Molecular differences in brain regional vulnerability to aging between males and females

Xianxiao Zhou, Jiqing Cao, Li Zhu, Kurt Farrell, Minghui Wang, Lei Guo, Jialiang Yang, Andrew McKenzie, John F. Crary, Dongming Cai, Zhidong Tu, Bin Zhang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: Aging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive. Results: Using the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer’s disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases. Conclusions: This integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD.

Original languageEnglish (US)
Article number1153251
JournalFrontiers in Aging Neuroscience
StatePublished - 2023
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported in parts by grants from the National Institutes of Health (NIH)/National Institute on Aging (R01AG046170, RF1AG057440, R01AG057907, U01AG052411, R01AG062355, and U01AG058635), NIH/National Institute of Allergy and Infectious Diseases (U01AI111598), NIH/National Institute of Dental and Craniofacial Research (R03DE026814), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118243) to BZ, NIH R01AG048923 to DC, (RF1AG054014, RO1AG068030, and R56AG058655) to DC and BZ, Department of Veteran Affairs BLRD (I01BX003380) and RR&D (I01RX002290) to DC, grant from NIA/NIH (F32AG056098) to KF, grants from NIH (R01AG054008 and R01NS095252) to JFC, and grant from NIH (R01AG055501) to ZT. This work was also supported in part by the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.

Publisher Copyright:
Copyright © 2023 Zhou, Cao, Zhu, Farrell, Wang, Guo, Yang, McKenzie, Crary, Cai, Tu and Zhang.


  • Alzheimer’s disease
  • brain aging
  • gender differences
  • gene co-expression network
  • key regulators

PubMed: MeSH publication types

  • Journal Article


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