Mechanisms of spermidine-induced autophagy and geroprotection


  • Fontana, L. The scientific basis of caloric restriction leading to longer life. Curr. Opin. Gastroenterol. 25, 144–150 (2009).

    Article 
    CAS 

    Google Scholar
     

  • Lee, C. & Longo, V. Dietary restriction with and without caloric restriction for healthy aging. F1000Res 5, F1000 (2016).

    Article 

    Google Scholar
     

  • Green, C. L., Lamming, D. W. & Fontana, L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat. Rev. Mol. Cell. Biol. https://doi.org/10.1038/s41580-021-00411-4 (2021).

  • Longo, V. D., Di Tano, M., Mattson, M. P. & Guidi, N. Intermittent and periodic fasting, longevity and disease. Nat. Aging 1, 47–59 (2021).

    Article 

    Google Scholar
     

  • Hofer, S. J., Carmona-Gutierrez, D., Mueller, M. I. & Madeo, F. The ups and downs of caloric restriction and fasting: from molecular effects to clinical application. EMBO Mol. Med. https://doi.org/10.15252/emmm.202114418 (2021).

  • Hofer, S. J., Davinelli, S., Bergmann, M., Scapagnini, G. & Madeo, F. Caloric restriction mimetics in nutrition and clinical trials. Front. Nutr. 8, 717343 (2021).

  • Ingram, D. K. & Roth, G. S. Glycolytic inhibition as a strategy for developing calorie restriction mimetics. Exp. Gerontol. 46, 148–154 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Ingram, D. K. et al. Calorie restriction mimetics: an emerging research field. Aging Cell 5, 97–108 (2006).

    Article 
    CAS 

    Google Scholar
     

  • Madeo, F., Carmona-Gutierrez, D., Hofer, S. J. & Kroemer, G. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential. Cell Metab. 29, 592–610 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).

    Article 

    Google Scholar
     

  • Pegg, A. E. Mammalian polyamine metabolism and function. IUBMB Life 61, 880–894 (2009).

    Article 
    CAS 

    Google Scholar
     

  • Teixeira, D., Santaolaria, M. L., Meneu, V. & Alonso, E. Dietary arginine slightly and variably affects tissue polyamine levels in male swiss albino mice. J. Nutr. 132, 3715–3720 (2002).

    Article 
    CAS 

    Google Scholar
     

  • López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article 

    Google Scholar
     

  • Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    Article 
    CAS 

    Google Scholar
     

  • Gupta, V. K. et al. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat. Neurosci. 16, 1453–1460 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Nishimura, K., Shiina, R., Kashiwagi, K. & Igarashi, K. Decrease in polyamines with aging and their ingestion from food and drink. J. Biochem. 139, 81–90 (2006).

    Article 
    CAS 

    Google Scholar
     

  • Jänne, J., Raina, A. & Siimes, M. Spermidine and spermine in rat tissues at different ages. Acta Physiol. Scand. 62, 352–358 (1964).

    Article 

    Google Scholar
     

  • Ferioli, M. E. & Comolli, R. Changes of liver and kidney polyamine levels during ageing. Exp. Gerontol. 10, 13–15 (1975).

    Article 
    CAS 

    Google Scholar
     

  • Das, R. & Kanungo, M. S. Activity and modulation of ornithine decarboxylase and concentrations of polyamines in various tissues of rats as a function of age. Exp. Gerontol. 17, 95–103 (1982).

    Article 
    CAS 

    Google Scholar
     

  • Ferioli, M. E., Sessa, A., Tunici, P., Pinotti, O. & Perin, A. Aging and polyamine acetylation in rat kidney. Biochim. Biophys. Acta 1317, 15–18 (1996).

    Article 

    Google Scholar
     

  • Liu, P., Gupta, N., Jing, Y. & Zhang, H. Age-related changes in polyamines in memory-associated brain structures in rats. Neuroscience 155, 789–796 (2008).

    Article 
    CAS 

    Google Scholar
     

  • Zwighaft, Z. et al. Circadian clock control by polyamine levels through a mechanism that declines with age. Cell Metab. 22, 874–885 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Pekar, T. et al. Spermidine in dementia: relation to age and memory performance. Wien. Klin. Wochenschr. 132, 42–46 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Pucciarelli, S. et al. Spermidine and spermine are enriched in whole blood of nona/centenarians. Rejuvenation Res. 15, 590–595 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Zhang, H. et al. Polyamines control eIF5A hypusination, TFEB translation and autophagy to reverse B cell senescence. Mol. Cell 76, 110–125 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Alsaleh, G. et al. Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. eLife 9, e57950 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Elworthy, P. & Hitchcock, E. Polyamine levels in red blood cells from patient groups of different sex and age. Biochim Biophys. Acta 993, 212–216 (1989).

    Article 
    CAS 

    Google Scholar
     

  • Soda, K., Uemura, T., Sanayama, H., Igarashi, K. & Fukui, T. Polyamine-rich diet elevates blood spermine levels and inhibits pro-inflammatory status: an interventional study. Med. Sci. 9, 22 (2021).

