Research reveals a paradoxical effect in a therapeutic target for age-related diseases

A study involving researchers from the Blas Cabrera Institute of Physical Chemistry (IQF-CSIC) has identified an unexpected inflammatory mechanism that promotes the chronic, low-grade inflammation associated with aging, known as inflammaging.

The findings show that partial inhibition of a key inflammatory protein accelerates aging in animal models, suggesting that future anti-inflammatory therapies may require more sophisticated approaches than targeting a single molecular pathway.

Researchers from the Blas Cabrera Institute of Physical Chemistry (IQF-CSIC), in collaboration with the Pablo de Olavide University (UPO) in Seville, have uncovered an unexpected inflammatory mechanism that explains how therapies designed to suppress inflammation may produce unintended effects if interactions between immune pathways are overlooked. Published in Science Advances, the study identifies a previously unrecognized interaction between the NLRP1 and NLRP3 inflammasomes, providing new insights for the development of therapies against age-related diseases.

The study demonstrates that partial reduction of the NLRP3 inflammasome a major therapeutic target in aging-related disorders can trigger a compensatory response that accelerates aging in animal models.

“NLRP3 is a protein complex that acts as an intracellular danger sensor and plays a central role in activating inflammatory responses. Dysregulated NLRP3 activity has been linked to chronic inflammation and to cardiovascular, metabolic, and neurodegenerative diseases, including Alzheimer’s disease, making it one of the most promising targets for anti-inflammatory therapies,” explains Javier Oroz, researcher at IQF-CSIC and co-author of the study.

However, the researchers found that partially inhibiting NLRP3 does not always reduce inflammation. In haploinsufficient models, where NLRP3 expression is only partially reduced, cells compensate by increasing the expression of a second inflammasome, NLRP1.

The study further reveals that NLRP1 and NLRP3 can directly interact to form a hybrid NLRP1–NLRP3 complex. This interaction excessively amplifies inflammatory signaling, particularly through IL-18, promoting the chronic inflammatory state associated with aging, known as inflammaging.

In the animal models, this process resulted in accelerated aging characterized by progressive physical decline, weight loss, metabolic abnormalities, alopecia, kyphosis, corneal opacity, and reduced fertility. Internal signs of systemic inflammation, including fatty liver disease and macrophage infiltration in the heart, were also observed.

Important implications for translational medicine.

One of the study’s most significant findings is that simultaneous inhibition of both NLRP1 and NLRP3 more effectively reduced inflammation and improved aging-related parameters than targeting NLRP3 alone. These results suggest that future anti-inflammatory therapies may require dual-target strategies rather than inhibition of a single molecular target.

The findings have important implications for translational medicine. As NLRP3 is widely considered a promising therapeutic target for age-related diseases, the authors emphasize the need to carefully evaluate the long-term consequences of its partial inhibition, particularly in chronic disorders. In interconnected biological systems, blocking one pathway may activate compensatory mechanisms with unintended consequences.

To address this challenge, the research team, led by Dr. Mario D. Cordero at UPO, is developing dual-inhibition strategies targeting multiple inflammasomes. According to the authors, these approaches have shown high efficacy in preventing inflammaging-associated complications and may improve the safety of future treatments for chronic inflammatory diseases.

The study also opens new avenues for investigating interactions between inflammasomes, which have largely been considered independent systems. In addition, it highlights the need to further explore the role of NLRP1 in age-related disorders, including neurodegenerative, cardiovascular, and metabolic diseases.

Overall, the findings provide a more comprehensive view of the inflammatory system and underscore the importance of designing therapies that account for the plasticity and compensatory capacity of interconnected inflammatory pathways.

Referencia: Muela-Zarzuela I, Alcocer-Gómez E, Suarez-Rivero JM, Low E, Ishaq A, Azkargorta M, Luque-Sierra A, Martin F, Elortza F, Astorga-Gamaza A, Antón R, Bali S, Tamargo-Azpilicueta J, Guerra-Castellano A, Díaz-Moreno I, Joachimiak LA, Oroz J, Ruiz-Cabello J, von Zglinicki T, Sanz A, Cordero MD. NLRP3 haploinsufficiency unmasks a compensatory NLRP1-NLRP3 interaction that drives accelerated aging in mice. Sci Adv. 2026 Jun 26;12(26):eaec9499. doi: 10.1126/sciadv.aec9499. Epub 2026 Jun 26. PMID: 42361162; PMCID: PMC13308588.