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

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.

Key points

  • According to geroscience, inflammation is one of the seven evolutionarily conserved mechanistic pillars of ageing that are shared by age-related diseases, including metabolic diseases.

  • Inflammaging is the long-term result of the chronic physiological stimulation of the innate immune system, which can become damaging during ageing — a period of life largely unpredicted by evolution.

  • Inflammaging is the by-product of the degeneracy of a few receptors that can sense a variety of non-self, self and quasi-self damage signals (or ‘garbage’) and activate the innate immune system.

  • Inflammaging and metaflammation largely share the same molecular mechanisms, in which metaflammation can be conceptualized as a specific situation of chronic inflammation caused by nutrient excess.

  • The gut microbiota has a central role in metaflammation and inflammaging, as it can release inflammatory products and contribute to the circadian rhythms and crosstalk with other organs and systems.

  • Biomarkers of biological age, such as DNA methylation, glycomics, metabolomics and lipidomics, can be successfully applied to metabolic diseases.

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Fig. 1: The seven pillars of ageing.
Fig. 2: The bow tie architecture of the inflammaging machinery.
Fig. 3: The gut microbiota as a key modulator of nutrition and inflammation.
Fig. 4: Inflammaging, age trajectories and age-related diseases.

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Acknowledgements

This work was partly supported by Fondazione Cassa di Risparmio delle Province Lombarde (CARIPLO) (Rif. 2015–0564 to C.F. and Rif. 2016–0835); European Union (EU) FP7 Project HUMAN (Health and the Understanding of Metabolism, Aging and Nutrition) (grant agreement 602757) and EU Joint Programme – Neurodegenerative Disease Research (JPND) Adage to C.F.; EU H2020 Project PROPAG-AGEING (grant agreement 634821) to C.F. and P.G.; the Italian Ministry of Health Ricerca Finalizzata Young Researchers (under 40)–Giovani Ricercatori (GR-2013-02358026) to A.S.; Basic Research Projects of the Alma Mater Studiorum - University of Bologna (ALMA-IDEA-2017) to C.G.; and a grant of the Ministry of Education and Science of the Russian Federation (agreement 074-02-2018-330) "Digitalized and Personalized Medicine of Healthy Aging (DPM-AGEING)" at Lobachevsky State University of Nizhny Novgorod to C.F.

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Glossary terms

Geroscience

A research field that tries to understand the molecular relationship and link between ageing and age-related chronic diseases; the basic assumption is that the mechanisms driving ageing and those driving age-related diseases largely overlap.

Inflammasome

A multiprotein intracellular complex that detects pathogenic microorganisms and sterile stressors.

Immunosenescence

A process that refers to all of the most marked changes that occur with ageing in the adaptive immune system; this process is responsible for the increased susceptibility of elderly individuals to new infectious diseases and it is also linked to inflammatory age-related diseases.

Mitokines

Signalling proteins and peptides produced in response to mitochondrial stress (such as oxidative stress and unfolded proteins); they can either be encoded by nuclear DNA or mitochondrial DNA.

Poikilotherms

Cold-blooded animals that have biological strategies that allow them to elude or endure exposures to environmental temperatures that are below the freezing point of their body fluid.

Homeotherms

Organisms with a constant body temperature that is largely independent of the temperature of its surroundings.

Metabolic endotoxaemia

A low-grade, chronic elevation in plasma lipopolysaccharide (10–50 times lower than septic conditions).

Metabolomics

The systematic identification and quantification of the small molecule metabolic products (the metabolome) of a biological system.

Lipidomics

The study of the structure and function of the complete set of lipids (the lipidome).

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Franceschi, C., Garagnani, P., Parini, P. et al. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14, 576–590 (2018). https://doi.org/10.1038/s41574-018-0059-4

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