Role of the central nervous system in cell non-autonomous signaling mechanisms of aging and longevity in mammals.

Multiple organs orchestrate the maintenance of proper physiological function in organisms throughout their lifetimes. Recent studies have uncovered that aging and longevity are regulated by cell non-autonomous signaling mechanisms in several organisms. In the brain, particularly in the hypothalamus, aging and longevity are regulated by such cell non-autonomous signaling mechanisms. Several hypothalamic neurons have been identified as regulators of mammalian longevity, and manipulating them promotes lifespan extension or shortens the lifespan in rodent models. The hypothalamic structure and function are evolutionally highly conserved across species. Thus, elucidation of hypothalamic function during the aging process will shed some light on the mechanisms of aging and longevity and, thereby benefiting to human health.

Illuminating intercellular autophagy: A comprehensive review of cell non-autonomous autophagy.

Macro-autophagy (autophagy hereafter) is an evolutionarily conserved cellular process that has long been recognized as an intracellular mechanism for maintaining cellular homeostasis. It involves the formation of a membraned structure called the autophagosome, which carries cargo that includes toxic protein aggregates and dysfunctional organelles to the lysosome for degradation and recycling. Autophagy is primarily considered and studied as a cell-autonomous mechanism. However, recent studies have illuminated an underappreciated facet of autophagy, i.e., non-autonomously regulated autophagy. Non-autonomously regulated autophagy involves the degradation of autophagic components, including organelles, cargo, and signaling molecules, and is induced in neighboring cells by signals from primary adjacent or distant cells/tissues/organs. This review provides insight into the complex molecular mechanisms governing non-autonomously regulated autophagy, highlighting the dynamic interplay between cells within tissue/organ or distinct cell types in different tissues/organs. Emphasis is placed on modes of intercellular communication that include secreted molecules, including microRNAs, and their regulatory roles in orchestrating this phenomenon. Furthermore, we explore the multidimensional roles of non-autonomously regulated autophagy in various physiological contexts, spanning tissue development and aging, as well as its importance in diverse pathological conditions, including cancer and neurodegeneration. By studying the complexities of non-autonomously regulated autophagy, we hope to gain insights into the sophisticated intercellular dynamics within multicellular organisms, including mammals. These studies will uncover novel avenues for therapeutic intervention to modulate intercellular autophagic pathways in altered human physiology.

Functional Roles and Genomic Impact of Miniature Inverted-Repeat Transposable Elements (MITEs) in Prokaryotes.

Prokaryotic genomes are dynamic tapestries that are strongly influenced by mobile genetic elements (MGEs), including transposons (Tn's), plasmids, and bacteriophages. Of these, miniature inverted-repeat transposable elements (MITEs) are undoubtedly the least studied MGEs in bacteria and archaea. This review explores the diversity and distribution of MITEs in prokaryotes and describes what is known about their functional roles in the host and involvement in genomic plasticity and evolution.

How Plant Toxins Cause Early Larval Mortality in Herbivorous Insects: An Explanation by Modeling the Net Energy Curve.

Plants store chemical defenses that act as toxins against herbivores, such as toxic isothiocyanates (ITCs) in Brassica plants, hydrolyzed from glucosinolate (GLS) precursors. The fitness of herbivorous larvae can be strongly affected by these toxins, causing immature death. We modeled this phenomenon using a set of ordinary differential equations and established a direct relationship between feeding, toxin exposure, and the net energy of a larva, where the fitness of an organism is proportional to its net energy according to optimal foraging theory. Optimal foraging theory is widely used in ecology to model the feeding and searching behavior of organisms. Although feeding provides energy gain, plant toxins and foraging cause energy loss for the larvae. Our equations explain that toxin exposure and foraging can sharply reduce larval net energy to zero at an instar. Since herbivory needs energy, the only choice left for a larva is to stop feeding at that time point. If that is significantly earlier than the end of the last instar stage, the larva dies without food. Thus, we show that plant toxins can cause immature death in larvae from the perspective of optimal foraging theory.

Feedback control of collective dynamics in an oscillator population with time-dependent connectivity.

