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Review
. 2021 Jun 28;6(1):245.
doi: 10.1038/s41392-021-00646-9.

Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Xudong Zhu #  1 , Zhiyang Chen #  2 , Weiyan Shen  2 , Gang Huang  3 , John M Sedivy  4 , Hu Wang  5   6 , Zhenyu Ju  7
Affiliations
Review

Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Xudong Zhu et al. Signal Transduct Target Ther. .

Abstract

Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art techniques are also discussed.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Dysregulated inflammation, alteration of epigenetic modifications, and metabolic imbalance converge to cell senescence and ageing. Cross talks among epigenetic modifiers (writers, readers, and erasers), inflammatory gene expression and immune cell response, and metabolic alterations contribute to senescent phenotypes and organ degeneration. MiDAS mitochondrial dysfunction-associated senescence, SASP senescence-associated secretory phenotype, OXPHOS oxidative phosphorylation, ROS reactive oxygen species, TCA tricarboxylic acid
Fig. 2
Fig. 2
The hallmarks of cell senescence
Fig. 3
Fig. 3
Inflammatory sources lead to senescence-associated secretory phenotype (SASP). Several pro-inflammatory sources have been identified to trigger the chronic inflammation during cellular senescence and organismal ageing, featured by the activation of a group of SASP-related genes, and subsequently the release of SASP components
Fig. 4
Fig. 4
Inflammageing and its associated diseases. Multiple inflammatory signaling pathways, such as the NF-kB, NOTCH/JAG1, toll-like receptor, DNA damage response, cytosolic DNA sensing, autophagy, mRNA stabilization, and mTOR signaling pathways have been linked to age-related chronic diseases in various organs
Fig. 5
Fig. 5
Epigenetic regulators and interventions in ageing. Age-dependent epigenetic remodeling by various (de-)methylases and (de-)acetylases affects chromatin accessibility, thereby regulating gene transcription and expression. Interventions, such as calorie restriction and drug treatment, may reverse the age-dependent degeneration in an epigenetic-modifying manner. HDACs histone deacetylases, DNMTs DNA methyltransferases, TET ten–eleven translocation, HMT histone methyltransferase, TSS transcriptional start site, SAM S-adenosylmethionine, α-KG alpha-ketoglutarate, NAD nicotinamide adenine dinucleotide
Fig. 6
Fig. 6
Intrinsic cues to metabolic reprogramming during ageing. Six aspects, namely protein homeostasis, genetic and epigenetic instability, organelle dysfunction, redox imbalance, immune response, and altered signaling pathways, lead to the metabolic regulation of ageing
Fig. 7
Fig. 7
Approaches to alter local and systemic metabolism. Six aspects, including environmental stimuli, sleep modulation, exercise, intestinal microbes, diet, and drug interventions, may reprogram the metabolism thereby benefiting to healthy ageing
Fig. 8
Fig. 8
Novel techniques accelerate the discovery of anti-ageing mechanisms and therapies. Illustrations of three advanced approaches, i.e., single-cell sequencing, 3D-genome analysis, and genetically encoded fluorescent probes in dissecting genetic, epigenetic, and metabolic alterations in ageing and anti-ageing research
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