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Review
. 2023 Aug:74:101755.
doi: 10.1016/j.molmet.2023.101755. Epub 2023 Jun 15.

Chronic inflammation and the hallmarks of aging

Jordan J Baechle  1 , Nan Chen  2 , Priya Makhijani  3 , Shawn Winer  4 , David Furman  5 , Daniel A Winer  6
Affiliations
Review

Chronic inflammation and the hallmarks of aging

Jordan J Baechle et al. Mol Metab. 2023 Aug.

Abstract

Background: Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research.

Scope of review: This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing," given the scope of Molecular Metabolism. The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases.

Main conclusions: The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.

Keywords: Ageing; Aging; Inflammaging; Inflammation; Nutrient sensing; Senescence.

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Conflict of interest statement

Declaration of competing interest DF is co-founder and & Chairman of the Scientific Advisory Board of Edifice Health, a company that utilizes Inflammatory Age (iAge) to quantify chronic inflammation and immune health. The remaining authors declare no competing interests.

Figures

Figure 1
Figure 1
Chronic Inflammation and the Hallmarks of Aging: Relationships of chronic inflammation and other hallmarks of aging: genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, and disabled autophagy grouped as the primary hallmarks; deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence grouped as the antagonistic hallmarks; altered intercellular communication, stem cell exhaustion, and dysbiosis grouped as the integrative hallmarks (López-Otín, 2023).
Figure 2
Figure 2
Proposed Mechanisms of Relationships Underlying Chronic Inflammation and the Hallmarks of Aging: Chronic inflammation interacts with other hallmarks of aging via a complex network of intra- and extracellular signalings, including but not limited to nutrient-sensing, danger-sensing, and autophagy pathways, acting as both a cause and a result of aging. A = adenine, AID = activation-induced cytidine deaminase, AKT = Protein kinase B, AMPK = 5′-adenosine monophosphate-activated protein kinase, ATP = adenosine triphosphate, CASP1 = caspase-1, cGAS = cyclic GMP–AMP synthase (cGAS), DAMPs = deoxyribonucleic acid damage-associated molecular patterns, DDR = deoxyribonucleic acid damage response, DNMT = methyltransferase, EV = extracellular vesicle, FoxO = forkhead box protein O, G = guanine, GSTM2 = Glutathione S-transferase Mu 2, GTP = guanine triphosphate, hTERT = human telomerase reverse transcriptase, IFN = interferon, IGFR = insulin-like growth factor receptor, IKK = inhibitor of nuclear factor-κB (IκB) kinase, IL = interleukin, IR = insulin receptor, IRF = Interferon regulatory factors, JNK = jun n-terminal kinase, LKB-1 = Liver Kinase B1, Me3 = methyl, MMR = mismatch repair, mtDNA = mitochondrial eoxyribonucleic acid, mTORC = mechanistic target of rapamycin complex, NAD/NADH = nicotinamide adenine dinucleotide, NER = nucleotide excision repair, NF-κB = nuclear factor kappa B, NLRP3 = nod-like receptor family pyrin domain-containing 3, PAMPs = pathogen-associated molecular pattern molecules, PDK1 = 3-phosphoinositide-dependent protein kinase-1, PP2C = Protein phosphatase 2C, ROS = reactive oxygen species, S6K = Ribosomal protein S6 kinase, SASP = senescence-associated secretory phenotype, SCFA = short chain fatty acid, STING = stimulator of interferon genes, TBK = tank-binding kinase 1, TLR = toll-like receptor, TNF = tumor necrosis factor, TSC = tuberous sclerosis complex.
Figure 3
Figure 3
Clinical and Molecular Drivers Underlying the Loop of Chronic Inflammation and the Hallmarks of Aging: Through various molecular mechanisms and environmental triggers, chronic inflammation can drive aging and age-related diseases, which in turn can exacerbate chronic inflammation along with other hallmarks of aging. DAMPs = deoxyribonucleic acid damage-associated molecular patterns, ER = endoplasmic reticulum, NAD/NADH = nicotinamide adenine dinucleotide, NF-κB = nuclear factor kappa B, NLRP3 = nod-like receptor family pyrin domain-containing 3, PAMPs = pathogen-associated molecular pattern molecules, TLR = toll-like receptor.
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