{"doi":"10.3389/fmolb.2025.1710944","title":"The legacy of Bruce Ames and mitochondrial DNA mutagenicity: integrating oxidative stress, aging, and modern perspectives","abstract":"Introduction Bruce Ames stands among the most influential biochemists of the past half-century, leaving a profound mark on genetics, toxicology, nutrition, and aging research. Best known for developing the Ames test, a bacterial assay that detects mutagenic chemicals, Ames helped establish the principle that environmental mutagens can be reliably measured and systematically screened (1). This transformed toxicology and cancer prevention, saving countless lives by enabling the regulation of carcinogens. Yet Ames's legacy extends beyond mutagen detection. In the latter part of his career, he focused on oxidative stress and mitochondrial DNA (mtDNA) mutagenicity as central players in the biology of aging (2). While the foundational ideas of oxidative damage and mitochondrial contribution to aging were first proposed by researchers such as Gershman and Harman, Ames contributed by integrating these concepts with experimental observations on mitochondrial decay, nutrition, and disease. He highlighted how reactive oxygen species (ROS) produced during mitochondrial respiration could contribute to cumulative mtDNA damage, potentially impairing mitochondrial function over time. Ames also emphasized the role of micronutrients in modulating this process, proposing that suboptimal nutrition could accelerate oxidative damage and mitochondrial decline through his triage theory (3) (Figure 1). His work helped translate earlier theoretical ideas into a broader framework linking oxidative stress, mitochondrial function, and age-related health outcomes. While this concept was groundbreaking, the field has since evolved. Contemporary research has revealed a more complex picture, with some scientists challenging the causal role of mtDNA damage in aging, proposing instead that mitochondrial dysfunction may arise from signaling changes, metabolic imbalances, or programmed processes rather than cumulative mutations (4). This paper will examine Bruce Ames's contributions, with particular focus on mtDNA mutagenicity, and critically assess how his theories shaped — and continue to spark debate within — modern biogerontology. The Ames Test and the Assessment of Mutagenicity In the 1970s, Ames introduced a simple yet powerful tool for detecting chemical mutagens: a bacterial assay using strains of Salmonella typhimurium engineered to be highly sensitive to DNA mutations. If exposure to a chemical restored growth via human or rat liver-activated metabolism in these bacteria (via reversion mutations), the compound was considered mutagenic. Importantly, Ames demonstrated that many environmental chemicals, including industrial pollutants, food additives, and pesticides, scored positive in the assay — and many of these same compounds later proved carcinogenic in animals (5). The test revolutionized toxicology by offering a rapid, inexpensive alternative to long-term rodent studies. Regulatory agencies worldwide adopted it to screen thousands of compounds, dramatically reducing public exposure to carcinogens. The \"Ames test\" also established a broader principle: genetic mutagenesis underpins carcinogenesis, and therefore, mutagens can be used as predictors of cancer risk. This work reflected Ames's larger intellectual project: to bridge laboratory assays with real-world human health, from chemical safety to disease prevention. A Shift Toward Oxidative Stress and mtDNA Damage By the 1980s, Ames expanded his focus from exogenous mutagens (environmental chemicals) to endogenous sources of DNA damage within the cell. He became especially interested in mitochondria, the cellular organelles that generate energy but also produce ROS as a byproduct of oxidative phosphorylation (6-46). Unlike nuclear DNA, mtDNA is highly vulnerable. It is located near the electron transport chain, where ROS are generated, lacks protective histones, and has more limited repair mechanisms. Ames proposed that cumulative mtDNA mutations lead to a decline in mitochondrial efficiency, greater","journal":"Frontiers in Molecular Biosciences","year":2025,"id":579403,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9612,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1490000,"name":"Jia Yu Liou","orcid":null,"position":1,"is_corresponding":false},{"id":1490001,"name":"Rida Mullah","orcid":null,"position":2,"is_corresponding":false},{"id":378845,"name":"Cecilia Giulivi","orcid":"0000-0003-1033-7435","position":3,"is_corresponding":false},{"id":1489999,"name":"Jeffrey Dang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T02:58:30.282164Z","pmid":"41234541","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":[]}