Here, researchers demonstrate restoration of lost memory function in old rats though increased levels of FKBP1b in the hippocampus. This is a very intriguing paper, firstly for the size of the effect, and secondly because it touches on the question of the degree to which dysfunction in the aging brain is damage versus inappropriate cellular reactions to damage. Inappropriate reactions can be overridden, at least for a time. Ever-increasing damage always wins in the end, however, which is why damage repair after the SENS model should be more efficient and cost-effective as an approach. Further, repairing damage doesn't require researchers to learn how to safely manipulate a very complex disease state, or even to learn exactly how the damage produces that disease state; it is a reversion to a known good state. Given this, it is either a tragedy or a hidden benefit that sometimes overriding an inappropriate reaction looks good enough to justify the expenditure of serious effort on development of a therapy. Which of those two options is the case is really only possible to determine in hindsight.
Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca2+ release, reverses aging-induced memory impairment and neuronal Ca2+ dysregulation. Here, we test the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13-months-of-age (long-term) or 19-months-of-age (short-term) and tested memory performance in the Morris water maze at 21-months-of-age. Aged rats treated short- or long-term with FKBP1b substantially outperformed age-matched vector controls and performed similarly to each other and young controls.
Transcriptional profiling in the same animals identified 2342 genes whose hippocampal expression was up-/down-regulated in aged controls vs. young controls (the aging effect). Of these aging-dependent genes, 876 (37%) also showed altered expression in aged FKBP1b-treated rats compared to aged controls, with FKBP1b restoring expression of essentially all such genes (872/876, 99.5%) in the direction opposite the aging effect and closer to levels in young controls. This inverse relationship between the aging and FKBP1b effects suggests that the aging effects arise from FKBP1b deficiency.
Functional category analysis revealed that genes downregulated with aging and restored by FKBP1b associated predominantly with diverse brain structure categories, including cytoskeleton, membrane channels, and extracellular region. Conversely, genes upregulated with aging but not restored by FKBP1b associated primarily with glial-neuroinflammatory, ribosomal and lysosomal categories. Immunohistochemistry confirmed aging-induced rarefaction, and FKBP1b-mediated restoration, of neuronal microtubular structure. Thus, a previously-unrecognized genomic network modulating diverse brain structural processes is dysregulated by aging and restored by FKBP1b overexpression.