Review
Inflammaging and ‘Garb-aging’

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Human aging is characterized by a state of chronic, low-grade, sterile inflammation (inflammaging), the causes of which are poorly understood.

A possible cause of inflammaging is the continuous stimulation of macrophages by molecular garbage whose generation–disposal balance becomes impaired with age.

Misplaced self-molecules can be sensed by macrophage receptors and contribute to inflammaging by activating the inflammasome.

Self-molecules (nuclear and/or mtDNA), and other cellular garbage and signaling molecules (miRNAs) freely circulate in bodily fluids within extracellular vesicles carrying inflammatory signals that can spread to distal cells and tissues.

Age-related mitochondrial dysfunction could be linked to inflammaging (source of oxidative stress) and ‘self garbage’ (mtDNA, cardiolipin, or formyl peptides) that can be sensed by macrophages.

‘Inflammaging’ refers to the chronic, low-grade inflammation that characterizes aging. Inflammaging is macrophage centered, involves several tissues and organs, including the gut microbiota, and is characterized by a complex balance between pro- and anti-inflammatory responses. Based on literature data, we argue that the major source of inflammatory stimuli is represented by endogenous/self, misplaced, or altered molecules resulting from damaged and/or dead cells and organelles (cell debris), recognized by receptors of the innate immune system. While their production is physiological and increases with age, their disposal by the proteasome via autophagy and/or mitophagy progressively declines. This ‘autoreactive/autoimmune’ process fuels the onset or progression of chronic diseases that can accelerate and propagate the aging process locally and systemically. Consequently, inflammaging can be considered a major target for antiaging strategies.

Section snippets

Aging Is Characterized by Chronic Low-Grade Inflammation

It is well established that aging is a major risk factor for all chronic diseases and geriatric syndromes [cardiovascular diseases (CVD) and neurodegenerative diseases, cancer, type 2 diabetes mellitus (T2DM), arthritis, chronic obstructive pulmonary disease, sarcopenia, frailty, among others] that negatively affect health span and longevity. Many epidemiological and biodemographic studies show that biomarkers of inflammation are robust predictors of morbidity (chronic diseases) and mortality

Inflammaging and Anti-Inflammaging: The Biological Structure of Inflammatory Markers

In most studies, inflammaging has been assessed and tested by measuring a limited number of inflammatory molecules, namely cytokines, chemokines, and acute-phase proteins, in the blood of older subjects [4]. By contrast, in the ‘InCHIANTI’ study, 19 inflammatory biomarkers were measured and principal component analysis (PCA) was used to reveal an unexpected relation among these markers [5]. The first component of the PCA was driven largely by the soluble tumor necrosis factor receptors (STNF-RI

Inflammaging and Anti-Inflammaging: The Results of Metabolomics and Lipidomics

A study involving 143 centenarians, 210 offspring of centenarians, 73 offspring of nonlong-lived parents and 21 young subjects, identified a metabolomics signature of aging and longevity involving amino acids [tryptophan (Trp), tyrosine, and phenylalanine], lysophosphatidylcholines, sphingomyelins, glycerophospholipids, and an age-related complex remodeling of arachidonic acid products with a concomitant increase in both pro-inflammatory leukotrienes and anti-inflammatory compounds (HETE and

Inflammaging and Anti-Inflammaging: The Contribution of Gut Microbiota

The age-related differences in the gut microbiota (GM) composition among young adults, older humans, and centenarians, were recently explored [15]. It was observed that, in centenarians, the GM is characterized by a rearrangement in the Firmicutes population, an enrichment in facultative anaerobes, notably ‘pathobionts’ (i.e., opportunistic proinflammatory bacteria generally present in the adult gut ecosystem in low numbers), and a marked decrease in Faecalibacterium prauznitzii and its

Inflammaging within the New Perspective of Geroscience

Over the past 10–15 years, a consistent and coherent literature has accumulated suggesting that, beyond the immune system, a variety of organs, tissues, and cells, including skeletal muscle and adipose tissue (AT), are capable of producing proinflammatory compounds [19]. Within this perspective, inflammaging should be considered a multifactorial, multiorgan, and systemic process, characterized by complex interactions of a plethora of molecular mediators within a larger network of basic

Where Do the Stimuli Fuelling Inflammaging Come From?

Previous research suggested that inflammatory stimuli that trigger and sustain inflammaging largely derive from long-lasting exposure to persistent viral infections and are modulated by one's own clinical history (‘immune biography’) [21]. A large body of evidence indicates cellular debris and misplaced and/or misfolded self-molecules as important and perhaps dominant players in such a process (Figure 1). In fact, persistent viral infections appear to be dispensable, at least in part, in the

Inflammaging and Misplaced Self-Molecules

When cells actively proliferate, end-products of metabolism and catabolism, as well as damaged or dysfunctional proteins, become diluted into daughter cells; however, in nonproliferating cells, such as neurons, they can accumulate in vivo until a crucial threshold is reached, after which the cells die [43]. These products include lipofuscins, advanced glycation end-products (AGEs), Tau protein aggregates, alpha-synuclein fibrils, and beta-amyloid networks. All these products can be recognised

Propagation of Inflammaging: The Communicomes

Local and systemic inflammaging favors the onset of chronic diseases when additional determinants (genetic risk variants, unhealthy lifestyle, and early events favoring inflammation with late effects in adult and old age) are involved. It is likely that chronic diseases accelerate organismal aging in a vicious cycle that is difficult to stop [26]. In favor of this assumption, several data suggest that cell senescence propagates from cell to cell via a bystander effect (‘senescence-induced

Concluding Remarks and Future Perspectives

The search for the final determinants of aging is an endless quest. The link between chronic stress, the microbiota–gut–brain axis, and increased inflammatory state is emerging as a unified body–brain–mind framework that can be used to understand aging and age-related diseases [81]. We propose here a unifying perspective that has the potential to form a coherent framework of the fragmented pieces of evidence published in diverse fields from apoptosis, cell death, and cancer, to obesity. In its

Acknowledgments

This work was supported by the European Union (EU)’s H2020 Project ‘Propag-ageing’ (grant agreement no. 634821) to C.F. and P.G.; EU JPND ‘Adage’ to C.F., EU FP7 NU-AGE (grant agreement no. 266486) to C.F. and University of Bologna FARB linea 2 Project 2014 no. RFBO120790 to M.C.

Glossary

Communicome
a term coined by Tony Wyss-Coray [73] to indicate the proteins that carry information from one cell to another. In this review, ‘communicome’ is used to indicate all the molecules (not exclusively proteins) actively secreted or passively released in the blood stream. We intend that every organ and/or tissue has its own ‘communicome’, which can differ (totally or partially) from that of other organs and/or tissues.
‘Garbage’
used here to indicate all the cellular and molecular products

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