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This study investigates how natural killer (NK) cell phenotypes, functional markers, and metabolism differ between endurance-trained and untrained older adults. Ex vivo expanded NK cells from endurance-trained (63.6\u2009\u00b1\u20092.1 years) and untrained (64.3\u2009\u00b1\u20093.3 years) males were exposed to adrenergic blockade (propranolol; 0\u2013200 ng\/mL) or mTOR inhibition (rapamycin; 10\u2013100 ng\/mL), both with or without PMA-induced inflammatory stimulation. Flow cytometry assessed NK subsets, activation (CD38, CD57, CD107a, NKG2D), senescence (KLRG1), and inhibitory markers (PD-1, LAG-3, TIM-3, NKG2A). Seahorse analysis measured metabolic parameters. Trained participants displayed healthier immune profiles (lower NLR, SII) and higher effector NK cells with lower cytotoxic subsets. Propranolol at 100 ng\/mL blunted PMA-driven increases in CD57, CD107a, and NKG2D, while potentiating regulatory markers KLRG1, LAG-3, and PD-1 in the trained group, indicating stronger immunoregulation. With rapamycin, trained NK cells preserved NKG2D and CD107a at 10 ng\/mL, maintaining cytotoxicity and degranulation. In contrast, at 100 ng\/mL rapamycin plus PMA, trained NK cells shifted toward an effector phenotype with higher CD57 and CD107a, yet a blunted PMA-increased LAG-3 and TIM-3, suggesting resistance to exhaustion. PD-1 and KLRG1 remained elevated, reflecting balanced immune control. Mitochondrial analysis revealed that trained NK cells exhibited higher basal and maximal OCR, greater spare respiratory capacity, and OCR\/ECAR ratio, reflecting superior metabolic fitness. These findings indicate that endurance-trained older adults have NK cells with greater functional adaptability, reduced senescence, and enhanced metabolism under inflammatory and pharmacological stress.<\/jats:p>","DOI":"10.1038\/s41598-025-06057-y","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T15:25:22Z","timestamp":1752506722000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Natural killer cells from endurance-trained older adults show improved functional and metabolic responses to adrenergic blockade and mTOR inhibition"],"prefix":"10.1038","volume":"15","author":[{"given":"Luciele Guerra","family":"Minuzzi","sequence":"first","affiliation":[]},{"given":"Helena","family":"Batatinha","sequence":"additional","affiliation":[]},{"given":"Christopher","family":"Weyh","sequence":"additional","affiliation":[]},{"given":"Vidya Srokshna","family":"Balasubramanian Lakshmi","sequence":"additional","affiliation":[]},{"given":"Carmen","family":"Fiuza-Luces","sequence":"additional","affiliation":[]},{"given":"Beatriz G.","family":"G\u00e1lvez","sequence":"additional","affiliation":[]},{"given":"Alejandro","family":"Lucia","sequence":"additional","affiliation":[]},{"given":"Ana Maria","family":"Teixeira","sequence":"additional","affiliation":[]},{"given":"Natascha","family":"Sommer","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 Cesar","family":"Rosa-Neto","sequence":"additional","affiliation":[]},{"given":"Fabio Santos","family":"Lira","sequence":"additional","affiliation":[]},{"given":"Karsten","family":"Kr\u00fcger","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"6057_CR1","first-page":"1693","volume":"Publish Ah","author":"SS Aguiar","year":"2019","unstructured":"Aguiar, S. 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