Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1‐imidazoline receptor

Abstract

Repurposing drugs capable of extending lifespan and health span has a huge untapped potential in translational geroscience. Here, we searched for known compounds that elicit a similar gene expression signature to caloric restriction and identified rilmenidine, an I1‐imidazoline receptor agonist and prescription medication for the treatment of hypertension. We then show that treating Caenorhabditis elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress‐resilience, health span, and lifespan benefits of rilmenidine treatment in C. elegans are mediated by the I1‐imidazoline receptor nish‐1 , implicating this receptor as a potential longevity target. Consistent with the shared caloric‐restriction‐mimicking gene signature, supplementing rilmenidine to calorically restricted C. elegans , genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan. The rilmenidine‐induced longevity required the transcription factors FOXO/DAF‐16 and NRF1,2,3/SKN‐1. Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine‐induced longevity. Moreover, transcriptional changes similar to caloric restriction were observed in liver and kidney tissues in mice treated with rilmenidine. Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound.

Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology

“…However, possible explanation for the differing prognostic role of NISCH in different cancer types may be attributed exactly to the NISCH association with cancer metabolism. NISCH has an important role in the maintenance of the cellular metabolic homeostasis [ 15 , 84 , 85 ], and activated NISCH has a role in caloric restriction in tissues [ 86 ]. Cancers are heterogeneous in their metabolic dependencies and preferred energy sources, and this is influenced by the anatomical location and the microenvironment.…”

Icariin Improves Stress Resistance and Extends Lifespan in Caenorhabditis elegans through hsf-1 and daf-2-Driven Hormesis

“…The first signaling pathway associated with longevity and healthspan, uncovering the involvement of the deep molecular network behind aging, was the insulin/IGF-1/FOXO pathway [ 42 ]. As an ortholog of the human insulin/IGF-1 receptor, DAF-2 in C. elegans also plays a role in aging and longevity [ 43 , 44 , 45 ]. Functional DAF-2 triggers a series of downstream reactions, including the phosphorylation-driven activation of AKT-1/2.…”

Challenges in anti‐aging medicine–trends in biomarker discovery and therapeutic interventions for a healthy lifespan

“…Bennett et al 41 Nesprin-2 Enhancing nuclear autophagy ('nucleophagy') delays aging (in C. elegans and mice).…”

“…This was suggested after it was determined by HTS that its agonist, the antihypertensive drug rilmenidine, induces a transcriptional profile similar to caloric restriction in C. elegans and in the liver and kidney of mice. 41 However, it is not yet clear if the longevity benefit of rilmenidine in these animal models is entirely dependent on the imidazoline receptor activity or if other independent mechanisms, like activation of key autophagy genes, are involved. A summary of these putative molecular targets for the development of geroprotectors is presented in Table 1.…”