Leveraging mitochondrial stress to improve healthy aging

Abstract

Aging is characterized by a progressive decline in physiological function, driven by intrinsic mechanisms (primary aging) and modifiable factors (secondary aging), ultimately leading to multimorbidity, disability, and mortality. Mitochondrial dysfunction, a major hallmark of aging, plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia. With age, mitochondrial quality control processes, including biogenesis, mitophagy, and dynamics, become dysregulated, impairing energy metabolism and muscle homeostasis.

Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty, such as the decrease in walking speed and muscle strength, making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity. Mitohormetic agents induce reversible mitochondrial stress, triggering adaptive responses that enhance function. Among these interventions, physical exercise, particularly endurance and resistance training (RT), has been reported to be among the most effective, as it may modulate mitochondrial biogenesis, dynamics, and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) expression, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and mitochondrial content. Chronic RT can also elevate fusion and fission markers, potentially as a compensatory mechanism to mitigate mitochondrial damage.

Apart from exercise, mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field. By modulating mitochondrial bioenergetics and dynamics, they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.

Keywords

Frailty / Muscle homeostasis / Mitochondrial dysfunction / Mitohormesis / Resistance training / Phytochemicals

CRediT authorship contribution statement

Abril Gorgori-Gonzalez: Writing - original draft. Silvana Soto-Rodriguez: Writing - original draft. Eva Tamayo-Torres: Writing - review & editing. Esther Garcia-Dominguez: Writing - review & editing. Vicente Sebastia: Conceptualization. Juan Gambini: Writing - review & editing, Conceptualization. Gloria Olaso-Gonzalez: Writing - review & editing. Maria Carmen Gomez-Cabrera: Writing - review & editing, Writing - original draft, Supervision, Conceptualization.

Declaration of competing interest

Maria Carmen Gomez-Cabrera is an editorial member for Sports Medicine and Health Science and was not in the editorial review or the decision to publish this article. Otherwise the authors declare no competing interests. The authors confirm that AI-assisted technology, based on OpenAI's GPT-4 architecture, was used solely to enhance the readability and language of the work in specific paragraphs in the manuscript. This technology was not employed to replace tasks such as generating scientific insights, analyzing and interpreting data, or drawing scientific conclusions. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Acknowledgements

This work was supported by the following grants: Instituto de Salud Carlos III CB16/10/00435 (CIBERFES); (PID2022-142470OB-I00) from the Spanish Ministry of Innovation and Science; PROMETEO (CIPROM/2022/56) de "Consellería de Educación, Universidades, y Empleo de la Generalitat Valenciana"; EU Funded H2020- DIABFRAIL-LATAM (Ref: 825546); Red EXERNET-RED DE EJERCICIO FISICO Y SALUD (RED2022-134800-T) Agencia Estatal de Investigacion (Ministerio de Ciencias e Innovación). Part of the equipment used in this work has been funded by Generalitat Valenciana and co-financed with FEDER funds (OP FEDER of Comunitat Valenciana 2014-2020). A.G-G (FPU22/02539) and S.S-R (PREP2022-000563) received a predoctoral grant financed by the Spanish Ministry of Universities.

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