An Immune Pathway Drives Aging-Related Neurodegeneration and Cognitive Impairment
Post by Soumilee Chaudhuri
The takeaway
Chronic inflammation, a hallmark of underlying immune processes, is implicated in the aging process. A specific immune signaling pathway called cGAS-STING that detects the presence of DNA in cells, plays a critical role in driving chronic inflammation and functional decline during aging.
What's the science?
Natural aging is characterized by decreased organismal fitness, increased susceptibility to various diseases, and the compromise of multiple homeostatic mechanisms that interplay to balance human health. Chronic inflammation is a widely recognized factor contributing to aging and subsequent brain changes. Previous research has shown that the cyclic GMP–AMP synthase (cGAS) stimulator of interferon gene (STING) signaling pathway, or the cGAS-STING pathway, is a hallmark of aging. However, there is unclear evidence as to whether this pathway directly contributes to cellular senescence (i.e., irreversible cell cycle arrest) and age-related inflammation and dysfunction. The cGAS-STING pathway is a critical component of the innate immune system (i.e., the first immunological defense mechanism of the body) that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence. This week in Nature, Dr. Gulen and colleagues investigate the cGAS-STING signaling pathway and show that suppression of STING reduces aging-related inflammation and improves function in multiple tissues.
How did they do it?
The researchers used a series of robust molecular biology, biochemistry, and transcriptomics approaches in preclinical models of aged mice to uncover the direct impact of the cGAS-STING pathway on aging and neurodegeneration. Aged mice used in this study were either designated into the control group (no genetic changes in mice) or the experimental group (had a deletion of the STING protein). To test the effect of STING inhibition, mice underwent the Morris Water Maze test, fear conditioning tests, grip strength tests, and others to understand the change in spatial & associative memory and physical strength conferred by STING inhibition. Immunohistochemistry of mice tissue and obtained human tissues were used to visualize the microglial cellular patterns through RNA extraction and consequent bulk and single-nuclei RNA sequencing. The authors also used primary cell culture and intracellular DNA imaging to understand the effect of damaged mitochondrial DNA in eliciting inflammation-driven pathways in aging and neurodegeneration.
What did they find?
The authors showed that in naturally aged mice, cGAS-STING signaling contributes to a robust Type I Interferon (Type I IFN) response in brain cells and facilitates neuronal loss and cognitive impairment. They also found that beyond the cGAS and Type I IFN programs, there is a microglial gene expression program that might, synergistically or additively, contribute to similar neurodegeneration and could be a shared feature in many neurodegenerative diseases. This was important in highlighting the critical role of microglial-cGAS-STING signaling in mediating neurodegeneration. Furthermore, it was discovered that Tumor Necrosis Factor (TNF), a key neurotoxic factor, controlled the response of microglial cGAS-STING signaling and impacted other brain cells such as oligodendrocytes and astrocytes. Lastly, the authors blocked the STING protein in aged mice and were able to suppress inflammatory responses in senescent cells and tissues, leading to improvements in tissue function in the periphery as well as the brain. Animals receiving STING inhibitors displayed significant enhancements in spatial and associative memory and affected physical function with improved muscle strength and endurance.
What's the impact?
This study is the first to establish cGAS-STING as a significant driver of aging-related inflammation, neuron loss, and neurodegeneration in microglial communities in the brain. Further, this pathway facilitates a neuroimmune crosstalk mechanism in astrocytes and oligodendrocytes that could mediate senescence and neurodegeneration in the brain. This research opens avenues for further clinical research and therapeutic characterization of cognitive decline in neurodegenerative disorders like Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), or Frontotemporal dementia (FTD).