We present a numerical study of pulsatile feedback-based control of synchrony level in a highly-interconnected oscillatory network. We focus on a nontrivial case when the system is close to the synchronization transition point and exhibits collective rhythm with strong amplitude modulation. We pay special attention to technical but essential steps like causal real-time extraction of the signal of interest from a noisy measurement and estimation of instantaneous phase and amplitude. The feedback loop's parameters are tuned automatically to suppress synchrony. Though the study is motivated by neuroscience, the results are relevant to controlling oscillatory activity in ensembles of various natures and, thus, to the rapidly developing field of network physiology.

A Note on Stronger Forms of Sensitivity for Non-Autonomous Dynamical Systems on Uniform Spaces.

This paper introduces the notion of multi-sensitivity with respect to a vector within the context of non-autonomous dynamical systems on uniform spaces and provides insightful results regarding N-sensitivity and strongly multi-sensitivity, along with their behaviors under various conditions. The main results established are as follows: (1) For a k-periodic nonautonomous dynamical system on a Hausdorff uniform space (S,U), the system (S,fk∘⋯∘f1) exhibits N-sensitivity (or strongly multi-sensitivity) if and only if the system (S,f1,∞) displays N-sensitivity (or strongly multi-sensitivity). (2) Consider a finitely generated family of surjective maps on uniform space (S,U). If the system (S,f1,∞) is N-sensitive, then the system (S,fk,∞) is also N-sensitive. When the family f1,∞ is feebly open, the converse statement holds true as well. (3) Within a finitely generated family on uniform space (S,U), N-sensitivity (and strongly multi-sensitivity) persists under iteration. (4) We present a sufficient condition under which an nonautonomous dynamical system on infinite Hausdorff uniform space demonstrates N-sensitivity.

ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei.

The human ataxia telangiectasia mutated and Rad3-related (ATR) kinase functions in the nucleus to protect genomic integrity. Micronuclei (MN) arise from genomic and chromosomal instability and cause aneuploidy and chromothripsis, but how MN are removed is poorly understood. Here, we show that ATR is active in MN and promotes their rupture in S phase by phosphorylating Lamin A/C at Ser395, which primes Ser392 for CDK1 phosphorylation and destabilizes the MN envelope. In cells harboring MN, ATR or CDK1 inhibition reduces MN rupture. Consequently, ATR inhibitor (ATRi) diminishes activation of the cytoplasmic DNA sensor cGAS and compromises cGAS-dependent autophagosome accumulation in MN and clearance of micronuclear DNA. Furthermore, ATRi reduces cGAS-mediated senescence and killing of MN-bearing cancer cells by natural killer cells. Thus, in addition to the canonical ATR signaling pathway, an ATR-CDK1-Lamin A/C axis promotes MN rupture to clear damaged DNA and cells, protecting the genome in cell populations through unexpected cell-autonomous and cell-non-autonomous mechanisms.

Neuron-specific proteasome activation exerts cell non-autonomous protection against amyloid-beta (Aß) proteotoxicity in Caenorhabditis elegans.

Proteostasis reinforcement is a promising approach in the design of therapeutic interventions against proteinopathies, including Alzheimer's disease. Understanding how and which parts of the proteostasis network should be enhanced is crucial in developing efficient therapeutic strategies. The ability of specific tissues to induce proteostatic responses in distal ones (cell non-autonomous regulation of proteostasis) is attracting interest. Although the proteasome is a major protein degradation node, nothing is known on its cell non-autonomous regulation. We show that proteasome activation in the nervous system can enhance the proteasome activity in the muscle of Caenorhabditis elegans. Mechanistically, this communication depends on Small Clear Vesicles, with glutamate as one of the neurotransmitters required for the distal regulation. More importantly, we demonstrate that this cell non-autonomous proteasome activation is translated into efficient prevention of amyloid-beta (Αß)-mediated proteotoxic effects in the muscle of C. elegans but notably not to resistance against oxidative stress. Our in vivo data establish a mechanistic link between neuronal proteasome reinforcement and decreased Aß proteotoxicity in the muscle. The identified distal communication may have serious implications in the design of therapeutic strategies based on tissue-specific proteasome manipulation.

Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons.

