“Weak memory is normal as we get older.”We’ve all heard this phrase, often used as self-comfort. In the past, scientists typically attributed age-related memory loss to neuronal apoptosis and accumulation of β-amyloid (Aβ)—much like the implication of the term “neurodegenerative disease,” a gradual fading of memory over time.
However, a recent study published in Nature Aging by a team of scientists from The Third Affiliated Hospital of Sun Yat-sen University [1] reveals a different reality: Unlike the steady passage of time, aging is a self-reinforcing process. In other words, brain aging is more like a cascading collapse—and the first domino to fall is a special type of immune
1. BAM: The First Domino to Collapse
BAMs are macrophages residing in perivascular spaces and meningeal margins. This unique location allows them to interact with both cerebrospinal fluid (CSF) and exogenous stimuli. Their daily functions include mediating CSF flow and clearing metabolic waste in the brain—including the well-known Aβ.
By analyzing the brains of mice at different ages, scientists found that BAMs began to show cell cycle arrest and senescence-related phenotypes as early as 6 months of age (far earlier than other brain cells).
Figure Note: Scientists used multiple cellular senescence markers to characterize BAMs in the brain tissue of 3-, 6-, 12-, and 18-month-old mice. Fluorescence indicating cellular senescence became apparent at 6 months, and senescence indicators showed significant differences from the 3-month-old group at 6, 12, and 18 months (all P<0.001 unless otherwise stated).
Naturally, BAMs’ ability to clear Aβ declines accordingly, leading to observable Aβ accumulation in immunostaining. As we already know, Aβ is harmful—it not only accelerates BAM senescence but also promotes BAMs to release migrasomes: tiny vesicles once thought to be “useless waste” left behind as BAMs move, but in reality, far more damaging.
2. Migrasomes: “Aging Parcels” Set to Deliver
When cells move, they shed vesicles (0.5–3 μm in diameter) from their trailing edges—these are migrasomes. Their role in aging was previously unclear, so scientists conducted a series of experiments to investigate.
First, using fluorescent labeling, they detected migrasomes in BAMs and found that:
- Migrasome numbers increased significantly in 6-month-old mice (roughly equivalent to 30 years old in humans);
- By 18 months of age (roughly 60 years old in humans, as mouse aging is not perfectly linear to humans), migrasome levels were three times higher than in young mice.
Figure Note: Quantification of migrasomes in brain cells of 3-, 6-, 12-, and 18-month-old mice (females and males). Migrasome counts rose steadily with age (P<0.001 for key comparisons).
To account for differences between mice and humans, scientists also collected samples from human participants of different ages—and similarly observed that migrasome numbers increase with age.
Beyond aging itself, Aβ accumulated in BAMs also contributes. To verify Aβ’s impact, scientists treated mouse macrophages with Aβ, which indeed caused cell cycle arrest and telomere shortening. Fluorescent labeling further confirmed that Aβ significantly induces migrasome production.
Figure Note: Top panel: Control group (PBS-treated); Bottom panel: Aβ40-treated group. Migrasomes are labeled with green fluorescence. A significant increase in migrasomes was observed as early as 1 day after Aβ treatment (Scale bar = 10 μm).
A critical final step to confirm the “domino effect” was verifying migrasomes’ harmful impact:Scientists transferred migrasomes from 3-month-old (young) and 18-month-old (aged) mice into the brains of 3-month-old young mice. They first observed that the transferred migrasomes dispersed in the recipient brains (confirming the effect was indeed caused by migrasomes). Subsequently, they observed cell cycle arrest in the recipient mice’s brain cells—and in behavioral tests, the young mice showed significant cognitive decline.
Figure Note: Morris water maze test results for female (top) and male (bottom) 3-month-old recipient mice. Mice that received migrasomes from 18-month-old mice (red data points) showed markedly impaired memory compared to controls (P<0.001).
This confirms the complete “domino path”: Aging → BAM senescence → Aβ accumulation → migrasome release → accelerated aging.
3. The “Transaction” Between AIM and Microglia
Wait—we haven’t answered the most important question: What exactly in migrasomes causes aging?
Migrasomes are like “parcel boxes” left by BAMs; we need to open them to find the key “cargo.”
