Fight Aging!

Last year researchers showed that raising levels of osteocalcin in old mice reverses some of the age-related decline in exercise capacity. In the paper noted here, the same research group shows that increased osteocalcin also reverses some of the loss in memory function that takes place in later life, at least in mice. Taken together these are quite interesting demonstrations, and we might speculate on whether this could be a cause of improvements in the health of old mice obtained via heterochronic parabiosis, wherein the circulatory systems of an old and a young mouse are linked together. Osteocalcin levels decline with age, and in the osteocalcin studies, the increase in old mice provided by the simple approach of injection. So it doesn't seem implausible that parabiosis might increase the level of osteocalcin in the old mouse.

Currently there is some debate over how benefits emerge from the process of parabiosis. A recent study provided very good evidence to suggest that benefits occur due to a dilution of harmful factors in old blood rather than by provision of helpful factors from young blood. The studies of GDF11 levels that kicked off current interest in parabiosis are still being debated back and forth: it remains unclear as to whether the identification of GDF11 as a protein of interest is correct. So on the whole matters are still in flux in this area of study. That the researchers here produce benefits with plasma transfusion from young to old mice, something that has also had mixed evidence to date, is particularly interesting.

Back to osteocalcin; if researchers can find ways to produce some degree of benefit with supplementation of a few strategic circulating proteins, then all to the good. This nonetheless strikes me as adjusting downstream consequences of the root causes of aging - tinkering with the broken machinery to try to force it to behave rather than fixing the actual problem. Why do circulating protein levels change? They change because cells react to the accumulation of molecular damage in cells and tissues. That damage is the actual problem, and we should expect to find that repair or removal of the damage will revert changes in protein levels such as decline in osteocalcin. Given the advent of senolytic therapies to clear senescent cells - one form of repair treatment for a cause of aging - we should see that phenomenon begin to be cataloged in studies conducted over the next few years. Perhaps not for osteocalcin, depending on which form of damage causes this reaction, but certainly for some other changes.

Bone-Derived Hormone Reverses Age-Related Memory Loss in Mice

"In previous studies, we found that osteocalcin plays multiple roles in the body, including a role in memory. We also observed that the hormone declines precipitously in humans during early adulthood. That raised an important question: Could memory loss be reversed by restoring this hormone back to youthful levels? The answer, at least in mice, is yes, suggesting that we've opened a new avenue of research into the regulation of behavior by peripheral hormones."

Researchers conducted several experiments to evaluate osteocalcin's role in age-related memory loss. In one experiment, aged mice were given continuous infusions of osteocalcin over a two-month period. The infusions greatly improved the animals' performance on two different memory tests, reaching levels seen only in young mice. The same improvements were seen when blood plasma from young mice, which is rich in osteocalcin, was injected into aged mice. In contrast, there was no memory improvement when plasma from young mice engineered to be osteocalcin-deficient was given to aged mice. But adding osteocalcin to this plasma before injecting it into the aged mice resulted in memory improvement. The researchers also used anti-osteocalcin antibodies to deplete the hormone from the plasma of young mice, reducing their performance on memory tests.

The researchers then determined that osteocalcin binds to a receptor called Gpr158 that is abundant in neurons of the CA3 region of the hippocampus, the brain's memory center. This was confirmed by inactivating hippocampal Gpr158 in mice and subsequently giving them infusions of osteocalcin, which failed to improve their performance on memory tests. The researchers did not observe any toxic effects from giving the mice osteocalcin. "It's a natural part of our body, so it should be safe. But of course, we need to do more research to translate our findings into clinical use for humans."

Gpr158 mediates osteocalcin's regulation of cognition

That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-month-old mice.

A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify Gpr158, an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.