Aging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network. We have discovered the Caenorhabditis elegans homeodomain-interacting protein kinase (HPK-1) acts as a key transcriptional effector to preserve neuronal integrity, function, and proteostasis during aging. Loss of hpk-1 results in drastic dysregulation in expression of neuronal genes, including genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system more broadly than any other kinase. Within the aging nervous system, hpk-1 induction overlaps with key longevity transcription factors, which suggests that hpk-1 expression mitigates natural age-associated physiological decline. Consistently, pan-neuronal overexpression of hpk-1 extends longevity, preserves proteostasis both within and outside of the nervous system, and improves stress resistance. Neuronal HPK-1 improves proteostasis through kinase activity. HPK-1 functions cell non-autonomously within serotonergic and γ-aminobutyric acid (GABA)ergic neurons to improve proteostasis in distal tissues by specifically regulating distinct components of the proteostatic network. Increased serotonergic HPK-1 enhances the heat shock response and survival to acute stress. In contrast, GABAergic HPK-1 induces basal autophagy and extends longevity, which requires mxl-2 (MLX), hlh-30 (TFEB), and daf-16 (FOXO). Our work establishes hpk-1 as a key neuronal transcriptional regulator critical for preservation of neuronal function during aging. Further, these data provide novel insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis.

Proteins are essential for nearly every cellular process to sustain a healthy organism. A complex network of pathways and signalling molecules regulates the proteins so that they work correctly in a process known as proteostasis. As the body ages, this network can become damaged, which leads to the production of faulty proteins. Many proteins end up being misfolded ­ in other words, they are misshapen on the molecular level, which can be toxic for the cell. A build-up of such misfolded proteins is implicated in several neurological conditions, including Alzheimer's, Parkinson's and Huntington's disease. Cells have various ways to detect and respond to internal stressors, such as tissue or organ damage. For example, specific proteins in the nervous system can raise a 'central' alert when damage is detected, which then primes and coordinates the body's systems to respond in the peripheral cells and tissues. But exactly how this happens is still unclear. To find out more about the central coordination of stress responses, Lazaro-Pena et al. studied one such sensor protein, called HPK-1, in the roundworm C. elegans. They first overexpressed the protein in various tissues. This revealed that only when HPK-1 was overactive in nerve tissue, it protected proteins and prolonged the lifespan of the worms. An increased amount of HPK-1 improved the health span of the worms and older worms also moved better. However, genetically manipulated worms lacking HPK-1 in their nerve cells showed a faster decline in nervous system health as they aged, which could be reversed once HPK-1 was activated again. Lazaro-Pena et al. then measured the amount of HPK-1 in worms at different stages of their life. This showed that as the worms aged, the amount of HPK-1 increased in the nerve cells. The nerve cells in which HPK-1 levels increased overlapped with an increased expression of proteins associated with longevity. Moreover, when HPK-1 was overexpressed, it stimulated the release of other cell signals, which then triggered protective responses to prevent the misfolding and aggregation of proteins and to help degrade damaged proteins. This study shows for the first time that HPK-1 appears to play a protective role during normal ageing and that it may act as a key switch to stimulate other protective mechanisms. These findings may give rise to new insights into how the nervous system can coordinate many different stress responses, and ultimately delay ageing throughout the whole body.

A mathematical interpretation for outbreaks of bacterial meningitis under the effect of time-dependent transmission parameters.

We consider a SIR-type compartmental model divided into two age classes to explain the seasonal exacerbations of bacterial meningitis, especially among children outside of the meningitis belt. We describe the seasonal forcing through time-dependent transmission parameters that may represent the outbreak of the meningitis cases after the annual pilgrimage period (Hajj) or uncontrolled inflows of irregular immigrants. We present and analyse a mathematical model with time-dependent transmission. We consider not only periodic functions in the analysis but also general non-periodic transmission processes. We show that the long-time average values of transmission functions can be used as a stability marker of the equilibrium. Furthermore, we interpret the basic reproduction number in case of time-dependent transmission functions. Numerical simulations support and help visualize the theoretical results.

Drosophila melanogaster as a model to study autophagy in neurodegenerative diseases induced by proteinopathies.

Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington's disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer's disease (APP, Tau) Parkinson's disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases.

ER proteostasis regulators cell-non-autonomously control sleep.