    CAS 

    Google Scholar
     

  • Uemura, T., Akasaka, Y. & Ikegaya, H. Correlation of polyamines, acrolein-conjugated lysine and polyamine metabolic enzyme levels with age in human liver. Heliyon 6, e05031 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Morrison, L. D., Becker, L., Ang, L. C. & Kish, S. J. Polyamines in human brain: regional distribution and influence of aging. J. Neurochemistry 65, 636–642 (1995).

    Article 
    CAS 

    Google Scholar
     

  • Igarashi, K. & Kashiwagi, K. Use of polyamine metabolites as markers for stroke and renal failure. in Polyamines (eds. A. E. Pegg & R. A. Casero) vol. 720, 395–408 (Humana Press, 2011).

  • Cheng, M.-L. et al. Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics. J. Am. Coll. Cardiol. 65, 1509–1520 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Pan, X. et al. Alzheimer’s disease-like pathology has transient effects on the brain and blood metabolome. Neurobiol. Aging 38, 151–163 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Graham, S. F. et al. Untargeted metabolomic analysis of human plasma indicates differentially affected polyamine and l-arginine metabolism in mild cognitive impairment subjects converting to Alzheimer’s disease. PLoS ONE 10, e0119452 (2015).

    Article 

    Google Scholar
     

  • Schuller, A. P., Wu, C. C., Dever, T. E., Buskirk, A. R. & Green, R. eIF5A functions globally in translation elongation and termination. Mol. Cell 66, 194–205 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Lubas, M. et al. eIF5A is required for autophagy by mediating ATG3 translation. EMBO Rep. 19, e46072 (2018).

    Article 

    Google Scholar
     

  • Frankel, L. B. EIF5A mediates autophagy via translation of ATG3. Autophagy 14, 1288–1289 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Liang, Y. et al. eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. Cell Rep. 35, 108941 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Schroeder, S. et al. Dietary spermidine improves cognitive function. Cell Rep. 35, 108985 (2021).

  • Beyer, H. S., Ellefson, M., Sherman, R. & Zieve, L. Aging alters ornithine decarboxylase and decreases polyamines in regenerating rat liver but putrescine replacement has no effect. J. Lab. Clin. Med. 119, 38–47 (1992).

    CAS 

    Google Scholar
     

  • Wang, W. et al. Exercise training preserves ischemic preconditioning in aged rat hearts by restoring the myocardial polyamine pool. Oxid. Med. Cell. Longev. 2014, 457429 (2014).

    Article 

    Google Scholar
     

  • Wang, J. et al. Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function. Aging 12, 650–671 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Yang, D., Oike, H., Furuse, M. & Yasuo, S. Spermidine resets circadian clock phase in NIH3T3 cells. Biomed. Res 42, 221–227 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Madeo, F. et al. Nutritional aspects of spermidine. Annu. Rev. Nutr. 40, 135–159 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Yin, Z., Pascual, C. & Klionsky, D. J. Autophagy: machinery and regulation. Micro. Cell 3, 588–596 (2016).

    Article 

    Google Scholar
     

  • Klionsky, D. J. et al. Autophagy in major human diseases. EMBO J. 40, e108863 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Aman, Y. et al. Autophagy in healthy aging and disease. Nat. Aging 1, 634–650 (2021).

    Article 

    Google Scholar
     

  • Pyo, J.-O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013).

    Article 

    Google Scholar
     

  • Bjedov, I. et al. Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila. PLoS Genet 16, e1009083 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Schinaman, J. M., Rana, A., Ja, W. W., Clark, R. I. & Walker, D. W. Rapamycin modulates tissue aging and lifespan independently of the gut microbiota in Drosophila. Sci. Rep. 9, 7824 (2019).

    Article 

    Google Scholar
     

  • Bjedov, I. et al. Mechanisms of lifespan extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).

    Article 
    CAS 

    Google Scholar
     

  • Yue, F. et al. Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Res. 77, 2938–2951 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Hansen, M., Rubinsztein, D. C. & Walker, D. W. Autophagy as a promoter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19, 579–593 (2018).


    Google Scholar
     

  • Holbert, C. E. et al. Autophagy induction by exogenous polyamines is an artifact of bovine serum amine oxidase activity in culture serum. J. Biol. Chem. 295, 9061–9068 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Wang, L. et al. Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells. Sci. Rep. 8, 10384 (2018).

    Article 

    Google Scholar
     

  • Pietrocola, F. et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509–516 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Morselli, E. et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615–629 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Liu, X. et al. Spermidine inhibits vascular calcification in chronic kidney disease through modulation of SIRT1 signaling pathway. Aging Cell 20, e13377 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Liu, L., McKeehan, W. L., Wang, F. & Xie, R. MAP1S enhances autophagy to suppress tumorigenesis. Autophagy 8, 278–280 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Park, I.-H. & Kim, M.-M. Spermidine inhibits MMP-2 via modulation of histone acetyltransferase and histone deacetylase in HDFs. Int. J. Biol. Macromol. 51, 1003–1007 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Hai, Y., Shinsky, S. A., Porter, N. J. & Christianson, D. W. Histone deacetylase 10 structure and molecular function as a polyamine deacetylase. Nat. Commun. 8, 15368 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Jell, J. et al. Genetically altered expression of spermidine/spermine-N1-acetyltransferase affects fat metabolism in mice via Acetyl-CoA. J. Biol. Chem. 282, 8404–8413 (2007).

