation of inflammatory processes (Franceschi et al, 2007;Cevenini et al, 2013;Minciullo et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…It is recommended to consider the age factor here (Juster et al, 2010;Cool & Zappetti, 2019). Dysfunctions of these indicators are, at the same time, typical effects of radiation exposure (Korenev et al, 2009;Minchenko et al, 2013;Bilokur, 2018) and biomarkers of premature aging of the organism (López-Otín et al, 2013;Leonardi et al, 2018;McHugh & Gil, 2018).…”

Section: Introductionmentioning

confidence: 99%

Manifestations of allostatic load in residents of radiation contaminated areas aged 18–24 years

Sokolenko¹,

Sokolenko²

2019

Regul. Mech. Biosyst.

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We studied the features of allostatic load (AL) in 100 students aged 18–24 years old who, from birth to adulthood, lived in the territories assigned to the IV radiation zone after the Chornobyl accident (density of soil contamination by isotopes 137Cs 3.7–18.5∙104 Bq/m2) and underwent prolonged exposure to small doses of ionizing radiation. The examined students did not have any clinical signs of the immune-neuroendocrine system dysfunction. 50 people had signs of vegetative-vascular dystonia syndrome (VVD), 48 had signs of moderate hyperthyroidism and 21 had signs of moderate hypothyroidism. During the examination session, as a factor of additional psycho-emotional load, in 66 of the examined the immunoregulatory index CD4+/CD8+ went below the lower limit of the homeostatic norm, in 62 of the examined low density lipoprotein cholesterol (LDL-C) exceeded the upper level. The relative risk (RR) and attributable risk (AR) of the participation of potential secondary factors of allostatic load formation in CD4+/CD8+ immunoregulatory index going below the lower limit were calculated. The presence of statistically significant relative risk of participation in the formation of suppression of the index CD4+/CD8+: the state of hyperthyroidism, state of hypothyroidism, vegetative-vascular dystonia syndrome, higher than normal LDL-C. When the examined students combined the signs of hyperthyroidism, vegetative-vascular dystonia syndrome and higher level of LDL-C; with combination of signs of hypothyroidism, vegetative-vascular dystonia syndrome and higher level of LDL-C. The attributable risk in all cases exceeded 0.10, which confirmed the importance of some of these factors and their complexes in the formation of the effect of reduced immunoregulatory index. The CD4+/CD8+ index can be considered an important biomarker of AL and premature age-related changes in the immune system in residents of radiation-contaminated areas. The risk of AL formation in the case of occurrence of a complex of mediated secondary biomarkers (vegetative-vascular dystonia syndrome, thyroid dysfunction, hypercholesterolemia) is higher compared to their individual significance.

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Ageing: from inflammation to cancer

Cited by 163 publications

References 95 publications

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Manifestations of allostatic load in residents of radiation contaminated areas aged 18–24 years

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