{"doi":"10.1002/smi.3258","title":"Molecular underpinnings of physical activity and resilience: A brief overview of the state‐of‐science and research design needs","abstract":"Regular physical activity/exercise (PA/PE) has proven to have indisputable and powerful effects on maintaining health, preventing disease, extending the healthspan and lifespan, and may have implications for resilience (Guasch-Ferré et al., 2022; Moore et al., 2016; Piercy & Troiano, 2018; Scully et al., 1998). Although the terms physical activity and exercise are often used interchangeably, PA is considered as any bodily movement that results in energy expenditure. Currently, the COVID-19 pandemic continues to present significant challenges to health and resilience (Torales et al., 2020; Trabelsi et al., 2021). Recent findings show that consistently not meeting PA guidelines during the years preceding the pandemic is a strong risk factor for severe COVID-19 complications, including hospitalisation, admittance to the intensive care unit, and even death (Sallis et al., 2021). The effects of PA on fostering resilience should not be understated, yet significant knowledge and study design gaps remain. As is described in the current Special Issue, the Trans-NIH Resilience Working Group defines resilience as a system's capacity to recover, recover better, adapt, or resist perturbation from a challenge or stressor. Physical activity, as a multidimensional health behaviour that engages a constellation of health-promoting biological pathways, networks, and mechanisms, may facilitate this capacity. From molecular, cellular, and physiological levels of analysis, this brief report elucidates some of the processes and mechanisms involved in association with PA and resilience outcomes in response to physiological, psychosocial, and health-related stressors. Additionally, our study design analysis revealed four critical design features that would be imperative for future investigations to include to be considered a resilience study (see Table 1; Trans-NIH Resilience Working Group, n.d.). First, study designs must include a stressor or a proxy for a stressor to identify the biological responses before and after stressor exposures and their modulation by acute, chronic, or intermittent PA/PE to establish causal associations between PA/PE and resilience outcomes. Second, metrics and measurements should be developed and validated to capture changes that strengthen and empower an individual's psychological, physiological, and molecular capacity to be resilient. Third, there is much heterogeneity in the design and implementation of PA/PE interventions. The field would benefit from identifying the specific components of PA/PE interventions that confer resilience and/or drive molecular/cellular changes that enhance efficacy/effectiveness. Furthermore, future research would benefit by a clear and consistent operationalisation of resilience and subsequent design of studies that clarify the resilience outcomes evoked from a molecular/cellular/physiological level of analysis. These, and other recommendations, are described in detail and could stimulate more harmonious future research to enhance our understanding of PA as a modifiable resilience factor for health promotion and disease prevention. The benefits of PA have been identified at least partially to be mediated by exerkines, a family of signalling moieties including cytokines, nucleic acids, lipids, and metabolites that exert their effects through autocrine, paracrine, and endocrine pathways in response to exercise (Chow et al., 2022). The NIH Common Fund-supported Molecular Transducers of Physical Activity Consortium (MoTrPAC) (Sanford et al., 2020) is a national research initiative designed to discover and characterise the molecular transducers, including exerkines, that mediate the effects of exercise in humans and animal models. MoTrPAC has several design features that could be applied to appropriately investigate resilience, although by itself it cannot be considered a resilience study (see Table 1). In both humans and animals, this initiative collects and analyzes changes across multiple ti","journal":"Stress and Health","year":2023,"id":372829,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1133768,"name":"Bramaramba Kowtha","orcid":null,"position":1,"is_corresponding":false},{"id":1133426,"name":"Gabriela Riscuta","orcid":"0000-0001-7423-1512","position":2,"is_corresponding":false},{"id":1133769,"name":"Anil Wali","orcid":null,"position":3,"is_corresponding":false},{"id":838945,"name":"Yunling Gao","orcid":"0000-0002-6622-3253","position":4,"is_corresponding":false},{"id":675719,"name":"Jennifer N. Baumgartner","orcid":"0000-0002-1914-1343","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:15:58.101083Z","pmid":"37226691","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":[]}