    Article 
    CAS 

    Google Scholar
     

  • Kee, K. et al. Activated polyamine catabolism depletes acetyl-CoA pools and suppresses prostate tumor growth in TRAMP mice. J. Biol. Chem. 279, 40076–40083 (2004).

    Article 
    CAS 

    Google Scholar
     

  • Pegg, A. E. Spermidine/spermine-N1-acetyltransferase: a key metabolic regulator. Am. J. Physiol. Endocrinol. Metab. 294, E995–1010 (2008).

    Article 
    CAS 

    Google Scholar
     

  • Mariño, G. et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725 (2014).

    Article 

    Google Scholar
     

  • Puleston, D. J. et al. Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metab. 30, 352–363 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Zhang, J. et al. Importance of TFEB acetylation in control of its transcriptional activity and lysosomal function in response to histone deacetylase inhibitors. Autophagy 14, 1043–1059 (2018).

    CAS 

    Google Scholar
     

  • Klier, H. et al. Isolation and structural characterization of different isoforms of the hypusine-containing protein eIF-5A from HeLa cells. Biochemistry 34, 14693–14702 (1995).

    Article 
    CAS 

    Google Scholar
     

  • Tauc, M. et al. The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles. Cell Biosci. 11, 219 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Ishfaq, M. et al. Acetylation regulates subcellular localization of eukaryotic translation initiation factor 5A (eIF5A). FEBS Lett. 586, 3236–3241 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Hofer, S. J. et al. Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging. Autophagy 17, 2037–2039 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Padgett, L. R. et al. Deoxyhypusine synthase, an essential enzyme for hypusine biosynthesis, is required for proper exocrine pancreas development. FASEB J. 35, e21473 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Kar, R. K. et al. Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice. J. Biol. Chem. 297, 101333 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Barba-Aliaga, M. et al. Yeast translation elongation factor eIF5A expression is regulated by nutrient availability through different signalling pathways. Int. J. Mol. Sci. 22, 219 (2020).

    Article 

    Google Scholar
     

  • Barba-Aliaga, M. & Alepuz, P. The activator/repressor Hap1 binds to the yeast eIF5A-encoding gene TIF51A to adapt its expression to the mitochondrial functional status. FEBS Lett. 596, 1809–1826 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Melis, N. et al. Targeting eIF5A hypusination prevents anoxic cell death through mitochondrial silencing and improves kidney transplant outcome. J. Am. Soc. Nephrol. 28, 811–822 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Cougnon, M. et al. Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney. Cell Death Dis. 12, 283 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Karacay, C. et al. The effect of spermidine on autoimmunity and beta cell function in NOD mice. Sci. Rep. 12, 4502 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Carriche, G. M. et al. Regulating T cell differentiation through the polyamine spermidine. J. Allergy Clin. Immunol. 147, 335–348 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Sha, Y., Rao, L., Settembre, C., Ballabio, A. & Eissa, N. T. STUB1 regulates TFEB-induced autophagy–lysosome pathway. EMBO J. 36, 2544–2552 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Zhang, W., Li, X., Wang, S., Chen, Y. & Liu, H. Regulation of TFEB activity and its potential as a therapeutic target against kidney diseases. Cell Death Discov. 6, 32 (2020).

  • Zhao, E. & Czaja, M. J. TFEB: a central regulator of both the autophagosome and lysosome. Hepatol. 55, 1632–1634 (2012).

    Article 

    Google Scholar
     

  • Liang, W. et al. A reciprocal regulation of spermidine and autophagy in podocytes maintains the filtration barrier. Kidney Int. 98, 1434–1448 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Dever, T. E. & Ivanov, I. P. Roles of polyamines in translation. J. Biol. Chem. 293, 18719–18729 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Igarashi, K. & Kashiwagi, K. Modulation of protein synthesis by polyamines. IUBMB Life 67, 160–169 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Mandal, S., Mandal, A., Johansson, H. E., Orjalo, A. V. & Park, M. H. Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells. Proc. Natl Acad. Sci. USA 110, 2169–2174 (2013).

    Article 

    Google Scholar
     

  • Stein, K. C., Morales-Polanco, F., van der Lienden, J., Rainbolt, T. K. & Frydman, J. Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis. Nature 601, 637–642 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Jing, Y.-H. et al. Spermidine ameliorates the neuronal aging by improving the mitochondrial function in vitro. Exp. Gerontol. 108, 77–86 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Yang, X. et al. Spermidine inhibits neurodegeneration and delays aging via the PINK1–PDR1-dependent mitophagy pathway in C. elegans. Aging 12, 16852–16866 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Maglione, M. et al. Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses. Sci. Rep. 9, 19616 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Chai, N. et al. Spermidine prevents heart injury in neonatal rats exposed to intrauterine hypoxia by inhibiting oxidative stress and mitochondrial fragmentation. Oxid. Med. Cell. Longev. 2019, 5406468 (2019).

