Related Experiment Video

Updated: Aug 13, 2026

Measurement of Protein Turnover Rates in Senescent and Non-Dividing Cultured Cells with Metabolic Labeling and Mass Spectrometry
08:52

Measurement of Protein Turnover Rates in Senescent and Non-Dividing Cultured Cells with Metabolic Labeling and Mass Spectrometry

Published on: April 6, 2022

Senescent microglia with shortened telomeres secrete soluble DLK1 to induce aging-associated hypomyelination and

Bangyan Liu1, Matthew Mahoney1, Yilin Feng2

  • 1Helen and Robert Appel Institute for Alzheimer's Disease Research, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA.

Neuron
|August 11, 2026
PubMed

Insights

Aging accelerates brain dysfunction via microglial senescence. This process releases delta-like non-canonical Notch ligand 1 (DLK1), impairing myelin and neuronal function, contributing to neurodegeneration.

Area of Science:

  • Neuroscience
  • Cellular Biology
  • Aging Research

Background:

  • Aging is the primary risk factor for neurodegenerative diseases.
  • Mechanisms linking physiological aging to brain dysfunction are not fully understood.

Purpose of the Study:

  • To investigate the link between telomere shortening, aging, and brain dysfunction.
  • To identify molecular mechanisms driving age-related cognitive decline and neurodegeneration.

Main Methods:

  • Utilized telomere-shortened mice models.
  • Performed single-nucleus RNA sequencing (snRNA-seq) on mouse brains.
  • Developed human induced pluripotent stem cell (iPSC)-derived microglia senescence models.

Main Results:

  • Telomere shortening induced lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits.
  • snRNA-seq revealed accelerated glial aging and increased microglial senescence pathways.
  • Identified delta-like non-canonical Notch ligand 1 (DLK1) as a novel senescence-associated ligand, with increased soluble DLK1 (sDLK1) in aged mice cerebrospinal fluid.
  • In vivo sDLK1 elevation caused hypomyelination and blocked oligodendrocyte progression.
  • sDLK1 impaired human oligodendrocyte maturation and altered neuronal calcium signaling.

Conclusions:

  • Microglial senescence is a key consequence of telomere shortening and aging.
  • sDLK1 is a novel microglia-derived senescence ligand.
  • sDLK1 drives oligodendrocyte and neuronal dysfunction, contributing to aging-related brain deficits and neurodegeneration.
Keywords:
DLK1SASPmicroglianeuronal activityoligodendrocytesenescencetelomere erosion

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