The Alzheimer's-associated enzyme BACE1 was found to cleave the anti-aging protein α-Klotho at a specific peptide site, revealing a potential shared pathway linking aging to cognitive decline.
Specific Cleavage at F-T ResiduesBACE1 cleaves α-Klotho peptide 951-981 at the F-T site — a newly discovered enzymatic relationship linking the most studied Alzheimer's enzyme to the best-known anti-aging protein
What the researchers found
BACE1 was identified as an enzyme that cleaves α-Klotho peptide 951-981 at the F-T residues, confirmed by Coomassie blue staining, western blot, and MALDI-TOF mass spectrometry. When F-T was mutated to K-K, BACE1 could not cleave the peptide, confirming site specificity. Plasma α-Klotho was significantly lower in elderly vs. young participants (p<0.0001). In elderly adults, BACE1 and α-Klotho showed a significant positive correlation (p=0.009, r=0.469) not seen in young adults (p=0.170, r=-0.208), suggesting the BACE1/α-Klotho pathway becomes functionally relevant with aging.
Why it matters
α-Klotho is one of the most studied anti-aging proteins, and BACE1 is a major therapeutic target in Alzheimer's research. Discovering that BACE1 directly cleaves α-Klotho creates a new mechanistic link between aging and neurodegeneration. This could explain why α-Klotho levels drop with age and suggests that BACE1 inhibitors — already being developed for Alzheimer's — might also preserve α-Klotho levels and potentially slow aging.
How the study worked
The study recruited 30 elderly and 45 young participants. Researchers performed in vitro enzymatic digestion of α-Klotho peptide by BACE1, identifying cleavage products using Coomassie blue staining, western blot, and MALDI-TOF mass spectrometry. Site-directed mutagenesis confirmed the cleavage site. Plasma levels of both proteins were measured by ELISA, and correlations were analyzed between age groups.
What this study cannot tell us
The enzymatic cleavage was demonstrated in vitro, and it remains to be confirmed that this cleavage occurs at physiologically relevant rates in vivo. The human cohort (75 participants) is relatively small for correlation analyses. The positive correlation between BACE1 and α-Klotho in elderly adults is counterintuitive if BACE1 degrades α-Klotho, suggesting more complex regulatory dynamics that need investigation.
How to read the evidence
This is an original research study combining in vitro biochemistry with human plasma analysis. The enzymatic cleavage is well-demonstrated with multiple validation methods, though the clinical significance of this pathway needs confirmation in larger studies and in vivo models.
When this study was published
Published in 2025, this study presents a novel discovery linking two of the most actively researched proteins in aging and Alzheimer's disease.
The bigger picture
BACE1 inhibitors have been a major focus of Alzheimer's drug development, though clinical trials have had mixed results. This discovery that BACE1 also degrades α-Klotho adds a new dimension: BACE1 may contribute to aging beyond its known role in amyloid-beta production. The BACE1/α-Klotho axis could represent a common pathway for age-related cognitive decline, opening new angles for both aging and Alzheimer's research.
Questions still open
- Would BACE1 inhibitors preserve α-Klotho levels in vivo and slow age-related cognitive decline?
- Does the BACE1/α-Klotho cleavage pathway contribute to cognitive decline independently of amyloid-beta production?
- Why are BACE1 and α-Klotho positively correlated in elderly adults if BACE1 cleaves α-Klotho?
Common questions
What is α-Klotho and why is it called an anti-aging protein?
Could Alzheimer's drugs help slow aging?
Read the original research
Identification of the enzymatic cleavage relationship between anti-aging protein α-Klotho and Alzheimer's disease biomarker BACE1.
Journal of Alzheimer's disease : JAD, 104(2), 463-472
Citation
Gao, Xiang; Sun, Zuoli; Hu, Jia; Li, Yuhong; Deng, Qi; Li, Rena. (2025). Identification of the enzymatic cleavage relationship between anti-aging protein α-Klotho and Alzheimer's disease biomarker BACE1.. Journal of Alzheimer's disease : JAD, 104(2), 463-472. https://doi.org/10.1177/13872877251317730