  • Messerer, J. et al. Spermidine supplementation influences mitochondrial number and morphology in the heart of aged mice. J. Anat. https://doi.org/10.1111/joa.13618 (2021).

    Article 

    Google Scholar
     

  • Sass, F. et al. TFEB deficiency attenuates mitochondrial degradation upon brown adipose tissue whitening at thermoneutrality. Mol. Metab. 47, 101173 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Mansueto, G. et al. Transcription factor EB controls metabolic flexibility during exercise. Cell Metab. 25, 182–196 (2017).

    Article 

    Google Scholar
     

  • Wang, S. et al. Emerging role of transcription factor EB in mitochondrial quality control. Biomed. Pharmacother. 128, 110272 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Yan, J. et al. Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway. Br. J. Pharmacol. 176, 3126–3142 (2019).

    CAS 

    Google Scholar
     

  • Gomes, A. P., Schild, T. & Blenis, J. Adding polyamine metabolism to the mTORC1 toolkit in cell growth and cancer. Dev. Cell 42, 112–114 (2017).

    Article 

    Google Scholar
     

  • Zabala-Letona, A. et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547, 109–113 (2017).

    Article 

    Google Scholar
     

  • Martina, J. A., Chen, Y., Gucek, M. & Puertollano, R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903–914 (2012).

    Article 

    Google Scholar
     

  • Napolitano, G. et al. mTOR-dependent phosphorylation controls TFEB nuclear export. Nat. Commun. 9, 3312 (2018).

    Article 

    Google Scholar
     

  • Liao, C.-Y. et al. The autophagy inducer spermidine protects against metabolic dysfunction during overnutrition. J. Gerontol. A Biol. Sci. Med Sci. 76, 1714–1725 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Yang, Y. et al. Induction of autophagy by spermidine is neuroprotective via inhibition of caspase 3-mediated Beclin 1 cleavage. Cell Death Dis. 8, e2738 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Li, G. et al. Spermidine suppresses Inflammatory DC function by activating the FOXO3 pathway and counteracts autoimmunity. iScience 23, 100807 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Freitag, K. et al. Spermidine reduces neuroinflammation and soluble amyloid beta in an Alzheimer’s disease mouse model. J. Neuroinflammation 19, 172 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Ding, Y. et al. SOX15 transcriptionally increases the function of AOC1 to modulate ferroptosis and progression in prostate cancer. Cell Death Dis. 13, 673 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Jeong, J.-W. et al. Spermidine protects against oxidative stress in inflammation models using macrophages and zebrafish. Biomol. Ther. 26, 146–156 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Liu, S. et al. Spermidine suppresses development of experimental abdominal aortic aneurysms. J. Am. Heart Assoc. 9, e014757 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Sutter, B. M., Wu, X., Laxman, S. & Tu, B. P. Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell 154, 403–415 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Ouyang, Y., Wu, Q., Li, J., Sun, S. & Sun, S. S-adenosylmethionine: a metabolite critical to the regulation of autophagy. Cell Prolif. 53, e12891 (2020).

    Article 
    CAS 

    Google Scholar
     

  • LaRocca, T. J., Gioscia-Ryan, R. A., Hearon, C. M. & Seals, D. R. The autophagy enhancer spermidine reverses arterial aging. Mech. Ageing Dev. 134, 314–320 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Knott, A. B. & Bossy-Wetzel, E. Impact of nitric oxide on metabolism in health and age-related disease. Diabetes Obes. Metab. 12, 126–133 (2010).

    Article 
    CAS 

    Google Scholar
     

  • Valerio, A. & Nisoli, E. Nitric oxide, interorganelle communication, and energy flow: a novel route to slow aging. Front Cell Dev. Biol. 3, 6 (2015).

    Article 

    Google Scholar
     

  • Ni, Y.-Q. & Liu, Y.-S. New insights into the roles and mechanisms of spermidine in aging and age-related diseases. Aging Dis. 12, 16 (2021).

    Article 

    Google Scholar
     

  • Pillai, S. P. & Shankel, D. M. Polyamines and their potential to be antimutagens. Mutat. Res. 377, 217–224 (1997).

    Article 
    CAS 

    Google Scholar
     

  • Lee, C. -Y. et al. Promotion of homology-directed DNA repair by polyamines. Nat. Commun. 10, 65 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Cooke, M. S., Evans, M. D., Dizdaroglu, M. & Lunec, J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 17, 1195–1214 (2003).

    Article 
    CAS 

    Google Scholar
     

  • Ha, H. C. et al. The natural polyamine spermine functions directly as a free radical scavenger. Proc. Natl Acad. Sci. USA 95, 11140–11145 (1998).

    Article 
    CAS 

    Google Scholar
     

  • Khan, A. U., Mei, Y. H. & Wilson, T. A proposed function for spermine and spermidine: protection of replicating DNA against damage by singlet oxygen. Proc. Natl Acad. Sci. USA 89, 11426–11427 (1992).

    Article 
    CAS 

    Google Scholar
     

  • Vujcic, S., Diegelman, P., Bacchi, C. J., Kramer, D. L. & Porter, C. W. Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. Biochemical J. 367, 665–675 (2002).

