Therapeutic targeting of senescent cells in the CNS

doi:10.1038/s41573-024-01033-z

Review

. 2024 Nov;23(11):817-837.

doi: 10.1038/s41573-024-01033-z. Epub 2024 Sep 30.

Therapeutic targeting of senescent cells in the CNS

Markus Riessland^{1

2}, Methodios Ximerakis³, Andrew A Jarjour⁴, Bin Zhang^{5

6}, Miranda E Orr^{7

8}

Affiliations

¹ Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, USA.
² Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY, USA.
³ Merck & Co.,Inc., Cambridge, MA, USA.
⁴ MSD (UK) Ltd, London, UK.
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA. morr@wakehealth.edu.
⁸ Salisbury VA Medical Center, Salisbury, NC, USA. morr@wakehealth.edu.

PMID: 39349637
DOI: 10.1038/s41573-024-01033-z

Review

Therapeutic targeting of senescent cells in the CNS

Markus Riessland et al. Nat Rev Drug Discov. 2024 Nov.

. 2024 Nov;23(11):817-837.

doi: 10.1038/s41573-024-01033-z. Epub 2024 Sep 30.

Authors

Markus Riessland^{1

2}, Methodios Ximerakis³, Andrew A Jarjour⁴, Bin Zhang^{5

6}, Miranda E Orr^{7

8}

Affiliations

¹ Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, USA.
² Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY, USA.
³ Merck & Co.,Inc., Cambridge, MA, USA.
⁴ MSD (UK) Ltd, London, UK.
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA. morr@wakehealth.edu.
⁸ Salisbury VA Medical Center, Salisbury, NC, USA. morr@wakehealth.edu.

PMID: 39349637
DOI: 10.1038/s41573-024-01033-z

Abstract

Senescent cells accumulate throughout the body with advanced age, diseases and chronic conditions. They negatively impact health and function of multiple systems, including the central nervous system (CNS). Therapies that target senescent cells, broadly referred to as senotherapeutics, recently emerged as potentially important treatment strategies for the CNS. Promising therapeutic approaches involve clearing senescent cells by disarming their pro-survival pathways with 'senolytics'; or dampening their toxic senescence-associated secretory phenotype (SASP) using 'senomorphics'. Following the pioneering discovery of first-generation senolytics dasatinib and quercetin, dozens of additional therapies have been identified, and several promising targets are under investigation. Although potentially transformative, senotherapies are still in early stages and require thorough testing to ensure reliable target engagement, specificity, safety and efficacy. The limited brain penetrance and potential toxic side effects of CNS-acting senotherapeutics pose challenges for drug development and translation to the clinic. This Review assesses the potential impact of senotherapeutics for neurological conditions by summarizing preclinical evidence, innovative methods for target and biomarker identification, academic and industry drug development pipelines and progress in clinical trials.

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References

1. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). - PubMed - DOI
1. Lundblad, V. & Szostak, J. W. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57, 633–643 (1989). - PubMed - DOI
1. Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). - PubMed - DOI
1. Herbig, U., Ferreira, M., Condel, L., Carey, D. & Sedivy, J. M. Cellular senescence in aging primates. Science 311, 1257 (2006). - PubMed - DOI
1. Minamino, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002). - PubMed - DOI

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[1] Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). - PubMed - DOI

[2] Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). - PubMed - DOI

[3] Lundblad, V. & Szostak, J. W. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57, 633–643 (1989). - PubMed - DOI

[4] Lundblad, V. & Szostak, J. W. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57, 633–643 (1989). - PubMed - DOI

[5] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). - PubMed - DOI

[6] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). - PubMed - DOI

[7] Herbig, U., Ferreira, M., Condel, L., Carey, D. & Sedivy, J. M. Cellular senescence in aging primates. Science 311, 1257 (2006). - PubMed - DOI

[8] Herbig, U., Ferreira, M., Condel, L., Carey, D. & Sedivy, J. M. Cellular senescence in aging primates. Science 311, 1257 (2006). - PubMed - DOI

[9] Minamino, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002). - PubMed - DOI

[10] Minamino, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002). - PubMed - DOI

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Therapeutic targeting of senescent cells in the CNS

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Therapeutic targeting of senescent cells in the CNS

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