Mitochondrial dynamics as a limiting factor of exercise-increased healthspan in Caenorhabditis elegans

• Grant number: 19/18444-9
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: December 01, 2019
• End date: November 30, 2020
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Julio Cesar Batista Ferreira
• Grantee: Juliane Cruz Campos
• Supervisor: T Keith Blackwell
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 17/16540-5 - Exercise, lifespan and healthspan: a molecular and longitudinal approach to study their interactions, BP.PD

Abstract

Geroscience has been successful in identifying evolutionarily conserved genes and molecular mechanisms capable of increasing longevity, mainly in the nematode Caenorhabditis elegans (C. elegans). However, it is still not clear whether this prolonged period of life is associated with improved healthspan (either relative or absolute). Healthspan is defined by the period of life in which an organism manages to maintain a good health. Exercise is a well-known strategy capable of increasing healthspan in humans as well as different animal models. Exercise-induced healthspan benefits are mainly related to changes in mitochondrial connectivity and functionality, therefore rewiring cellular metabolism. Here we plan to study the role of mitochondrial dynamics in regulating the interplay between healthspan and lifespan in C. elegans. Mitochondrial dynamics is defined by the mitochondrial ability to adjust their size, shape and number through fusion and fission events. Our preliminary data suggest that increased lifespan is not always accompanied by improvements in healthspan (i.e. physical capacity) and exercise is able to delay the decline in healthspan in wildtype C. elegans, but not in long-lived mutants (isp-1, nuo6, eat-2 and daf-2). Moreover, our results suggest that reduced healthspan correlates with altered transcript profile of mitochondrial dynamics genes (obtained from publicly available RNA sequencing data lists). We plan to characterize swimming capacity after acute and chronic exercise in mutant C. elegans with compromised mitochondrial fusion (fzo-1) and fission (drp-1). These experiments will show the contribution of mitochondrial dynamics to exercise effects on both healthspan and lifespan. We identified that acute exercise induces mitochondrial fission in muscle cells from wildtype C. elegans, which is associated with reduced physical capacity over time. Of interest, mitochondrial network is re-established 24h after exercise was ceased. We also plan to investigate the impact of tissue-specific disruption of mitochondrial fusion and fission on healthspan and lifespan in long-lived C. elegans. Manipulating mitochondrial dynamics will show whether lifespan and healthspan require different mitochondrial network states.The current research proposal is a joint effort between the labs of Dr. Julio Ferreira and Dr. T. Keith Blackwell. Dr. Blackwell's lab focuses on uncover mechanisms that promote longevity and healthy aging, with focus on metabolic pathways. His lab has several tools to better characterize and understand how cells and organisms (i.e. C. elegans) defend themselves against environmental and metabolic stresses. Therefore, this international cooperation will allow us to investigate a potential mitochondrial phenotype that dissociates lifespan from healthspan in the context of exercise. We expect that the findings obtained from this partnership will open up new strategies to achieve healthy aging. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CAMPOS, JULIANE C.; CHEN, CHE-HONG; FERREIRA, JULIO C. B.. Comment on: ``Aldehyde dehydrogenases contribute to skeletal muscle homeostasis in healthy, aging, and Duchenne muscular dystrophy patients{''} by Etienne et al.. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, JUL 2020. (15/22814-5, 17/16540-5, 19/25049-9, 19/18444-9)

CAMPOS, JULIANE C.; CHEN, CHE-HONG; FERREIRA, JULIO C. B.. Comment on: "Aldehyde dehydrogenases contribute to skeletal muscle homeostasis in healthy, aging, and Duchenne muscular dystrophy patients" by Etienne et al.. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 11, n. 6, p. 2-pg., 2020-07-29. (15/22814-5, 17/16540-5, 19/18444-9, 19/25049-9)

CAMPOS, JULIANE CRUZ; MARCHESI BOZI, LUIZ HENRIQUE; KRUM, BARBARA; GRASSMANN BECHARA, LUIZ ROBERTO; FERREIRA, NIKOLAS DRESCH; ARINI, GABRIEL SANTOS; ALBUQUERQUE, RUDA PRESTES; TRAA, ANNIKA; OGAWA, TAKAFUMI; VAN DER BLIEK, ALEXANDER M.; et al. Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 120, n. 2, p. 11-pg., 2023-01-10. (13/07937-8, 19/18444-9, 17/16540-5, 19/07221-9, 19/25049-9, 15/22814-5, 16/09611-0, 17/16694-2)

CAMPOS, JULIANE C.; WU, ZIYUN; RUDICH, PAIGE D.; SOO, SONJA K.; MISTRY, MEETA; FERREIRA, JULIO C. B; BLACKWELL, T. KEITH; VAN RAAMSDONK, JEREMY M.. Mild mitochondrial impairment enhances inn3ate immunity and longevity through ATFS-1 and p38 signaling. EMBO REPORTS, v. 22, n. 12, OCT 2021. (19/18444-9)