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Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice

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Abstract

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG activation and excitation of orexin neurons by systemic IGF-I are abrogated in old mice. Moreover, orthodromical responses of LH neurons are facilitated by either systemic or local IGF-I in young mice, but not in old ones. As orexin neurons of old mice show dysregulated IGF-I receptor (IGF-IR) expression, suggesting disturbed IGF-I sensitivity, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

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Data availability

Data generated during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are thankful to M. Garcia for technical support.

Funding

This work was funded by a grant from Ciberned and is part of the project SAF2016-76462 funded by MCIN/AEI/https://doi.org/10.13039/501100011033. J.A. Zegarra-Valdivia acknowledges the financial support of the National Council of Science, Technology and Technological Innovation (CONCYTEC, Perú) through the National Fund for Scientific and Technological Development (FONDECYT, Perú). J. Fernandes received a post-doc fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP: # 2017/14742–0; # 2019/03368–5).

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Authors and Affiliations

  1. Cajal Institute (CSIC), Madrid, Spain

    Jonathan A. Zegarra-Valdivia, Jansen Fernandes, Maria Estrella Fernandez de Sevilla, Angel Trueba-Saiz, Jaime Pignatelli, Kentaro Suda, Laura Martinez-Rachadell, Ana Maria Fernandez & Julio Esparza

  2. CIBERNED, Madrid, Spain

    Jonathan A. Zegarra-Valdivia, Maria Estrella Fernandez de Sevilla, Angel Trueba-Saiz, Jaime Pignatelli, Laura Martinez-Rachadell, Ana Maria Fernandez & Ignacio Torres Aleman

  3. Universidad Nacional de San Agustín de Arequipa, Arequipa, Perú

    Jonathan A. Zegarra-Valdivia

  4. Achucarro Basque Center for Neuroscience, Leioa, Spain

    Jonathan A. Zegarra-Valdivia & Ignacio Torres Aleman

  5. Universidade Federal São Paulo, São Paulo, Brazil

    Jansen Fernandes

  6. Kobe University Graduate School of Medicine, Kobe, Japan

    Kentaro Suda

  7. Allinky Biopharma, Madrid, Spain

    Miguel Vega

  8. Department of Neurosciences, School of Medicine, UAM, Madrid, Spain

    Angel Nuñez

  9. IKERBASQUE Basque Science Foundation, Bilbao, Spain

    Ignacio Torres Aleman

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  1. Jonathan A. Zegarra-Valdivia
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Contributions

JAZV conducted experiments, prepared figures, and results and wrote part of the manuscript. JF, ATS, MEFS, JP, and AMF conducted experiments and prepared figures. KS and LMR conducted experiments. MN provided experimental expertise. JE analyzed data. MV provided reagents and data on AIK3a305. AN designed and conducted experiments and wrote part of the manuscript. ITA designed the study and wrote the manuscript.

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Correspondence to Ignacio Torres Aleman.

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Competing interests

MV and ITA have shares in Allinky BioPharma, manufacturer of AIK3a.

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Supplementary Information

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11357_2022_589_MOESM1_ESM.pdf

Supplementary file1 (PDF 169 kb) Supplementary Figure 1: A, ECoG band analysis of young male and female mice (WT ≤ 6 months old; n=15, and n=8 respectively; ordinary Two-Way ANOVA, group factor: F(1,103)=0.0697; p=0.7923). B, ECoG band analysis of old male and female mice (WT ≥ 18 months old; n= 4 each group;, ordinary Two-Way ANOVA, group factor: F (1, 30) = 1,104e-013, p>0.999). C, Latency of evoked potentials registered in the PeF after stimulation of the LC in young and old mice (young= 0,003379 ± 0,0001655, old= 0,003651 ± 0,0001691; Unpaired t-test, t=1.15, df=39, p=0.2572, young=15, old=13). D, Area under the curve of the basal evoked potential (mV2) in young and old mice (young= 0,1235 ± 0,02201, old= 0,1396 ± 0,02147; Unpaired t-test, t=0.526, df=39.78, p=0.6018; young=15, old=13). E, Mean number/microscope field of immunoreactive orexin neurons in young and old WT mice (young=32, 12.94 ± 1.297; old=26, 12.62 ± 1.646; Unpaired t-test, t=0.1559, df=56, p= 0,8766; young=32 cells, old=26 cells). Supplementary Figure 2: A, AIK3 sensitizes astrocytes to IGF-I. After treatment with LPS (1 μg/ml), astrocytes become unresponsive to IGF-I, as determined by lack of phosphorylated Akt (pAkt) after 0.1 or 1 nM IGF-I. Astrocytes simultaneously receiving AIK3a305 (27 mM) regain sensitivity to IGF-I, as phosphorylated Akt was readily detected. A representative blot is shown. B, Concentration along time in the blood (blue trace) and brain (red trace) after oral administration of AIK3a305 (10 mg/kg) in adult male mice (Swiss albino; n= 3). C, ECoG band analysis of young mice (WT ≤ 6 months old), old mice (WT ≥ 18 months old), and old mice treated with AIK3 (young=19, old=13, old+AIK3a305=10). D, Basal evoked potential in LH after LC stimulation in young, old, and old+AIK mice (One-way ANOVA, p=0.1028; n=13 group).

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Zegarra-Valdivia, J.A., Fernandes, J., Fernandez de Sevilla, M.E. et al. Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice. GeroScience 44, 2243–2257 (2022). https://doi.org/10.1007/s11357-022-00589-1

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