Fight Aging!

Neurogenesis is assessed in the hippocampus in most studies, connected to the processes of memory. Neurogenesis is the production of new neurons from neural stem cells and their integration into existing neural circuits. The areas of the brain responsible for memory must change, but it is an open question as to how much neurogenesis is going on elsewhere, and particularly in the adult human brain, where studies are far more limited than is the case for mice.

Increased neurogenesis is thought to be generally beneficial to cognitive function at all ages, and it may be an important mechanism by which, for example, exercise improves memory and other capabilities. Beyond this, sizable increases in neurogenesis may be a path towards better maintenance of the aging brain, and recovery from injury, though this is more of an open question at the present time.

Thus approaches capable of increasing neurogenesis are of interest to those of us who would like to be less impacted by the processes of aging. As yet, doing better than exercise is challenging, given the classes of mechanism and approach that are most explored. On the one hand, exercise and the production of butyrate by the gut microbiome lead to upregulation of BDNF, which promotes neurogenesis. On the other hand, SSRIs as a class of drug are known to increase neurogenesis, though with side-effects that make them undesirable for general use. In today's research materials, researchers find a way to trigger a regulator of neural stem cell activity, which may prove to be the basis for new classes of therapy that more directly increase neurogenesis.

Oleic acid, a key to activating the brain's 'fountain of youth'

Years ago, scientists thought that the adult mammalian brain was not able to repair and regenerate. But research has shown that some brain regions have the capacity of generating new neurons, a process called neurogenesis. The hippocampus region of the adult mammalian brain has the ongoing capacity to form new neurons, to repair and regenerate itself, enabling learning and memory and mood regulation during the adult life.

'We knew that neurogenesis has a 'master regulator,' a protein within neural stem cells called TLX that is a major player in the birth of new neurons. We did not know what stimulated TLX to do that. Nobody knew how to activate TLX. We discovered that a common fatty acid called oleic acid binds to TLX and this increases cell proliferation and neurogenesis in the hippocampus of both young and old mice."

While oleic acid also is the major component in olive oil, however, this would not be an effective source of oleic acid because it would likely not reach the brain. It must be produced by the cells themselves. The finding that oleic acid regulates TLX activation has major therapeutic implications. "TLX has become a 'druggable' target, meaning that knowing how it is activated naturally in the brain helps us to develop drugs capable of entering the brain and stimulating neurogenesis."

Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis

Neural stem cells, the source of newborn neurons in the adult hippocampus, are intimately involved in learning and memory, mood, and stress response. Despite considerable progress in understanding the biology of neural stem cells and neurogenesis, regulating the neural stem cell population precisely has remained elusive because we have lacked the specific targets to stimulate their proliferation and neurogenesis. The orphan nuclear receptor TLX/NR2E1 governs neural stem cell and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is not well understood because its endogenous ligand is not known.

Here, we identify oleic acid as such a ligand. We first show that oleic acid is critical for neural stem cell survival. Next, we demonstrate that it binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell-cycle and neurogenesis genes, which in turn increases neural stem cell mitotic activity and drives hippocampal neurogenesis in mice. Interestingly, oleic acid-activated TLX strongly up-regulates cell cycle genes while only modestly up-regulating neurogenic genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation and drive the progeny toward neuronal lineage. Oleic acid thus serves as a metabolic regulator of TLX activity that can be used to selectively target neural stem cells, paving the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.