Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging

Area of Science:

• Cellular Biology
• Aging Research
• Immunology

Background:

• Macroautophagy, a key cellular process, declines with age, representing a hallmark of aging.
• The age-related changes in mitophagy, the selective removal of mitochondria via autophagy, remain largely uncharacterized.
• Understanding mitophagy's role in aging is crucial for developing interventions to promote healthy aging.

Purpose of the Study:

• To investigate whether mitophagy declines with age.
• To explore the relationship between aging, mitophagy, and inflammatory pathways.
• To evaluate the therapeutic potential of mitophagy induction in mitigating age-associated decline.

Main Methods:

• Utilized the mito-QC reporter mouse model to assess mitophagy across various organs in young and old mice.
• Performed transcriptomic analysis on retinal tissues from old mice to identify molecular changes.
• Examined primary human fibroblasts from elderly donors to validate findings in a human context.
• Administered urolithin A to old mice to pharmacologically induce mitophagy and assess its effects.

Main Results:

• Contrary to expectations, mitophagy was found to be either increased or unchanged in old versus young mice.
• Old mice exhibited an upregulation of the type I interferon response in the retina, linked to increased cytosolic mitochondrial DNA (mtDNA) and cGAS/STING pathway activation.
• These age-associated inflammatory alterations were successfully replicated in human fibroblasts from elderly individuals.
• Pharmacological induction of mitophagy with urolithin A in old mice led to the attenuation of cGAS/STING activation and improvement in neurological function.

Conclusions:

• Mitophagy does not appear to decrease with age; instead, age-associated mitochondrial dysfunction may trigger compensatory mitophagy.
• The study identifies a link between aging, increased cytosolic mtDNA, cGAS/STING pathway activation, and type I interferon response.
• Mitophagy induction, exemplified by urolithin A treatment, presents a promising therapeutic strategy for reducing age-associated inflammation and enhancing healthspan.