Clinical trial NCT06249620: Oral Supplementation With AM3, Hesperidin and Spermidine Supplementation on Immunity Response and Biological Age.
Official title: A Randomized Controlled Trial of Oral Suplementation With AM3, Hesperidin and Spermidine on Immunity Response and Biological Age in Healthy Volunteers.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Healthy
Keywords: AM3
Biological age
Inmunology clock
Spermidine
Hesperidin
Lead sponsor: Industrial Farmacéutica Cantabria, S.A.
Sponsor class: INDUSTRY
First posted: 2024-02-08
Enrollment: 41
Sex: ALL
Minimum age (years): 29
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: The goal of this interventional study is to know the immune status of healthy participants and to obtain their biological age before and after two months of ingesting a dietary supplement. These individuals are compared with others who will be given a product of similar appearance, but without containing active components, being the constituents of the placebo group.

The study has a duration of 8 weeks, with 2 interventional visits (complete blood samples will be collected) at baseline and at 8 weeks.

In order to be included in the trial, the patient must read the Patient Information Sheet and sign the informed consent form.

The dosage regimen is two capsules per day in a single dose.

Detailed description: Forty consenting volunteers will be included in this prospective, randomized, double-blind study and will be randomized by a statistician independent of the research team.

The study consists of two milestones, in which different parameters are evaluated to finally reach the main goal, to measure their immune status and their biological age after taking the supplement (whose active ingredients include AM3, polyamines and flavonoids):

- Complete blood samples are collected from participants at milestone 1. To determine immune functions; neutrophils, lymphocytes and NK cells are measured. The adherence and chemotaxis capacity of neutrophils and lymphocytes is determined, as well as neutrophil phagocytosis and lymphocyte proliferation. In addition, the release of pro-inflammatory and anti-inflammatory cytokines is assessed.

In parallel, each participant will be given a survey to assess their perception of stress, which they will have to complete before and after 2 months of ingestion of the product (experimental and placebo).

- In milestone 2, oxidative and inflammatory stress parameters are analyzed. Regarding oxidative stress: catalase activity, glutathione reductase activity and reduced glutathione concentration are measured. In terms of inflammatory stress: concentrations of both proinflammatory and anti-inflammatory cytokines released are measured.

Eligibility criteria: Inclusion Criteria:

* Healthy volunteers who give their consent for the study will be included after having read and understood the information provided in the informed consent document
* Between 29-65 years old
* Residents in the Community of Madrid

Exclusion Criteria:

* Volunteers with no allergies or intolerances to the product
* Patologies
* Excessive alcohol consumption
* Pregnant women
* Antioxidants intake from supplements

