Recently, a group of South Korean scientists has analyzed the blood proteome of mice to determine how it changes with age and to identify aging-related proteins that have previously eluded researchers. After identifying several such proteins, the group focused on a specific protein, cadherin-13, that seems to prevent age-related bone loss [1].
The plasma proteome changes with age
As we age, our tissues significantly change the ensemble of proteins that they secrete into our blood. Studying these changes can potentially elucidate many mechanisms of aging, detect new therapeutic targets, and provide more reliable methods of assessing biological age. The importance of plasma composition for aging has been proven time and again. For instance, some studies have shown that adding young plasma to the blood causes various anti-aging effects [2], rejuvenating the brain, muscles, bones, liver, and heart.
Osteoporosis: age-related and deadly
One of the unmistakable signs of aging is the loss of bone density. It causes osteoporosis, a dangerous disease that can go unnoticed until a fracture occurs. Hip fractures in the elderly result in up to 20-24% mortality in the first year alone. Bone homeostasis depends on both estrogen and testosterone, but women are disproportionately affected by osteoporosis, since estrogen levels drop sharply during menopause and they have lower bone density to begin with. Therefore, 75% of hip fractures in people after 50 happen to women, and a 50-year-old woman has a 2.8% risk of dying from the consequences of a hip fracture during her remaining lifetime – roughly the same as of dying of breast cancer.
Bone homeostasis depends, in part, on the intricate balance of osteoclastic and osteoblastic activity [3]. Osteoblasts are cells that differentiate from mesenchymal stem cells and are responsible for bone deposition, the creation of the bone extracellular matrix through the secretion of dense collagen and other proteins. Osteoclasts, derived from macrophages, are large, multinucleated cells that play a central role in the opposite process: bone resorption. Osteoclasts secrete acid and collagenase that disassemble bone tissue. This seemingly destructive activity is critical for maintenance, repair, and remodeling of bones, but with age, osteoclast-induced bone resorption outpaces osteoblast-induced bone deposition, leading to a gradual loss of bone mass.
Identifying the target
The researchers analyzed blood plasma taken from 12 young and 12 aged mice. They were able to identify a total of around 600 proteins that were present in all the samples, and some of them varied considerably in concentration between young and old mice, indicating that the plasma proteome does change with age. From among these proteins, seven candidates were selected, as they were downregulated in aged mice and had not been previously studied by longevity researchers.
To test if any of those proteins played a role in bone mineral density (BMD) decline, the scientists applied them to bone marrow-derived macrophages that were undergoing an induced differentiation into osteoclasts. Among the candidates, cadherin-13 was the only one that demonstrated significant ability to inhibit osteoclast differentiation while neither being toxic to the cells nor impairing osteoblast differentiation.
Cadherin-13: promising but mysterious
Cadherin-13 is an odd member of the cadherin superfamily. As it lacks the transmembrane domain, it cannot participate in cell-cell adhesion, which seems to be the main purpose of other cadherins. Instead, cadherin-13 has been shown to play a role in cell migration and phenotype changes, and it acts as an LDL (low density lipoproteins) receptor. Elevated levels of cadherin-13 have been associated with ADHD, depression, and other psychiatric disorders as well as with some cardiovascular diseases, such as atherosclerosis [4]. Nevertheless, cadherin-13’s functions and mechanisms of action remain mainly undetermined.
Osteoclast formation requires the presence of two chemicals: receptor activator of nuclear factor κβ ligand (RANKL) and Macrophage colony-stimulating factor (M-CSF). The researchers hypothesized that cadherin-13 might be causing disruption in one of these pathways. The tests revealed that cadherin-13 did substantially obstruct signaling down the RANKL pathway by inhibiting RANKL phosphorylation of several signaling molecules.
After these encouraging findings, the researchers moved on to experimenting in vivo. Female mice were injected with cadherin-13 for 4 months, beginning at 15 months of age. The BMD of the mice’s femur bones had been periodically monitored in vivo using micro-computer tomography. Over the course of 16 weeks, BMD of the control group had declined dramatically. In mice that were being treated with cadherin-13, this decline was attenuated, while two other bone health indicators, bone volume fraction and trabecular thickness, increased.
Conclusion
Declining bone density is the immediate cause of osteoporosis, a potentially deadly aging-related disease that disproportionately affects women. Since current treatments leave much to be desired, new approaches to osteoporosis are desperately needed. This research opens an interesting novel possibility for intervention. It also illustrates how comparing plasma proteomes of young and old organisms can be used to discover new therapeutic targets for longevity research. On the other hand, the target that was identified, cadherin-13, remains largely unresearched, and various safety concerns might yet block its path to clinical use.
Literature
[1] Yang, Y. R., Kabir, M. H., Park, J. H., Park, J. I., Kang, J. S., Ju, S., … & Lee, K. P. (2020). Plasma proteomic profiling of young and old mice reveals cadherin-13 prevents age-related bone loss. Aging, 12.
[2] Baht, G. S., Silkstone, D., Vi, L., Nadesan, P., Amani, Y., Whetstone, H., … & Alman, B. A. (2015). Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nature communications, 6, 7131.
[3] Tanaka, Y., Nakayamada, S., & Okada, Y. (2005). Osteoblasts and osteoclasts in bone remodeling and inflammation. Current Drug Targets-Inflammation & Allergy, 4(3), 325-328.
[4] Philippova, M., Suter, Y., Toggweiler, S., Schoenenberger, A. W., Joshi, M. B., Kyriakakis, E., … & Resink, T. J. (2011). T-cadherin is present on endothelial microparticles and is elevated in plasma in early atherosclerosis. European heart journal, 32(6), 760-771.