    Article 
    CAS 

    Google Scholar
     

  • Vujcic, S., Liang, P., Diegelman, P., Kramer, D. L. & Porter, C. W. Genomic identification and biochemical characterization of the mammalian polyamine oxidase involved in polyamine back-conversion. Biochemical J. 370, 19–28 (2003).

    Article 
    CAS 

    Google Scholar
     

  • Wang, Y. et al. Cloning and characterization of a human polyamine oxidase that is inducible by polyamine analogue cxposure. Cancer Res. 61, 5370–5373 (2001).

    CAS 

    Google Scholar
     

  • Murray Stewart, T., Dunston, T. T., Woster, P. M. & Casero, R. A. Polyamine catabolism and oxidative damage. J. Biol. Chem. 293, 18736–18745 (2018).

    Article 

    Google Scholar
     

  • Pegg, A. E. Functions of polyamines in mammals. J. Biol. Chem. 291, 14904–14912 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Wirth, A. et al. Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length. GeroScience 43, 673–690 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Scherz-Shouval, R. & Elazar, Z. Regulation of autophagy by ROS: physiology and pathology. Trends Biochemical Sci. 36, 30–38 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Bose, R. & Kanungo, M. S. Polyamines modulate phosphorylation and acetylation of non-histone chromosomal proteins of the cerebral cortex of rats of various ages. Arch. Gerontol. Geriatrics 1, 339–348 (1982).

    Article 
    CAS 

    Google Scholar
     

  • Oehme, I. et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl Acad. Sci. USA 110, E2592–2601 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Burgio, G., Corona, D. F. V., Nicotra, C. M. A., Carruba, G. & Taibi, G. P/CAF-mediated spermidine acetylation regulates histone acetyltransferase activity. J. Enzyme Inhib. Med. Chem. 31, 75–82 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Hougaard, D. M., Nielsen, J. H. & Larsson, L. I. Localization and biosynthesis of polyamines in insulin-producing cells. Biochem J. 238, 43–47 (1986).

    Article 
    CAS 

    Google Scholar
     

  • Welsh, N. & Sjöholm, A. Polyamines and insulin production in isolated mouse pancreatic islets. Biochem J. 252, 701–707 (1988).

    Article 
    CAS 

    Google Scholar
     

  • Sjoholm, A. Role of polyamines in the regulation of proliferation and hormone production by insulin-secreting cells. Am. J. Physiol. 264, C501–C518 (1993).

    Article 
    CAS 

    Google Scholar
     

  • Ma, L. et al. Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes 12, 1832857 (2020).

    Article 

    Google Scholar
     

  • Wang, J. -Y. et al. Effect of spermidine on ameliorating spermatogenic disorders in diabetic mice via regulating glycolysis pathway. Reprod. Biol. Endocrinol. 20, 45 (2022).

    Article 

    Google Scholar
     

  • Tain, L. S. et al. Longevity in response to lowered insulin signaling requires glycine N-methyltransferase-dependent spermidine production. Aging Cell 19, e13043 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Rajeeve, V., Pearce, W., Cascante, M., Vanhaesebroeck, B. & Cutillas, P. R. Polyamine production is downstream and upstream of oncogenic PI3K signalling and contributes to tumour cell growth. Biochemical J. 450, 619–628 (2013).

    Article 
    CAS 

    Google Scholar
     

  • Chrisam, M. et al. Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice. Autophagy 11, 2142–2152 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Baek, A. R. et al. Spermidine attenuates bleomycin-induced lung fibrosis by inducing autophagy and inhibiting endoplasmic reticulum stress-induced cell death in mice. Exp. Mol. Med 52, 2034–2045 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Yuan, X. et al. Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression. Cell Biosci. 11, 107 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Xu, T.-T. et al. Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice. Aging 12, 6401–6414 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Qi, Y., Qiu, Q., Gu, X., Tian, Y. & Zhang, Y. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Sci. Rep. 6, 24700 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Han, X. et al. Spermidine regulates mitochondrial function by enhancing eIF5A hypusination and contributes to reactive oxygen species production and ganoderic acids biosynthesis in Ganoderma lucidum. Appl. Environ. Microbiol. https://doi.org/10.1128/AEM.02037-21 (2022).

  • Rayess, H., Wang, M. B. & Srivatsan, E. S. Cellular senescence and tumor suppressor gene p16. Int. J. Cancer 130, 1715–1725 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Che, H. et al. Rebalance of the polyamine metabolism suppresses oxidative stress and delays senescence in nucleus pulposus cells. Oxid. Med. Cell. Longev. 2022, 8033353 (2022).

    Article 

    Google Scholar
     

  • García-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016).

    Article 

    Google Scholar
     

  • Balnis, J. et al. Deaccelerated myogenesis and autophagy in genetically induced pulmonary emphysema. Am. J. Respir. Cell Mol. Biol. 66, 623–637 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Ramot, Y. et al. Polyamines and hair: a couple in search of perfection. Exp. Dermatol. 19, 784–790 (2010).

