Alzheimer's Enzyme BACE1 Cuts Anti-Aging Protein Klotho: A New Link Between Aging and Cognitive Decline

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.

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.

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.

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.

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.