Sleep is regulated by peripheral tissues under fatigue. The molecular pathways in peripheral cells that trigger systemic sleep-related signals, however, are unclear. Here, a forward genetic screen in C. elegans identifies 3 genes that strongly affect sleep amount: sel-1, sel-11, and mars-1. sel-1 and sel-11 encode endoplasmic reticulum (ER)-associated degradation components, whereas mars-1 encodes methionyl-tRNA synthetase. We find that these machineries function in non-neuronal tissues and that the ER unfolded protein response components inositol-requiring enzyme 1 (IRE1)/XBP1 and protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α)/activating transcription factor-4 (ATF4) participate in non-neuronal sleep regulation, partly by reducing global translation. Neuronal epidermal growth factor receptor (EGFR) signaling is also required. Mouse studies suggest that this mechanism is conserved in mammals. Considering that prolonged wakefulness increases ER proteostasis stress in peripheral tissues, our results suggest that peripheral ER proteostasis factors control sleep homeostasis. Moreover, based on our results, peripheral tissues likely cope with ER stress not only by the well-established cell-autonomous mechanisms but also by promoting the individual's sleep.

Pool dynamics of time-dependent compartmental systems with application to the terrestrial carbon cycle.

Compartmental models play an important role to describe the dynamics of systems that involve mass movements between different types of pools. We develop a theory to analyse the average ages of mass in different pools in a linear compartmental system with time-dependent (i.e. non-autonomous) transfer rates, which involves transit times that characterize the average time a particle has spent in a particular pool. We apply our theoretical results to investigate a nine-dimensional compartmental system with time-dependent fluxes between pools modelling the carbon cycle which is a modification of the Carnegie-Ames-Stanford approach model. Knowledge of transit time and mean age allows calculation of carbon storage in a pool as a function of time. The general result that has important implications for understanding and managing carbon storage is that the change in storage in different pools does not change monotonically through time: as rates change monotonically a pool which initially shows a decrease may then show an increase in storage or vice versa. Thus caution is needed in extrapolating even the direction of future changes in storage in carbon storage in different pools with global change.

A Year at the Forefront of Proteostasis and Aging.

During aging, animals experience a decline in proteostasis activity, including loss of stress-response activation, culminating in the accumulation of misfolded proteins and toxic aggregates, which are causal in the onset of some chronic diseases. Finding genetic and pharmaceutical treatments that can increase organismal proteostasis and lengthen life is an ongoing goal of current research. The regulation of stress responses by cell non-autonomous mechanisms appears to be a potent way to impact organismal healthspan. In this Review, we cover recent findings in the intersection of proteostasis and aging, with a special focus on articles and preprints published between November 2021 and October 2022. A significant number of papers published during this time increased our understanding of how cells communicate with each other during proteotoxic stress. Finally, we also draw attention to emerging datasets that can be explored to generate new hypotheses that explain age-related proteostasis collapse.

Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism.

Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies.

Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.

Mitochondrial perturbations within neurons communicate stress signals to peripheral tissues, coordinating organismal-wide mitochondrial homeostasis for optimal fitness. However, the neuronal control of the systemic stress regulation remains poorly understood. Here, we identified a G-protein-coupled receptor (GPCR), SRZ-75, that couples with Gαq signaling in a pair of chemosensory ADL neurons to drive the mitochondrial unfolded protein response (UPRmt) activation in the intestine via the release of neuropeptides in Caenorhabditis elegans. Constitutive activation of Gαq signaling in the ADL neurons is sufficient to induce the intestinal UPRmt, leading to increased stress resistance and metabolic adaptations. Ablation of ADL neurons attenuates the intestinal UPRmt activation in response to various forms of neuronal mitochondrial dysfunction. Thus, GPCR and its Gαq downstream signaling in two sensory neurons coordinate the systemic UPRmt activation, representing a previously uncharacterized, but potentially conserved, neuronal signaling for organismal-wide mitochondrial stress regulation.

A mathematical model for the spread of Varroa mites in honeybee populations: two simulation scenarios with seasonality.

