{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:33:28Z","timestamp":1781822008590,"version":"3.54.5"},"reference-count":70,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation (RSF)","doi-asserted-by":"publisher","award":["25-25-00391"],"award-info":[{"award-number":["25-25-00391"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The purpose of this study was to examine whether supplementation of ultra- and nanofiltered colostrum-based products, combined with egg yolk extract, nicotinamide mononucleotide (NMN), quercetin, alpha-ketoglutarate, white button mushroom, and celery seed extracts (the formula was patented by 4Life Research Company, USA and named as AgePro), modulate the functional activity of natural killer (NK) cells in vivo. We found that this supplement, taken orally in two capsules twice a day for 30 days, significantly enhanced the cytotoxic activity of NK cells. This was evidenced by the increased NK cell-mediated killing of carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled K562 human myeloid leukemia cells. As expected, this effect was dependent on the ratio between the effector (E) (e.g., peripheral blood mononuclear cells (PBMCs)) and target (T) (e.g., K562) cells, illustrating maximal killing of K562 cells at a 50:1 E\/T ratio. Of note, increased NK-mediated killing of K562 cells after taking AgePro correlated with increased perforin release, evidenced by the CD107a degranulation assay. In concordance with these findings, taking of AgePro for 1 month increased production of several cytokines and chemokines, including IL-1\u03b2, IL-1R\u03b1, IL-6, IL-8, IL-10, IFN-\u03b3, TNF-\u03b1, G-CSF, PDGF-AA, PDGF-AB\/BB, GRO, MCP-1, MCP-3, and MIP-1\u03b1, in PBMCs co-cultured with K562 cells. Of note, increased production of the cytokines correlated with the activation state of PBMCs, as evidenced by increased expression of the surface activation markers (e.g., the interleukin-2 receptor alpha chain\u2014CD25). A strong correlation was found between NK-based cytotoxic activity and the production of IL-1\u03b2, IL-6, TNF-\u03b1, and MIP-1\u03b1. Importantly, no increase in the aforementioned soluble factors and activation markers was detected in PBMCs cultured alone, thereby illustrating the potent immunoregulatory activity of AgePro only in the presence of the harmful target cells. Hematological parameters also remained unchanged over the entire study period. Collectively, we show herein the significant enhancement of the cytotoxic activity of NK cells against target tumor cells after taking AgePro for 1 month. Notably, this effect was observed for all age groups, including young, adult, and elderly participants. Moreover, a significant improvement in NK cytotoxic activity was also detected for participants with low basal (e.g., before taking AgePro) numbers of NK-mediated killing. The enhancement of NK-based cytotoxicity was associated with an increased release of several cytokines and chemokines involved in regulating a broad spectrum of mechanisms outside the cell-mediated cytotoxicity and killing of target cells. Of note, spontaneous activation of PBMCs, particularly NK cells, was not detected after taking AgePro. Given that spontaneous activation of autoreactive lymphocytes is a feature associated with autoimmunity and taking into account our data illustrating the AgePro-induced activation of NK cells detected only in the presence of the potentially harmful cells, we conclude that our innovative product exhibits potent immunoregulatory activity and high safety profile.<\/jats:p>","DOI":"10.3390\/ijms26072897","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T07:46:50Z","timestamp":1742802410000},"page":"2897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enhancement of NK Cell Cytotoxic Activity and Immunoregulatory Effects of a Natural Product Supplement Across a Wide Age Span: A 30-Day In Vivo Human Study"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2415-1084","authenticated-orcid":false,"given":"Sergei","family":"Boichuk","sequence":"first","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"},{"name":"Central Research Laboratory, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0293-2974","authenticated-orcid":false,"given":"Aigul","family":"Galembikova","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Vollmer","sequence":"additional","affiliation":[{"name":"Scientific Research Division, 4Life Research, Sandy, UT 84070, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1007\/BF00199858","article-title":"Effects of orally administered retinol on natural killer cell activity in wild type BALB\/c and congenitally athymic BALB\/c mice","volume":"21","author":"Fraker","year":"1986","journal-title":"Cancer Immunol. 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