Primary outcomes:
measure: Change in Biological Age
timeFrame: Baseline and Week 8
Secondary outcomes:
measure: Change in catalase activity with the use of a spectrophotometer
timeFrame: Baseline and week 8
measure: Change in Glutathione peroxidase levels
timeFrame: Baseline and week 8
measure: Change in Glutathione reductase levels
timeFrame: Baseline and week 8
measure: Change in reduced/oxized glutathione concentrations (GSH/GSSG)
timeFrame: Baseline and week 8
measure: Change in inflammatory and anti-inflammatory cytokines levels
timeFrame: Baseline and week 8
measure: Change in Malondialdehyde concentrations
timeFrame: Baseline and week 8
measure: Change in neutrophil levels
timeFrame: Baseline and week 8
measure: Change in lymphocyte levels
timeFrame: Baseline and week 8
measure: Change in cytotoxic activity of natural killer
timeFrame: Baseline and week 8
measure: Change in chemotaxis index
timeFrame: Baseline and week 8
measure: Change in lymphoproliferation levels
timeFrame: Baseline and week 8
measure: Change in phagocytosis activity
timeFrame: Baseline and week 8
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Facultad de Biología Universidad Complutense de Madrid
Study officials:
References:
citation: Wayne SJ, Rhyne RL, Garry PJ, Goodwin JS. Cell-mediated immunity as a predictor of morbidity and mortality in subjects over 60. J Gerontol. 1990 Mar;45(2):M45-8. doi: 10.1093/geronj/45.2.m45.
citation: De la Fuente M, Miquel J. An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des. 2009;15(26):3003-26. doi: 10.2174/138161209789058110.
citation: Foreman KJ, Marquez N, Dolgert A, Fukutaki K, Fullman N, McGaughey M, Pletcher MA, Smith AE, Tang K, Yuan CW, Brown JC, Friedman J, He J, Heuton KR, Holmberg M, Patel DJ, Reidy P, Carter A, Cercy K, Chapin A, Douwes-Schultz D, Frank T, Goettsch F, Liu PY, Nandakumar V, Reitsma MB, Reuter V, Sadat N, Sorensen RJD, Srinivasan V, Updike RL, York H, Lopez AD, Lozano R, Lim SS, Mokdad AH, Vollset SE, Murray CJL. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories. Lancet. 2018 Nov 10;392(10159):2052-2090. doi: 10.1016/S0140-6736(18)31694-5. Epub 2018 Oct 16.
citation: Medvedev ZA. An attempt at a rational classification of theories of ageing. Biol Rev Camb Philos Soc. 1990 Aug;65(3):375-98. doi: 10.1111/j.1469-185x.1990.tb01428.x. No abstract available.
citation: HARMAN D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956 Jul;11(3):298-300. doi: 10.1093/geronj/11.3.298. No abstract available.
citation: Martinez de Toda I, Mate I, Vida C, Cruces J, De la Fuente M. Immune function parameters as markers of biological age and predictors of longevity. Aging (Albany NY). 2016 Nov 28;8(11):3110-3119. doi: 10.18632/aging.101116.
citation: Martinez de Toda I, Vida C, Diaz-Del Cerro E, De la Fuente M. The Immunity Clock. J Gerontol A Biol Sci Med Sci. 2021 Oct 13;76(11):1939-1945. doi: 10.1093/gerona/glab136.
citation: Martinez de Toda I, Ceprian N, Diaz-Del Cerro E, De la Fuente M. The Role of Immune Cells in Oxi-Inflamm-Aging. Cells. 2021 Nov 1;10(11):2974. doi: 10.3390/cells10112974.
citation: Arranz L, Fernandez C, Rodriguez A, Ribera JM, De la Fuente M. The glutathione precursor N-acetylcysteine improves immune function in postmenopausal women. Free Radic Biol Med. 2008 Nov 1;45(9):1252-62. doi: 10.1016/j.freeradbiomed.2008.07.014. Epub 2008 Jul 27.
citation: Maggini S, Pierre A, Calder PC. Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients. 2018 Oct 17;10(10):1531. doi: 10.3390/nu10101531.
citation: Garrido A, Cruces J, Ceprian N, De la Fuente M. Improvements in Behavior and Immune Function and Increased Life Span of Old Mice Cohabiting With Adult Animals. J Gerontol A Biol Sci Med Sci. 2018 Jun 14;73(7):873-881. doi: 10.1093/gerona/gly043.
citation: Rojo JM, Rejas MT, Ojeda G, Portoles P, Barasoain I. Enhancement of lymphocyte proliferation, interleukin-2 production and NK activity by inmunoferon (AM-3), a fungal immunomodulator: variations in normal and immunosuppressed mice. Int J Immunopharmacol. 1986;8(6):593-7. doi: 10.1016/0192-0561(86)90031-7.
