{"doi":"10.1016/j.it.2021.04.005","title":"The impact of age-related hypomethylated DNA on immune signaling upon cellular demise","abstract":"Aging is associated with decreased antigen-specific immunity and increased chronic inflammation. While DNA-sensing pathways might be involved, the molecular factors underlying these age-related aberrancies in immune signaling are unclear. Here, we consider the potential role of aging-induced hypomethylated DNA as a putative stimulant of age-associated inflammation. Aging is associated with decreased antigen-specific immunity and increased chronic inflammation. While DNA-sensing pathways might be involved, the molecular factors underlying these age-related aberrancies in immune signaling are unclear. Here, we consider the potential role of aging-induced hypomethylated DNA as a putative stimulant of age-associated inflammation. Emerging evidence from pathology, epidemiology, and animal studies conducted in mice, rats, and non-human primates alludes to a close relationship between aging and immune dysregulation [1.Aprahamian T. et al.Ageing is associated with diminished apoptotic cell clearance in vivo.Clin. Exp. Immunol. 2008; 152: 448-455Crossref PubMed Scopus (89) Google Scholar,2.Simon M. et al.LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation.Cell Metab. 2019; 29: 871-885Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar]. However, the molecular underpinnings behind this relationship remain a mystery. A better understanding of how aging contributes to inflammation is needed to ideally improve the treatment and diagnosis of age-related diseases (ARDs) (see Glossary), such as cancer, rheumatoid arthritis, and Alzheimer’s disease (AD). While advances in DNA sequencing have shown that age-dependent epigenetic changes can impact gene regulation, there is little understanding of how these altered epigenetic patterns may impact cells of the mammalian immune system when nuclear DNA and chromatin are released into the extracellular space upon cellular demise. In this forum article, we provide a perspective on how hypomethylated DNA, arising during aging, can stimulate the immune system by activating immune receptors thought to be involved in detecting foreign (viral and bacterial) DNA. We discuss evidence supporting the hypothesis that aged hypomethylated DNA might be immunogenic and perhaps act as an overlooked, but key regulator of immune signaling during aging. The mammalian immune system recognizes molecular patterns indicative of infection, injury, or tissue dysfunction through a common set of pattern recognition receptors (PRRs), which detect conserved molecular structures known as pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Recently, the term DAMPs was expanded to include self-derived biomolecules that are damaged, misfolded, or displaced into the extracellular space, collectively termed ‘altered or misplaced self-molecules’ [3.Franceschi C. et al.Inflammaging and ‘garb-aging’.Trends Endocrinol. Metab. 2017; 28: 199-212Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar]. While cellular repair and protein degradation mechanisms exist to combat molecular damage to DNA, proteins, and lipids, a key feature of aging is the accumulation of altered and misplaced self-derived molecules due to an aging-dependent decline of such molecular pathways [3.Franceschi C. et al.Inflammaging and ‘garb-aging’.Trends Endocrinol. Metab. 2017; 28: 199-212Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar]. In addition, a decline in proteolytic activity is also observed in aged cells; this results in impaired autophagy and efferocytosis [1.Aprahamian T. et al.Ageing is associated with diminished apoptotic cell clearance in vivo.Clin. Exp. Immunol. 2008; 152: 448-455Crossref PubMed Scopus (89) Google Scholar,3.Franceschi C. et al.Inflammaging and ‘garb-aging’.Trends Endocrinol. Metab. 2017; 28: 199-212Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar]. Defects in autophagy are linked to accelerated ag","journal":"Trends in Immunology","year":2021,"id":175411,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9434,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":716502,"name":"Annie Trinh","orcid":"0000-0002-9320-4891","position":1,"is_corresponding":false},{"id":276832,"name":"Eric Pearlman","orcid":"0000-0003-0137-7582","position":2,"is_corresponding":false},{"id":294461,"name":"Albert Siryaporn","orcid":"0000-0002-2056-9937","position":3,"is_corresponding":false},{"id":235176,"name":"Timothy L. Downing","orcid":"0000-0002-5197-3684","position":4,"is_corresponding":false},{"id":294457,"name":"Lauren A. Urban","orcid":"0000-0001-5606-7712","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T23:47:15.431199Z","pmid":"33994111","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}