Olga Yu. Rybina

Revealing gene expression patterns is essential for comprehending the genetic control of complex traits like lifespan. Analyzing structural variation in gene regulatory regions within natural populations is a promising approach in functional genetics, allowing us to identify regulatory sites that influence transcription and phenotype in vivo. We describe the structural variability of the 5′ regulatory region of the shuttle craft (stc) gene in the Alexandrov population (Russia) of Drosophila melanogaster, encoding a transcription factor homologous to human NF-X1. We evaluated the association of frequently occurring polymorphisms with fly lifespan from inbred lines sampled in 2010, 2011, and 2014. Two polymorphisms in the stc 5′ regulatory region exhibit strong associations with both lifespan and embryonic stc transcript levels. Their role in expression regulation was evaluated via reporter gene assays conducted in S2 Drosophila cell culture. The ‘C’ allele at one polymorphic site and ‘T’ at the other are associated with increased longevity and decreased embryonic stc transcription, reaffirming the link between gene expression and lifespan we previously established. Furthermore, comparing stc 5′ regulatory region variability across Alexandrov, European and African populations suggests that the macro-geographic distribution of these longevity-associated variants is consistent with a potential role in latitudinal or climatic adaptation.

Investigating the effects of chemical compounds on longevity is a critical approach to studying aging mechanisms and identifying potential geroprotectors. At the initial screening stage, it is essential not only to identify the effects of tested compounds but also to strictly regulate the delivery conditions, as these can significantly alter the observed phenotype and complicate data interpretation. Accordingly, the choice of experimental model and mode of administration is essential for ensuring reproducibility and validity of the results. The Drosophila melanogaster model is widely used in aging research as an experimental system that enables quantitative assessment of the effects of various compounds on lifespan. In such experiments, different methods of compound administration are employed, including incorporation into food and application to the food surface, which allows variation of exposure conditions. In this study, we examined the effects of dimethyl sulfoxide (DMSO), prepared in water or sodium dihydrogen phosphate solution, on the lifespan of the D. melanogaster Oregon-R strain when applied to the surface of the food medium. DMSO exhibited a dose-dependent, nonlinear effect on lifespan. A high concentration (50%) reduced lifespan, concentrations (30, 8, and 4%) had no consistent significant effect. In contrast, an intermediate concentration (16%) increased lifespan independent of the solvent used. In addition, we evaluated the potential contribution of bacterial load as a factor underlying the observed effects. No significant association was found between lifespan changes and culturable bacterial load on food surface, suggesting no relationship between this factor and the observed lifespan effects of DMSO.

A particularly well-studied evolutionary model is the vinegar fly Drosophila melanogaster, a cosmopolitan insect of ancestral southern-central African origin. Recent work suggests that it expanded out of Africa ∼9,000 years ago, and spread from the Middle East into Europe ∼1,800 years ago. During its global expansion, this human commensal adapted to novel climate zones and habitats. Despite much work on phenotypic differentiation and adaptation on several continents (especially North America and Australia), typically in the context of latitudinal clines, little is known about phenotypic divergence among European populations. Here, we sought to provide a continent-wide study of phenotypic differentiation among European populations of D. melanogaster. In a consortium-wide phenomics effort, we assayed 16 fitness-related traits on a panel of 173 isofemale lines from 9 European populations, with the majority of traits measured by several groups using semi-standardized protocols. For most fitness-related traits, we found significant differentiation among populations on a continental scale. Despite inevitable differences in assay conditions among labs, the reproducibility and hence robustness of our measurements were overall remarkably good. Several fitness components (e.g., viability, development time) exhibited significant latitudinal or longitudinal clines, and populations differed markedly in multivariate trait structure. Notably, populations experiencing higher humidity/rainfall and lower maximum temperature showed higher viability, fertility, starvation resistance, and lifespan at the expense of lower heat-shock survival, suggesting a pattern of local adaptation. Our results indicate that derived populations of this tropical fly have been shaped by pervasive spatially varying multivariate selection and adaptation to different climates on the European continent.

Various age-related disorders accumulate during aging, causing a decline in tissue and organ function, raising the risk of disease development, and leading to death. Age-related phenotypes are tightly related to an increase in coordinated, progressive changes in the transcriptome, proteome, metabolome, microbiome, and epigenome. Age-dependent modifications of the transcriptome, caused by changes in epigenetic, transcriptional, and post-transcriptional regulation of gene expression, lead to the accumulation of age-related changes in the proteome and metabolome. In turn, dynamic changes in the microbiota during aging also affect gene expression and thus lead to age-related changes in the proteome and metabolome. Recent studies have shown that multi-omic rejuvenation technologies decrease age-related disorders and extend longevity. For example, the short-term induction of the expression of transcription factors that ensure the reprogramming of somatic cells into pluripotent stem cells is accompanied by the restoration of the DNA methylation pattern and transcriptome expression profile characteristic of younger tissues, resulting in an increased lifespan. In this review, we discuss existing multi-omic rejuvenation technologies and the prospects for extending and improving life.

Biomarkers are biological indicators that may be used to evaluate the functional status of an organism, monitor the aging process, and predict the transition of it to a pathological state. Age-related changes in gene expression determine the development of specific age-related phenotypes considered as biomarkers of aging, such as changes in chromatin structure, loss of proteostasis, mitochondrial dysfunction, impaired intercellular communication, chronic inflammation, and imbalances in nutrient uptake. Aging biomarkers are considered to be essential in developing techniques to assess the efficacy of geroprotective treatments. In this context, assessment of the possibility, feasibility, and limitations of the practical use of biomarkers requires a thorough understanding of their molecular nature and careful evidence of their objective association with aging and lifespan. The review considers the data on the effectiveness of the influence of several geroprotectors on aging biomarkers and the lifespan of model organisms and discusses the prospects for using biomarkers of aging to evaluate the efficacy of drug therapy for aging.

Transcription regulation is required for correct differential gene expression, which determines the development and function of all cells in the organism throughout the lifespan, ensuring adaptability to continuously changing environments. Altered transcriptional regulation causes gene function rearrangements, which alter the phenotype, including aging rate and lifespan. In this regard, there has recently been a great interest in the application of technologies based on the “rejuvenation” of the transcriptome due to the modification of regulatory mechanisms that determine the level and pattern of gene expression. To develop such an approach to slowing down aging and prolonging life, it is important to understand how the transcription of individual genes and the entire transcriptome changes with age, as well as how the transcriptional machinery of the cell and mechanisms of transcription regulation are related to the aging process and longevity control. Addressing these issues in the review, we discuss the prospects of using transcription regulation as a strategy for extending life and improving its quality.