Review
Abstract
Beyond serving as a structural organ, the skeleton undergoes continuous remodeling and functions as an endocrine organ by secreting bioactive factors that regulate the physiology of distant tissues. Indeed, the concept of a “bone-vascular axis” has long been recognized, supported by epidemiological evidence linking osteoporosis and low bone mass to increased cardiovascular morbidity and mortality. Emerging findings now extend this paradigm to the brain, suggesting that bone- and bone marrow–derived signals influence cerebrovascular structure, function, and aging. Given that cerebrovascular dysfunction is a central driver of age-related cognitive decline, dementia, and neurodegenerative diseases, understanding this “bone-cerebrovascular axis” may offer novel opportunities for prevention and intervention. Here, we outline the cellular and molecular mechanisms underlying age-associated neurovascular impairment and summarize the biology of major bone and bone marrow cell populations, with emphasis on age-related alterations in their secretome. A central focus of this Review is the emerging evidence that age-related skeletal alterations exert systemic effects on the cerebrovasculature, highlighting how bone- and bone marrow–derived factors shape neurovascular health and pathology, which may subsequently contribute to CNS aging and neurodegeneration. A deeper understanding of these systemic interactions reframes brain aging within a whole-body context and may uncover innovative biomarkers and therapeutic strategies to mitigate neurodegeneration and other age-associated disorders.
Authors
Jiekang Wang, Xu Cao, Mei Wan
Abstract
Cholesterol biosynthesis is indispensable for CNS development and function. The developing brain relies almost entirely on intrinsic sterol synthesis to support membrane biogenesis, axonal outgrowth, synaptogenesis, and myelination. Pathogenic variants in sterol biosynthetic enzymes, including DHCR7 and DHCR24, result in complex neurodevelopmental disorders such as Smith-Lemli-Opitz syndrome and desmosterolosis. In addition to cholesterol-lowering drugs (statins), some other pharmacological agents such as antipsychotics, antidepressants, and beta blockers can also inhibit cholesterol biosynthesis due to off-target effects. This inhibition produces dual pathophysiological effects: cholesterol depletion and accumulation of its precursor, 7-dehydrocholesterol, an exceptionally oxidizable molecule that spontaneously generates toxic oxysterols. Given the intense demand for cholesterol synthesis in the developing brain, prenatal exposure to sterol biosynthesis–inhibiting medications may have far-reaching effects. In this Review, we describe convergent biochemical, genetic, and epidemiologic data that implicate developmental sterol dysregulation as a modifiable risk factor for neurodevelopmental pathology and underscore the urgent need for routine sterol pathway safety assessment in drug development and prenatal pharmacotherapy.
Authors
Eric S. Peeples, Zeljka Korade, Karoly Mirnics
Abstract
Alternative splicing is a pervasive mechanism that expands the coding potential and functional complexity of the human genome. Dysregulated isoform usage alters gene functions and contributes broadly to human disease across developmental, neurodegenerative, and cancer settings. Technologies for characterizing splicing and isoforms have advanced rapidly, evolving from Sanger sequencing of individual cDNA clones to high-throughput next-generation sequencing of splice junctions, and more recently to long-read sequencing that resolves full-length transcripts at bulk, single-cell, and spatial resolutions. With the growing recognition of their critical roles in human disease, multiple therapeutic modalities have been developed to precisely target splicing and isoform regulation at the DNA, RNA, and protein levels. Clinical-grade small molecules and antisense oligonucleotides that modulate aberrant RNA splicing and isoform switching have become available, offering new hope for previously incurable diseases. Here, we review this crucial yet underexplored layer of transcriptomic regulation in human disease, encompassing regulatory mechanisms, technological advances, therapeutic strategies, and future directions.
