{"doi":"10.1113/jp280929","title":"Chronic aerobic exercise: targeting two birds with one stone","abstract":"Cardiovascular diseases (CVDs) are the leading cause of death globally and are strongly associated with advancing age, obesity and sedentary lifestyle (Donato et al. 2018). Reduced endothelial dependent dilatation (EDD) and increased large artery stiffness are hallmarks of vascular dysfunction, predicting future clinical cardiovascular events (Donato et al. 2018). In response to chemical (i.e. acetylcholine, insulin) and mechanical (i.e. shear stress) stimuli, the vascular endothelium synthesizes and releases nitric oxide (NO) that subsequently diffuses into vascular smooth muscle cells (VSMCs), initiating a signalling cascade resulting in VSMC relaxation and vasodilatation, i.e. EDD. Additionally, NO inhibits vascular wall immune cell adhesion and infiltration and platelet aggregation and enhances tissue oxygen delivery (Gimbrone & Garcia-Cardena, 2016). Increases in arterial stiffness lead to reduced compliance, increased blood pressure, elevated pulse pressure, increased ventricular afterload, cardiac hypertrophy and diminished coronary perfusion (Donato et al. 2018). Advancing age, sedentary lifestyle and Western dietary patterns promote oxidative stress and chronic sterile inflammation which are characterized by increases in reactive oxygen species (O2−, H2O2, etc.) in the face of attenuated or unchanged antioxidant defenses and enhanced proinflammatory cytokines such as IL-6, IL-1β, TNF-α and INF-γ (Donato et al. 2018). Oxidative stress and inflammation feedforward to promote endothelial dysfunction, reduced NO bioavailability and structural changes such as altered collagen and elastin expression that promote arterial stiffening (Donato et al. 2018). While an effective therapeutic to prevent the development of endothelial dysfunction and arterial stiffness with ageing is elusive, lifestyle modification such as increased physical exercise is a key preventive strategy. Previous animal studies have demonstrated the beneficial effects of exercise on the aged vasculature (Durrant et al. 2009). However, human ageing is often accompanied by an unhealthy diet and sedentary lifestyle, which interact over a lifespan to exacerbate vascular dysfunction associated with ageing per se. Therefore, a better understanding of the complex interactions of these detrimental factors as they occur over a lifetime is critical to better translate preclinical findings into recommendations for clinical practice. In this issue of The Journal of Physiology, Gioscia-Ryan et al. (2021) report an elegant study aimed at elucidating the complex interaction of age, diet, and exercise on EDD and arterial stiffness across the lifespan of mice. Young male C57BL/6 mice were divided into groups consuming either normal chow or a Western diet (WD) over their lifespan. These groups were further subdivided and either maintained in standard cages or housed in cages equipped with running wheels to allow for lifelong voluntary aerobic exercise. Arterial stiffness, EDD, oxidative stress and inflammation were assessed at set intervals from 6 to 27 months corresponding to young, middle-age and older adulthood in humans. Gioscia-Ryan et al. (2021) demonstrate that the combination of ageing and lifelong WD exacerbates endothelial dysfunction and large artery stiffening, both of which are accompanied by increased oxidative stress and inflammation. However, while oxidative stress and inflammation track closely with declines in EDD, the emergence of increased arterial stiffness does not correspond to the observed elevations in markers of either oxidative stress or inflammation. This finding may suggest that either (1) a novel mechanism may underlie increased arterial stiffening with ageing and WD or (2) that oxidative stress and inflammation underlie both impaired EDD and increased arterial stiffening but the time course for development of dysfunction in response to these insults is prolonged for arterial stiffness compared to EDD, possibilities that require further elucidati","journal":"The Journal of Physiology","year":2020,"id":112045,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":530698,"name":"Shelby A. Hall","orcid":"0000-0002-4672-9716","position":1,"is_corresponding":false},{"id":376583,"name":"Lisa A. Lesniewski","orcid":"0000-0002-2138-1450","position":2,"is_corresponding":false},{"id":376580,"name":"Md Torikul Islam","orcid":"0000-0001-8263-0628","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-18T23:13:09.353152Z","pmid":"33289103","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":[]}