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TIMP2: The Key to Revitalizing the Aging Brain?

Review of “Human umbilical cord plasma proteins revitalize hippocampal function in aged mice” from Nature by Stuart P. Atkinson

Recent studies have suggested that exposure to factors contained within “young” blood plasma can reverse age-related decline in the central nervous system in animal models [1-3]. To evaluate the potency of human blood plasma, researchers from the laboratory of Tony Wyss-Coray (Stanford University School of Medicine, California, USA) have assessed the response of the aging mouse hippocampus to plasma isolated from an early developmental source: human cord blood. 

Their new study, published in Nature, suggests that Tissue inhibitor of metalloproteinases 2 (TIMP2) present in cord blood plasma can increase synaptic plasticity and boost hippocampal-dependent cognition in what may represent an exciting step towards the successful treatment of age-related neuronal dysfunction in human patients [4].

Initial assessment assessed the reaction of naturally aged mice to blood plasma from the umbilical cord, young adult, and elderly human donors. Only treatment with cord blood plasma led to the reversal of hippocampal dysfunction observed upon normal aging including improved signs of long-term potentiation (LTP - a persistent strengthening of synapses) and the activation of memory.

But what factor mediated these responses? The answer came from comparisons of plasma proteins of young and old blood samples from human and mouse and systemic testing of candidate recombinant proteins in aged mice. From this screening, the authors concentrated on the TIMP2, finding high levels in young donor blood plasma and an age-related decline in TIMP2 levels both in the plasma and in some regions of the hippocampus. Systemic injection and shuttling of TIMP2 from the blood into the brain mediated increased synaptic plasticity in the normally functioning hippocampus and induced significant improvements in behavior, LTP, and memory in aged mice.

While TIMP2 appears to be the key to revitalizing the aging brain, the authors note there is still much to learn. New research targets for the group include ascertaining the cellular targets of TIMP2 and discovering just how they affect the activity of synapses.

Keep your brains (both young and old!) in gear and up to date with all the new research into brain rejuvenation at the Stem Cells Portal.


  1. Katsimpardi L, Litterman NK, Schein PA, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014;344:630-634.
  2. Villeda SA, Luo J, Mosher KI, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011;477:90-94.
  3. Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014;20:659-663.
  4. Castellano JM, Mosher KI, Abbey RJ, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 2017;544:488-492.