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

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.

The role of immunomodulators in treatment-resistant depression: case studies.

Depression is a common mental disorder affecting more than 264 million people worldwide. The first-line treatment for most cases of depression are selective serotonin reuptake inhibitors (SSRIs), such as sertraline, reboxetine and fluoxetine. Recently, it has been found that one-quarter of depressed patients have excessive activation of the immune system. This potentially warrants sub-categorisation of depressed patients into inflammatory and non-inflammatory subtypes. Such a sub-category of depression already exists for those not responding to various traditional antidepressants and is known as treatment-resistant depression. Those with treatment-resistant depression are far more likely to have raised inflammatory markers relative to those whose depression is treatment-responsive. Chronic, low-level inflammation seems to trigger depression via a multitude of mechanisms. These include kynurenine pathway and microglial cell activation, resulting in a reduction in hippocampal volume. Raised inflammatory cytokines also cause perturbations in monoaminergic signalling, which perhaps explains the preponderance of treatment resistance in those patients with inflammatory depression. Therefore, if treatment-resistant depression and inflammatory depression are semi-synonymous then it should follow that anti-inflammatory drugs will display high efficacy in both sub-types. Ketamine is a drug recently approved for use in depression in the USA and displays a particularly good response rate in those patients with treatment resistance. It has been suggested that the antidepressant efficacy of ketamine results from its anti-inflammatory effects. Ketamine seems to produce anti-inflammatory effects via polarisation of monocytes to M2 macrophages. Furthermore, another anti-inflammatory drug with potential use in treatment-resistant depression is Celecoxib. Celecoxib is a long-acting, selective COX-2 inhibitor. Early clinical trials show that Celecoxib has an adjuvant effect with traditional antidepressants in treatment-resistant patients. This paper highlights the importance of classifying depressed patients into inflammatory and non-inflammatory subtypes; and how this may lead to the development of more targeted treatments for treatment-resistant depression.

Targeting aging mechanisms: pharmacological perspectives.

Geroprotectors slow down aging and promote healthy longevity in model animals. Although hundreds of compounds have been shown to extend the life of laboratory model organisms, clinical studies on potential geroprotectors are exceedingly rare, especially in healthy elders. This review aims to classify potential geroprotectors based on the mechanisms by which they influence aging. These pharmacological interventions can be classified into the following groups: those that prevent oxidation; proteostasis regulators; suppressors of genomic instability; epigenetic drugs; those that preserve mitochondrial function; inhibitors of aging-associated signaling pathways; hormetins; senolytics/senostatics; anti-inflammatory drugs; antifibrotic agents; neurotrophic factors; factors preventing the impairment of barrier function; immunomodulators; and prebiotics, metabiotics, and enterosorbents.