With a rapidly expanding human population at advanced ages and age as the main driver for chronic diseases, we face the challenge of understanding tissue aging and devising new therapeutic interventions. Cellular senescence is an important hallmark of all aging tissues and has emerged as a potential key driver of chronic lung diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and asthma. This comprehensive review recapitulates current knowledge of pathways and processes involved in cellular senescence with emphasis on the role of mitochondrial dysfunction and the "4 Ms" (morphology, mitophagy, metabolism, and metabolites). We review our current knowledge of healthy lung aging, discuss which pathomechanisms in chronic lung disease are characterized by senescence, and summarize current target therapeutics and their impact on lung disease. Within this exponentially growing field, we propose emerging concepts and current gaps in knowledge that need to be addressed to develop better opportunities for therapeutic strategies and future investigations.

Smooth muscle is vital to hollow organs such as vessels, airways, bladder, prostate, uterus, and gastrointestinal tract. Its ability to contract and relax is essential for organ function. In vessels, vascular smooth muscle cells or arterial myocytes help regulate blood pressure and ensure proper blood flow to tissues. However, during diseases such as atherosclerosis, hypertension, and restenosis, these myocytes undergo a major transformation. They shift from a quiescent, contractile state to an active, synthetic one. In this synthetic state, they behave like inflammatory cells: secreting cytokines and signaling molecules, remodeling the surrounding matrix, and becoming migratory and proliferative. This shift is tied to a remodeling of their ion transport repertoire. Here, we build and refine a cohesive model whereby synthetic myocytes adopt a phenotype resembling nonexcitable cells. We propose that their ion transport toolkit changes as a coordinated unit, creating a distinct calcium signaling signature that supports their new roles in growth, movement, inflammation, and secretion, while sacrificing their contractile features. Focusing mainly on arterial myocytes, we examine how disease-driven changes in ion transport reshape the calcium signaling landscape. This shift moves away from classical excitation-contraction, mediated by L-type calcium channels and ryanodine receptors, and toward channels such as store-operated stromal interaction molecule (STIM)/Orai and transient receptor potential (TRP) channels, which are activated by growth and vasoactive factors and operate best at hyperpolarized membrane potentials. We also explore the remodeling of ion channels, transporters, and pumps within internal organelles and emphasize how understanding these changes could reveal new therapeutic targets for treating disease.

A-kinase anchoring proteins (AKAPs) received their name based on their ability to bind protein kinase A (PKA). Now, AKAPs have grown to a diverse family of more than 50 proteins, coordinating molecules far beyond PKA and the PKA signaling pathway. AKAPs are scaffolding proteins spanning in size between 15 and several hundred kDalton and can directly engage in protein interactions with other signaling proteins, their upstream regulators, and their downstream effectors. AKAPs possess unique targeting domains directing them to defined cellular compartments to coordinate cellular signaling spatially and temporally. A few AKAPs possess their own catalytic activity. AKAPs are crucial in directing cAMP signaling locally and in mediating crosstalk with other second messenger systems. This review introduces individual AKAPs and their physiological functions in their respective cellular compartments and illustrates how they organize local signal transduction. The crucial role of AKAPs in coordinating cAMP-responses to extracellular cues and how they facilitate specific responses to each stimulus will be exemplified. Dysregulation of AKAPs is associated with or causes disease. We will examine the pathophysiological roles of AKAPs in inherited and non-inherited non-communicable disease, such as cardiovascular diseases and cancer. Due to the lack of understanding of molecular mechanisms underlying most of these diseases, the available therapeutic approaches often only slow progression and cause side effects. This review will discuss unique opportunities AKAPs provide to address the medical need for novel therapeutic concepts. Finally, gaps in our knowledge about AKAPs will be outlined and future directions in AKAP research will be suggested.

Changes in local proton concentrations within the body occur during synaptic transmission and metabolic activity and along the digestive tract. Perturbations to the strictly controlled physiological tissue pH are often associated with pathological processes. As such, many cell types require the ability to sense and respond to changes in local proton concentrations. Acid-sensing ion channels (ASICs) have been identified in all groups of Bilateria except for nematodes, arthropods, and mollusks. They are part of the epithelial Na+ channel/degenerin (ENaC/DEG) family, which encompasses ion channels across a wide range of tissues and organisms. ENaC/DEG channels are constitutively active or can be activated by various stimuli, such as mechanical stimuli or the binding of peptides or protons. ASICs are low pH-activated Na+-selective channels, formed by the assembly of three identical or homologous subunits around a central pore. In mammals, ASICs are mostly expressed in the nervous system. Extensive structure-function studies have identified residues involved in ion permeation and in the control and modulation of ASIC activity. The biological functions of ASICs are associated with situations of lowered pH, such as high neuronal activity, ischemia, and inflammation. Experiments with rodents showed roles of ASICs in the expression of fear, learning, pain sensation, and neurodegeneration. This review comprehensively examines ASICs, covering their evolutionary origins, biophysical properties, structure-function relationships, physiological and pathological roles, and their regulation and pharmacology.

