Senescent microglia with shortened telomeres secrete soluble DLK1 to induce aging-associated hypomyelination and neuronal dysfunction
5 affiliations
- 1Helen and Robert Appel Institute for Alzheimer’s Disease Research, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
- 2Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY, 10065, USA
- 3Gladstone Institutes, San Francisco, CA, 94158, USA
- 4Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
- 5Lead contact
Abstract
Aging is the major risk factor for neurodegenerative disease, yet the mechanisms linking physiological aging to brain dysfunction remain unclear. We investigated the brains of telomere-shortened mice and observed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single-nucleus RNA sequencing (snRNA-seq) revealed accelerated glial aging and elevated microglial senescence pathways. In a senescence model of human induced pluripotent stem cell (iPSC)-derived microglia, delta-like non-canonical Notch ligand 1 (DLK1) was identified as a novel senescence-associated ligand. Soluble DLK1 (sDLK1) was increased in the cerebrospinal fluid of telomere-shortened and naturally aged mice, and this increase was eliminated by microglial depletion. In vivo elevation of sDLK1 caused hypomyelination and blocked oligodendrocyte lineage progression, and these effects demonstrate the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.
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BibTeX
@article{liu2026senescent,
title = {{Senescent microglia with shortened telomeres secrete soluble DLK1 to induce aging-associated hypomyelination and neuronal dysfunction}},
author = {Bangyan Liu and Matthew Mahoney and Yilin Feng and Maria Telpoukhovskaia and Alice Maria Giani and Eileen Ruth Torres and Lihong Zhan and Pearly Ye and Jingjie Zhu and Nessa R Foxe and Daphne Zhu and Xinran Tong and Deepak Srivastava and Christina V. Theodoris and Shiaoching Gong and Mingrui Zhao and Li Fan and Li Gan},
journal = {Neuron},
year = {2026},
month = aug,
doi = {10.1016/j.neuron.2026.07.021},
url = {https://doi.org/10.1016/j.neuron.2026.07.021},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Senescent microglia with shortened telomeres secrete soluble DLK1 to induce aging-associated hypomyelination and neuronal dysfunction
AU - Bangyan Liu
AU - Matthew Mahoney
AU - Yilin Feng
AU - Maria Telpoukhovskaia
AU - Alice Maria Giani
AU - Eileen Ruth Torres
AU - Lihong Zhan
AU - Pearly Ye
AU - Jingjie Zhu
AU - Nessa R Foxe
AU - Daphne Zhu
AU - Xinran Tong
AU - Deepak Srivastava
AU - Christina V. Theodoris
AU - Shiaoching Gong
AU - Mingrui Zhao
AU - Li Fan
AU - Li Gan
PY - 2026
DA - 2026/08/11
JO - Neuron
DO - 10.1016/j.neuron.2026.07.021
UR - https://doi.org/10.1016/j.neuron.2026.07.021
AB - Aging is the major risk factor for neurodegenerative disease, yet the mechanisms linking physiological aging to brain dysfunction remain unclear. We investigated the brains of telomere-shortened mice and observed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single-nucleus RNA sequencing (snRNA-seq) revealed accelerated glial aging and elevated microglial senescence pathways. In a senescence model of human induced pluripotent stem cell (iPSC)-derived microglia, delta-like non-canonical Notch ligand 1 (DLK1) was identified as a novel senescence-associated ligand. Soluble DLK1 (sDLK1) was increased in the cerebrospinal fluid of telomere-shortened and naturally aged mice, and this increase was eliminated by microglial depletion. In vivo elevation of sDLK1 caused hypomyelination and blocked oligodendrocyte lineage progression, and these effects demonstrate the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.
SN - 0896-6273
SN - 1097-4199
ER -