Age-associated changes in transcriptional elongation and their effects on homeostasis.

Cellular homeostasis declines with age due to the declining fidelity of biosynthetic processes and the accumulation of molecular damage. Yet, it remains largely elusive how individual processes are affected during aging and what their specific contribution to age-related functional decline is. This review discusses a series of recent publications that has shown that transcription elongation is compromised during aging due to increasing DNA damage, stalling of RNA polymerase II (RNAPII), erroneous transcription initiation in gene bodies, and accelerated RNAPII elongation.

Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study.

Background: Ageing hallmarks, characterising features of cellular ageing, have a role in the pathophysiology of many age-related diseases. We examined whether obesity is associated with an increased risk of developing such hallmark-related diseases.

Methods: In this multicohort study, we included people aged 38-72 years with data on weight, height, and waist circumference measured during a clinical examination at baseline between March 13, 2006, and Oct 1, 2010, from the UK Biobank with follow-up until Nov 12, 2021.

Critical importance of DNA binding for CSL protein functions in fission yeast.

CSL proteins [named after the homologs CBF1 (RBP-Jκ in mice), Suppressor of Hairless and LAG-1] are conserved transcription factors found in animals and fungi. In the fission yeast Schizosaccharomyces pombe, they regulate various cellular processes, including cell cycle progression, lipid metabolism and cell adhesion. CSL proteins bind to DNA through their N-terminal Rel-like domain and central β-trefoil domain.

Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension.

Objective: Rapamycin, a powerful geroprotective drug, can have detrimental effects when administered chronically. We determined whether intermittent treatment of mice can reduce negative effects while maintaining benefits of chronic treatment.

Methods: From 6 months of age, male and female C3B6F1 hybrid mice were either continuously fed with 42 mg/kg rapamycin, or intermittently fed by alternating weekly feeding of 42 mg/kg rapamycin food with weekly control feeding.

Broad functional profiling of fission yeast proteins using phenomics and machine learning.

Many proteins remain poorly characterized even in well-studied organisms, presenting a bottleneck for research. We applied phenomics and machine-learning approaches with for broad cues on protein functions. We assayed colony-growth phenotypes to measure the fitness of deletion mutants for 3509 non-essential genes in 131 conditions with different nutrients, drugs, and stresses.

Genetic effects on molecular network states explain complex traits.

The complexity of many cellular and organismal traits results from the integration of genetic and environmental factors via molecular networks. Network structure and effect propagation are best understood at the level of functional modules, but so far, no concept has been established to include the global network state. Here, we show when and how genetic perturbations lead to molecular changes that are confined to small parts of a network versus when they lead to modulation of network states.

Metabolic heterogeneity and cross-feeding within isogenic yeast populations captured by DILAC.

Genetically identical cells are known to differ in many physiological parameters such as growth rate and drug tolerance. Metabolic specialization is believed to be a cause of such phenotypic heterogeneity, but detection of metabolically divergent subpopulations remains technically challenging. We developed a proteomics-based technology, termed differential isotope labelling by amino acids (DILAC), that can detect producer and consumer subpopulations of a particular amino acid within an isogenic cell population by monitoring peptides with multiple occurrences of the amino acid.

Perturbed fatty-acid metabolism is linked to localized chromatin hyperacetylation, increased stress-response gene expression and resistance to oxidative stress.

Oxidative stress is associated with cardiovascular and neurodegenerative diseases, diabetes, cancer, psychiatric disorders and aging. In order to counteract, eliminate and/or adapt to the sources of stress, cells possess elaborate stress-response mechanisms, which also operate at the level of regulating transcription. Interestingly, it is becoming apparent that the metabolic state of the cell and certain metabolites can directly control the epigenetic information and gene expression.

Barcode sequencing and a high-throughput assay for chronological lifespan uncover ageing-associated genes in fission yeast.

Ageing-related processes are largely conserved, with simple organisms remaining the main platform to discover and dissect new ageing-associated genes. Yeasts provide potent model systems to study cellular ageing owing their amenability to systematic functional assays under controlled conditions. Even with yeast cells, however, ageing assays can be laborious and resource-intensive.

Recombination and biased segregation of mitochondrial genomes during crossing and meiosis of different strains.