Authors
Timothy Pan, Lina Lu, Ruli Gao
Abstract
As a widely distributed network of cells, tissues, and organs, the human immune system is profoundly vulnerable to the effects of aging. Intrinsic and extrinsic stressors progressively erode its structural integrity and functional resilience, weakening core protective responses and increasing susceptibility to infection, malignancy, and tissue degeneration. At the same time, aging heightens the risk of chronic inflammation and autoimmune disease. Hematopoietic stem cells become uniquely compromised as aging intensifies metabolic and replicative stress. Their continuous high-volume turnover results in diminished self-renewal capacity, skewed lineage output, and dominance of expanded clones. These changes undermine innate immune competence and amplify inflammatory activity. Adaptive immune function declines with age through coordinated cellular and molecular programs. T and B lymphocytes exhibit a decline in naive cells, progressive loss of stemness, shortened lifespan, and constrained clonal diversity. Aging lymphocytes reconfigure transcriptional networks, undergo widespread organelle dysfunction, develop maladaptive stress responses, and redistribute into noncanonical tissue niches. Collectively, these alterations reduce antigen specificity and precision, promote innate-like immune behavior, and confer resistance to tolerance. These mechanisms result in concurrent immunodeficiency and autoimmunity, exemplified by two autoimmune diseases disproportionately affecting older adults: rheumatoid arthritis and giant cell arteritis.
Authors
Cornelia M. Weyand, Jörg J. Goronzy
Abstract
The reality of an aging population demands a deeper understanding of aging as a biological process, rather than as a chronological descriptor. Chronological age poorly captures interindividual heterogeneity in physiological and functional decline, disease susceptibility, and mortality risk. In contrast, biological age encompasses deterioration at the molecular, cellular, tissue, organ, functional, and organismal levels and provides insight into why two individuals with the same chronological age exhibit differences in physiological function, disease susceptibility, and mortality risk. While early models of biological age relied on functional markers or composite scores derived largely from longitudinal cohort studies, more recent models integrate molecular profiling with machine learning to ascertain biological aging trajectories. In parallel, new artificial intelligence tools have been applied to various imaging modalities and other forms of complex data to elucidate latent patterns and estimate biological age. In this state-of-the-art Review, we explore historical and modern approaches to estimating biological age and highlight key conceptual, technical, and translational challenges that remain unresolved. As geroscience-guided interventions are incorporated into clinical evaluations, robust and accurate interpretable measures of biological aging are crucial to ascertain treatment effects in clinical trials.
Authors
Baljash S. Cheema, Bedirhan Boztepe, Moses O. Awofolaju, Mallory S. Hubbard, William B. Marcus, Frank J. Palella, Mohamed Abdel-Mohsen, David M. Liebovitz, Manjot K. Gill, R. James Cotton, John T. Wilkins, Douglas E. Vaughan
Abstract
Each year, sepsis claims more lives in the United States than many major cancers and HIV/AIDS combined, yet therapeutic progress has been modest. Adding to this crisis is the alarming rise of multidrug-resistant “superbugs,” which increasingly render conventional antibiotics ineffective. Pathogen-targeted antibiotics will always remain a cornerstone of sepsis treatment, and research into novel antibiotics must continue unabated. However, the consistent mortality in sepsis tells us this approach is insufficient. Most deaths in sepsis do not occur during the early cytokine storm–driven hyper-inflammatory phase but rather days or weeks after the initial insult, during a protracted phase of immune suppression. Here, we make the case that a crucial way to reduce sepsis mortality lies in restoration of the patient’s immune competence, enabling the patient to contain and kill the invading microbes. Adjuvant immune therapies will not only enable killing of the initial, invading pathogens but also prevent secondary, hospital-acquired infections. Immunotherapy revolutionized oncology by challenging the assumption that cancer was best treated through cytotoxic or targeted tumor-directed approaches, and sepsis now stands at a similar inflection point. We argue that embracing immune restoration as a core therapeutic objective offers the most promising means to improve survival in this lethal disorder.
