Compound combinations targeting longevity: Challenges and perspectives.

Aging is one of the world's greatest concerns, requiring urgent, effective, large-scale interventions to decrease the number of late-life chronic diseases and improve human healthspan. Anti-aging drug therapy is one of the most promising strategies to combat the effects of aging. However, most geroprotective compounds are known to successfully affect only a few aging-related targets. Given this, there is a great biological rationale for the use of combinations of anti-aging interventions. In this review, we characterize the various types of compound combinations used to modulate lifespan, discuss the existing evidence on their role in life extension, and present some key points about current challenges and future prospects for the development of combination drug anti-aging therapy.

Shuttle craft Gene Affects Lifespan of Drosophila melanogaster by Controlling Early Development and Modifying Aging Program.

Fundamental mechanisms underlying genetic control of lifespan are intensively studied and discussed due to the increasing importance of extending healthy human life. The stc gene of the model organism Drosophila melanogaster encodes a transcription factor, homolog of the human transcription factor NF-X1, involved in regulation of neuronal development and other processes, as well as in control of lifespan. In this work, we demonstrate that the stc knockdown in embryonic and nerve cells leads to changes in lifespan, with the nature of changes depending on the cell type and sex of individuals. Based on our results, we suggest that stc gene is involved in transcription regulation throughout life, and, as a result, also affects a complex integral trait, lifespan. At the same time, we show that the reduction of stc expression in neurons can alleviate the negative effect of glutamate on longevity, possibly preventing development of glutamate excitotoxicity, thus modifying the cell death program and preventing death of individuals due to phenoptosis.

Epigenetic enzymes: A role in aging and prospects for pharmacological targeting.

The development of interventions aimed at improving healthspan is one of the priority tasks for the academic and public health authorities. It is also the main objective of a novel branch in biogerontological research, geroscience. According to the geroscience concept, targeting aging is an effective way to combat age-related disorders. Since aging is an exceptionally complex process, system-oriented integrated approaches seem most appropriate for such an interventional strategy. Given the high plasticity and adaptability of the epigenome, epigenome-targeted interventions appear highly promising in geroscience research. Pharmaceuticals targeted at mechanisms involved in epigenetic control of gene activity are actively developed and implemented to prevent and treat various aging-related conditions such as cardiometabolic, neurodegenerative, inflammatory disorders, and cancer. In this review, we describe the roles of epigenetic mechanisms in aging; characterize enzymes contributing to the regulation of epigenetic processes; particularly focus on epigenetic drugs, such as inhibitors of DNA methyltransferases and histone deacetylases that may potentially affect aging-associated diseases and longevity; and discuss possible caveats associated with the use of epigenetic drugs.

Knockdown of the neuronal gene Lim3 at the early stages of development affects mitochondrial function and lifespan in Drosophila.

Understanding the molecular mechanisms underlying variation in lifespan is central to ensure long life. Lim3 encoding a homolog of the vertebrate Lhx3/4 transcription factors plays a key role in Drosophila neuron development. Here, we demonstrated that Lim3 knockdown early in life decreased survival of adult flies. To study the mechanisms underlying this effect, we identified embryonic Lim3 targets using combined RNA-seq and RT-qPCR analyses complemented by in silico analysis of Lim3 binding sites. Though genes with neuronal functions were revealed as Lim3 targets, the characteristics of neurons were not affected by Lim3 depletion. Many of the direct and indirect Lim3 target genes were associated with mitochondrial function, ATP-related activity, redox processes and antioxidant defense. Consistent with the observed changes in the embryonic transcription of these genes, ROS levels were increased in embryos, which could cause changes in the transcription of indirect Lim3 targets known to affect lifespan. We hypothesize that altered mitochondrial activity is crucial for the decrease of adult lifespan caused by Lim3 knockdown early in life. In adults that encountered Lim3 depletion early in life, the transcription of several genes remained altered, and mitochondrial membrane potential, ATP level and locomotion were increased, confirming the existence of carry-over effects.

Polycomb/Trithorax group-dependent regulation of the neuronal gene Lim3 involved in Drosophila lifespan control.

Molecular mechanisms governing gene expression and defining complex phenotypes are central to understanding the basics of development and aging. Here, we demonstrate that naturally occurring polymorphisms of the Lim3 regulatory region that are associated with variation in gene expression and Drosophila lifespan control are located exclusively in the Polycomb response element (PRE). We find that the Polycomb group (PcG) protein Polycomb (PC) is bound to the PRE only in embryos where Lim3 is present in both repressed and active states. In contrast, the Trithorax group (TrxG) protein absent, small, or homeotic discs 1 (ASH1) is bound downstream of the PRE, to a region adjacent to the Lim3 transcription start site in embryos and adult flies, in which Lim3 is in an active state. Furthermore, mutations in Pc and ash1 genes affect Lim3 expression depending on the structural integrity of the Lim3 PRE, thus confirming functional interactions between these proteins and Lim3 regulatory region. In addition, we demonstrate that the evolutionary conserved Lim3 core promoter provides basic Lim3 expression, whereas structural changes in the Lim3 PRE of distal promoter provide stage-, and tissue-specific Lim3 expression. Therefore, we hypothesize that PcG/TrxG proteins, which are directly involved in Lim3 transcription regulation, participate in lifespan control.

Tissue-specific transcription of the neuronal gene Lim3 affects Drosophila melanogaster lifespan and locomotion.

The identity of neuronal cell types is established and maintained by the expression of neuronal genes coding for ion channels, neurotransmitters, and neuropeptides, among others. Some of these genes have been shown to affect lifespan; however, their role in lifespan control remains largely unclear. The Drosophila melanogaster gene Lim3 encodes a transcription factor involved in complicated motor neuron specification networks. We previously identified Lim3 as a candidate gene affecting lifespan. To obtain direct evidence of the involvement of Lim3 in lifespan control, Lim3 overexpression and RNAi knockdown were induced in the nervous system and muscles of Drosophila using the GAL4-UAS binary system. We demonstrated that Lim3 knockdown in the nervous system increased survival at an early age and that Lim3 knockdown in muscles both increased survival at an early age and extended median lifespan, directly establishing the involvement of Lim3 in lifespan control. Lim3 overexpression in nerves and muscles was deleterious and led to lethality and decreased lifespan, respectively. Lim3 misexpression in both nerves and muscles increased locomotion regardless of changes in lifespan, which indicated that the effects of Lim3 on lifespan and locomotion can be uncoupled. Decreased synaptic activity was observed in the neuromuscular junctions of individuals with Lim3 overexpression in muscles, in association with decreased lifespan. However, no changes in NMJ activity were associated with the positive shift in locomotion observed in all misexpression genotypes. Our data suggested that modifications in the microtubule network may be induced by Lim3 misexpression in muscles and cause an increase in locomotion.