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Age-related myelin degradation burdens the clearance function of microglia during aging
Open accessAbstract
Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We found that myelin pieces were gradually released from aging myelin sheaths and were subsequently cleared by microglia. Myelin fragmentation increased with age and led to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial, leading to lysosomal storage and contributing to microglial senescence and immune dysfunction in aging.
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“Dysregulation of microglial phagocytosis of synapses has been implicated in the pathology of diverse neurological diseases (Hong et al., 2016; Lui et al., 2016; Vasek et al., 2016), failure to clear myelin debris contributes to CNS regenerative failure (Vargas and Barres, 2007), and problems with microglial uptake and clearance may contribute to aging-associated cognitive decline (Safaiyan et al.,”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Safaiyan et al., 2016
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“Cholesterol-rich lysosomes and LDs in dysfunctional microglia have also been observed in the context of demyelination mouse models and human iPS cell models9–12.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [9]
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“Age decreases microglia-mediated clearance of myelin fragments [329], but white matter-restricted microglia (WAM) are an age-dependent state able to clear age-associated damaged myelin [330].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [329]
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“Microglial dysfunction is a hallmark of the aging brain, as cells accumulate excessive myelin debris and acquire a DAM transcriptional state”
From TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge (2020) · cites this paper as Safaiyan et al., 2016
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“Removal of damaged myelin components and apoptotic cells is a requisite for remyelination (4, 5).”
From Reduced Angiopoietin-Like 4 Expression in Multiple Sclerosis Lesions Facilitates Lipid Uptake by Phagocytes via Modulation of Lipoprotein-Lipase Activity (2019) · cites this paper as [5]
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“Inflammaging in the brain is characterized by increased levels of proinflammatory cytokines, aberrant activation of astrocytes and microglia, and increased oxidative stress2–4.”
From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [4]
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“Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [2]
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“In recent years, increasing evidence has suggested that neuroinflammation is a major contributor to cognitive impairment2–4.”
From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [4]
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“For example, demyelination is an early sign of brain ageing, and shed myelin sheaths can accumulate in microglia, leading to microglial ageing and dysfunction.158”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [158]
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Metadata
- Authors
- Safaiyan, S., Kannaiyan, N., Snaidero, N., Brioschi, S., Biber, K., Yona, S., Edinger, A. L., Jung, S., Rossner, M. J., & Simons, M.
- Affiliations
- Max Planck Institute of Experimental Medicine (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Freiburg (DE)
- University Medical Center Groningen (NL)
- Weizmann Institute of Science (IL)
- University of California, Irvine (US)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Simons, Mikael
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2016-08
- Volume
- 19
- Issue
- 8
- Pages
- 995-998
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC7116794
- OpenAlex
- W2439312023
- Cited by
- 604
- References
- 29
- Citations by year
- 2026: 61 · 2025: 77 · 2024: 71 · 2023: 65 · 2022: 66 · 2021: 74 · 2020: 52 · 2019: 51 · 2018: 49 · 2017: 33 · 2016: 4
- FWCI
- 25.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- DZNE Pub (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- microglia, aging, myelin debris clearance, lysosomal storage, lipofuscin, microglial senescence, neuroinflammation
- MeSH terms
- Aging, Animals, Brain, Demyelinating Diseases, Lipofuscin, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath, Microglia
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