Researchers publishing in Aging Cell have elucidated a relationship between aging, the loss of smell, and NAD+ in a mouse model.
Olfactory ability declines with age
Roughly half of people over the age of 65 experience a decreased ability to smell [1], and research has shown that it is an early biomarker for neurodegenerative diseases, such as Alzheimer’s and Parkinson’s [2]. However, it can also occur even without such diseases.
Tests have been thoroughly developed to determine performance in four major areas of olfaction: detection, sensitivity, habituation, and discrimination. These four areas are common between mice and human beings [2]. These four tests, along with biomarker examinations, were incorporated into this study.
A detailed examination
In the detection test, hungry wild-type mice were placed into an enclosure with buried food, and the amount of time needed to find and dig up the food was measured. Mice at 5, 13, and 21 months of age all performed similarly; however, mice at 31 months of age were much slower. As all of these mice moved at similar speeds, the results were not due to mobility.
Younger mice were much more able to differentiate pure water from water mixed with orange extract at a very low concentration. This sensitivity was shown to decrease somewhat at 21 months, and it was severely impaired at 31 months.
Mice spend less time sniffing at odors they recognize, and this fact was used for habituation tests. While older mice spent less time sniffing in general, even old mice were able to become habituated to familiar odors.
Like many other social mammals, such as dogs, mice can identify each other by the smell of their urine, and this fact was used as part of the discrimination test. This particular ability seemed to be steadily lost after the age of five months. However, discrimination testing for food odors showed that even the old mice could distinguish between such foods as lemons and limes.
Biomarker tests run on the mice’s olfactory tissue corroborated these results. Cholesterol metabolism was altered, some metabolites showed effects on the immune system, and osmolytes, which are responsible for cellular volume and can affect neuronal function [3], were altered as well. Inflammation was also found to be increased, as were immune-related microglia and astrocytes. As expected, biomarkers of DNA damage were increased in the older mice.
NR restored some ability
As occurs in many other tissues with aging, the older mice had reduced levels of NAD+ in their olfactory centers. While 24-month-old mice given NR in their water for eight months did not show any advantages over a control group in olfactory sensitivity or discrimination, they did significantly improve in the buried food test. The treated mice lived longer on average, and proteins related to DNA damage were also significantly decreased, which corroborates a previous study [4].
Conclusion
While this study sheds considerable light on how mice age in their sense of smell, and what biomarkers in the olfactory region change with age, more research is needed to understand the root causes and develop potential treatments. NAD+ does seem to be a piece of this puzzle, but more pieces will need to be filled in if the sense of smell can be fully restored to older mice and to older people.
Literature
[1] Palmquist, E., Larsson, M., Olofsson, J. K., Seubert, J., Bäckman, L., & Laukka, E. J. (2020). A prospective study on risk factors for olfactory dysfunction in aging. The Journals of Gerontology: Series A, 75(3), 603-610.
[2] Dan, X., Wechter, N., Gray, S., Mohanty, J. G., Croteau, D. L., & Bohr, V. A. (2021). Olfactory dysfunction in aging and neurodegenerative diseases. Ageing Research Reviews, 70, 101416.
[3] Fisher, S. K., Heacock, A. M., Keep, R. F., & Foster, D. J. (2010). Receptor regulation of osmolyte homeostasis in neural cells. The Journal of Physiology, 588(18), 3355-3364.
[4] Hou, Y., Wei, Y., Lautrup, S., Yang, B., Wang, Y., Cordonnier, S., … & Bohr, V. A. (2021). NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS–STING. Proceedings of the National Academy of Sciences, 118(37), e2011226118.