As someone who will not be seeing the age of 50 again, I find a good deal of hope in a study out this week from Eric Kandel and co-workers at Columbia. In Science Translational Medicine, they report results from a gene expression study in human brain samples. Looking at the dentate gyrus region of the hippocampus, long known to be crucial in memory formation and retrieval, they found several proteins to have differential expression in younger tissue samples versus older ones. Both sets were from otherwise healthy individuals - no Alzheimer's, for example.
RbAp48 (also known as RBBP4 and NURF55), a protein involved in histone deacetylation and chromatin remodeling, stood out in particular. It was markedly decreased in the samples from older patients, and the same pattern was seen for the homologous mouse protein. Going into mice as a model system, the paper shows that knocking down the protein in younger mice causes them to show memory problems similar to elderly ones (object recognition tests and the good old Morris water maze), while overexpressing it in the older animals brings their performance back to the younger levels. Overall, it's a pretty convincing piece of work.
It should set off a lot of study of the pathways the protein's involved in. My hope is that there's a small-molecule opportunity in there, but it's too early to say. Since it's involved with histone coding, it could well be that this protein has downstream effects on the expression of others that turn out to be crucial players (but whose absolute expression levels weren't changed enough to be picked up in the primary study). Trying to find out what RbAp48 is doing will keep everyone busy, as will the question of how (and/or why) it declines with age. Right now, I think the whole area is wide open.
It is good to hear, though, that age-related memory problems may not be inevitable, and may well be reversible. My own memory seems to be doing well - everyone who knows me well seems convinced that my brain is stuffed full of junk, which detritus gets dragged out into the sunlight with alarming frequency and speed. But, like anyone else, I do get stuck on odd bits of knowledge that I think I should be able to call up quickly, but can't. I wonder if I'm as quick as I was when I was on Jeopardy almost twenty years ago, for example?
(If you don't have access to the journal, here's the news writeup from Science, and here's Sharon Begley at Bloomberg).