Research Lab

Neuronal senescence and brain aging

Emerging evidence suggests that certain populations of fully differentiated neurons in the brain may undergo a cell cycle-like process during both normal aging and certain neurodegenerative diseases. For two decades since their first discoveries in the 90s, histology-based techniques remained as the mainstay study approaches of these cells. However, due to their scarcities and unpredictable distributions within the brain, the molecular profiles and specific variations associated with these cells remain unclear. We are the first group to devise a bioinformatics solution that allows integrated analyses of multiple single-nucleus transcriptome datasets to identify and characterize these rare cell populations [Selected publication #1].The robustness of this tool is validated in multiple independent cohorts of human brain samples obtained from individuals with Alzheimer’s disease (AD), as well as in datasets of human Parkinson’s Disease-Lewy Body Dementia (PD-LBD) and a mouse model of brain aging [Selected publication #1]. We are also the very first group identified the key molecular differences in cell cycle re-engaging senescent neurons emerged from human AD versus non-affected brains, tying to aberrant fuel metabolism related to chronic insulin signalling  [Selected publication #1].This indeed validated our earlier findings in mice published in 2019 [Selected publication #5], which reported age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence. Building upon these finding, we have ongoing work understanding how life style risk factors of AD is linked to this cellular phenomenon, such as binge drinking [Selected publication #4].

Hyperinsulinemia-induced insulin resistance is a modifiable risk factor for pathological (brain) aging

The pressing issue of an aging population has prompted policymakers to prioritize strategies aimed at maintaining good health among the public. By performing an integrated analysis using multiple human blood transcriptome and DNA methylome data, our work presents an initial exploration of how the innate immune system in human  (instead of the adaptive immune system reported in other studies) contributes to extreme longevity and overall well-being in multiple cohorts of long lived individuals from various geographical origins and ethnicities [Selected publication #3].  Specifically, our major findings demonstrate that the life cycle and phagocytic activities of innate monocytes, extracted from aging champions and supercentenarians belonging to various ethnic backgrounds, exhibit a consistent enhancement which is supported by an immune-metabolic network influenced by insulin signalling, as also matched with the findings from the Monozygotic Twin Study. This therefore emphasizes the significance of preserving insulin sensitivity as a critical factor in promoting health span and extending lifespan, complementing the relationship between insulin resistance/ type 2 diabetes and the development of various non-communicable diseases, including AD/ADRD. Our previous studies indeed also highlighted that insulin resistance in neurons is related to accelerated brain aging and functional decline [Selected publication #5]; and that occurs in microglia is associated with defective phagocytosis, more advanced pathologies and cognitive decline in female AD brains [Selected publication #2].

1. Jacquelyne Ka-Li Sun, Amy Zexuan Peng, Ronald P. Hart, Karl Herrup, Deng WU, Genper Chi-Ngai Wong, Kim Hei-Man Chow. (2025) Perimenopausal state oestradiol to progesterone imbalance drives Alzheimer’s risk via ERRα dysregulation and energy dyshomeostasis. Nature Communications. 2025 Nov 22;16(1):11546. doi: 10.1038/s41467-025-66726-4
   • CUHK press release
2. Jacquelyne Ka-Li Sun, Ronald P. Hart, Karl Herrup, Amy Zexuan Peng, Genper Chi-Ngai Wong, Deng WU, Kin-Ming Kwan, Kim Hei-Man Chow. (2025) Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia. Nature Communications. 2025 Oct 21;16(1):9312. doi: 10.1038/s41467-025-64360-8
   • CUHK press release
3. Deng Wu, Jacquelyne Ka Li Sun, Kim Hei-Man Chow. (2024) Neuronal cell cycle re-entry events in the aging brain are more prevalent in neurodegeneration and lead to cellular senescence. PLOS Biology. 2024 Apr 23;22(4):e3002559. doi: 10.1371/journal.pbio.3002559
   • PLOS Biology editors’ top picks for 2024
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4. Deng Wu, Xiaoman Bi, Kim Hei-Man Chow. (2024) Identification of female-enriched and disease-associated microglia (FDAMic) contributes to sexual dimorphism in late-onset Alzheimer’s disease. Journal of Neuroinflammation. 2024 Jan 4;21(1):1. doi: 10.1186/s12974-023-02987-4
5. Deng Wu, Xiaoman Bi, Peihu Li, Dahua Xu, Jianmin Qiu, Kongning Li, Shaojiang Zheng, Kim Hei-Man Chow. (2023) Enhanced insulin-regulated phagocytic activities support extreme health span and longevity in multiple populations. Aging Cell 2023 Mar 8;e13810. doi: 10.1111/acel.13810
   • CUHK press release
6. Jacquelyne Ka-Li Sun, Deng Wu, Genper Chi-Ngai Wong, Tsun-Ming Lau, Meigui Yang, Ronald P Hart, Kin-Ming Kwan, Ho-Yin Edwin Chan, Hei-Man Chow. (2023) Chronic alcohol metabolism results in DNA repair infidelity and cell-cycle-induced senescence in neurons. Aging Cell 2023 Feb; 22(2):e13772. doi: 10.1111/acel.13772
7. Hei-Man Chow, Jacquelyne Ka-Li Sun, Ronald P Hart, Kenneth King-Yip Cheng, Clara HL Hung, Tsun-Ming Lau, Kin-Ming Kwan. (2021) Low-density lipoprotein receptor-related protein 6 cell surface availability regulates fuel metabolism in astrocytes. Advanced Science. 2021 Aug;8(16):e2004993. doi: 10.1002/advs.202004993
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8. Hei-Man Chow, Meng Shi, Aifang Cheng, Yuehong Gao, Guimiao Chen, Xuan Song, Raphaella Wai Lam So, Jie Zhang, Karl Herrup. (2019) Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence. Nature Neuroscience. 2019 Nov;22(11):1806-1819. doi: 10.1038/s41593-019-0505-1
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9. Hei-Man Chow, Aifang Cheng, Xuan Song, Mavis R Swerdel, Ronald P Hart, Karl Herrup. (2019) ATM is activated by ATP depletion and modulates mitochondrial function through NRF1. Journal of Cell Biology. 2019 Mar 4;218(3):909-928. doi: 10.1083/jcb.201806197
   • Journal spotlight and commentary article
10. Hei-Man Chow, Karl Herrup. (2015) Genomic integrity and the ageing brain. Nature Reviews Neuroscience. 2015 Nov;16(11):672-84. doi: 10.1038/nrn4020