Scientists focused on Apoptosis Inhibitor of Macrophages (AIM)—the main functional cargo in migrasomes [2]. Experiments showed that:
- AIM expression increases sharply with mouse age;
- AIM directly induces senescence.
Figure Note: AIM expression in migrasomes from 3-month-old vs. 18-month-old mice. AIM levels in aged mice were approximately three times higher than in young mice (P=0.009).
Next, scientists identified the “recipient” of AIM via flow cytometry: microglia (the most abundant recipient). When different cell types were stimulated with AIM, only microglia showed a significant increase in senescence markers.
In other words, while other brain cells may also take up small amounts of AIM, their uptake and subsequent damage are far less than in microglia.
Figure Note: Flow cytometry analysis of migrasome recipient cells. Microglia accounted for the highest proportion of AIM uptake (P=0.023 vs. neurons).
To rule out other possibilities (e.g., “do microglia just ‘like receiving parcels,’ with senescence caused by other cargo?”), scientists conducted a control experiment: They removed AIM from aged migrasomes. Results showed that only aged migrasomes containing AIM induced significant senescence in microglia—senescent phenotypes dropped significantly after AIM removal.
4. “Aging Parcels” Intercepted
If migrasomes are “parcels,” they can be intercepted.
Previous studies have shown that Tetraspanin 4 (TSPAN4) is a key protein for migrasome assembly [3]. Thus, scientists designed liposome-encapsulated TSPAN4-targeting siRNA: This “blocks” migrasome assembly by depleting a critical component, leaving batches of AIM-containing “parcels” stuck in BAMs—so microglia never receive them, and the domino effect is halted.
When this siRNA was injected directly into the CSF of aged mice:
- Migrasome production dropped sharply;
- Microglial senescence was inhibited;
- In behavioral tests (e.g., Morris water maze), aged mice showed significant recovery in memory function.
Figure Note: Morris water maze test results for female (top) and male (bottom) 18-month-old mice. Mice treated with TSPAN4 siRNA (blue data points) had significantly better memory than controls (empty liposomes or non-targeting siRNA; P<0.001 for key comparisons).
Looking beyond microglia, scientists also tested other neural functions in aged mice: They observed improved microglial activity, enhanced white matter integrity, and increased neuronal activity in the hippocampus.
In short, intercepting these “aging parcels”—removing one domino—improved overall brain neural function, restoring the brain to a more youthful state.
5. More Than Just One Domino
As we noted earlier, aging is self-reinforcing and cascade-amplifying—which is hardly good news.
But this study offers a new opportunity: Anti-aging doesn’t have to be a “single-front battle.” We can intervene earlier with more precise targets—by removing just one domino.
In ancient myths, Nuwa mended the sky with five-colored stones; today, who’s to say we can’t fill the “cognitive gaps” of aging by blocking these tiny “aging parcels”?
Author & Funding Information
- Article Title: Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia
- Corresponding Authors: Prof. Zhengqi Lu (Chief Physician, Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University), Dr. Wei Cai (Associate Researcher)
- First Authors: Mengyan Hu, Xinmei Kang, Zhiruo Liu
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Funding Sources:
National Natural Science Foundation of China (82271348, 82471338, 82471335, 82171307, 81971110);Guangdong Basic and Applied Basic Research Foundation (2024B1515020021);China Postdoctoral Science Foundation (2023M744023);Guangdong Science and Technology Program (2023B1212060018);Guangzhou Key Research Program on Brain Science (202206060001);Guangzhou Science and Technology Program Key Project (202007030010);Guangzhou Science and Technology Program (202201020588);Guangzhou University-Hospital Joint Funding for Key Laboratory Construction (202102010009).
References
[1] Hu, M., Kang, X., Liu, Z., et al. (2025). Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia. Nature Aging. https://doi.org/10.1038/s43587-025-00956-5[2] Hu, M., Li, T., Ma, X., et al. (2023). Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-39693-x[3] Huang, Y., Zucker, B., Zhang, S., et al. (2019). Migrasome formation is mediated by assembly of micron-scale tetraspanin macrodomains. Nature Cell Biology, 21(8), 991–1002. https://doi.org/10.1038/s41556-019-0367-5