Microglial Aging Is Determined by Their Environment

Old cells behaved younger in young brains.

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September 9, 2025

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Key Findings from Calico's Study

• Microglia receive signals from their environment causing them to behave like older or younger cells.
• These signals originate from specific immune cells.
• It is possible to create microglia that do not respond to these signals.

A new preprint study from Calico has revealed that the local brain environment influences microglial aging. After being transplanted into old brains, young cells adopted aged characteristics; however, their susceptibility to these signals could be mitigated [1].

Microglia Grow Old and Irritable

Brain aging represents a significant challenge in the field of longevity, acting as one of the strongest limiting factors. Despite advancements in rejuvenating the body through organ replacement, the brain contains our memories and personality, thereby requiring strategies for rejuvenation vital for meaningful lifespan extension.

Research indicates that glial cells, including microglia, age faster than neurons. Aged microglia, a kind of specialized immune cell in the brain, tend to adopt a more aggressive and pro-inflammatory phenotype, which is believed to drive neurodegeneration [2].

Intrinsic vs. Extrinsic Aging Signals

The study focused on understanding whether microglial aging results from a predetermined internal clock (cell-intrinsic) or if signals from a deteriorating environment (cell-extrinsic) accelerate aging. Researchers sought to differentiate between these influences by swapping microglia with donor myeloid cells from young and old brains.

Young Cells for Aged Brains

The research team developed a method to replace native microglia in mice with new myeloid cells derived from the bone marrow of young female donor mice. These cells were genetically modified to express an enhanced version of green fluorescent protein (EGFP) for tracking purposes and Cas9 for potential gene editing.

To create space for the donor stem cells, the bone marrow niche of the aged recipient mice was depleted. Simultaneously, a drug that inhibits CSF1R, a protein vital for microglial survival, was used to eliminate old microglia. This allowed the young, donor-derived myeloid cells to enter the brain and develop into microglia-like cells.

Upon investigation, it was revealed that the environment had a profound influence. Young cells transplanted into aging brains quickly began expressing characteristics of aged microglia, especially in the cerebellum, and inherited a “Cerebellar Accelerated Aging Signature” (CAAS)—a molecular fingerprint involving 403 genes.

“What did the old brain tell the young cells? To get old, fast,” said Oliver Hahn, Ph.D., principal investigator at Calico and senior author of the study. “These young ‘reconstituted cells’ adopted aging signatures typical of old microglia, particularly pronounced in the cerebellum.”

Aging Signals Blocked

The analysis of gene expression profiles highlighted a prominent pro-inflammatory interferon response signature in aged microglia. Researchers tested if dampening this response could reverse microglial aging by knocking out the Stat1 gene, a crucial regulator of interferon signaling.

Using the Cas9 platform, the team generated Stat1-deficient young cells and repeated the transplantation protocol. Remarkably, these modified young cells showed resistance to environmental aging signals and did not activate the CAAS signature.

Upon investigation, it was determined that the natural killer (NK) cells, not T cells, triggered the aging signals through the interferon pathway. Depleting NK cells in aged mice significantly reduced the age-related response in microglia.

“The local brain environment drives microglia aging, with NK cells acting as an unexpected upstream trigger,” Hahn noted. “Interestingly, Stat1 knockout also shielded young cells from pro-aging cues, challenging simplistic ideas around ‘rejuvenation-by-replacement’.”

Future Implications

This study opens new avenues for understanding microglial aging and suggests that targeting environmental signals could lead to innovative therapies for combating age-related neuroinflammation and neurodegeneration. The researchers aim to use their scalable eHSC system for further exploration of pro-aging signaling pathways.

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Literature Cited

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About the Author

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span politics, science, and philosophy. With a background in economics and international relations, he is deeply engaged in the social dimensions of longevity and life extension.

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