Connecting aging biology and inflammation in the omics era
Keenan A. Walker, … , David M. Wilson III, Luigi Ferrucci
Keenan A. Walker, … , David M. Wilson III, Luigi Ferrucci
Published July 15, 2022
Citation Information: J Clin Invest. 2022;132(14):e158448. https://doi.org/10.1172/JCI158448.
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Connecting aging biology and inflammation in the omics era

Abstract

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging — and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.

Authors

Keenan A. Walker, Nathan Basisty, David M. Wilson III, Luigi Ferrucci

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Figure 1

Interplay between cellular senescence, mitochondrial dysfunction, and the aging immune system.

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Interplay between cellular senescence, mitochondrial dysfunction, and th...
During aging, increasing dysfunctional mitochondria contribute to inflammation through several pathways and interact with other hallmarks of aging such as cellular senescence and autophagy. Mitochondrial-derived damage-associated molecular patterns (mtDAMPs) accumulate in the cytosol, including mitochondrial DNA (mtDNA), oxidized mtDNA (ox-mtDNA), and cardiolipin. Accumulation of mtDAMPs leads to downstream production of inflammatory cytokines, type I interferons (IFNs), and chemokines via intracellular pattern recognition receptors to activate an immune response. The collective secretion of mtDAMPs, IFNs, cytokines, and chemokines into the extracellular environment contributes to inflammaging. With age, an increasing mitochondrial dysfunction and production of ROS lead to increased levels of senescent cells, which accumulate naturally with age and in response to multiple stimuli. The accumulation of senescent cells and the SASP increases the release of bioactive molecules, including cytokines, recruitment factors, and DAMPs, into circulation, thereby driving inflammaging. In turn, the accumulation of senescent lymphocytes in the aging immune system further propagates cellular senescence in peripheral tissues.