TIMP2 dosage and evidence

What is TIMP2?

How does TIMP2 work?

In mice, TIMP2 given through the body gets into the brain. It helps connections in the memory centre adapt and improves the kind of memory that centre handles. It is also needed for the memory benefit of human cord plasma. Blocking it with an antibody stops brain connections from strengthening in slices of tissue. TIMP2 made by nerve cells controls how complex the scaffolding around them is. In people, the known biology is the plain version. TIMP2 blocks enzymes that break down that scaffolding. TIMP-2 and IGFBP7 together push cells to pause their growth cycle, which is why they work as kidney injury markers. Nothing links the mouse brain effect to an outcome in a person.

What have studies in people found about TIMP2?

Nobody has been given TIMP2 as a treatment. There is a large body of measurement data in people: a urine test with TIMP-2 and IGFBP7 warns of kidney injury, studied in more than a thousand seriously ill adults. That is human TIMP2 data about kidneys, not about ageing or memory.

• Human marker data (Critical Care 2013): 522 seriously ill adults were used to find the marker, across sepsis, shock, major surgery and trauma, with over 300 markers screened. 728 more seriously ill adults were used to confirm it, and 14 percent of them went on to get moderate to severe kidney injury. The urine test combining TIMP-2 and IGFBP7 did well at picking out who would, and it sharpened the risk estimate even on top of a nine-item clinical score.
• No study of any kind has given TIMP2 to a person. No early trial, no safety data, no information on how the body handles it, and no registered trial of it as a treatment.
• The human material behind the mouse experiments is human umbilical cord plasma, which is a human product. But the experiments themselves are in old mice.

What this does not tell you: The kidney marker work tells you that TIMP-2 can be measured reliably in people and that it rises in one specific illness. It tells you nothing about whether giving TIMP2 to an older person would do anything for memory, and nothing about whether it would be safe. Giving a brake on scaffolding-breaking enzymes through the whole body raises obvious questions, because those enzymes are involved in rebuilding tissue, healing wounds and how tumours behave. None of those questions has been asked in a person.

The state of the research

The evidence, in charts

The studies we cite

• Study in people2013
  Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

  This is the biggest body of human TIMP-2 data, and none of it is about ageing. Two observational studies followed critically ill adults: 522 people in the first, with over 300 markers checked, and 728 in a second group to confirm the result. A urine test combining TIMP-2 with another marker spotted serious kidney injury within 12 hours better than any marker tried before. Nobody was given TIMP-2. This is a test that reads the body, not a treatment.

  Human, and the largest body of TIMP-2 data in people, though it is not about ageing. Two multicentre observational studies in critically ill adults: 522 in discovery across sepsis, shock, major surgery and trauma cohorts with over 300 markers examined, and 728 in the Sapphire validation cohort. Urinary TIMP-2 combined with IGFBP7 gave an area under the curve of 0.80 for moderate to severe acute kidney injury within 12 hours, significantly better than all previously described markers (p < 0.002), none of which exceeded 0.72.

  PMID 23388612 Critical Care
• Animal study2017
  Human umbilical cord plasma proteins revitalize hippocampal function in aged mice

  In mice, plasma from human umbilical cords improved how the memory centre of the brain worked and how old mice did on memory tests. The protein doing the work was TIMP2, found in high amounts in cord plasma, in young mouse plasma and in young mouse brains. Given through the body, it reached the brain, helped connections adapt and improved memory in old mice. Taking TIMP2 out of the cord plasma removed the benefit. Funded by the US National Institutes of Health with other support.

  Mouse. Human umbilical cord plasma improved hippocampal function and cognition in aged mice. TIMP2, enriched in cord plasma, young mouse plasma and young mouse hippocampi, appeared in the brain after systemic administration and increased synaptic plasticity and hippocampal-dependent cognition in aged mice. Depleting TIMP2 removed the benefit of cord plasma. NIH funded with non-US government and non-PHS support.

  PMID 28424512 Nature
• Animal study2023
  Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity

  In mice, TIMP2 made by nerve cells themselves controls how the memory centre adapts and how complex the scaffolding around those cells is. That takes the whole-body finding down to one cell type. Funded by the US National Institutes of Health.

  Mouse. Neuronal TIMP2 regulates hippocampus-dependent plasticity and the complexity of the extracellular matrix, extending the systemic finding to a cell-type-specific mechanism. NIH funded.

  PMID 37914840 Molecular Psychiatry
• Animal study2011
  The ageing systemic milieu negatively regulates neurogenesis and cognitive function

  In mice, joining a young and an old animal's blood supply showed that something carried in blood controls the growth of new brain cells, and that it depends on age. That is the framework the cord plasma and TIMP2 work sits inside.

  Mouse. The parabiosis work establishing that blood-borne factors regulate adult neurogenesis in an age-dependent way, which is the framework the cord plasma and TIMP2 work sits inside.

  PMID 21886162 Nature