Studies based on the transfer of blood or plasma from young mice to old mice are resulting in a number of interesting discoveries regarding important differences in the cell signaling environment that occur with age. Whether it is possible to exploit this knowledge to produce significant gains in human health remains an open question. Early tests of plasma transfer did not produce compelling results, while efforts focused on specific proteins have yet to reach the point of clinical trials. The research noted here is illustrated of many lines of inquiry presently underway, in which a novel signal molecule is identified and shown to produce benefits in old mice. It is unusual in that it turned up a molecule that doesn’t in fact change with age, but is related to the effects of exercise on brain health.

Researchers collected plasma from either 6- or 18-month-old mice that were allowed to run on a wheel, and injected that into 18-month-old sedentary mice eight times over three weeks. The shots upped BDNF in the brain by a quarter, neurogenesis by half, and also improved the old mice’s performance in the radial arm water maze and contextual fear conditioning tests.

To find the factors responsible, the authors analyzed the plasma of exercising mice by mass spectrometry. They identified 12 proteins that were consistently elevated by exercise in both age groups. They were mostly metabolic proteins made by the liver. Among the dozen, Gpld1 and serum paraoxonase 1 stood out as key. Each is involved in numerous metabolic processes, such as cholesterol efflux, hormone response, and processing ammonium, ethanolamine, and organic hydroxy compounds.

Overexpressing serum paraoxonase 1 in old mice did them no good. In contrast, overexpression of Gpld1 elevated the mice’s hippocampal BDNF by 40 percent and nearly tripled their neurogenesis. One to two months later, the rodents did better on the radial-arm water maze, Y maze, and object-recognition tests. This was a surprise, since Gpld1 had not been linked previously to aging or cognition. In fact, its expression does not change with age in mice, the authors found. It goes up in the liver, but not other organs, after exercise. Its expression does not rise in the hippocampus after exercise.

How, then, might Gpld1 help the brain? Using a tagged construct, the authors found that very little of the enzyme gets past the blood-brain barrier, suggesting that it somehow exerts its effects from outside. How Gpld1 does this is still a mystery, but it may act by dampening peripheral inflammation, and that that may influence neuroinflammation.