ArticlemedRxiv : the preprint server for health sciences2025
Brain-rejuvenating factor TIMP2 is associated with brain health and neuroprotective lifestyle in aged subjects.
Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
16 authors.
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Abstract
Background: Tissue inhibitor of metalloproteinases 2 (TIMP2) has been shown to revitalize aspects of synaptic plasticity and hippocampus-dependent cognition in aged mice. We examined TIMP2's relevance in human brain aging and tested whether TIMP2 may be modifiable via known pro-plasticity behaviors in humans and mice. Methods: Plasma TIMP2 levels were quantified via SomaScan in three independent human cohorts, including two cross-sectional (UCSF: n=83; Stanford: n=31) and one with longitudinal measurement (ROSMAP: n=213). We examined associations of plasma TIMP2 with cognitive performance, brain volumes, and engagement in neuroprotective lifestyle behaviors, including objectively measured physical activity (UCSF) and a multi-domain lifestyle composite (ROSMAP). We used mouse models to directly test effects of environmental enrichment on (1) plasma TIMP2 levels and (2) hippocampal neurogenesis in wildtype versus TIMP2 knockout mice. Results: Higher plasma TIMP2 associated with better global cognition and larger brain volumes across human cohorts. Longitudinal decreases in plasma TIMP2 associated with steeper cognitive decline. Physical activity positively associated with plasma TIMP2 cross-sectionally, and longitudinal changes in multi-domain lifestyle factors positively associated with change in TIMP2 levels over time in humans. Mice exposed to an enriched environment for 3 weeks exhibited elevated plasma TIMP2 levels. While wildtype mice exposed to enrichment exhibited elevated adult hippocampal neurogenesis, this effect was lost in mice in which TIMP2 had been deleted. Conclusions: TIMP2 demonstrates clinical relevance for brain aging in humans and may represent a mechanism through which lifestyle behaviors confer neuroprotection. Further examination of TIMP2 as a potential therapeutic target for prevention of cognitive decline is warranted.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.