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To decelerate ageing, various strategies have been applied to model organisms and evaluated for health and lifespan benefits. Dietary restriction (DR, also known as caloric restriction) is a well\u2010established long\u2010term intervention recognized for its universal anti\u2010ageing effects. DR temporarily suppresses growth, and when applied to progeroid DNA repair\u2010deficient mice doubles\u00a0lifespan with systemic health benefits. Counterintuitively, attenuation of myostatin\/activin signalling by soluble activin receptor (sActRIIB), boosts the growth of muscle and, in these animals, prevents muscle wasting, improves kidney functioning, and compresses morbidity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we investigated a combined approach, applying an anabolic regime (sActRIIB) at the same time as DR to <jats:italic>Ercc1<\/jats:italic><jats:sup>\u0394\/\u2212<\/jats:sup> progeroid mice. Following both single treatments and combined, we monitored global effects on body weight, lifespan and behaviour, and local effects on muscle and tissue weight, muscle morphology and function, and ultrastructural and transcriptomic changes in muscle and kidney.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lifespan was mostly influenced by DR (extended from approximately 20 to 40\u00a0weeks; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), with sActRIIB clearly increasing muscle mass (35\u201365%) and tetanic force (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). The combined regime yielded a stable uniform body weight, but increased compared with DR alone, synergistically improved motor coordination and further delayed the onset and development of balance problems. sActRIIB significantly increased muscle fibre size (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in mice subjected to DR and lowered all signs of muscle damage. <jats:italic>Ercc1<\/jats:italic><jats:sup>\u0394\/\u2212<\/jats:sup> mice showed abnormal neuromuscular junctions. Single interventions by sActRIIB treatment or DR only partially rescued this phenotype, while in the double intervention group, the regularly shaped junctional foldings were maintained. In kidney of <jats:italic>Ercc1<\/jats:italic><jats:sup>\u0394\/\u2212<\/jats:sup> mice, we observed a mild but significant foot process effacement, which was restored by either intervention. Transcriptome analysis also pointed towards reduced levels of DNA damage in muscle and kidney by DR, but not sActRIIB, while these levels retained lower in the double intervention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In muscle, we found synergistic effects of combining sActRIIB with DR, but not in kidney, with an overall better health in the double intervention group. Crucially, the benefits of each single intervention are not lost when administered in combination, but rather strengthened, even when sActRIIB was applied late in life, opening opportunities for translation to human.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13570","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T06:40:21Z","timestamp":1725864021000},"page":"2361-2374","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Improved health by combining dietary restriction and promoting muscle growth in DNA repair\u2010deficient progeroid mice"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9690-1385","authenticated-orcid":false,"given":"Wilbert P.","family":"Vermeij","sequence":"first","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht Netherlands"},{"name":"Oncode Institute  Utrecht Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Alyodawi","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Reading  Reading UK"},{"name":"College of Medicine Wasit University  Kut Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivar","family":"van Galen","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht Netherlands"},{"name":"Oncode Institute  Utrecht Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennie L.","family":"von der Heide","sequence":"additional","affiliation":[{"name":"III. Department of Medicine University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Hamburg Center for Kidney Health (HCKH)  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda B.","family":"Birkisd\u00f3ttir","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht Netherlands"},{"name":"Oncode Institute  Utrecht Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisanne J.","family":"van't Sant","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Erasmus University Medical Center Rotterdam  Rotterdam Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rutger A.","family":"Ozinga","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht Netherlands"},{"name":"Oncode Institute  Utrecht Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne S.J.","family":"Komninos","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht Netherlands"},{"name":"Oncode Institute  Utrecht Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Smit","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht Netherlands"},{"name":"Oncode Institute  Utrecht Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne M.A.","family":"Rijksen","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht Netherlands"},{"name":"Oncode Institute  Utrecht Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata M.C.","family":"Brandt","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC Cancer Institute Erasmus University Medical Center Rotterdam  Rotterdam Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander","family":"Barnhoorn","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC Cancer Institute Erasmus University Medical Center Rotterdam  Rotterdam Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick","family":"Jaarsma","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Erasmus University Medical Center Rotterdam  Rotterdam Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sathivel","family":"Vaiyapuri","sequence":"additional","affiliation":[{"name":"School of Pharmacy University of Reading  Reading UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olli","family":"Ritvos","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias B.","family":"Huber","sequence":"additional","affiliation":[{"name":"III. 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