Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline

Claudia Schwarz, Slaven Stekovic, Miranka Wirth, Gloria Benson, Philipp Royer, Stephan J Sigrist, Thomas Pieber, Christopher Dammbrueck, Christoph Magnes, Tobias Eisenberg, Tobias Pendl, Jens Bohlken, Theresa Köbe, Frank Madeo, Agnes Flöel, Claudia Schwarz, Slaven Stekovic, Miranka Wirth, Gloria Benson, Philipp Royer, Stephan J Sigrist, Thomas Pieber, Christopher Dammbrueck, Christoph Magnes, Tobias Eisenberg, Tobias Pendl, Jens Bohlken, Theresa Köbe, Frank Madeo, Agnes Flöel

Abstract

Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings allow for longer-term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.

Keywords: aging; dietary supplement; polyamines; safety; spermidine; subjective cognitive decline.

Conflict of interest statement

CONFLICTS OF INTEREST: Drs. Slaven Stekovic, Stephan J. Sigrist, Tobias Eisenberg, and Frank Madeo have a financial interest in TLL. The other authors have nothing to disclose.

Figures

Figure 1
Figure 1
Levels of spermidine, spermine, putrescine, and L-Ornithine in whole blood (A,B), brain (C,D) and heart (E,F) after a 28-day oral spermidine supplementation using spermidine-rich plant extract in female (A,C,E) and male (B,D,F) mice (post mortem analysis). The measurements have been conducted on frozen, murine tissue samples using LC/MS-MS analysis of polyamine metabolites. Data is depicted by box plots extending from 25th to 75th percentile and whiskers ranging from the minimum to the maximum value. Individual data points are marked as dots. (n = 5-10 per gender and group).
Figure 2
Figure 2
CONSORT diagram indicating the number of participants at each stage of the study

