Calreticulin and ERp57 Reduction with Age Reveals the ER Stress-related roles in Cell Viability and Organismal Lifespan Regulation

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Abstract
Defects in Calreticulin (Calr) and ERp57, two tandem endoplasmic reticulum (ER) resident proteins, are associated with pathologies ranging from protein conformational disorders to impaired immune responses but are not directly linked to aging. Here, we report that Calr and ERp57 expression is ubiquitously decreased with age in mouse tissues, and RNAi inhibition of Calr and/or ERp57 homologs in C. elegans led to ER stress-related lifespan shortening. Knockdown of Calr and/or ERp57 in N2a cells reduced cellular viability by exacerbating protein aggregation, ER stress, and activation of pro-apoptotic pathways. Overexpression of Calr and/or ERp57 in N2a cells, however, resulted in a robust increase in cell stress tolerance, cell viability, and inhibition of apoptotic signaling pathways. Taken together, our findings suggest that the age-related reduction of Calr and ERp57 may serve as a potential pro-aging biomarker, contributing to the disruption of ER homeostasis and affecting cell survival and organismal lifespan.
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Authors Neuber- Schlicht, Sophie
Journal Frontiers in surgery
Year Year not found
DOI
10.3389/fragi.2026.1758247
URL
https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2026.1758247/full
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