    Article 
    CAS 

    Google Scholar
     

  • Ramot, Y. et al. Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions. PLoS ONE 6, e22564 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Zhang, D. et al. AMD1 is essential for ESC self-renewal and is translationally down-regulated on differentiation to neural precursor cells. Genes Dev. 26, 461–473 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Chen, T. et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 10, 908–911 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Ma, L. et al. Spermidine ameliorates high-fat diet-induced hepatic steatosis and adipose tissue inflammation in preexisting obese mice. Life Sci. 265, 118739 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Gassen, N. C. et al. SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals. Nat. Commun. 12, 3818 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Wagner, A. et al. Metabolic modeling of single TH17 cells reveals regulators of autoimmunity. Cell 184, 4168–4185 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Pietrocola, F., Bravo-San Pedro, J. M., Galluzzi, L. & Kroemer, G. Autophagy in natural and therapy-driven anticancer immunosurveillance. Autophagy 13, 2163–2170 (2017).

    Article 
    CAS 

    Google Scholar
     

  • Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Holbert, C. E., Cullen, M. T., Casero, R. A. & Stewart, T. M. Polyamines in cancer: integrating organismal metabolism and antitumour immunity. Nat. Rev. Cancer 22, 467–480 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Alexander, E. T., Minton, A., Peters, M. C., Phanstiel, O. & Gilmour, S. K. A novel polyamine blockade therapy activates an anti-tumor immune response. Oncotarget 8, 84140–84152 (2017).

    Article 

    Google Scholar
     

  • Hayes, C. S. et al. Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol. Res. 2, 274–285 (2014).

    Article 
    CAS 

    Google Scholar
     

  • Fan, Y. & Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 19, 55–71 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Ramos-Molina, B., Queipo-Ortuño, M. I., Lambertos, A., Tinahones, F. J. & Peñafiel, R. Dietary and gut microbiota polyamines in obesity- and age-related diseases. Front. Nutr. 6, 24 (2019).

  • Wang, D. et al. Oral spermidine targets brown fat and skeletal muscle to mitigate diet-induced obesity and metabolic disorders. Mol. Nutr. Food Res. 65, 2100315 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Bui, T. I., Gill, A. L., Mooney, R. A. & Gill, S. R. Modulation of gut microbiota metabolism in obesity-related type 2 diabetes reduces osteomyelitis severity. Microbiol. Spectr. 10, e0017022 (2022).

    Article 

    Google Scholar
     

  • Liu, S. et al. Effects of spermidine on gut microbiota modulation in experimental abdominal aortic aneurysm mice. Nutrients 14, 3349 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Reggiori, F. & Klionsky, D. J. Autophagic processes in yeast: mechanism, machinery and regulation. Genetics 194, 341–361 (2013).

    Article 

    Google Scholar
     

  • Zimmermann, A. et al. Autophagy: one more Nobel Prize for yeast. Microb. Cell 3, 579–581 (2016).

    Article 

    Google Scholar
     

  • Carmona-Gutierrez, D. et al. Guidelines and recommendations on yeast cell death nomenclature. Microb. Cell 5, 4–31 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Yamaguchi, O. & Otsu, K. Role of autophagy in aging. J. Cardiovasc Pharmacol. 60, 242–247 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Büttner, S. et al. Spermidine protects against α-synuclein neurotoxicity. Cell Cycle 13, 3903–3908 (2014).

    Article 

    Google Scholar
     

  • Bito, T. et al. Involvement of spermidine in the reduced lifespan of Caenorhabditis elegans during vitamin B12 deficiency. Metabolites 9, 192 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Ao, Y. et al. Lamin A buffers CK2 kinase activity to modulate aging in a progeria mouse model. Sci. Adv. https://doi.org/10.1126/sciadv.aav5078 (2019).

    Article 

    Google Scholar
     

  • Soda, K., Dobashi, Y., Kano, Y., Tsujinaka, S. & Konishi, F. Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp. Gerontol. 44, 727–732 (2009).

    Article 
    CAS 

    Google Scholar
     

  • Matsumoto, M., Kurihara, S., Kibe, R., Ashida, H. & Benno, Y. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS ONE 6, e23652 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Kibe, R. et al. Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. Sci. Rep. 4, 4548 (2014).

    Article 

    Google Scholar
     

  • Filfan, M. et al. Long-term treatment with spermidine increases healthspan of middle-aged Sprague-Dawley male rats. GeroScience 42, 937–949 (2020).

    Article 

    Google Scholar
     

  • Fernández, Á. F. et al. Autophagy couteracts weight gain, lipotoxicity and pancreatic β-cell death upon hypercaloric pro-diabetic regimens. Cell Death Dis. 8, e2970 (2017).

    Article 

    Google Scholar
     

  • Partridge, L., Fuentealba, M. & Kennedy, B. K. The quest to slow ageing through drug discovery. Nat. Rev. Drug Discov. 19, 513–532 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Janssens, G. E. & Houtkooper, R. H. Identification of longevity compounds with minimized probabilities of side effects. Biogerontology 21, 709–719 (2020).

