Links Between Immunity, Aging, and Neurodegeneration Explored
A crucial role in promoting chronic inflammation and age-related functional decline during aging is attributed to a molecular signaling pathway known as cGAS/STING. By blocking the STING protein, the researchers were able to suppress inflammatory responses in senescent cells and tissues, leading to improvements in tissue function ().
cGAS/STING is a molecular signaling pathway that detects the presence of DNA in cells. It involves two proteins, cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). When activated, cGAS/STING triggers an immune response to defend against viral and bacterial infections.
‘The detailed understanding of the interplay between neuroimmune communication that regulates microglia-mediated neurotoxicity also offers potential for advancing research into neurodegenerative disorders. #aging’
Previous work by Ablasser and her colleagues has linked cGAS/STING to a number of biological processes, including cellular senescence, a hallmark of aging. Based on this, the researchers investigated whether it might underlie maladapted immune responses during aging.
STING Protein Activation and Gene Activity Patterns in Microglia
The research found that activating the STING protein triggers specific patterns of gene activity in microglia, the brain's first-line-of-defense immune cells. These gene-activation patterns matched those arising in microglia in distinct neurodegenerative conditions, such as Alzheimer`s disease and aging."In search for a mechanism that would engage the cGAS-STING pathway in aging, we considered aberrant mitochondrial DNA species," says Ablasser. "Mitochondria, the organelles that are responsible for energy production are well-known for disturbed functioning in aging and disease. Indeed, in microglia from old, but not young mice, DNA from mitochondria accumulated in the cell cytoplasm, suggesting a possible mechanism by which the cGAS-STING pathway contributes to inflammation in the aging brain."
The researchers studied the effects of blocking the STING protein in aged mice. As expected by its central role in driving inflammation, inhibiting STING alleviated markers of inflammation both in the periphery and in the brain. More importantly, animals receiving STING inhibitors displayed significant enhancements in spatial and associative memory. STING blockade also affected physical function with improved muscle strength and endurance.
The study advances our understanding of aging-related inflammation and also offers potential strategies for slowing cognitive deterioration in age-associated neurodegenerative conditions.
Reference:
- cGAS-STING drives ageing-related inflammation and neurodegeneration - (https:www.nature.com/articles/s41586-023-06373-1)