Review 

Nat Rev Endocrinol

. 2018 Oct;14(10):576-590. doi: 10.1038/s41574-018-0059-4.

Inflammaging: a new immune-metabolic viewpoint for age-related diseases

Claudio Franceschi 1, Paolo Garagnani 2 3 4 5, Paolo Parini 3, Cristina Giuliani 6 7, Aurelia Santoro 2 8

Affiliations Expand

• PMID: 30046148

•  DOI: 10.1038/s41574-018-0059-4

Abstract

Ageing and age-related diseases share some basic mechanistic pillars that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation - called inflammaging - develops, which contributes to the pathogenesis of age-related diseases. From an evolutionary perspective, a variety of stimuli sustain inflammaging, including pathogens (non-self), endogenous cell debris and misplaced molecules (self) and nutrients and gut microbiota (quasi-self). A limited number of receptors, whose degeneracy allows them to recognize many signals and to activate the innate immune responses, sense these stimuli. In this situation, metaflammation (the metabolic inflammation accompanying metabolic diseases) is thought to be the form of chronic inflammation that is driven by nutrient excess or overnutrition; metaflammation is characterized by the same mechanisms underpinning inflammaging. The gut microbiota has a central role in both metaflammation and inflammaging owing to its ability to release inflammatory products, contribute to circadian rhythms and crosstalk with other organs and systems. We argue that chronic diseases are not only the result of ageing and inflammaging; these diseases also accelerate the ageing process and can be considered a manifestation of accelerated ageing. Finally, we propose the use of new biomarkers (DNA methylation, glycomics, metabolomics and lipidomics) that are capable of assessing biological versus chronological age in metabolic diseases.

Review 

Nat Rev Cardiol

. 2018 Sep;15(9):505-522. doi: 10.1038/s41569-018-0064-2.

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

Luigi Ferrucci 1, Elisa Fabbri 2

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• PMID: 30065258

•  PMCID: PMC6146930

•  DOI: 10.1038/s41569-018-0064-2

Abstract

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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Science

. 2004 Mar 5;303(5663):1532-5. doi: 10.1126/science.1092385.

Neutrophil extracellular traps kill bacteria

Volker Brinkmann 1, Ulrike Reichard, Christian Goosmann, Beatrix Fauler, Yvonne Uhlemann, David S Weiss, Yvette Weinrauch, Arturo Zychlinsky

Affiliations Expand

• PMID: 15001782

•  DOI: 10.1126/science.1092385

Free article

Abstract

Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.

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Nat Med

. 2015 Aug;21(8):880-6. doi: 10.1038/nm.3913. Epub 2015 Jul 27.

Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin

Elena Zenaro 1, Enrica Pietronigro 1, Vittorina Della Bianca 1, Gennj Piacentino 1, Laura Marongiu 1, Simona Budui 1, Ermanna Turano 2, Barbara Rossi 1, Stefano Angiari 1, Silvia Dusi 1, Alessio Montresor 3, Tommaso Carlucci 1, Sara Nanì 1, Gabriele Tosadori 3, Lucia Calciano 4, Daniele Catalucci 5, Giorgio Berton 1, Bruno Bonetti 2, Gabriela Constantin 3

Affiliations Expand

• PMID: 26214837

•  DOI: 10.1038/nm.3913

Abstract

Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-β (Aβ) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aβ42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease-like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease.

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Acta Neuropathol Commun. 2023 Jun 12;11:93. doi: 10.1186/s40478-023-01590-1

Chronic cerebral hypoperfusion: a critical feature in unravelling the etiology of vascular cognitive impairment

Vismitha Rajeev 1,2, Yuek Ling Chai 1,2,#, Luting Poh 1,2,#, Sharmelee Selvaraji 1,2,3,#, David Y Fann 1, Dong-Gyu Jo 4, T Michael De Silva 5, Grant R Drummond 5, Christopher G Sobey 5, Thiruma V Arumugam 4,5, Christopher P Chen 1,2,6, Mitchell K P Lai 1,2,6,✉

• Author information

• Article notes

• Copyright and License information

PMCID: PMC10259064  PMID: 37309012

Abstract

Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus allowing preventive interventions instead of symptomatic treatments.

Keywords: Vascular dementia, Neuronal cell death, Chronic cerebral hypoperfusion, White matter lesions

Neuron. Author manuscript; available in PMC: 2014 Nov 20.

Published in final edited form as: Neuron. 2013 Nov 20;80(4):10.1016/j.neuron.2013.10.008. doi: 10.1016/j.neuron.2013.10.008

The pathobiology of vascular dementia

Costantino Iadecola 1

• Author information

• Copyright and License information

PMCID: PMC3842016  NIHMSID: NIHMS531326  PMID: 24267647

The publisher's version of this article is available at Neuron

Abstract

Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer’s disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that links inextricably the well being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer’s disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.

Alzheimers Dement

. 2019 Jan;15(1):158-167. doi: 10.1016/j.jalz.2018.07.222.

Vascular dysfunction-The disregarded partner of Alzheimer's disease

Melanie D Sweeney 1, Axel Montagne 1, Abhay P Sagare 1, Daniel A Nation 2, Lon S Schneider 3, Helena C Chui 4, Michael G Harrington 5, Judy Pa 6, Meng Law 7, Danny J J Wang 6, Russell E Jacobs 1, Fergus N Doubal 8, Joel Ramirez 9, Sandra E Black 10, Maiken Nedergaard 11, Helene Benveniste 12, Martin Dichgans 13, Costantino Iadecola 14, Seth Love 15, Philip M Bath 16, Hugh S Markus 17, Rustam Al-Shahi Salman 8, Stuart M Allan 18, Terence J Quinn 19, Rajesh N Kalaria 20, David J Werring 21, Roxana O Carare 22, Rhian M Touyz 23, Steve C R Williams 24, Michael A Moskowitz 25, Zvonimir S Katusic 26, Sarah E Lutz 27, Orly Lazarov 27, Richard D Minshall 28, Jalees Rehman 29, Thomas P Davis 30, Cheryl L Wellington 31, Hector M González 32, Chun Yuan 33, Samuel N Lockhart 34, Timothy M Hughes 34, Christopher L H Chen 35, Perminder Sachdev 36, John T O'Brien 37, Ingmar Skoog 38, Leonardo Pantoni 39, Deborah R Gustafson 40, Geert Jan Biessels 41, Anders Wallin 42, Eric E Smith 43, Vincent Mok 44, Adrian Wong 45, Peter Passmore 46, Frederick Barkof 47, Majon Muller 48, Monique M B Breteler 49, Gustavo C Román 50, Edith Hamel 51, Sudha Seshadri 52, Rebecca F Gottesman 53, Mark A van Buchem 54, Zoe Arvanitakis 55, Julie A Schneider 55, Lester R Drewes 56, Vladimir Hachinski 57, Caleb E Finch 58, Arthur W Toga 59, Joanna M Wardlaw 8, Berislav V Zlokovic 60

Affiliations Expand

• PMID: 30642436

•  PMCID: PMC6338083

•  DOI: 10.1016/j.jalz.2018.07.222

Erratum in

• Erratum.

• [No authors listed]

• Alzheimers Dement. 2022 Mar;18(3):522. doi: 10.1002/alz.12483. Epub 2022 Feb 2.

• PMID: 35112491 No abstract available.

Abstract

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Keywords: Alzheimer's disease; Biomarkers; Blood-brain barrier; Cerebral blood flow; MRI; Vascular.

Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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