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Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner

Nature Neuroscience volume 16, pages 1453–1460 (2013)Cite this article

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Abstract

Age-dependent memory impairment is known to occur in several organisms, including Drosophila, mouse and human. However, the fundamental cellular mechanisms that underlie these impairments are still poorly understood, effectively hampering the development of pharmacological strategies to treat the condition. Polyamines are among the substances found to decrease with age in the human brain. We found that levels of polyamines (spermidine, putrescine) decreased in aging fruit flies, concomitant with declining memory abilities. Simple spermidine feeding not only restored juvenile polyamine levels, but also suppressed age-induced memory impairment. Ornithine decarboxylase-1, the rate-limiting enzyme for de novo polyamine synthesis, also protected olfactory memories in aged flies when expressed specifically in Kenyon cells, which are crucial for olfactory memory formation. Spermidine-fed flies showed enhanced autophagy (a form of cellular self-digestion), and genetic deficits in the autophagic machinery prevented spermidine-mediated rescue of memory impairments. Our findings indicate that autophagy is critical for suppression of memory impairments by spermidine and that polyamines, which are endogenously present, are candidates for pharmacological intervention.

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Figure 1: Spermidine feeding prevents the age-related decline of endogenous spermidine and putrescine levels.
Figure 2: Spermidine-feeding rescues AMI.
Figure 3: Ca2+ imaging in the Kenyon cells in response to odors in aging wild-type flies.
Figure 4: Spermidine feeding induces autophagy in the Drosophila brain.
Figure 5: Autophagy is required for spermidine's effects on AMI.
Figure 6: Spermidine feeding induces widespread transcriptional changes in fly heads during aging.
Figure 7: Brain-specific expression of Odc-1 is sufficient to suppress AMI.

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Acknowledgements

We would like to thank T. Neufeld (University of Minnesota), L. Luo (Stanford University) and the Bloomington Stock Center for fly stocks, and S. Gaumer (University Versailles) for ref(2)P antibody. We are also grateful to M.G. Holt and B. Gerber for critically reading the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft to S.J.S. (Exc257, FOR1363), as well as A6/SFB 958 and DynAge Focus Area (Freie Universität Berlin) to S.J.S., the European Union (FP7 Gencodys HEALTH-241995) to H.G.S. and A.S., a VIDI grant from the Netherlands Organization for Scientific Research (917-96-346) to A.S., the BMBF (BCCNII, grant number 01GQ1005A) to A.F., and the Emmy Noether Program to M.S. F.M. is grateful to the FWF for grants LIPOTOX, P23490, P24381 and I1000 (DACH). T.E. is recipient of an APART fellowship of the Austrian Academy of Sciences.

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Authors and Affiliations

  1. Institute for Biology/Genetics, Freie Universität Berlin, Berlin, Germany

    Varun K Gupta, Lisa Scheunemann, Sara Mertel, Anuradha Bhukel, Karen S Y Liu, Martin Schwaerzel & Stephan J Sigrist

  2. NeuroCure, Charité, Berlin, Germany

    Varun K Gupta, Anuradha Bhukel, Karen S Y Liu & Stephan J Sigrist

  3. Institute of Molecular Biosciences, University of Graz, Graz, Austria

    Tobias Eisenberg, Sabrina Schroeder & Frank Madeo

  4. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Tom S Koemans, Jamie M Kramer & Annette Schenck

  5. Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands

    Hendrik G Stunnenberg

  6. Health Institute for Biomedicine and Health Sciences, Joanneum Research Forschungs GesmBH, Graz, Austria

    Frank Sinner, Christoph Magnes & Thomas R Pieber

  7. Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Austria

    Frank Sinner & Thomas R Pieber

  8. Georg-August-Universität Göttingen, Molecular Neurobiology of Behavior, Göttingen, Germany

    Shubham Dipt & André Fiala

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Contributions

V.K.G., F.M. and S.J.S. designed the study. V.K.G., L.S., T.E., C.M., S.M., T.S.K., J.M.K., A.B., S.D., K.S.Y.L., S.S. and C.M. performed the experiments. V.K.G., L.S., T.E., T.S.K., J.M.K., A.B., K.S.Y.L., S.S., S.D., C.M., F.M. and S.J.S. analyzed the data. F.S., M.S., T.R.P., A.F. and H.G.S. provided protocols, reagents and advice. All of the authors commented on the manuscript. V.K.G., A.S., F.M. and S.J.S. wrote the manuscript.

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Correspondence to Frank Madeo or Stephan J Sigrist.

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Integrated supplementary information

Supplementary Figure 1 Effect of spermidine feeding on spermine levels.