References

    1. Minois N, Carmona-Gutierrez D, Madeo F. Polyamines in aging and disease. Aging (Albany NY). 2011; 3:716–32. 10.18632/aging.100361
    1. Das R, Kanungo MS. Activity and modulation of ornithine decarboxylase and concentrations of polyamines in various tissues of rats as a function of age. Exp Gerontol. 1982; 17:95–103. 10.1016/0531-5565(82)90042-0
    1. Soda K, Kano Y, Nakamura T, Kasono K, Kawakami M, Konishi F. Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. J Immunol. 2005; 175:237–45. 10.4049/jimmunol.175.1.237
    1. Pucciarelli S, Moreschini B, Micozzi D, De Fronzo GS, Carpi FM, Polzonetti V, Vincenzetti S, Mignini F, Napolioni V. Spermidine and spermine are enriched in whole blood of nona/centenarians. Rejuvenation Res. 2012; 15:590–95. 10.1089/rej.2012.1349
    1. Vivó M, de Vera N, Cortés R, Mengod G, Camón L, MartA-nez E. Polyamines in the basal ganglia of human brain. Influence of aging and degenerative movement disorders. Neurosci Lett. 2001; 304:107–11. 10.1016/S0304-3940(01)01776-1
    1. Morrison LD, Becker L, Ang LC, Kish SJ. Polyamines in human brain: regional distribution and influence of aging. J Neurochem. 1995; 65:636–42. 10.1046/j.1471-4159.1995.65020636.x
    1. Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F. Long-term oral polyamine intake increases blood polyamine concentrations. J Nutr Sci Vitaminol (Tokyo). 2009; 55:361–66. 10.3177/jnsv.55.361
    1. Gupta VK, Scheunemann L, Eisenberg T, Mertel S, Bhukel A, Koemans TS, Kramer JM, Liu KS, Schroeder S, Stunnenberg HG, Sinner F, Magnes C, Pieber TR, et al.. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci. 2013; 16:1453–60. 10.1038/nn.3512
    1. Eisenberg T, Knauer H, Schauer A, BAüttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L, Fussi H, Deszcz L, Hartl R, et al.. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009; 11:1305–14. 10.1038/ncb1975
    1. Soda K, Dobashi Y, Kano Y, Tsujinaka S, Konishi F. Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp Gerontol. 2009; 44:727–32. 10.1016/j.exger.2009.08.013
    1. Nowotarski SL, Woster PM, Casero RA Jr. Polyamines and cancer: implications for chemotherapy and chemoprevention. Expert Rev Mol Med. 2013; 15:e3. 10.1017/erm.2013.3
    1. Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A, Tong M, Ruckenstuhl C, Dammbrueck C, et al.. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016; 22:1428–38. 10.1038/nm.4222
    1. Yue F, Li W, Zou J, Jiang X, Xu G, Huang H, Liu L. Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy. Cancer Res. 2017; 77:2938–51. 10.1158/0008-5472.CAN-16-3462
    1. Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, Levesque S, Castoldi F, Jacquelot N, Yamazaki T, Senovilla L, Marino G, Aranda F, et al.. Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell. 2016; 30:147–60. 10.1016/j.ccell.2016.05.016
    1. Soda K, Kano Y, Chiba F, Koizumi K, Miyaki Y. Increased polyamine intake inhibits age-associated alteration in global DNA methylation and 1,2-dimethylhydrazine-induced tumorigenesis. PLoS One. 2013; 8:e64357. 10.1371/journal.pone.0064357
    1. Jessen F, Wolfsgruber S, Wiese B, Bickel H, Mösch E, Kaduszkiewicz H, Pentzek M, Riedel-Heller SG, Luck T, Fuchs A, Weyerer S, Werle J, van den Bussche H, et al., and German Study on Aging, Cognition and Dementia in Primary Care Patients. AD dementia risk in late MCI, in early MCI, and in subjective memory impairment. Alzheimers Dement. 2014; 10:76–83. 10.1016/j.jalz.2012.09.017
    1. Gupta VK, Pech U, Bhukel A, Fulterer A, Ender A, Mauermann SF, Andlauer TF, Antwi-Adjei E, Beuschel C, Thriene K, Maglione M, Quentin C, Bushow R, et al.. Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release. PLoS Biol. 2016; 14:e1002563. 10.1371/journal.pbio.1002563
    1. Uda K, Tsujikawa T, Fujiyama Y, Bamba T. Rapid absorption of luminal polyamines in a rat small intestine ex vivo model. J Gastroenterol Hepatol. 2003; 18:554–59. 10.1046/j.1440-1746.2003.03020.x
    1. Brodal BP, Eliassen KA, RAönning H, Osmundsen H. Effects of dietary polyamines and clofibrate on metabolism of polyamines in the rat. J Nutr Biochem. 1999; 10:700–08. 10.1016/S0955-2863(99)00058-3
    1. Crous-Bou M, Minguillón C, Gramunt N, Molinuevo JL. Alzheimer's disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017; 9:71. 10.1186/s13195-017-0297-z
    1. Beier J, Fuhr R, Seoane B, Massana E, de Miquel G, Pujol H, Ruiz S. Efficacy, safety, and tolerability of once-daily abediterol in patients with stable, persistent asthma: a Phase II, randomized, 7-day, crossover study. Pharmacol Res Perspect. 2017; 5:e00356. 10.1002/prp2.356
    1. Magnes C, Fauland A, Gander E, Narath S, Ratzer M, Eisenberg T, Madeo F, Pieber T, Sinner F. Polyamines in biological samples: rapid and robust quantification by solid-phase extraction online-coupled to liquid chromatography-tandem mass spectrometry. J Chromatogr A. 2014; 1331:44–51. 10.1016/j.chroma.2013.12.061
    1. Byun JA, Lee SH, Jung BH, Choi MH, Moon MH, Chung BC. Analysis of polyamines as carbamoyl derivatives in urine and serum by liquid chromatography-tandem mass spectrometry. Biomed Chromatogr. 2008; 22:73–80. 10.1002/bmc.898
    1. Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, ChA(c)telat G, Dubois B, Dufouil C, Ellis KA, van der Flier WM, Glodzik L, van Harten AC, de Leon MJ, et al., and Subjective Cognitive Decline Initiative (SCD-I) Working Group. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement. 2014; 10:844–52. 10.1016/j.jalz.2014.01.001
    1. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res. 1982-1983; 17:37–49. 10.1016/0022-3956(82)90033-4
    1. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state"". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12:189–98. 10.1016/0022-3956(75)90026-6
    1. Wechsler D. 1987. WMS-R: Wechsler Memory Scale--Revised: manual. (San Antonio, TX: Psychological Corporation/Harcourt Brace Jovanovich).
    1. Reitan RM. Validity of the trailmaking test as an indication of organic brain damage. Percept Mot Skills. 1958; 8:271–76. 10.2466/pms.1958.8.3.271
    1. Wechsler D. 1997. Wechsler Adult Intelligence Scale-III. (San Antonio, TX: The Psychological Corporation).
    1. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016; 7:27–31. 10.4103/0976-0105.177703
    1. Buyukuslu N, Hizli H, Esin K, Garipagaoglu M. A Cross-Sectional Study: Nutritional Polyamines in Frequently Consumed Foods of the Turkish Population. Foods. 2014; 3:541–57. 10.3390/foods3040541
    1. Zoumas-Morse C, Rock CL, Quintana EL, Neuhouser ML, Gerner EW, Meyskens FL Jr. Development of a polyamine database for assessing dietary intake. J Am Diet Assoc. 2007; 107:1024–27. 10.1016/j.jada.2007.03.012
    1. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996; 34:220–33. 10.1097/00005650-199603000-00003
    1. Ware J, A. Kosinski M and D. Keller S. (1998). SF-12: How to Score the SF-12 Physical and Mental Health Summary Scales 1988.
    1. Gandek B, Ware JE, Aaronson NK, Apolone G, Bjorner JB, Brazier JE, Bullinger M, Kaasa S, Leplege A, Prieto L, Sullivan M. Cross-validation of item selection and scoring for the SF-12 Health Survey in nine countries: results from the IQOLA Project. International Quality of Life Assessment. J Clin Epidemiol. 1998; 51:1171–78. 10.1016/S0895-4356(98)00109-7

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