citation: Moya P, Baixeras E, Barasoain I, Rojo JM, Ronda E, Alonso ML, Portoles A. Immunoferon (AM3) enhances the activities of early-type interferon inducers and natural killer cells. Immunopharmacol Immunotoxicol. 1987;9(2-3):243-56. doi: 10.3109/08923978709035213.
citation: Sanchez Palacios A, Garcia Marrero JA, Schamann F. [Immunologic clinical evaluation of a biological response modifier, AM3, in the treatment of childhood infectious respiratory pathology]. Allergol Immunopathol (Madr). 1992 Jan-Feb;20(1):35-9. Spanish.
citation: Villarrubia VG, Valladolid JM, Elorza FL, Sada G, Vilchez JG, Jimenez M, Herrerias JM. Therapeutic response of chronic active hepatitis B (CAHB) to a new immunomodulator: AM3. Immunohematological effects. Immunopharmacol Immunotoxicol. 1992;14(1-2):141-64. doi: 10.3109/08923979209009217.
citation: Villarrubia VG, Moreno Koch MC, Calvo C, Gonzalez S, Alvarez-Mon M. The immunosenescent phenotype in mice and humans can be defined by alterations in the natural immunity reversal by immunomodulation with oral AM3. Immunopharmacol Immunotoxicol. 1997 Feb;19(1):53-74. doi: 10.3109/08923979709038533.
citation: Serrano-Gomez D, Martinez-Nunez RT, Sierra-Filardi E, Izquierdo N, Colmenares M, Pla J, Rivas L, Martinez-Picado J, Jimenez-Barbero J, Alonso-Lebrero JL, Gonzalez S, Corbi AL. AM3 modulates dendritic cell pathogen recognition capabilities by targeting DC-SIGN. Antimicrob Agents Chemother. 2007 Jul;51(7):2313-23. doi: 10.1128/AAC.01289-06. Epub 2007 Apr 23.
citation: Martin-Vilchez S, Molina-Jimenez F, Alonso-Lebrero JL, Sanz-Cameno P, Rodriguez-Munoz Y, Benedicto I, Roda-Navarro P, Trapero M, Aragoneses-Fenoll L, Gonzalez S, Pivel JP, Corbi AL, Lopez-Cabrera M, Moreno-Otero R, Majano PL. AM3, a natural glycoconjugate, induces the functional maturation of human dendritic cells. Br J Pharmacol. 2008 Jun;154(3):698-708. doi: 10.1038/bjp.2008.87. Epub 2008 Apr 14.
citation: Albillos A, Nieto M, Ubeda M, Munoz L, Fraile B, Reyes E, Lledo L, Blanco I, Pastor O, Salas C, Lario M, Monserrat J, Bataller R, Alvarez-Mon M. The biological response modifier AM3 attenuates the inflammatory cell response and hepatic fibrosis in rats with biliary cirrhosis. Gut. 2010 Jul;59(7):943-52. doi: 10.1136/gut.2008.168831. Epub 2010 May 4.
citation: Yuan CL, Lin SW, Cheng MH. Inhibition of Molecular Signaling in Huh-7 Cells by AM3: A Novel Chemotherapeutic Agent for Hepatocellular Carcinoma. Med Chem. 2016;13(1):49-56. doi: 10.2174/1573406412666160622130036.
citation: Fernandez-Lazaro D, Fernandez-Lazaro CI, Mielgo-Ayuso J, Adams DP, Garcia Hernandez JL, Gonzalez-Bernal J, Gonzalez-Gross M. Glycophosphopeptical AM3 Food Supplement: A Potential Adjuvant in the Treatment and Vaccination of SARS-CoV-2. Front Immunol. 2021 Jun 17;12:698672. doi: 10.3389/fimmu.2021.698672. eCollection 2021.
citation: Larque E, Sabater-Molina M, Zamora S. Biological significance of dietary polyamines. Nutrition. 2007 Jan;23(1):87-95. doi: 10.1016/j.nut.2006.09.006. Epub 2006 Nov 20.
citation: Ramani D, De Bandt JP, Cynober L. Aliphatic polyamines in physiology and diseases. Clin Nutr. 2014 Feb;33(1):14-22. doi: 10.1016/j.clnu.2013.09.019. Epub 2013 Oct 6.
citation: Hesterberg RS, Cleveland JL, Epling-Burnette PK. Role of Polyamines in Immune Cell Functions. Med Sci (Basel). 2018 Mar 8;6(1):22. doi: 10.3390/medsci6010022.
citation: Handa AK, Fatima T, Mattoo AK. Polyamines: Bio-Molecules with Diverse Functions in Plant and Human Health and Disease. Front Chem. 2018 Feb 5;6:10. doi: 10.3389/fchem.2018.00010. eCollection 2018.
citation: Munoz-Esparza NC, Latorre-Moratalla ML, Comas-Baste O, Toro-Funes N, Veciana-Nogues MT, Vidal-Carou MC. Polyamines in Food. Front Nutr. 2019 Jul 11;6:108. doi: 10.3389/fnut.2019.00108. eCollection 2019.
citation: Ramos-Molina B, Queipo-Ortuno MI, Lambertos A, Tinahones FJ, Penafiel R. Dietary and Gut Microbiota Polyamines in Obesity- and Age-Related Diseases. Front Nutr. 2019 Mar 14;6:24. doi: 10.3389/fnut.2019.00024. eCollection 2019.
citation: Nakanishi S, Cleveland JL. Polyamine Homeostasis in Development and Disease. Med Sci (Basel). 2021 May 13;9(2):28. doi: 10.3390/medsci9020028.
citation: Sagar NA, Tarafdar S, Agarwal S, Tarafdar A, Sharma S. Polyamines: Functions, Metabolism, and Role in Human Disease Management. Med Sci (Basel). 2021 Jun 9;9(2):44. doi: 10.3390/medsci9020044.
citation: Negrel S, Brunel JM. Synthesis and Biological Activities of Naturally Functionalized Polyamines: An Overview. Curr Med Chem. 2021;28(17):3406-3448. doi: 10.2174/0929867327666201102114544.
citation: Bravo-San Pedro JM, Senovilla L. Immunostimulatory activity of lifespan-extending agents. Aging (Albany NY). 2013 Nov;5(11):793-801. doi: 10.18632/aging.100619.
citation: Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018 Jan 26;359(6374):eaan2788. doi: 10.1126/science.aan2788.
citation: Stacchiotti A, Corsetti G. Natural Compounds and Autophagy: Allies Against Neurodegeneration. Front Cell Dev Biol. 2020 Sep 22;8:555409. doi: 10.3389/fcell.2020.555409. eCollection 2020.
citation: Soda K. Spermine and gene methylation: a mechanism of lifespan extension induced by polyamine-rich diet. Amino Acids. 2020 Feb;52(2):213-224. doi: 10.1007/s00726-019-02733-2. Epub 2019 Apr 19.
citation: Zhang M, Wang H, Tracey KJ. Regulation of macrophage activation and inflammation by spermine: a new chapter in an old story. Crit Care Med. 2000 Apr;28(4 Suppl):N60-6. doi: 10.1097/00003246-200004001-00007.
citation: Proietti E, Rossini S, Grohmann U, Mondanelli G. Polyamines and Kynurenines at the Intersection of Immune Modulation. Trends Immunol. 2020 Nov;41(11):1037-1050. doi: 10.1016/j.it.2020.09.007. Epub 2020 Oct 12.
citation: Zhang H, Simon AK. Polyamines reverse immune senescence via the translational control of autophagy. Autophagy. 2020 Jan;16(1):181-182. doi: 10.1080/15548627.2019.1687967. Epub 2019 Nov 6.
citation: Latour YL, Gobert AP, Wilson KT. The role of polyamines in the regulation of macrophage polarization and function. Amino Acids. 2020 Feb;52(2):151-160. doi: 10.1007/s00726-019-02719-0. Epub 2019 Apr 23.
citation: Barreca D, Gattuso G, Bellocco E, Calderaro A, Trombetta D, Smeriglio A, Lagana G, Daglia M, Meneghini S, Nabavi SM. Flavanones: Citrus phytochemical with health-promoting properties. Biofactors. 2017 Jul 8;43(4):495-506. doi: 10.1002/biof.1363. Epub 2017 May 12.
citation: Mas-Capdevila A, Teichenne J, Domenech-Coca C, Caimari A, Del Bas JM, Escote X, Crescenti A. Effect of Hesperidin on Cardiovascular Disease Risk Factors: The Role of Intestinal Microbiota on Hesperidin Bioavailability. Nutrients. 2020 May 20;12(5):1488. doi: 10.3390/nu12051488.
citation: Xiong H, Wang J, Ran Q, Lou G, Peng C, Gan Q, Hu J, Sun J, Yao R, Huang Q. Hesperidin: A Therapeutic Agent For Obesity. Drug Des Devel Ther. 2019 Nov 12;13:3855-3866. doi: 10.2147/DDDT.S227499. eCollection 2019.
citation: Tejada S, Pinya S, Martorell M, Capo X, Tur JA, Pons A, Sureda A. Potential Anti-inflammatory Effects of Hesperidin from the Genus Citrus. Curr Med Chem. 2018;25(37):4929-4945. doi: 10.2174/0929867324666170718104412.
citation: Hajialyani M, Hosein Farzaei M, Echeverria J, Nabavi SM, Uriarte E, Sobarzo-Sanchez E. Hesperidin as a Neuroprotective Agent: A Review of Animal and Clinical Evidence. Molecules. 2019 Feb 12;24(3):648. doi: 10.3390/molecules24030648.
citation: Li C, Schluesener H. Health-promoting effects of the citrus flavanone hesperidin. Crit Rev Food Sci Nutr. 2017 Feb 11;57(3):613-631. doi: 10.1080/10408398.2014.906382.
citation: Estruel-Amades S, Massot-Cladera M, Perez-Cano FJ, Franch A, Castell M, Camps-Bossacoma M. Hesperidin Effects on Gut Microbiota and Gut-Associated Lymphoid Tissue in Healthy Rats. Nutrients. 2019 Feb 2;11(2):324. doi: 10.3390/nu11020324.
citation: Camps-Bossacoma M, Franch A, Perez-Cano FJ, Castell M. Influence of Hesperidin on the Systemic and Intestinal Rat Immune Response. Nutrients. 2017 Jun 6;9(6):580. doi: 10.3390/nu9060580.
citation: Homayouni F, Haidari F, Hedayati M, Zakerkish M, Ahmadi K. Hesperidin Supplementation Alleviates Oxidative DNA Damage and Lipid Peroxidation in Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Clinical Trial. Phytother Res. 2017 Oct;31(10):1539-1545. doi: 10.1002/ptr.5881. Epub 2017 Aug 14.
citation: Li Y, Kandhare AD, Mukherjee AA, Bodhankar SL. Acute and sub-chronic oral toxicity studies of hesperidin isolated from orange peel extract in Sprague Dawley rats. Regul Toxicol Pharmacol. 2019 Jul;105:77-85. doi: 10.1016/j.yrtph.2019.04.001. Epub 2019 Apr 13.