Authors
Richard S. Hotchkiss, Guillaume Monneret
Abstract
Polycystic ovary syndrome (PCOS), also known as polyendocrine metabolic ovarian syndrome (PMOS), is the most common endocrinologic disorder to affect women. Despite this, the pathophysiology of the disease is not entirely known. This has hindered the diagnosis of the disease and appropriate treatment for millions of individuals. In this Review, we discuss the proposed pathophysiology of PCOS from a translational perspective. We review the existing diagnostic criteria of PCOS and current management strategies. Finally, we discuss the long-term health sequelae associated with PCOS, future directions, and areas of needed research in this often-overlooked disease.
Authors
Jessica L. Chan, Irene Masini, Margareta D. Pisarska
Abstract
Recent advances in cerebrovascular genomics, single-cell biology, pharmacology, and gene editing technology are transforming our understanding of brain arteriovenous malformations (bAVMs) — a leading cause of pediatric hemorrhagic stroke. Once considered static anatomical defects, bAVMs are now recognized as dynamic, genetically driven lesions resulting from somatic mutations in KRAS, BRAF, and pathways involved in arteriovenous specification, angiogenesis, and vascular remodeling. By integrating human genetics, animal models, and endovascular innovations, researchers have uncovered convergent mechanisms that link endothelial Ras/MAPK hyperactivation to abnormal vessel growth and higher rupture risk. These insights provide a foundation for precision medicine approaches that combine molecular diagnostics — such as liquid or endoluminal biopsies — with mutation-specific pharmacotherapies and emerging CRISPR-based gene editing strategies. We suggest that genotype-guided interventions, tailored by spatial and developmental cerebrovascular context, could ultimately reclassify bAVMs from surgically incurable malformations to treatable molecular conditions.
Authors
Andrew T. Hale, Adam J. Kundishora, Pazhanichamy Kalailingam, Tanyeri Barak, Phan Q. Duy, Christopher M. Ramundo, Baojian Fan, Qiang Li, Priscilla K. Brastianos, Ganesh M. Shankar, Seth L. Alper, Benjamin P. Kleinstiver, Patricia L. Musolino, Kristopher T. Kahle
Abstract
Type 1 diabetes mellitus (T1D) has been recognized as a chronic autoimmune disease for five decades, but therapy has relied on the exogenous replacement of insulin, which is an imperfect substitute for normal β cell function. In recent years, there has been progress in the development of new therapeutics that target the primary causes of the disease: failed immunologic tolerance and β cell killing. One agent, teplizumab, was shown to attenuate loss of β cell function that occurs over time and delay progression to clinical disease in individuals at risk, leading to its regulatory approval in 2022. Other immunologic agents show promise in modulating the immunologic imbalance. Moreover, a role for β cells in T1D pathogenesis has been identified and may be targeted. Now that the first disease-modifying therapeutic agent is available, future studies may involve combinations of agents to extend immunologic tolerance and protect and restore β cells so that lasting metabolic remission can be achieved.
Authors
Kevan C. Herold, Carmella Evans-Molina
Abstract
Anemia affects one-third of the population globally and is marked by impaired erythropoiesis that results in substantial mortality and morbidity. Over the past few decades, our understanding of the molecular mechanisms underlying anemia has progressed but translating that knowledge into effective targeted therapeutics remains challenging. Preclinical and clinical studies substantiate the efficacy of modulating erythropoietin-driven signaling pathways to stimulate erythropoiesis. Additional approaches include strategies to maintain iron homeostasis and control iron metabolism, using small molecules and oral supplements. New frontiers in molecular regulation of anemia include perturbation of regulatory genes and spliceosome proteins in erythroid cells, as well as mutation-specific therapeutic approaches. Finally, new evidence supporting the importance of neuronal signaling and mitochondrial dynamics in shaping erythropoiesis is pointing toward novel interventions. Here, we discuss the molecular and genetic factors underlying defective erythropoiesis and highlight current and emerging therapies, including molecular targets to overcome drug resistance.
Authors
Nilesh Rai, Omar Abdel-Wahab, Lingbo Zhang
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ISSN: 0021-9738 (print), 1558-8238 (online)