Fight Aging!

Researchers are making strides in uncovering the low-level details of how memory operates in mammalian brains, just as they are making strides in all areas of biology. Sometimes the process of discovery comes hand in hand with a demonstration of utility, as is the case here. Putting to one side the consequences of an Alzheimer's-like build up of amyloid deposits and its associated neural dysfunction, the research quoted below demonstrates that the rest of the decline in memory function due to old age in mice can be mostly reversed by increasing the levels of one particular protein. This is very interesting, as it suggests that the processes of memory are not greatly inhibited by most of the forms of cellular damage that causes aging, at least in mice, and that this portion of mental decline occurs due to one of the epigenetic responses to that damage.

We might well ask why this came to pass in the course of evolutionary adaptation, but any sort of theorizing on my part would be very speculative at this point, following the party line on antagonistic pleiotropy in the context of aging.

A Major Cause of Age-Related Memory Loss Identified

A team of Columbia University Medical Center (CUMC) researchers [has] found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible. The hippocampus, a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory. Studies have shown that Alzheimer's disease hampers memory by first acting on the entorhinal cortex (EC), a brain region that provides the major input pathways to the hippocampus. It was initially thought that age-related memory loss is an early manifestation of Alzheimer's, but mounting evidence suggests that it is a distinct process that affects the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the EC.

The researchers began by performing microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88, all of whom were free of brain disease. The team also analyzed cells from their EC, which served as controls since that brain structure is unaffected by aging. The analyses identified 17 candidate genes that might be related to aging in the DG. The most significant changes occurred in a gene called RbAp48, whose expression declined steadily with aging across the study subjects. To determine whether RbAp48 plays an active role in age-related memory loss, the researchers turned to mouse studies.

When the researchers genetically inhibited RbAp48 in the brains of healthy young mice, they found the same memory loss as in aged mice, as measured by novel object recognition and water maze memory tests. When RbAp48 inhibition was turned off, the mice's memory returned to normal. The researchers also did functional MRI (fMRI) studies of the mice with inhibited RbAp48 and found a selective effect in the DG, similar to that seen in fMRI studies of aged mice, monkeys, and humans. This effect of RbAp48 inhibition on the DG was accompanied by defects in molecular mechanisms similar to those found in aged mice. The fMRI profile and mechanistic defects of the mice with inhibited RbAp48 returned to normal when the inhibition was turned off.

In another experiment, the researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice. "We were astonished that not only did this improve the mice's performance on the memory tests, but their performance was comparable to that of young mice."

It seems unlikely that what is going on under the hood is simple, even as the result of a single gene change. Researchers still can't fully and comprehensively explain any of the forms of life extension achieved through single gene manipulations, and some of those have been known for more than fifteen years. Altered levels of a single protein can trigger all sorts of sweeping changes in metabolism. I predict that much of the next decade will pass before even a rough sketch of what is going on here is assembled. Fortunately, full understanding isn't required to demonstrate the potential for therapies - it just improves the odds of producing a feasible, useful medical technology.

Here's the paper for those who like to see the original sources:

Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48

To distinguish age-related memory loss more explicitly from Alzheimer's disease (AD), we have explored its molecular underpinning in the dentate gyrus (DG), a subregion of the hippocampal formation thought to be targeted by aging. We carried out a gene expression study in human postmortem tissue harvested from both DG and entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of AD. Using expression in the EC for normalization, we identified 17 genes that manifested reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation.

To test whether the RbAp48 decline could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. We next generated a transgenic mouse that expressed a dominant-negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG, and this corresponded to a regionally selective decrease in histone acetylation.

Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation. Together, these findings show that the DG is a hippocampal subregion targeted by aging, and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention.