What goes up must come down: dynamics of type 1 interferon signaling across the lifespan

Abstract

Type 1 interferons (T1IFNs) are typically expressed in low concentrations under homeostatic conditions, but upon pathogenic insult or perturbation of the pathway, these critical immune signaling molecules can become either protectors from or drivers of pathology. While essential for initiating antiviral defense and modulating inflammation, dysregulation of T1IFN signaling can contribute to immunopathology, making it and its associated pathways prime targets for immune evasion and disruption by pathogens. This review focuses on the changes in T1IFN signaling across the lifespan, with particular emphasis on the role of the Stimulator of Interferon Genes (STING) pathway in autoimmune and infectious disease susceptibility, especially in the context of viral infections. Aging is associated with diminished T1IFN responsiveness, partially resulting from chronic stimulation of the STING pathway, which contributes to increased susceptibility and impaired viral clearance. Conversely, neonates and young children also show increased vulnerability to certain viral infections, but whether this is driven by T1IFN differences or another mechanism remains incompletely understood. Despite growing interest in T1IFN-based immunotherapies, pediatric and elderly populations remain underrepresented in clinical trials. Here, we advocate for a deeper molecular and systems understanding of how the interferon response evolves across the human lifespan, to inform age-tailored therapeutic approaches and more inclusive study designs, thereby improving outcomes in both the youngest and oldest patients.

Keywords: COVID-19; SARS-CoV-2; STING; age-related; interferon; pediatric; type 1 interferon; viral infection.

Figure 1

Type 1 interferon (T1IFN) signaling during viral infection with black arrows showing signal transduction within the cytosol from Pathogen Recognition Receptors (PRRs) and the Interferon Alpha Receptor (IFNAR) heterodimer complex to the transcription factors and response elements, the blue arrow showing the release and direct effects of T1IFNs and the green pathway showing the release and effects of Interferon Stimulated Genes (ISGs). During a viral infection and viral entry, viral components are detected through various PRRs in the cytosol and the endosome (A). Cytosolic sensing works through the Stimulator of Interferon Genes (STING) and Retinoic acid-Inducible Gene I (RIG-I) pathways, while endosomal sensing functions involve several Toll-Like Receptor (TLR) pathways. These signal through the endoplasmic reticulum to release Interferon Regulatory Factors (IRFs). Binding of IRFs to promoter regions induces the transcription of T1IFNs, such as IFNA and IFNB (B). These T1IFNs are then released into the extracellular space where they exert antiviral effects such as signaling infected cells to die, recruitment and differentiation of immune cells, RNA degradation, and control of inflammatory response (C). All T1IFNs signal through the same IFNAR heterodimer complex, initiating a Signal Transducer and Activator of Transcription (STAT) cascade, ultimately resulting in transcription of various Interferon ISGs through Interferon-Sensitive Response Elements (ISRE) and Gamma-Activated Sites (GAS) promoter regions (D). These ISGs are released into the extracellular space alongside the T1IFNs, further perpetuating the antiviral and inflammatory responses (E). Figures created in BioRender. Hartnell, L. (2025) https://BioRender.com/ua8nw9b.

Figure 2

(A) Type 1 interferon (T1IFN) signaling in early life is believed to be diminished resulting from immature and decreased numbers of immune cells. (B) T1IFN signaling increases after puberty, with hormones significantly affecting T1IFN signaling pathways. (C) The true immunological ‘peak’ of T1IFN is still unknown. (D) Lower baseline T1IFNs through chronic STING stimulation, combined with lower circulating T1IFN-producing cells results in decreased sensitivity and responsiveness in elderly individuals. Figures created in BioRender. Hartnell, L. (2025) https://BioRender.com/x7l3f99.