Review
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
Breakthroughs in rare genetic disease research elucidate the relationships among cytosolic DNA sensing, genome instability, and autoimmune disease phenotypes. Cytosolic self-DNA is a potent trigger of innate immunity, activating the DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING). This pathway is negatively regulated by the DNA-degrading enzyme three-prime repair exonuclease 1 (TREX1); loss-of-function TREX1 variants lead to accumulation of cytosolic DNA, resulting in STING-mediated autoinflammation. Similarly, STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy, another disease characterized by multi-organ damage, disability, and premature death. The TREX1-cGAS-STING pathway has also been implicated in regulation of genome stability. Indeed, DNA damage lies at the heart of a separate TREX1-mediated disease, known as retinal vasculopathy with cerebral leukoencephalopathy, where the aberrant nuclear activity of mislocalized TREX1 damages genomic DNA, resulting in multi-organ degeneration syndrome with features of autoimmunity. Thus, monogenic autoimmune diseases and DNA damage syndromes sometimes overlap clinically, and the study of these diseases has created pathways for developing first-in-class small molecule therapeutics.
Authors
Debby J. Park, Kate M. Jones, Jessica B. Anderson, Amanda V. Finck, Jonathan J. Miner
Abstract
Identification of the genetic mutations underlying the ultrarare monogenic conditions STING-associated vasculopathy with onset in infancy (SAVI) and coatomer protein complex subunit alpha (COPA) syndrome revealed a role for the stimulator of interferon genes (STING) immune pathway in the pathogenesis of interstitial lung disease (ILD) in these conditions. STING-focused therapeutics could be a potential avenue for the treatment of SAVI and COPA syndrome in the future, yet the relevance of STING to more common types of ILD is not clear. Here, we provide an overview of SAVI and COPA syndrome, the nature of ILD in these conditions, and current evidence regarding STING activity in their pathogenesis. We discuss data from studies of a variety of other ILDs and model systems and explore the potential role for STING in more common forms of ILD.
Authors
Prasad Palani Velu, Gaofeng Zhu, Karen J. Mackenzie
Abstract
The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central mediator of cytosolic DNA–induced innate immune responses, driving the production of type I IFNs and pro-inflammatory cytokines. Beyond its canonical role in cytosolic DNA sensing, increasing attention has been directed toward the noncanonical functions of cGAS and STING, particularly within the nucleus. Recent studies implicate dysregulated cGAS-STING signaling in neurodegenerative diseases and brain aging, with a prominent contribution to glial activation–associated neuroinflammation, a hallmark of many neurological disorders. In this Review, we first summarize the molecular mechanisms underlying the canonical cGAS-STING pathway in DNA sensing and innate immune activation. We then discuss emerging noncanonical roles of cGAS in chromatin organization and RNA metabolism, drawing on insights from evolutionary conservation and protein interactome analyses. Finally, we outline the involvement of cGAS-STING signaling in diverse aspects of brain function, including glial state regulation, neuronal homeostasis, blood-brain barrier integrity, and peripheral immune surveillance, highlighting their contributions to neuroinflammation and neuropathology. We also summarize current pharmacological inhibitors targeting cGAS and STING and discuss their therapeutic potential for modulating cGAS-STING signaling to manage brain disorders.
Authors
Weixi Feng, Abulimiti Aikedan, Subhash C. Sinha, Li Gan
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
Abstract
Bone is a highly dynamic and purposefully organized structure that remodels constantly throughout adult life. Disordered bone remodeling, in which resorption of old bone by osteoclasts exceeds new bone formation by osteoblasts, results in bone loss, which, in turn, is associated with debilitating conditions, including osteoporosis and metastatic bone disease. The past decade has revealed vital new insights into the role of the central nervous system in skeletal regulation. These studies have led to a better understanding of physiologic circuitry, enabled us to revisit disease pathophysiology, and in doing so, prompted the creation of candidate therapeutics. The central neural control of bone is exerted through two arms — an amplitude-modulated (AM) neurohormonal arm that relies on changes in circulating levels of anterior and posterior pituitary hormones, which act on bone directly, and a frequency-modulated (FM) arm that arises from changes in the firing frequency of sympathetic, parasympathetic, and sensory nerves that innervate bone. Here, we review the medical consequences arising from the dysfunction of the AM and FM arms, as well as studies that have unmasked promising therapeutic targets.
Authors
Mone Zaidi, Se-Min Kim, Vitaly Ryu, Daria Lizneva, Terry F. Davies, Clifford J. Rosen, Tony Yuen, Andrea Giustina
No posts were found with this tag.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)