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Caloric restriction decelerates premature aging and cognitive decline in mice with deficient DNA repair

Chris Z Wei1,2, Yejie Shi3,4, Wenting Zhang1,2

  • 1Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, USA.

Communications Biology
|May 7, 2026
PubMed

Insights

Apurinic/apyrimidinic endonuclease-1 (Apex1) is vital for brain health during aging. Caloric restriction mitigates cognitive decline in mice lacking Apex1, suggesting its role in aging brain defenses.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Oxidative DNA damage drives senescence and aging.
  • Apurinic/apyrimidinic endonuclease-1 (Apex1) is crucial for DNA repair.
  • Apex1's role in brain aging is not well understood.

Purpose of the Study:

  • To investigate the function of Apex1 in the aging brain.
  • To determine the impact of Apex1 deficiency on cognitive function.
  • To evaluate the potential of caloric restriction (CR) in mitigating age-related brain decline.

Main Methods:

  • Conditional knockout (cKO) of Apex1 in mouse forebrain neurons.
  • Behavioral tests assessing spatial learning and memory.
  • Biochemical analysis of synaptic proteins and neuronal morphology.
  • Assessment of long-term potentiation (LTP).
  • Implementation of a 30% caloric restriction (CR) regimen.

Main Results:

  • Apex1 cKO mice exhibited early and progressive cognitive impairment.
  • Deficits in spatial learning and memory were observed.
  • Reduced synaptic proteins, altered neuronal morphology, and impaired LTP were noted.
  • Caloric restriction significantly attenuated premature aging phenotypes and improved cognitive outcomes in Apex1 cKO mice.

Conclusions:

  • Apex1 is a critical factor for genomic maintenance in the aging brain.
  • Apex1 deficiency leads to accelerated cognitive decline and neurodegeneration.
  • Caloric restriction demonstrates a protective effect against age-related cognitive deterioration in the context of DNA repair deficiency.
  • The Apex1 cKO mouse model is valuable for studying brain aging and interventions.

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