Ghrelin alleviates aging-related cognitive impairment by restoring microglial autophagy
Researchers identified ghrelin as a key metabolic factor that reduces microglial senescence and inflammation through the SHBG/JNK1/Beclin1 signaling axis.
Aging cell · Zhou L et al. · Paper published 29 Sep 2026
In human cohorts, aging and D-galactose-treated mice, and microglial cell cultures, researchers investigated metabolic drivers of aging-related cognitive impairment. Human cohort analyses identified ghrelin as the factor most strongly linked to cognitive impairment. Both older and chemically aged mice exhibited cognitive decline, microglial senescence, elevated inflammation, and higher baseline ghrelin levels. Ghrelin treatment improved cognitive function in these mice, attenuated microglial senescence, and suppressed inflammatory activity, though high doses caused desensitization of the GHSR receptor. In cell models, ghrelin downregulated cytoplasmic sex hormone-binding globulin (SHBG) and modulated autophagy markers by increasing Beclin1 and LC3 while decreasing p62. Overexpressing SHBG or inhibiting JNK1 blocked these autophagy-related and anti-senescent changes, whereas Beclin1 overexpression partially rescued the effects.
Why it matters
The findings link metabolic signaling directly to brain immune health during aging. Modulating microglial autophagy via ghrelin-associated pathways represents a potential avenue for treating age-related cognitive decline.
Caveats
Most therapeutic and mechanistic insights were demonstrated in mice and cultured cells rather than clinical trials. Additionally, high doses of ghrelin triggered GHSR receptor desensitization, highlighting a narrow therapeutic window.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
Ghrelin Alleviates Aging-Related Cognitive Impairment by Regulating Autophagy-Related Signaling via the SHBG/JNK1/Beclin1 Axis in Microglia
Zhou L, Cheng Y, Zhao W et al.
Aging cell · 29 Sep 2026 · Peer-reviewed
- Relevance
- Core geroscience
- News value
- Notable
- Evidence
- Animals
- Status
- Peer-reviewed
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