Inflammaging and ‘Garb-aging’

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. ‘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. a term coined by Tony Wyss-Coray [73Ray S. et al.Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins.Nat. Med. 2007; 13: 1359-1362Crossref PubMed Scopus (673) Google Scholar] 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. used here to indicate all the cellular and molecular products usually disposed of by specific enzymes or enzymatic complexes. These products can also be recognized by cleaning receptors and phagocytosed by other cells, activating the inflammatory response. Here, the new term ‘garb-aging’ is proposed (contraction of ‘garbage + aging’). This term indicates the production and eventually accumulation of ‘garbage’ (i.e., misfolded/misplaced self-molecules) as a cause of inflammation and inflammaging. interdisciplinary field aimed at understanding the relation between aging and age-related diseases. Since aging is the major risk factor for most nongenetic chronic diseases, understanding the role of aging in the onset of disease will open new avenues for disease prevention and cure. a term coined by Claudio Franceschi [3Franceschi C. et al.Inflamm-aging. An evolutionary perspective on immunosenescence.Ann. N.Y. Acad. Sci. 2000; 908: 244-254Crossref PubMed Google Scholar] and is the contraction of ‘inflammation + aging’ to indicate the low-grade chronic inflammation characterizing the aging process (Box 1, main text). a term coined by Gökhan S. Hotamisligil [30Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity.Annu. Rev. Immunol. 2011; 29: 415-445Crossref PubMed Scopus (1342) Google Scholar] that indicates metabolically triggered inflammation. It is mainly triggered by nutrients and metabolic surplus, while exploiting the same signaling pathways involved in classical inflammation. the most advanced techniques of DNA/RNA sequencing based on cDNA fragments, library preparation, and massive parallel sequencing with third-generation instruments. unsupervised statistical analysis applied to reduce sample variance when many data are analyzed simultaneously. The use of orthogonal components and data transformation into vectors allows the identification of groups of data with similar variance or covariance. all secreted molecules. The term is more often referred to as the secreted proteins of a proteome in a given species. The communicome can be considered to partially overlap the secretome. approach used to decode a genome by shredding (‘shotgunning’) it into smaller fragments of DNA that can then be individually sequenced. The sequences of these fragments are then ordered, based on overlaps in the genetic code, and finally reassembled into the complete sequence.