    Article 

    Google Scholar
     

  • Schwarz, C. et al. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging 10, 19–33 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Moskalev, A. et al. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell 15, 407 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Binh, P. N. T., Soda, K., Maruyama, C. & Kawakami, M. Relationship between food polyamines and gross domestic product in association with longevity in Asian countries. Health 2, 1390–1396 (2010).

    Article 

    Google Scholar
     

  • Kiechl, S. et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am. J. Clin. Nutr. 108, 371–380 (2018).

    Article 

    Google Scholar
     

  • Soda, K., Kano, Y. & Chiba, F. Food polyamine and cardiovascular disease—an epidemiological study. Glob. J. Health Sci. 4, 170–178 (2012).

    Article 

    Google Scholar
     

  • Zoumas-Morse, C. et al. Development of a polyamine database for assessing dietary intake. J. Am. Diet. Assoc. 107, 1024–1027 (2007).

    Article 
    CAS 

    Google Scholar
     

  • Muñoz-Esparza, N. C. et al. Polyamines in Food. Front. Nutr. 6, 108 (2019).

    Article 

    Google Scholar
     

  • Buyukuslu, N., Hizli, H., Esin, K. & Garipagaoglu, M. A cross-sectional study: nutritional polyamines in frequently consumed foods of the Turkish population. Foods 3, 541–557 (2014).

    Article 

    Google Scholar
     

  • Binh, P. N. T., Soda, K. & Kawakami, M. Mediterranean diet and polyamine intake: possible contribution of increased polyamine intake to inhibition of age-associated disease. NDS 3, 1–7 (2010).


    Google Scholar
     

  • Bardócz, S. Polyamines in food and their consequences for food quality and human health. Trends Food Sci. Technol. 6, 341–346 (1995).

    Article 

    Google Scholar
     

  • Ali, M. A., Poortvliet, E., Strömberg, R. & Yngve, A. Polyamines: total daily intake in adolescents compared to the intake estimated from the Swedish Nutrition Recommendations Objectified (SNO). Food Nutr. Res. 55 (2011).

  • Schwarz, C. et al. Spermidine intake is associated with cortical thickness and hippocampal volume in older adults. NeuroImage 221, 117132 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Atiya Ali, M., Poortvliet, E., Strömberg, R. & Yngve, A. Polyamines in foods: development of a food database. Food Nutr. Res. 55 (2011).

  • Wirth, M. et al. The effect of spermidine on memory performance in older adults at risk for dementia: a randomized controlled trial. Cortex 109, 181–188 (2018).

    Article 

    Google Scholar
     

  • Wirth, M. et al. Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)-study protocol for a randomized controlled trial. Alzheimers Res Ther. 11, 36 (2019).

    Article 

    Google Scholar
     

  • Schwarz, C. et al. Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline: a randomized clinical trial. JAMA Netw. Open 5, e2213875 (2022).

    Article 

    Google Scholar
     

  • Witkowska, A. M. Soluble ICAM-1: a marker of vascular inflammation and lifestyle. Cytokine 31, 127–134 (2005).

    Article 
    CAS 

    Google Scholar
     

  • Pekar, T. et al. The positive effect of spermidine in older adults suffering from dementia: first results of a 3-month trial. Wien. Klin. Wochenschr. 133, 484–491 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Huang, J. et al. Spermidine exhibits protective effects against traumatic brain injury. Cell Mol. Neurobiol. 40, 927–937 (2020).

    Article 
    CAS 

    Google Scholar
     

  • Guerra, G. P., Rubin, M. A. & Mello, C. F. Modulation of learning and memory by natural polyamines. Pharm. Res. 112, 99–118 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Matsumoto, M. & Benno, Y. Consumption of Bifidobacterium lactis LKM512 yogurt reduces gut mutagenicity by increasing gut polyamine contents in healthy adult subjects. Mutat. Res. 568, 147–153 (2004).

    Article 
    CAS 

    Google Scholar
     

  • Matsumoto, M., Kitada, Y. & Naito, Y. Endothelial function is improved by inducing microbial polyamine production in the gut: a randomized placebo-controlled trial. Nutrients 11, 1188 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Rinaldi, F., Marzani, B., Pinto, D. & Ramot, Y. A spermidine-based nutritional supplement prolongs the anagen phase of hair follicles in humans: a randomized, placebo-controlled, double-blind study. Dermatol. Pract. Concept. 7, 17–21 (2017).

    Article 

    Google Scholar
     

  • Chai, M. et al. Stimulation of hair growth by small molecules that activate autophagy. Cell Rep. 27, 3413–3421 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Vargas, A. J. et al. Dietary polyamine intake and risk of colorectal adenomatous polyps. Am. J. Clin. Nutr. 96, 133–141 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Vargas, A. J. et al. Dietary polyamine intake and colorectal cancer risk in postmenopausal women. Am. J. Clin. Nutr. 102, 411–419 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Pietrocola, F. et al. Spermidine reduces cancer-related mortality in humans. Autophagy 15, 362–365 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Gobert, A. P. et al. Protective role of spermidine in colitis and colon carcinogenesis. Gastroenterology 162, 813–827 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Chin, A., Bieberich, C. J., Stewart, T. M. & Casero, R. A. Polyamine depletion strategies in cancer: remodeling the tumor immune microenvironment to enhance anti-tumor responses. Med. Sci. 10, 31 (2022).