We formulate and study a mathematical model for a honeybee colony infected with Varroa mites which describes the parallel phenomena of the spread of both the mites and the virus transmitted by them. We extend our previous model by including infected forager bees and considering model parameters as time-periodic functions. Firstly, we study the autonomous model and show the stability of equilibria. We present two simulation scenarios to study the impact of seasonality on the spread of Varroa mites and the disease they carry. Numerical studies are given to show how the parameter changes might lead to the colony's failure.

Temperature-Dependent Regulation of Proteostasis and Longevity.

Temperature is an important environmental condition that determines the physiology and behavior of all organisms. Animals use different response strategies to adapt and survive fluctuations in ambient temperature. The hermaphrodite Caenorhabditis elegans has a well-studied neuronal network consisting of 302 neurons. The bilateral AFD neurons are the primary thermosensory neurons in the nematode. In addition to regulating thermosensitivity, AFD neurons also coordinate cellular stress responses through systemic mechanisms involving neuroendocrine signaling. Recent studies have examined the effects of temperature on altering various signaling pathways through specific gene expression programs that promote stress resistance and longevity. These studies challenge the proposed theories of temperature-dependent regulation of aging as a passive thermodynamic process. Instead, they provide evidence that aging is a well-defined genetic program. Loss of protein homeostasis (proteostasis) is one of the key hallmarks of aging. Indeed, proteostasis pathways, such as the heat shock response and aggregation of metastable proteins, are also controlled by thermosensory neurons in C. elegans. Prolonged heat stress is thought to play a critical role in the development of neurodegenerative protein misfolding diseases in humans. This review presents the latest evidence on how temperature coordinates proteostasis and aging. It also discusses how studies of poikilothermic organisms can be applied to vertebrates and provides new therapeutic strategies for human disease.

Protein disulfide isomerase PDI-6 regulates Wnt secretion to coordinate inter-tissue UPRmt activation and lifespan extension in C. elegans.

Coordination of inter-tissue stress signaling is essential for organismal fitness. Neuronal mitochondrial perturbations activate the mitochondrial unfolded-protein response (UPRmt) in the intestine via the mitokine Wnt signaling in Caenorhabditis elegans. Here, we found that the protein disulfide isomerase PDI-6 coordinates inter-tissue UPRmt signaling via regulating the Wnt ligand EGL-20. PDI-6 is expressed in the endoplasmic reticulum (ER) and interacts with EGL-20 through disulfide bonds that are essential for EGL-20 stability and secretion. pdi-6 deficiency results in misfolded EGL-20, which leads to its degradation via ER-associated protein degradation (ERAD) machinery. Expression of PDI-6 declines drastically with aging, and animals with pdi-6 deficiency have decreased lifespan. Overexpression of PDI-6 is sufficient to maintain Wnt/EGL-20 protein levels during aging, activating the UPRmt, and significantly extending lifespan in a Wnt- and UPRmt-dependent manner. Our study reveals that protein disulfide isomerase facilitates Wnt secretion to coordinate the inter-tissue UPRmt signaling and organismal aging.

Cell autonomous and non-autonomous consequences of deviations in translation machinery on organism growth and the connecting signalling pathways.

Translation machinery is responsible for the production of cellular proteins; thus, cells devote the majority of their resources to ribosome biogenesis and protein synthesis. Single-copy loss of function in the translation machinery components results in rare ribosomopathy disorders, such as Diamond-Blackfan anaemia in humans and similar developmental defects in various model organisms. Somatic copy number alterations of translation machinery components are also observed in specific tumours. The organism-wide response to haploinsufficient loss-of-function mutations in ribosomal proteins or translation machinery components is complex: variations in translation machinery lead to reduced ribosome biogenesis, protein translation and altered protein homeostasis and cellular signalling pathways. Cells are affected both autonomously and non-autonomously by changes in translation machinery or ribosome biogenesis through cell-cell interactions and secreted hormones. We first briefly introduce the model organisms where mutants or knockdowns of protein synthesis and ribosome biogenesis are characterized. Next, we specifically describe observations in Caenorhabditis elegans and Drosophila melanogaster, where insufficient protein synthesis in a subset of cells triggers cell non-autonomous growth or apoptosis responses that affect nearby cells and tissues. We then cover the characterized signalling pathways that interact with ribosome biogenesis/protein synthesis machinery with an emphasis on their respective functions during organism development.