During meiosis, tethering of parental mitochondria to opposite cell poles inhibits the mixing of mitochondria with different genomes and ensures uniparental inheritance in thestandard laboratory strain of fission yeast. We here investigate mitochondrial inheritance in crosses between natural isolates using tetrad dissection and next-generation sequencing. We find that colonies grown from single spores can sometimes carry a mix of mitochondrial genotypes, that mitochondrial genomes can recombine during meiosis, that in some cases tetrads do not follow the 2:2 segregation pattern, and that certain crosses may feature a weak bias towards one of the parents.

Independent glial subtypes delay development and extend healthy lifespan upon reduced insulin-PI3K signalling.

Background: The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases.

Mitochondrial Signature in Human Monocytes and Resistance to Infection in During Fumarate-Induced Innate Immune Training.

Monocytes can develop immunological memory, a functional characteristic widely recognized as innate immune training, to distinguish it from memory in adaptive immune cells. Upon a secondary immune challenge, either homologous or heterologous, trained monocytes/macrophages exhibit a more robust production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, than untrained monocytes. , β-glucan, and BCG are all inducers of monocyte training and recent metabolic profiling analyses have revealed that training induction is dependent on glycolysis, glutaminolysis, and the cholesterol synthesis pathway, along with fumarate accumulation; interestingly, fumarate itself can induce training.

The GATA Transcription Factor Gaf1 Represses tRNAs, Inhibits Growth, and Extends Chronological Lifespan Downstream of Fission Yeast TORC1.

Target of Rapamycin Complex 1 (TORC1) signaling promotes growth and aging. Inhibition of TORC1 leads to reduced protein translation, which promotes longevity. TORC1-dependent post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less understood.

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 effects of IIS at the organismal level.

Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis.

Alzheimer's disease is the leading cause of dementia. Its increased prevalence in developed countries, due to the sharp rise in ageing populations, presents one of the costliest challenges to modern medicine. In order to find disease-modifying therapies to confront this challenge, a more complete understanding of the pathogenesis of Alzheimer's disease is necessary.

C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies.

Aging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause senescent pathology. In C.

Parkinson's Disease: Mitochondria Parked at the ER Hit the Snooze Button.

Parkinson's disease patients report sleep disturbances well ahead of motor symptoms. In this issue of Neuron, Valadas et al. (2018) report that the disease genes pink1 and parkin exert novel, cell-type-specific effects to modulate ER-mitochondria contacts, neuropeptidergic transmission, and sleep patterns.

Coupling of Rigor Mortis and Intestinal Necrosis during C. elegans Organismal Death.

Organismal death is a process of systemic collapse whose mechanisms are less well understood than those of cell death. We previously reported that death in C. elegans is accompanied by a calcium-propagated wave of intestinal necrosis, marked by a wave of blue autofluorescence (death fluorescence).

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

Lifespan and health in older age are strongly influenced by diet. Feeding 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.

Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing.

The field of the biology of ageing has received increasing attention from a biomedical point of view over the past decades. The main reason has been the realisation that increases in human population life expectancy are accompanied by late onset diseases. Indeed, ageing is the most important risk factor for a number of neoplastic, neurodegenerative and metabolic pathologies.

The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease.

Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in the gene. There is an established association between mutations and Parkinson's disease (PD), and indeed mutations are now considered to be the greatest genetic risk factor for PD. Impaired lysosomal-autophagic degradation of cellular proteins, including α-synuclein (α-syn), is implicated in the pathogenesis of PD, and there is increasing evidence for this also in GD and -PD.

Matching Dietary Amino Acid Balance to the In Silico-Translated Exome Optimizes Growth and Reproduction without Cost to Lifespan.

Balancing the quantity and quality of dietary protein relative to other nutrients is a key determinant of evolutionary fitness. A theoretical framework for defining a balanced diet would both reduce the enormous workload to optimize diets empirically and represent a breakthrough toward tailoring diets to the needs of consumers. Here, we report a simple and powerful in silico technique that uses the genome information of an organism to define its dietary amino acid requirements.

Nutritional Programming of Lifespan by FOXO Inhibition on Sugar-Rich Diets.

Consumption of unhealthy diets is exacerbating the burden of age-related ill health in aging populations. Such diets can program mammalian physiology to cause long-term, detrimental effects. Here, we show that, in Drosophila melanogaster, an unhealthy, high-sugar diet in early adulthood programs lifespan to curtail later-life survival despite subsequent dietary improvement.

A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin.

Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD.