Brains love bone juice

Posted by Ricardo Lozoya on July 15, 2022 in Behavioral Neuroscience, Cognition, Developmental Neuroscience, Exercise, Hormones, Memory, Neuroscience | Leave a comment

Skeletons as a hormone-secreting organ

In the early 2000s, researchers in Dr. Gerard Karsenty’s group were studying a protein secreted by bones named osteocalcin (OCN) to see  if it played a role in bone mineralization (i.e. how our skeleton attracts the minerals needed for its structure). Even though they found that OCN isn’t involved in bone mineralization, they noticed that mice lacking the gene encoding OCN were unusually docile [1]. This surprised the researchers because it implied that a component originating from bones had some effect on behavior and, thus likely the brain. Usually the only compounds secreted by peripheral organs (and yes, your bones can be considered an organ) to affect the brain are hormones, meaning that the researchers discovered that bones are hormone-producing organs. It’s wild to think that this realization happened so recently given how long we’ve had the opportunity to look and study skeletons.

 In follow-up studies, several behavioral assays showed that these OCN-lacking mice were also more anxious and worse at spatial memory tasks than their normal counterparts [2]. They proceeded to carry out more experiments to figure out why this might be. OCN is secreted from bones and makes its way to the bloodstream, acting like a hormone, and binds to neurons in several key brain regions such as the hippocampus, which is important for learning and memory. OCN-lacking mice had a marked decrease in their brain’s ability to produce monoamine neurotransmitters, which neurons use to communicate with each other, and had increased levels of the inhibitory neurotransmitter GABA  [2]. In perhaps, their most surprising finding, the researchers discovered that during a mouse’s pregnancy, the mother’s bones will secrete OCN which is taken up by her pups [2]. This OCN was found to be essential for the proper development of the pup’s hippocampus and that without it, the pup is born with a shrunken hippocampus.

All this indicates that losing OCN is damaging for overall brain health.

What happens to your brain with more bone juice?

After these results were published, several researchers began to perform observational studies in humans to see what our OCN levels look like. They found that circulating OCN levels drop quite dramatically beginning at age 30 in men and age 45 in women [3]. Given OCN’s link to brain health and that humans typically begin to lose cognitive skills as they age, researchers wondered if there was a link between the loss of OCN and age-dependent cognitive decline.

In a study 2017 [4], the authors injected aged mice (which have low baseline levels of OCN) with either OCN or saline and had them perform anxiety and spatial memory tests. They found that older mice injected with OCN had similar levels of spatial memory as young mice, and improved levels of anxiety (although anxiety improvement was not enough to be considered statistically significant). This suggests that OCN pushed older brains into a “younger state.”  When they pried further, the authors found that young mice treated with OCN had increased activity of neurons in the hippocampus, and both old and young OCN-treated mice had increased production of a protein called brain-derived neurotrophic factor (BDNF). This protein has been studied for decades and found to be key in conducting changes in neurons important for learning and memory, amongst many other things related to overall brain health [5]. They also saw that there was increased trafficking of BDNF towards synapses (the space where two neurons meet), suggesting that OCN improves communication between neurons. 

A link between exercise, OCN, and brain health

If you’ve been reading up on ways to improve your brain or stave off a neurological disease like Alzheimer’s later in life, chances are that you have repeatedly seen that the best strategy for both is to get some exercise. There is a tsunami of studies showing that regular exercise improves cognition, helps prevent the onset of neurodegenerative diseases, and keeps your mind sharp as you age [6-10]. We’ve even written about it here on this blog before. However, exactly how exercise improves the brain is still unclear.

In the publication looking at OCN levels in humans, researchers also found that circulating OCN levels increased after a bout of exercise [3]. Separately, it’s been noted that exercise also increases BDNF levels in the brain [5]. Given the results highlighted in the previous section, it appears that there is a possible connection between OCN and the documented beneficial effects of exercise on brain health. One could speculate that consistent exercise stimulates bones to release more OCN throughout someone’s life, which in turn, stimulates the production of BDNF and improves or maintains cognitive skills as they age. Even though this has yet to be definitively proven, this hypothesis provides a potential idea of why exercise is so beneficial to our brains. 

Where can I get some OCN??

Before you go out and drink a bowl of bone soup, it’s important to keep in mind that the research linking OCN and brain performance is still quite young (pun very much intended). There could be, and very likely are, several other factors that link exercise’s effect on the brain. There are some studies that suggest that OCN could be imparting its effect by improving whole-body efficiency of energy metabolism rather than by acting directly on the brain [11]. In addition, the beneficial effect of OCN is still unclear in humans, where observational studies have shown both increased [12] and decreased [13] mortality being positively correlated with OCN levels in older men. However, the authors of these studies noted that there may be an ideal “middle range” where OCN is beneficial and not detrimental to one’s health. OCN is also found to be secreted by several solid tumors and higher OCN levels were associated with high-risk mammograms in obese post-menopausal women [14, 15]. Whether OCN secretion in these latter cases is causal or simply a consequence of cancer is yet to be determined. 

The importance of OCN for normal brain function, particularly in its development, is pretty clear, but several questions still need to be answered before we can claim OCN as the miracle link between exercise and brain health. Regardless, the beneficial effects of exercise on brain health are well documented and written in stone. If I get a little natural boost of OCN from going on a jog, in addition to helping out my heart, then I’m all for it–even if it later turns out that OCN isn’t the link between cognition and exercise. 

References

1.       Karsenty, G. & Olson, E. N. Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication. Cell 164, 1248–1256 (2016).

2.       Oury, F. et al. Maternal and offspring pools of osteocalcin influence brain development and functions. Cell 155, 228 (2013).

3.       Mera, P. et al. Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab 23, 1078 (2016).

4.       Khrimian, L. et al. Gpr158 mediates osteocalcin’s regulation of cognition. Journal of Experimental Medicine 214, 2859–2873 (2017).

5.     Miranda, M., Morici, J. F., Zanoni, M. B. & Bekinschtein, P. Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Frontiers in Cellular Neuroscience 13, 363 (2019).

6.     Ahlskog, J. E., Geda, Y. E., Graff-Radford, N. R. & Petersen, R. C. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc 86, 876–884 (2011).

7.     Hogan, C. L., Mata, J. & Carstensen, L. L. Exercise holds immediate benefits for affect and cognition in younger and older adults. Psychol Aging 28, 587–594 (2013).

8.      Maleki, S. et al. Associations of cardiorespiratory fitness and exercise with brain white matter in healthy adults: A systematic review and meta-analysis. Brain Imaging Behav (2022) doi:10.1007/S11682-022-00693-Y.

9.      Górna, S. & Domaszewska, K. The Effect of Endurance Training on Serum BDNF Levels in the Chronic Post-Stroke Phase: Current Evidence and Qualitative Systematic Review. J Clin Med 11, 3556 (2022).

10.      Farhani, F., Shahrbanian, S., Auais, M., Hekmatikar, A. H. A. & Suzuki, K. Effects of Aerobic Training on Brain Plasticity in Patients with Mild Cognitive Impairment: A Systematic Review of Randomized Controlled Trials. Brain Sci 12, 732 (2022).

11.    Shan, C. et al. Roles for osteocalcin in brain signalling: Implications in cognition- and motor-related disorders. Molecular Brain 12, 1–11 (2019).

12.    Yeap, B. B. et al. Associations of total osteocalcin with all-cause and cardiovascular mortality in older men. The Health In Men Study. Osteoporos Int 23, 599–606 (2012).

13.    Confavreux, C. B. et al. Higher serum osteocalcin is associated with lower abdominal aortic calcification progression and longer 10-year survival in elderly men of the MINOS cohort. J Clin Endocrinol Metab 98, 1084–1092 (2013).

14.    Koeneman, K. S. et al. Osteocalcin-directed gene therapy for prostate-cancer bone metastasis. World J Urol 18, 102–110 (2000).

15.    Vega, S. et al. Similar to Adiponectin, Serum Levels of Osteocalcin are Associated with Mammographic Breast Density in Postmenopausal Women. Journal of obstetrics and gynaecology Canada : JOGC = Journal d’obstetrique et gynecologie du Canada : JOGC 40, 186–192 (2018).