Candidate molecular targets uncovered in mouse lifespan extension studies

Multiple interventions have demonstrated an increase in mouse lifespan. However, non-standardized controls, sex or strain-specific factors, and insufficient focus on targets, hinder the translation of these findings into clinical applications. We examined the effects of genetic and drug-based interventions on mice from databases DrugAge, GenAge, the Mouse Phenome Database, and publications from PubMed that led to a lifespan extension of more than 10%, identifying specific molecular targets that were manipulated to achieve the maximum lifespan in mice. Subsequently, we characterized 10 molecular targets influenced by these interventions, with particular attention given to clinical trials and potential indications for each. To increase the translational potential of mice life-extension studies to clinical research several factors are crucial: standardization of mice lifespan research approaches, the development of clear criteria for control and experimental groups, the establishment of criteria for potential geroprotectors, and focusing on targets and their clinical application. Pinpointing the targets affected by geroprotectors helps in understanding species-specific differences and identifying potential side effects, ensuring the safety and effectiveness of clinical trials. Additionally, target review facilitates the optimization of treatment protocols and the evaluation of the clinical feasibility of translating research findings into practical therapies for humans.</p

Influence of low doses of γ-irradiation on the lifespan of <i>Drosophila melanogaster</i>, wild-type line <i>Canton-S</i>.

<p>A–males, B–females, *—p<0.05, **—p<0.01, (Kolmogorov-Smirnov test).</p

Strehler-Mildvan correlation between the parameters of the Gompertz function in <i>Drosophila melanogaster</i> wild-type <i>Canton-S</i> individuals exposed to low doses of ionizing radiation.

<p>Strehler-Mildvan correlation between the parameters of the Gompertz function in <i>Drosophila melanogaster</i> wild-type <i>Canton-S</i> individuals exposed to low doses of ionizing radiation.</p

The genes selected for expression analysis in the samples of <i>Drosophila melanogaster</i> wild-type strain <i>Canton-S</i> 72 hours after radiation exposure in doses from 5 cGy to 40 cGy.

<p>The genes selected for expression analysis in the samples of <i>Drosophila melanogaster</i> wild-type strain <i>Canton-S</i> 72 hours after radiation exposure in doses from 5 cGy to 40 cGy.</p

Analysis of the gene expression by the qPCR in the samples of <i>Drosophila melanogaster</i> wild-type strain <i>Canton-S</i> 72 hours after radiation exposure in doses from 5 cGy to 40 cGy (Female/male).

<p>n–FC absolute value < 2; ǀLog₂FCǀ<1</p><p>+–Log₂FC > 1</p><p>-–Log₂FC < -1</p><p>*—p-value < 0.05</p><p>Analysis of the gene expression by the qPCR in the samples of <i>Drosophila melanogaster</i> wild-type strain <i>Canton-S</i> 72 hours after radiation exposure in doses from 5 cGy to 40 cGy (Female/male).</p

The differentially expressed genes in <i>Drosophila melanogaster</i> males and females after the radiation exposure.

<p>A– 5 cGy, B– 10 cGy, C– 20 cGy, D– 40 cGy, 1 –males, 2 –females. Only gene changes with Log₂FC > 1 and p-value < 0.05 during at least one time range are presented.</p

Effect of Low Doses (5-40 cGy) of Gamma-irradiation on Lifespan and Stress-related Genes Expression Profile in <i>Drosophila melanogaster</i>

<div><p>Studying of the effects of low doses of γ-irradiation is a crucial issue in different areas of interest, from environmental safety and industrial monitoring to aerospace and medicine. The goal of this work is to identify changes of lifespan and expression stress-sensitive genes in <i>Drosophila melanogaster</i>, exposed to low doses of γ-irradiation (5 – 40 cGy) on the imaginal stage of development. Although some changes in life extensity in males were identified (the effect of hormesis after the exposure to 5, 10 and 40 cGy) as well as in females (the effect of hormesis after the exposure to 5 and 40 cGy), they were not caused by the organism “physiological” changes. This means that the observed changes in life expectancy are not related to the changes of organism physiological functions after the exposure to low doses of ionizing radiation. The identified changes in gene expression are not dose-dependent, there is not any proportionality between dose and its impact on expression. These results reflect nonlinear effects of low dose radiation and sex-specific radio-resistance of the postmitotic cell state of <i>Drosophila melanogaster </i>imago.</p></div

The Impacts of Megahydraulic Engineering. Projects from a Dutch Perspective

Differentially expressed genes in response to the fucoxanthin treatment. (XLSX 15 kb

List of unique genes which are up- and down-regulated in both sexes after a particular treatment.

*<p>Gene names were obtained from <a href="http://flybase.org" target="_blank">http://flybase.org</a>.</p>**<p><a href="http://www.uniprot.org" target="_blank">http://www.uniprot.org</a>.</p>***<p>According to Gene Expression Atlas, <a href="http://www.ebi.ac.uk/gxa" target="_blank">http://www.ebi.ac.uk/gxa</a>.</p

Gene-concept networks by gene ontology analysis for toluene treated males and females.

<p><i>Genes, up-regulated in males:</i> Upregulated genes were known to be involved in the protein folding, circadian sleep/wake regulation, positive regulation of transcription from RNA polymerase II promoter and proteolysis regulation. <i>Genes, down-regulated in males:</i> The large number of downregulated genes in this treatment were functionally clustered to four main groups: response to stress (including related functional category of response to heat), response to biotic stimulus, proteolysis and oxidation-reduction process. <i>Genes, up-regulated in females:</i> The overexpressed genes were functionally clustered into four main clusters: oxidation-reduction process, proteolysis, response to stress, response to biotic stimulus and the smaller cluster of cellular response to heat. <i>Genes, down-regulated in females:</i> The cell communication functional category was extremely downregulated in this treatment. Smaller gene clusters, involved in the phototransduction and regulation of response to external stimulus, were also revealed.</p