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GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21

Summary

As we age, brain cells called excitatory neurons undergo senescence, similar to cellular ageing. This study found that a protein called GDF11 protects these neurons from ageing. When GDF11 was removed from excitatory neurons in mice, the neurons aged faster, leading to memory problems and shorter lifespans. The research reveals that GDF11 works by blocking p21, a molecule that promotes cellular ageing.

Background

Cellular senescence is a fundamental mechanism underlying organismal ageing and occurs in post-mitotic neurons. Excitatory neurons are the predominant senescent cell type in the aged brain, yet the molecular mechanisms driving their senescence remain unknown.

Objective

To determine how excitatory neurons acquire senescence and whether GDF11 plays a role in regulating neuronal senescence, brain ageing, and lifespan in mice.

Results

GDF11 is predominantly expressed in excitatory neurons across mouse, marmoset, and human brains. Selective knockout of GDF11 in excitatory neurons induces senescence, neuronal hyperexcitability, dendrite pruning, reduced synaptic input, impaired object recognition memory, and shortened lifespan. GDF11 deletion induces senescence via Smad2-mediated transcription of p21.

Conclusion

Endogenous GDF11 acts as a brake on excitatory neuronal senescence and brain ageing. This work identifies a molecular mechanism linking GDF11 to neuronal senescence, brain ageing, cognitive decline, and lifespan regulation.
  • Published in:Nature Communications,
  • Study Type:Experimental Research,
  • Source: PMID: 37978295, DOI: 10.1038/s41467-023-43292-1
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