Endogenous level of Spermine in chronologically aging wild-type flies fed with food supplemented by 1 mM or 5mM spermidine (Spd1mM+ or Spd5mM+ respectively), compared with normal food (Spd–). Data are shown normalized to spermine levels of 1-day old (1d) flies on Spd– food (or Spd–, 1d; n=4 for all data; F=10.37 for Spd– flies, F=5.78 for Spd1mM+ flies, F=12.31 for Spd5mM+ flies; one-way-ANOVA with Bonferroni correction). *:p<0.05; **:p<0.01, ns: p>0.05, not significant; all values are mean ± SEM.

Source data

Supplementary Figure 2 Effect of spermidine on 3-d-old wild-type flies trained with two electric shocks.

(a) Aversive olfactory-associative memory performance in 3-min after training (STM) deficit in chronologically aging wild-type (n=10 for all data; F=8.50; one-way-ANOVA with Bonferroni correction). (b) Short-term memory (STM) performance 3min after training (training under non-saturating conditions, 2-shocks instead of 12 electricshocks) of 3d- Spd1mM+ and Spd5mM+ as compared to Spd– flies with (n=8-9 for all data; F=0.77; one-way-ANOVA with Bonferroni correction). **:p<0.01; ***:p<0.001, ns: p>0.05, not significant; all values are mean ± SEM.

Source data

Supplementary Figure 3 Climbing ability of aged flies was not rescued by spermidine feeding.

Climbing ability of aged Spd5mM+ as compared to to Spd– flies (n=6 for all data; F=35.87; one-way-ANOVA with Bonferroni correction). ***:p<0.001, ns: p>0.05, not significant; all values are mean ± SEM.

Source data

Supplementary Figure 4 Kinetics of age-related decline of polyamines.

Level of Spermidine (a) and Putrescine (b) in chronologically aging wild-type flies fed with food supplemented with 5mM spermidine (Spd5mM+), and compared to age-matched control flies (Spd–). Data are shown normalized to the level of respective polyamines found in 1-day old (1d) flies on Spd– food (or Spd–, 1d; n=3 for all data; F=19.32 for (a) and F=16.31 for (b) respectively; one-way-ANOVA with Bonferroni correction). *: p<0.05; ns: p>0.05, not significant; all values are mean ± SEM.

Source data

Supplementary Figure 5 Graph of estimated dispersion versus base mean expression values.

Per gene dispersion values (orange dots) and estimated dispersion values (black line) determined using DESeq, plotted against the base mean expression level. In cases where the per-gene dispersion was greater than estimated, we used the per-gene dispersion value to determine the probability of differential expression.

Supplementary Figure 6 Changes in gene expression under spermidine treatment as determined by RNA-seq and quantitative real-time PCR (qPCR).

Several of the genes found be modulated by spermidine feeding (by RNA-seq) were analyzed and validated by quantitative real-time PCR (qPCR; data represent the mean of two independent aging experiments for both 10 day old Spd5mM+ as as well as Spd– flies).

Source data

Supplementary Figure 7 Mushroom body–specific expression of Odc-1 in 3-d-old flies.

(a) Aversive associative memory performance in 3 min after training (STM) in 3 day-old female flies expressing UAS-Odc-1 only in mushroom body (n=7-8 for all data; F=0.05; one-way-ANOVA with Bonferroni correction) (b) Aversive associative memory performance in 3hr after training (ITM), anesthesia-resistant memory (ARM) and anesthesia-sensitive memory (ASM) in 3 day-old female flies with UAS-Odc-1 expressed specifically in mushroom body (n=7 for all data; F=2.81 for ITM, F=0.27 for ARM, F=1.12 for ASM; one-way-ANOVA with Bonferroni correction). ns: p>0.05, not significant; all values are mean ± SEM.

Source data

Supplementary Figure 8 Upregulation of autophagy was not sufficient to suppress AMI.

(a) Aversive associative memory performance in 3 min after training (STM) in 3d-female flies pan-neuronal expression of Atg8a (n=8 for all data; F=1.21; one-way-ANOVA with Bonferroni correction) (b) Pan-neuronal expression of Atg8a in a wildtype background (using appl-Gal4) did not suppress AMI in 30d-female flies (n=8 for all data; F=8.66; one-way-ANOVA with Bonferroni correction). **:p<0.01; ns: p>0.05, not significant; all values are mean ± SEM.

Source data

Supplementary Figure 9 Full-length image of the blots presented in Figure 4.

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Supplementary Figures 1–9 and Supplementary Tables 1–5 (PDF 9526 kb)

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Gupta, V., Scheunemann, L., Eisenberg, T. et al. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci 16, 1453–1460 (2013). https://doi.org/10.1038/nn.3512

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