Age-related memory loss may be reversed by boosting blood levels of osteocalcin, a hormone produced by bone cells, according to studies led by researchers at Columbia University Medical Center and supported by the Columbia Aging Center at the Columbia University Mailman School of Public Health. The research team also identified a receptor for osteocalcin in the brain, paving the way for a novel approach to treating age-related cognitive decline. The paper was published in the online edition of the Journal of Experimental Medicine.
“In previous studies, we found that osteocalcin plays multiple roles in the body, including a role in memory,” said lead author Dr. Gerard Karsenty, Dr. Paul A. Marks, professor and chair, department of genetics & development, and research fellow at the Columbia Aging Center. “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.”
Dr. Karsenty’s group, in collaboration with the laboratory of Dr. Eric Kandel, university professor and Kavli Professor of Brain Science at Columbia University and a key contributor to this study, 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, osteocalcin-deficient mice 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, although more research is needed to translate the findings into clinical use for humans.
In addition to support by the Columbia Aging Center, this work was funded by grants from the National Institutes of Health (2P01 AG032959-06A1), Fondation pour la Recherche Medicale, Human Frontier Scientific Program, Philippe Foundation, and the Howard Hughes Medical Institute.