Ageing research reviewsOct 10, 2026

How Changes in Cellular Energy Signals Connect Aging Signs to Chronic Inflammation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 11, 2026

Abstract

Aging is associated with chronic, low-grade sterile inflammation known as inflammaging, which contributes to various age-related disorders.

Inflammaging reflects a decline in cellular homeostasis linked to neurodegenerative, cardiometabolic, and neoplastic disorders.
The Aging Purinome framework describes age-related changes in extracellular purinergic signaling and its metabolic interactions.
Aging modifies extracellular ATP availability, affecting receptor-specific responses and causing dysregulation of the CD39-CD73-adenosine axis.
P2X7-NLRP3 signaling links extracellular ATP to sterile inflammation, highlighting one aspect of a broader purinergic remodeling process.
Alterations in purinergic communication may impact mitochondrial dysfunction, cellular senescence, and inflammatory resolution in aging.
Potential strategies for restoring homeostatic signaling include exercise, nutritional approaches, and pharmacological modulation of related pathways.

Simplified

Aging is characterized by a progressive decline in cellular homeostasis accompanied by chronic, low-grade sterile inflammation, termed inflammaging, which contributes to the development of neurodegenerative, cardiometabolic, and neoplastic disorders. Although inflammaging represents a convergence point of multiple hallmarks of aging, the molecular networks linking these processes remain incompletely understood. Here, we propose the Aging Purinome as a systems-level framework describing the progressive, age-associated remodeling of extracellular purinergic signaling and its metabolic interfaces. This network encompasses extracellular nucleotides and nucleosides, nucleotide release and transport mechanisms, ectonucleotidases, P2X and P2Y receptors, adenosine receptors, and interconnected metabolic pathways. Available evidence indicates that aging alters extracellular ATP availability and produces receptor-, cell-, and tissue-specific changes across the P2X and P2Y receptor repertoire, together with dysregulation of the CD39-CD73-adenosine axis and increased CD38-dependent NAD+ consumption. Among these pathways, P2X7-NLRP3 signaling represents a well-characterized mechanism linking extracellular ATP to sterile inflammation, but it constitutes only one component of a broader purinergic remodeling process. We discuss how these changes may influence mitochondrial dysfunction, cellular senescence, altered intercellular communication, impaired inflammatory resolution, and age-related diseases. We further examine exercise, nutritional approaches, and pharmacological modulation of purinergic and NAD+-related pathways as potential strategies to restore homeostatic signaling. The Aging Purinome is therefore proposed as an integrative framework for investigating how age-dependent changes in purinergic communication may contribute to inflammaging and as a testable basis for future mechanistic and translational studies.

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How Changes in Cellular Energy Signals Connect Aging Signs to Chronic Inflammation

Abstract

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