This article systematically reviews the central role of DNA damage in the aging process and proposes enhancing DNA repair capacity as a novel therapeutic direction for delaying aging and preventing age-related diseases, covering various pharmacological intervention strategies and potential targets.
Literature Overview
This article, 'Targeting DNA damage in ageing: towards supercharging DNA repair,' published in the journal Nature Reviews. Drug Discovery, reviews and summarizes DNA damage as a core mechanism driving aging, systematically elaborating its impact on genomic stability, cellular function, and tissue homeostasis. The article further explores various pharmacological strategies targeting the DNA damage response (DDR) and enhancing DNA repair capacity, including clearance of senescent cells, inhibition of inflammatory signaling pathways, and regulation of key repair factors, aiming to delay the aging process and prevent age-related diseases such as cancer and neurodegenerative disorders. The entire section is coherent and logically structured, ending with a Chinese period.Background Knowledge
Aging is the primary risk factor for a wide range of chronic diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases. In recent years, genomic instability—particularly the persistent accumulation of DNA damage—has been widely recognized as one of the fundamental drivers of aging. Endogenous factors such as oxidative stress, replication errors, and metabolic byproducts, as well as exogenous factors like radiation and chemical agents, can all cause various types of DNA lesions, including single- and double-strand breaks, base modifications, and crosslinks. If not promptly repaired, these damages can obstruct transcription and replication, trigger cell cycle arrest, cellular senescence, or apoptosis, and may lead to somatic mutations and structural genomic alterations, thereby promoting carcinogenesis.
Cells maintain genomic integrity through multiple DNA repair pathways (e.g., nucleotide excision repair [NER], homologous recombination repair [HRR], and non-homologous end joining [NHEJ]). However, with age, repair capacity declines and damage accumulates, creating a vicious cycle. Patients with progeroid syndromes (e.g., Cockayne syndrome, Hutchinson-Gilford progeria) carry mutations in DNA repair-related genes and exhibit accelerated aging phenotypes, further supporting the causal role of DNA repair deficiencies in aging.
Targeting the DNA damage response has become a major direction for anti-aging interventions. Senolytics (drugs that clear senescent cells) or senomorphics (agents that suppress the senescence-associated secretory phenotype) can improve tissue function; inhibiting inflammatory pathways activated by cytosolic DNA, such as the cGAS-STING pathway, can alleviate chronic inflammation. Moreover, directly enhancing DNA repair capacity—for example, by activating key repair factors or modulating their expression—holds promise for fundamentally delaying aging. However, major challenges remain, including how to safely enhance repair without promoting tumorigenesis, how to achieve tissue-specific interventions, and how to accurately assess individual DNA damage burden.
Research Methods and Experiments
This paper is a review study based on a systematic synthesis of extensive research literature from recent years in the fields of aging and DNA damage repair. The authors comprehensively analyzed data from genetic models (e.g., DNA repair-deficient mouse models, progeria animal models), cell biology studies (e.g., senolytic experiments, DNA damage induction models), pharmacological intervention studies (e.g., use of senolytics and cGAS-STING inhibitors), and preclinical and clinical trial data, systematically outlining the mechanisms by which DNA damage contributes to aging and identifying potential therapeutic targets.Key Conclusions and Perspectives
Research Significance and Prospects
This review emphasizes enhancing DNA repair capacity as a central anti-aging intervention strategy, providing a clear direction for the development of novel geroprotectors. By systematically summarizing existing drug targets and clinical progress, it offers valuable guidance for translational research. Pharmacological interventions targeting pathways such as cGAS-STING and senolytics have already shown significant therapeutic potential.
Future research should focus on developing more specific and safer DNA repair enhancers and exploring their efficacy in different tissues and disease models. Reliable biomarkers are also needed to assess individual DNA damage levels and repair capacity to enable precision interventions. Furthermore, balancing enhanced repair with tumor suppression—avoiding the expansion of potentially cancerous clones—remains a critical challenge. Ultimately, multi-target combination therapies may become an effective approach to delay overall aging and extend healthspan.
Conclusion
This article systematically elucidates the central role of DNA damage in driving the aging process and proposes 'enhancing DNA repair' as a fundamental strategy for delaying aging. The paper highlights that DNA damage not only leads to genomic instability and somatic mutations—thereby promoting cancer—but also induces cellular senescence and activates inflammatory pathways such as cGAS-STING, resulting in chronic inflammation, all of which collectively drive the development of multiple age-related diseases. Consequently, various interventions targeting the DNA damage response—including senolytics to clear senescent cells, senomorphics to suppress their pro-inflammatory secretory phenotype, and direct enhancement of DNA repair capacity—have emerged as frontier directions in anti-aging research. The authors summarize several promising drug classes and their mechanisms of action, such as the D+Q combination, BCL-2 inhibitors, and cGAS and STING inhibitors, while emphasizing the necessity of combination therapeutic strategies. This study provides an important theoretical framework and translational roadmap for developing novel anti-aging therapies centered on maintaining genomic stability, with the potential to significantly extend healthspan.