Thanks to its extensive intrinsic (enteric) neural networks spanning its entire length, the gastrointestinal (GI) tract has long been recognized for its ability to operate independently of the central nervous system (CNS). Despite that, the CNS provides both sympathetic and parasympathetic inputs to the GI tract, which confers an additional layer of regulation, modulation, and integration over GI functions. The sympathetic nervous system provides neurovascular control of GI blood flow in addition to its effects to decrease mucosal secretion, regulate sphincter tone, and modulate motility, principally via prejunctional and presynaptic actions. The parasympathetic nervous system, however, exerts both excitatory and inhibitory effects; the extent to which this influences gut functions varies throughout the length of the GI tract. Recent studies have also demonstrated that, in addition to regulation via the autonomic nervous system, "higher" CNS nuclei also provide a significant degree of influence over GI functions under both physiological and pathophysiological conditions. In addition to describing the anatomical neurocircuits and physiological functions of the extrinsic inputs to the GI tract, this review also discusses the roles of brain stem, midbrain, and cortical nuclei that influence the gut within the context of relevant physiological and pathophysiological conditions.

Many countries face an unprecedented challenge in aging demographics. This has led to an exponential growth in research on aging, which, coupled to a massive financial influx of funding in the private and public sectors, has resulted in seminal insights into the underpinnings of this biological process. However, critical validation in humans has been hampered by the limited translatability of results obtained in model organisms, additionally confined by the need for extremely time-consuming clinical studies in the ostensible absence of robust biomarkers that would allow monitoring in shorter time frames. In the future, molecular parameters might hold great promise in this regard. In contrast, biomarkers centered on function, resilience, and frailty are available at the present time, with proven predictive value for morbidity and mortality. In this review, the current knowledge of molecular and physiological aspects of human aging, potential antiaging strategies, and the basis, evidence, and potential application of physiological biomarkers in human aging are discussed.

Mammals maintain body heat by adaptive energy expenditure through different organ specific mechanisms. The glycerolipid/free fatty acid cycle (glycerolipid cycle), encompassing triglyceride lipolysis and free fatty acid (FFA) release followed by their reesterification is an ATP-consuming process that contributes to energy expenditure, heat production and various lipid signaling pathways. The glycerolipid cycle, which was originally described as a whole-body process, is now known to also occur intracellularly in many organs. This review focuses on the thermogenic and signaling roles of glycerolipid cycling in adipose and other tissues and offers insight into the various pathophysiological conditions where its activity is altered. We discuss its substrates and products, enzyme components and regulation. We present evidence that this cycling process, besides acting as the complete triglyceride/FFA cycle, is in fact composed of multiple shorter sub-cycles, which can be activated individually. We highlight the importance of this energy dissipating cycle in adaptive thermogenesis and energy expenditure in animals and humans, and discuss the latest methodological advances to quantify its flux. The much renewed interest in this area has begun to showcase the central role of glycerolipid cycling mediated thermogenesis and signaling in metabolic disorders that could be harnessed for therapy.

Cysteine residues are uniquely equipped to sense redox signals because of the reactivity of their thiol side chains, which can undergo oxidation to form various modifications. By sensing changes within the intracellular redox environment, reactive cysteine thiols add a distinct shape and a charge characteristic that can induce protein conformational changes, ultimately triggering specific effector responses that alter cellular and tissue function. Redox sensing is essential within the cardiovascular system, where it regulates both cardiac and vascular function and significantly influences disease progression. This review provides a brief introduction to cysteine thiol redox sensors, outlines methodologies for their detection, and explores their roles in the cardiovascular system. Also discussed are recent advancements in identifying cysteine-targeted therapies and a proposal for a redefined perspective on the role of redox biology within the cardiovascular system.

Skeletal muscle is the main site of glucose deposition in the body during meals and the major glucose utilizer during physical activity. Although in both instances the supply of glucose from the circulation to the muscle is of paramount importance, in most conditions the rate-limiting step in glucose uptake, storage, and utilization is the transport of glucose across the muscle cell membrane. This step is dependent upon the translocation of the insulin- and contraction-responsive glucose transporter GLUT4 from intracellular storage sites to the sarcolemma and T tubules. Here, we first analyze how glucose can traverse the capillary wall into the muscle interstitial space. We then review the molecular processes that regulate GLUT4 translocation in response to insulin and muscle contractions and the methodologies utilized to unravel them. We further discuss how physical activity and inactivity, respectively, lead to increased and decreased insulin action in muscle and touch upon sex differences in glucose metabolism. Although many key processes regulating glucose uptake in muscle are known, the advent of newer and bioinformatics tools has revealed further molecular signaling processes reaching a staggering level of complexity. Much of this molecular mapping has emerged from cellular and animal studies and more recently from application of a variety of -omics in human tissues. In the future, it will be imperative to validate the translatability of results drawn from experimental systems to human physiology.