    CAS 

    Google Scholar
     

  • Faundes, V. et al. Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine. Nat. Commun. 12, 833 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Murray-Stewart, T., Dunworth, M., Foley, J. R., Schwartz, C. E. & Casero, R. A. Polyamine homeostasis in Snyder-Robinson syndrome. Med. Sci. 6, 112 (2018).

    CAS 

    Google Scholar
     

  • Larcher, L. et al. The complete loss of function of the SMS gene results in a severe form of Snyder-Robinson syndrome. Eur. J. Med. Genet. 63, 103777 (2020).

    Article 

    Google Scholar
     

  • Lauren Cason, A. et al. X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. Eur. J. Hum. Genet 11, 937–944 (2003).

    Article 

    Google Scholar
     

  • Li, C. et al. Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome. Nat. Commun. 8, 1257 (2017).

    Article 

    Google Scholar
     

  • Murray Stewart, T. et al. (R,R)-1,12-Dimethylspermine can mitigate abnormal spermidine accumulation in Snyder-Robinson syndrome. J. Biol. Chem. 295, 3247–3256 (2020).

    Article 

    Google Scholar
     

  • Kapur, M. & Ackerman, S. L. mRNA translation gone awry: translation fidelity and neurological disease. Trends Genet. 34, 218–231 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Schultz, C. R., Bupp, C. P., Rajasekaran, S. & Bachmann, A. S. Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation. Biochemical J. 476, 2047–2057 (2019).

    Article 
    CAS 

    Google Scholar
     

  • VanSickle, E. A. et al. Expanding the phenotype: four new cases and hope for treatment in Bachmann-Bupp syndrome. Am. J. Med. Genet. A 185, 3485–3493 (2021).

    Article 

    Google Scholar
     

  • Bupp, C. P., Schultz, C. R., Uhl, K. L., Rajasekaran, S. & Bachmann, A. S. Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features. Am. J. Med. Genet. A 176, 2548–2553 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Rodan, L. H. et al. Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities. Am. J. Med. Genet. A 176, 2554–2560 (2018).

    Article 
    CAS 

    Google Scholar
     

  • Rajasekaran, S. et al. Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease. Elife 10, e67097 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Mayeux, R. Biomarkers: potential uses and limitations. NeuroRx 1, 182–188 (2004).

    Article 

    Google Scholar
     

  • Strimbu, K. & Tavel, J. A. What are biomarkers? Curr. Opin. HIV AIDS 5, 463–466 (2010).

    Article 

    Google Scholar
     

  • Amin, M. et al. Polyamine biomarkers as indicators of human disease. Biomarkers 26, 77–94 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Maksymiuk, A. W. et al. Spermidine/spermine-N1-acetyltransferase-1 as a diagnostic biomarker in human cancer. Future Sci. OA 4, FSO345 (2018).

  • Morrison, L. D. & Kish, S. J. Brain polyamine levels are altered in Alzheimer’s disease. Neurosci. Lett. 197, 5–8 (1995).

    Article 
    CAS 

    Google Scholar
     

  • Saiki, S. et al. A metabolic profile of polyamines in Parkinson disease: a promising biomarker. Ann. Neurol. 86, 251–263 (2019).

    Article 
    CAS 

    Google Scholar
     

  • Sternberg, Z. et al. Elevated spermidine serum levels in mild cognitive impairment, a potential biomarker of progression to Alzheimer dementia, a pilot study. J. Clin. Neurosci. 100, 169–174 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Xu, J. et al. Non-linear association between serum spermidine and mild cognitive impairment: results from a cross-sectional and longitudinal study. Front. Aging Neurosci. 14, 924984 (2022).

  • Polis, B., Karasik, D. & Samson, A. O. Alzheimer’s disease as a chronic maladaptive polyamine stress response. Aging 13, 10770–10795 (2021).

    Article 

    Google Scholar
     

  • Zheng, L. et al. Serum spermidine in relation to risk of stroke: a multilevel study. Front Nutr. 9, 843616 (2022).

    Article 

    Google Scholar
     

  • Yu, Z. et al. Effect of serum spermidine on the prognosis in patients with acute myocardial infarction: a cohort study. Nutrients 14, 1394 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Omar, E. M., Omar, R. S., Shoela, M. S. & El Sayed, N. S. A study of the cardioprotective effect of spermidine: a novel inducer of autophagy. Chin. J. Physiol. 64, 281–288 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Magnes, C. et al. Polyamines in biological samples: rapid and robust quantification by solid-phase extraction online-coupled to liquid chromatography–tandem mass spectrometry. J. Chromatogr. A 1331, 44–51 (2014).

    Article 
    CAS 

    Google Scholar
     

  • Srivastava, V. et al. Distinct designer diamines promote mitophagy, and thereby enhance healthspan in C. elegans and protect human cells against oxidative damage. Autophagy 0, 1–31 (2022).

    Article 

    Google Scholar
     



  • Source link

    Ozinize
    Logo
    Shopping cart