Background Senescent cells accumulate in tissues over time as part of the natural ageing process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular senescence in cancer that can be detrimental to recovery. Thus, it would be beneficial to develop a senolytic that acts not only on ageing cells but also senescent cancer cells to prevent cancer recurrence or progression. Methods We used molecular modelling to develop a series of rationally designed peptides to mimic and target FOXO4 disrupting the FOXO4-TP53 interaction and releasing TP53 to induce apoptosis. We then tested these peptides as senolytic agents for the elimination of senescent cells both in cell culture and in vivo. Findings Here we show that these peptides can act as senolytics for eliminating senescent human cancer cells both in cell culture and in orthotopic mouse models. We then further characterized one peptide, ES2, showing that it disrupts FOXO4-TP53 foci, activates TP53 mediated apoptosis and preferentially binds FOXO4 compared to TP53. Next, we show that intratumoural delivery of ES2 plus a BRAF inhibitor results in a significant increase in apoptosis and a survival advantage in mouse models of melanoma. Finally, we show that repeated systemic delivery of ES2 to older mice results in reduced senescent cell numbers in the liver with minimal toxicity. Interpretation Taken together, our results reveal that peptides can be generated to specifically target and eliminate FOXO4+ senescent cancer cells, which has implications for eradicating residual disease and as a combination therapy for frontline treatment of cancer. Funding This work was supported by the Cancer Early Detection Advanced Research Center at Oregon Health & Science University.

Allatostatins (AST) are neuropeptides with variable function ranging from regulation of developmental processes to the feeding behavior in insects. They exert their effects by binding to cognate GPCRs, called Allatostatin receptors (AlstR), which emerge as promising targets for pesticide design. However, AlstRs are rarely studied. This study is the first reported structural study on AlstR-AST interaction. In this work, the first C type AlstR from the stick insect Carausius morosus (CamAlstR-C) was identified and its interaction with type C AST peptide was shown to be physically consistent with the experimental results. The proposed structure of CamAlstR-C revealed a conserved motif within the third extracellular loop, which, together with the N-terminus is essential for ligand binding. In this work, computational studies were combined with molecular and nano-scale approaches in order to introduce an unknown GPCR-ligand system. Consequently, the data obtained provided a reliable target region for future agonist/inverse agonist studies on AlstRs.

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Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimers and Parkinsons Disease. It has also been beneficial against noise induced hearing loss and in hearing loss associated with premature aging. However, its impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.

Neuropeptides constitute an important part of the nervous system, since the simple nerve nets (i.e. of Hydra). The assigned functions of these peptides vary enormously. For instance, besides inhibiting or stimulating the release of some hormones, they can be responsible for tentacle contraction of the Hydra, dropping the tail of the lizard, postnatal care of the beetles and also aggressiveness of humans. They perform these tasks via activating their cognate GPCRs, which are hypothesized to be coevolved with their ligand neuropeptides. In this chapter, we will introduce the concept of neuropeptide, its intracellular maturation process, characteristics of some typical neuropeptide families and the common properties of their cognate GPCRs. At last, we will try to give information about the widely used methods for studying GPCR-neuropeptide interactions.

G protein-coupled receptors (GPCRs) are 7-transmembrane proteins that transduce various extracellular signals into intracellular pathways. They are the major target of neuropeptides, which regulate the development, feeding behavior, mating behavior, circadian rhythm, and many other physiological functions of insects. In the present study, we performed RNA sequencing and de novo transcriptome assembly to uncover the GPCRs expressed in the stick insect Carausius morosus. The transcript assemblies were predicted for the presence of 7-transmembrane GPCR domains. As a result, 430 putative GPCR transcripts were obtained and 43 of these revealed full-length sequences with highly significant similarity to known GPCR sequences in the databases. Thirteen different GPCRs were chosen for tissue expression analysis. Some of these receptors, such as calcitonin, inotocin, and tyramine receptors, showed specific expression in some of the tissues. Additionally, GPCR prediction yielded a novel uncharacterized GPCR sequence, which was specifically expressed in the central nervous system and ganglia. Previously, the only information about the anatomy of the stick insect was on its gastrointestinal system. This study provides complete anatomical information about the adult insect.

Ageing is known to be the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. They are currently incurable and worsen over time, which has broad implications in the context of lifespan and healthspan extension. Adding years to life and even to physical health is suboptimal or even insufficient, if cognitive ageing is not adequately improved. In this review, we will examine how interventions that have the potential to extend lifespan in animals affect the brain, and if they would be able to thwart or delay the development of cognitive dysfunction and/or neurodegeneration. These interventions range from lifestyle (caloric restriction, physical exercise and environmental enrichment) through pharmacological (nicotinamide adenine dinucleotide precursors, resveratrol, rapamycin, metformin, spermidine and senolytics) to epigenetic reprogramming. We argue that while many of these interventions have clear potential to improve cognitive health and resilience, large-scale and long-term randomised controlled trials are needed, along with studies utilising washout periods to determine the effects of supplementation cessation, particularly in aged individuals.

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