Research Article: The role of inflammation in age-related disease

Date Published: January 30, 2013

Publisher: Impact Journals LLC

Author(s): T. Kevin Howcroft, Judith Campisi, Germaine Buck Louis, Martyn T. Smith, Bradley Wise, Tony Wyss-Coray, Alison Deckhut Augustine, Janet E. McElhaney, Ron Kohanski, Felipe Sierra.

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Abstract

The National Institutes of Health (NIH) Geroscience Interest Group (GSIG) sponsored workshop, The Role of Inflammation in Age-Related Disease, was held September 6th-7th, 2012 in Bethesda, MD. It is now recognized that a mild pro-inflammatory state is correlated with the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. Four sessions explored the intrinsic, environmental exposures and immune pathways by which chronic inflammation are generated, sustained, and lead to age-associated diseases. At the conclusion of the workshop recommendations to accelerate progress toward understanding the mechanistic bases of chronic disease were identified.

Partial Text

The NIH Geroscience Interest Group (GSIG) sponsored workshop, The Role of Inflammation in Age-Related Disease, was held September 6th-7th in Bethesda, MD. The workshop opened with a plenary talk by Luigi Ferrucci (NIA, NIH) who presented an overview of the literature supporting the emergence a mild pro-inflammatory state that is closely linked to the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. For many, inflammation is simply understood as a trajectory of biomarkers, for example the appearance of IL-6 or C-reactive protein (CRP), associated with a disease. However, inflammation is a very complex response to an injury, infection, or other stimulus, in which many different cells types and secreted factors orchestrate protective immunity, tissue repair, and resolution of tissue damage. Whereas acute inflammation limits tissue damage and resolves, chronic prolongation of the inflammatory state leads to progressive tissue damage. A central question, then, is how do we describe and begin to understand the mild pro-inflammatory state of aging. Among the causal pathways linked to the major diseases associated with aging, including physical frailty, are changes in body composition, energy imbalance, homeostatic dysregulation, and neurodegeneration. Chronic inflammation is strongly connected with each of these aging phenotypes. The inflammatory mediators IL-6, IL-18, and CRP increase with age in both women and men and are highly correlated with obesity and degenerative disease. Muscle strength, as measured by walking speed, also correlates with circulating IL-6 levels. Individuals with the lowest circulating levels had the highest walking speed. Further, in mouse models, reducing inflammation through ablation of the β subunit of the inhibitor of NFκB kinase (IKK), IKKb, improved skeletal muscle strength, maintained mass, and promoted regeneration. These data suggest that inflammation blocks critical metabolic signals that support muscle maintenance. In addition, anti-inflammatory drugs ameliorate type II diabetes and prevent cognitive decline in humans. In mouse models, blocking the NFκB pathway prevented insulin resistance and improved glucose metabolism. Lastly, systemic inflammation may predispose the microglia to a pro-inflammatory state that is associated with neurodegeneration. Although it is not clear what causes age-associated chronic inflammation, possible mechanisms include a disregulated NF-kB pathway, impaired mitochondrial function leading to excessive reactive oxygen species (ROS), the accumulation of senescent cells, and a decline in autophagy with age. Whether reducing inflammation will lead to beneficial effects on human health and function is the defining biological and medical challenge of the next decade. Following the plenary presentation were four scientific sessions, each considering in greater depth the relationships between aging, chronic inflammation, and the development of chronic diseases.

 

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