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Although it is the second most prevalent disorder of the central nervous system, current treatments primarily focus on symptom management and modestly slowing disease progression, ultimately failing to preserve the long-term quality of life of a substantial proportion of affected individuals. Innovative therapies that can restore neuronal function have emerged, such as the use of the secretome of Mesenchymal Stem Cells (MSCs) due to their rich composition of bioactive molecules. This therapy exhibits robust paracrine activity that drives most of the self-renewal capacity, differentiation potential, and immune regulation of MSCs without presenting compatibility issues often associated with stem cell-based therapies. While conceptually appealing, the clinical application of this approach is still limited by the availability and proliferation capacity of MSCs, as it impacts not only secretome production but also its quality. Various protocols have been developed to enhance secretome action by adding various compounds to cell culture media, given the high environmental plasticity of MSCs. Some of the compounds already used are Caloric Restriction Mimetics (CRMs), molecules that mimic Caloric Restriction (CR) conditions, which have been demonstrated to extend lifespan and reduce age-related diseases in various organisms. While not sufficient to cure neurodegenerative disorders, these compounds may potentiate secretome efficiency by enhancing autophagy pathways and relieving oxidative stress burden from MSCs. Therefore, in this article, we aim to explore the effects of CRMs priming on MSCs and how it may help bridge existing gaps in regenerative therapies for PD.<\/jats:p>","DOI":"10.3390\/molecules30112260","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T07:04:28Z","timestamp":1747897468000},"page":"2260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Caloric Restriction Mimetics as Priming Agents of Mesenchymal Stem Cells Secretome to Enhance Regenerative Responses to Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0069-8314","authenticated-orcid":false,"given":"B\u00e1rbara","family":"Carneiro-Pereira","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"given":"Filipa","family":"Ferreira-Antunes","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"given":"Jonas","family":"Campos","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3806-9823","authenticated-orcid":false,"given":"Ant\u00f3nio J.","family":"Salgado","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6580-0971","authenticated-orcid":false,"given":"Bel\u00e9m","family":"Sampaio-Marques","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e080952","DOI":"10.1136\/bmj-2024-080952","article-title":"Projections for Prevalence of Parkinson\u2019s Disease and Its Driving Factors in 195 Countries and Territories to 2050: Modelling Study of Global Burden of Disease Study 2021","volume":"388","author":"Su","year":"2025","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","article-title":"Parkinson Disease","volume":"3","author":"Poewe","year":"2017","journal-title":"Nat. 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