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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Problems with microglial uptake and clearance may contribute to aging-associated cognitive decline.
“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
The paper’s Abstract reports that myelin debris accumulates in aging microglia and may contribute to microglial senescence and immune dysfunction. It does not link impaired uptake or clearance to cognitive decline, so that attributed outcome is unsupported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCholesterol-rich lysosomes and lipid droplets in dysfunctional microglia have been observed in demyelination mouse models and human iPS cell models.
“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]
The passage on Pelizaeus–Merzbacher disease mice (page unavailable in our copy) reports demyelination, increased lipofuscin in microglia, and reduced microglial uptake function. The paper also describes lipofuscin as accumulating in lysosomes. It does not identify those lysosomes as cholesterol-rich or report lipid droplets or human iPS-cell models. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAge decreases microglia-mediated clearance of myelin fragments, but white matter-restricted microglia are an age-dependent state able to clear age-associated damaged myelin.
“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]
The paper reports that microglia clear myelin fragments in aging mice and that age-related myelin accumulation contributes to microglial senescence (Abstract; no page given). It does not directly show that aging decreases microglia-mediated clearance of myelin fragments: the reported decline in uptake concerns other materials or a disease model. The WAM clause carries a different citation and is not assessed here. (LLM, conf=0.82)
Experimental — accuracy not yet measuredLoss of myelin integrity is associated with secondary neuroinflammation.
“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]
Demyelination is an early sign of brain ageing, and shed myelin sheaths can accumulate in microglia, leading to microglial ageing and dysfunction.
“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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Microglia regulation of central nervous system myelin health and regeneration
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Microglia and lipids: how metabolism controls brain innate immunity
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Neuroimmune Connections in Aging and Neurodegenerative Diseases
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Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances
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Cellular correlates of cortical thinning throughout the lifespan
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Cellular and Molecular Characterization of Microglia: A Unique Immune Cell Population
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Local cholesterol metabolism orchestrates remyelination
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Brain macrophage development, diversity and dysregulation in health and disease
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Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy
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Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention
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Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons
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Microglia: Key Players in Retinal Ageing and Neurodegeneration
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Molecular and metabolic heterogeneity of astrocytes and microglia
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Microglial phagocytosis in aging and Alzheimer's disease
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White matter aging and its impact on brain function
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- 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 › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Epidemiology › 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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