Fight Aging!

The research company Prana Biotechnology has been touting the results of a recent study in which one of their drug candidates demonstrated a meaningful impact on cognitive decline in old mice:

Prana's PBT2 Reverses Memory Loss in Normal Aging (PDF)

Typically mice live for 24 to 30 months, developing progressive cognitive impairment from 16 to 18 months. Age related cognitive decline is associated with measurable structural and biochemical changes in the brain, which were significantly improved by PBT2. In the study 22 month old mice were treated with PBT2 for a total of 12 days. PBT2 restored learning and memory. The old mice treated with PBT2 performed learning and memory tasks to the same level exhibited by young mice and significantly better than untreated old mice. PBT2 Increases markers of neurogenesis and neuron number [and] increases numbers of synapses in the hippocampus.

So what is going on here under the hood? Prana researchers focus on the biochemistry of interactions between metals and proteins, in particular the role of what are known as metal chaperones, and they theorize that disruption of the normal adult state of these interactions is a significant contribution to age-related neurodegeneration. An open access position paper from last year outlines this viewpoint with a particular focus on Alzheimer's disease (AD):

Metal Chaperones: A Holistic Approach to the Treatment of Alzheimer's Disease

Metal chaperones (or metallochaperones) are compounds that function to shuttle metal ions to specific intracellular target proteins. This facilitation of metal transport is distinct from metal chelators or buffers, which function to exclude or deplete metals from discrete cellular compartments to thereby limit biological interactions of key metal ions. Cumulatively, however, these processes serve to maintain tight regulatory control over cellular metal ion homeostasis such that the intracellular concentration of freely available metal ions (such as copper and zinc) is close to zero.

Such a high level of control at many cellular "levels" is essential in limiting potentially deleterious interactions of redox active transition metal ions, which are implicated in the pathogenesis of a number of disorders including AD. The involvement of metal ions in disease extends the breadth from being involved in creating an adverse cellular milieu (which among other things, may promote cell death through the activation of particular pathways that lead to degeneration) through to direct involvement in the generation and toxicity of the principle toxic moiety in diseases such as AD.

Metal chaperones (which have also variously been referred to as "ionophores" and "metal-protein attenuating compounds") may represent the "sweet spot" of metal-targeted therapeutics for AD because they foster the maintenance and/or restoration of metal ion homeostasis which then impacts a raft of "healthy" and "pathological" cellular pathways that ultimately promotes "normal" function. Such context-dependent modulation of metal levels may prove critical for long-term therapeutic strategies that target metal ions.

The recent press and mouse study is accompanied by an open access paper. By the sound of it the mechanism of action here remains to be pinned down, but the outcomes are good enough to move this forward in the development process. So this compound may in the end turn out to work via means that have little to do with metals. It may or may not be in any way reducing levels of the fundamental cellular and molecular damage that cause aging, either directly or indirectly, and it may or may not be minimizing harmful responses to that damage. We shall see - only further research can determine the answers.

A Novel Approach To Rapidly Prevent Age-Related Cognitive Decline

The loss of cognitive function is a pervasive and often debilitating feature of the ageing process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis.

There was a breadth of biological effects within the brain following PBT2 treatment in the aged mice. While it is not possible to discern which of these was the principal driver of the cognitive benefit observed, it is likely to have resulted from a PBT2-mediated improvement in the function of different cellular pathways that are critical to synaptic plasticity and cognitive function. In the longer term, these improvements are likely to synergise with the effects observed on neuronal health and connectivity to foster a long-term improvement in both brain and cognitive health. As deficits in many of these same pathways are implicated in a variety of disorders, this also establishes a landscape where PBT2 may be efficacious in the treatment of a broad spectrum of diseases.

That this activity has also translated to improved cognition in a short-term Phase IIa human clinical trial of AD provides strong support for the efficacy of this compound in restoring normal brain function. The use of metal chaperones, such as PBT2, as novel therapeutic compounds for the treatment of both "normal" and "pathological" cognitive decline is strongly endorsed by these findings and warrant further mechanistic investigation into the precise mechanism of action of this class of compound, as well as human clinical trials to validate these rodent data.