Evolutionary conservation of transcription factors affecting longevity

Gene expression can be optimised for health and longevity through manipulation of transcription factor (TF) activity. The effects of many such TFs are conserved between animal species indicating evolutionary conservation of underlying mechanisms. Lifespan-determining TFs regulate a plethora of cellular and organismal functions, including stress resistance, metabolism and growth. They interact with each other both within and between cells. Manipulating their activity in a single cell type can often be sufficient to insure longevity. The evolutionary conservation of their effects on ageing is most likely a reflection of the conservation of their function in processes, such as reproduction, growth, and metabolism, that are important earlier in life. Their effects on early and late life can, however, often be uncoupled

Could cancer drugs provide ammunition against aging?

Recent advances in our understanding of the molecular and cellular signaling pathways that drive aging have revealed several genetic and environmental manipulations that can increase lifespan across different species. Research on the underlying biology of aging has not only revealed it to be a biologically malleable process but has also paved the way for the development of pharmacological interventions that could increase lifespan and delay the onset and/or progression of age-related disease

Of FOXes and Forgetful Worms

Age-related cognitive decline is one of the most haunting aspects of human aging. In a recent publication, Coleen Murphy and colleagues (Kaletsky et al., 2016) describe the transcriptional program that maintains youthful function of aging neurons in the nematode worm

Higher-capacity communication links based on two-mode phase-sensitive amplifiers

Optical communication links are usually made with erbium-doped fiber amplifiers, which amplify the signal waves in a phase-insensitive (PI) manner. They can also be made with parametric fiber amplifiers, in which the signal waves interact with idler waves. If information is transmitted using only the signals, parametric amplifiers are PI and their noise figures are comparable to those of erbium amplifiers. However, transmitting correlated information in the signals and idlers, or copying the signals prior to transmission, allows parametric amplifiers to be phase-sensitive (PS), which lowers their noise figures. The information capacities of two-mode PS links exceed those of the corresponding PI links by 2 b/s-Hz

Myc mouse and anti-ageing therapy

Reduction in the expression and activity of a well-known proto-oncogene, Myc, has a beneficial effect on mouse health and survival to old age, in part independently of cancer impact, a recent study reveals. Is this new anti-ageing intervention pointing a way towards new treatments for age-related diseases

Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue

The Insulin/IGF-1 signalling (IIS) pathway plays an essential role in the regulation of glucose and lipid homeostasis. At the same time, a reduction in the IIS pathway activity can extend lifespan and healthspan in various model organisms. Amongst a number of body organs that sense and respond to insulin/IGF-1, the adipose tissue has a central role in both the metabolic and lifespan efects of IIS at the organismal level. Genetic inactivation of IIS components specifcally in the adipose tissue has been shown before to improve metabolic profle and extend lifespan in various model organisms. We sought to identify conserved molecular mechanisms that may underlie the benefcial efects of IIS inhibition in the adipose tissue, specifcally at the level of phosphoinositide 3-kinase (PI3K), a key IIS efector molecule. To this end, we inactivated PI3K by genetic means in the fy fat body and by pharmacological inhibition in mammalian adipocytes. Gene expression studies revealed changes to metabolism and upregulation of mitochondrial activity in mouse adipocytes and fy fat bodies with downregulated PI3K, which were confrmed by biochemical assays in mammalian adipocytes. These data suggest that PI3K inactivation has a conserved efect of upregulating mitochondrial metabolism in both fy and mammalian adipose tissue, which likely contributes to the health- and life-span extending efect of IIS pathway downregulation

Using answer set programming to integrate RNA expression with signalling pathway information to infer how mutations affect ageing.

A challenge of systems biology is to integrate incomplete knowledge on pathways with existing experimental data sets and relate these to measured phenotypes. Research on ageing often generates such incomplete data, creating difficulties in integrating RNA expression with information about biological processes and the phenotypes of ageing, including longevity. Here, we develop a logic-based method that employs Answer Set Programming, and use it to infer signalling effects of genetic perturbations, based on a model of the insulin signalling pathway. We apply our method to RNA expression data from Drosophila mutants in the insulin pathway that alter lifespan, in a foxo dependent fashion. We use this information to deduce how the pathway influences lifespan in the mutant animals. We also develop a method for inferring the largest common sub-paths within each of our signalling predictions. Our comparisons reveal consistent homeostatic mechanisms across both long- and short-lived mutants. The transcriptional changes observed in each mutation usually provide negative feedback to signalling predicted for that mutation. We also identify an S6K-mediated feedback in two long-lived mutants that suggests a crosstalk between these pathways in mutants of the insulin pathway, in vivo. By formulating the problem as a logic-based theory in a qualitative fashion, we are able to use the efficient search facilities of Answer Set Programming, allowing us to explore larger pathways, combine molecular changes with pathways and phenotype and infer effects on signalling in in vivo, whole-organism, mutants, where direct signalling stimulation assays are difficult to perform. Our methods are available in the web-service NetEffects: http://www.ebi.ac.uk/thornton-srv/software/NetEffects

Corrigendum: RNA Polymerase III, Ageing and Longevity

[This corrects the article DOI: 10.3389/fgene.2021.705122.]

Ablation of insulin-producing cells prevents obesity but not premature mortality caused by a high-sugar diet in Drosophila

Ageing can be modulated by genetic as well as nutritional interventions. In female Drosophila melanogaster, lifespan is maximized at intermediate concentrations of sucrose as the carbohydrate source, and yeast as the protein source. Dampening the signal through the insulin/IGF signalling (IIS) pathway, by genetic ablation of median neurosecretory cells (mNSCs) that produce insulin-like peptides, extends lifespan and counteracts the detrimental effects of excess yeast. However, how IIS reduction impacts health on a high-sugar diet remains unclear. We find that, while the ablation of the mNSCs can extend lifespan and delay the age-related decline in the health of the neuromuscular system irrespective of the amount of dietary sugar, it cannot rescue the lifespan-shortening effects of excess sugar. On the other hand, ablation of mNSCs can prevent adult obesity resulting from excess sugar, and this effect appears independent from the canonical effector of IIS, dfoxo. Our study indicates that while treatments that reduce IIS have anti-ageing effects irrespective of dietary sugar, additional interventions may be required to achieve full benefits in humans, where excessive sugar consumption is a growing problem. At the same time, pathways regulated by IIS may be suitable targets for treatment of obesity

Sexually dimorphic effects of dietary sugar on lifespan, feeding and starvation resistance in Drosophila

Lifespan and health in older age are strongly influenced by diet. Feeding Drosophila melanogaster diets high in sugar has increasingly been used as an experimental model to understand the physiological effects of unhealthy, contemporary human diets. Several metabolic parameters and physiological responses to nutrition are known to be dependent on the sex of the animal. However, sexual dimorphism in the responses to high‐ sugar diets in fruit flies has not been examined. Here we show that a high‐sugar diet in Drosophila melanogaster elicits sexually dimorphic effects on feeding behaviour, starvation resistance and lifespan. Females feed less on such diets, while males feed more, and these feeding responses may have secondary consequences. Females, more than males, gain the ability to resist periods of starvation from high‐sugar diets, indicating that the female response to excess sugar may be geared towards surviving food shortages in early life. At the same time, female lifespan is more susceptible to the detrimental effects of high sugar diets. Our study reveals differences between Drosophila sexes in their responses to sugar‐rich diets, indicating the fruit fly could be used as a model to understand the sexually dimorphic features of human metabolic health