DESCRIPTION (provided by applicant): Loss of brain function is arguably the most dreaded consequence of getting old. We propose to test the hypothesis that restoration of youthful levels of mechano growth factor (MGF) will arrest the decline in adult neurogenesis that is linked to loss of brain function in old individuals. We will take advantage of an inducible gene expression system that utilizes control elements from the lac operon of E. coli to induce or repress transgene expression in the mouse. We will ask two questions: 1) if we induce transgenic MGF expression before endogenous MGF levels have started to decline in the mouse, can we prevent neuronal attrition in areas supplied by adult neurogenesis? And, 2) if we induce MGF when neurogenesis is already moderately or severely impaired, can we arrest neuronal attrition so that no further damage takes place or even repair the damage done up to that point? Mechano growth factor (MGF) is a non-hormonal form of insulin-like growth factor-1 (IGF-1), one of the most important postnatal hormones controlling growth in mammals. Like IGF-1, which peaks in adolescence when growth peaks and declines to low levels in old individuals, MGF is expressed in juvenile tissue at a much higher level than in tissue from old animals. MGF was discovered in adult muscle stem cells as a factor that stimulates proliferation after muscle stretch, stress, or damage. We have discovered that mechano growth factor is also expressed in adult neural stem cells (NSCs), where we think it might play a similar role. We propose that MGF is a critical juvenile protective factor that maintains brain function throughout life by stimulating the production of new neurons to replace those that have worn-out, become damaged, or died. The link between MGF, which is a non-secreted form of IGF-1, and the ability of stem cells to proliferate sheds new light on how the insulin/IGF system might regulate aging and longevity. Previous studies have shown very clearly that changes in the level of the insulin/IGF receptor and/or the activity of its associated signal transduction cascade can shorten or lengthen lifespan in a number of experimental animal species. Because MGF is not a hormone, but an isoform of IGF-1 that remains in the cell in which it is synthesized, it can have direct effects on cellular events that are independent of insulin/IGF signaling. In stem cells, the effect of insulin/IGF system on proliferation could be a combination of MGF intracellular activities and the activities of the signaling pathway. This could be one way the stem cell theory of aging and the known effects of the insulin/IGF-1 system on lifespan intersect. Loss of brain function is arguably the most dreaded consequence of getting old. We propose to test the hypothesis that restoration of youthful levels of mechano growth factor (MGF), a non-hormonal form of insulin-like growth factor (IGF)-1, will arrest the decline in adult neurogenesis that is linked to loss of brain function in old individuals. We will test this hypothesis in vivo, taking advantage of an inducible expression system our lab has developed that will allow us to flip the expression of MGF on and off at will.
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