Researchers have discovered a compound and a brain region that may be related to chronic pain in older people and published their findings in Aging Cell.
When one sense doesn’t decline
Aging destroys the senses over time, most notably sight and hearing [1]. Sensations related to touch are diminished as well, including cold, heat, movement, and vibration [2].
Pain, most notably, is not among the diminished senses. Instead, aging is largely associated with chronic pain, some of which can be attributed to chronic conditions such as arthritis [3]. Other research involving the primary somatosensory cortex (S1), a key brain region involved in the processing of pain signals [4], has found that pain inhibition pathways are reduced with aging [5].
Previous work has also found that PGC-1α, a compound involved in mitochondrial formation and function, also plays a role in the function of neurons, including the neurons involved in pain processing [6]. However, the relationship between PGC-1α, the S1, pain, and aging had not been fully explored.
Why younger animals recover more quickly from pain
The researchers examined populations of wild-type Black 6 mice, one at 4 weeks of age and another at 18 weeks of age, finding that the younger mice expressed nearly triple the amount of PGC-1α as the older mice did. These mice were then injured by constricting their sciatic nerves leading to their hind legs. The older mice took longer to recover from this injury, being more sensitive to touch stimuli and for a longer period of time. The researchers refer to this as ‘aging-associated pain chronification’.
To further examine this relationship, the researchers created a population of mice that had only one functional allele of PGC-1α, compared to normal mice that have two. (Mice with no copies of PGC-1α die very early of neurodegeneration.) At 4 weeks of age, both populations of mice sustained the same injury as in the previous experiment, and the mice with reduced PGC-1α fared even worse than the older mice, failing to fully recover within seven weeks. Male and female mice had similar results.
The brains of younger and older mice were also investigated after leg injury. At day 7, both younger and older mice had similar levels of activity in S1 excitation neurons; however, by day 35, this increased excitation had largely ceased in the younger animals but was still significantly more active in the older ones. Interneurons, which connect the S1 to the rest of the brain, had less activity at day 7 in both younger and older animals, but this was restored at day 35 only in the younger ones. Further experiments using highly specific drugs found that more interneuron activity resulted in behaviors suggesting less chronic pain.
Using an adeno-associated virus (AAV) to increase the production of PGC-1α in older animals reduced their chronic pain after injury approximately to the levels shown by younger animals. Also, just like in younger animals, the excitation neuron activity was decreased and the interneuron activity was increased at day 35 after injury.
These results demonstrate that the chronic pain associated with aging isn’t always attributable to a chronic condition such as arthritis. Rather, it can be attributed to an age-related decline in a crucial brain function, and future therapies that focus on restoring this function may become a key part of ameliorating this pain.
Literature
[1] Cavazzana, A., Röhrborn, A., Garthus-Niegel, S., Larsson, M., Hummel, T., & Croy, I. (2018). Sensory-specific impairment among older people. An investigation using both sensory thresholds and subjective measures across the five senses. PloS one, 13(8), e0202969.
[2] Dunn, W., Griffith, J. W., Sabata, D., Morrison, M. T., MacDermid, J. C., Darragh, A., … & Tanquary, J. (2015). Measuring change in somatosensation across the lifespan. The American Journal of Occupational Therapy, 69(3), 6903290020p1-6903290020p9.
[3] Marks, R. (2018). Successful aging and chronic osteoarthritis. Medicines, 5(3), 105.
[4] Ding, W., Yang, L., Chen, Q., Hu, K., Liu, Y., Bao, E., … & Shen, S. (2023). Foramen Lacerum impingement of trigeminal nerve root as a rodent model for trigeminal neuralgia. JCI insight, 8(11).
[5] González-Roldán, A. M., Terrasa, J. L., Sitges, C., van der Meulen, M., Anton, F., & Montoya, P. (2020). Age-related changes in pain perception are associated with altered functional connectivity during resting state. Frontiers in Aging Neuroscience, 12, 116.
[6] Miao, Z. F., Adkins-Threats, M., Burclaff, J. R., Osaki, L. H., Sun, J. X., Kefalov, Y., … & Mills, J. C. (2020). A metformin-responsive metabolic pathway controls distinct steps in gastric progenitor fate decisions and maturation. Cell Stem Cell, 26(6), 910-925.
