In Aging Cell, researchers have established a link between cellular senescence and cognitive decline in unmodified male mice.
Resilience versus decline
The authors begin their paper by noting that cognitive decline in older people varies greatly. Some people suffer serious cognitive defects; other people are scarcely impacted at all [1]. The researchers have developed an automated tool called PhenoTyper to measure this in unmodified male Black 6 mice, establishing a benchmark set at 5 to 7 months old and using it to classify older mice as either intact or impaired [2]. They previously used this benchmark to ascertain that some mice remain fully functioning throughout their lives while others suffer serious cognitive decline [3].
This decline has nothing to do with Alzheimer’s, which wild-type mice cannot get. Instead, the researchers point to reactive gliosis, which, under normal circumstances, is the brain’s response to injury [4]. Sustained, chronic inflammation in aging is known as inflammaging, and sustained reactive gliosis is this process in the brain. The same compounds that are responsible for systemic inflammaging, such as the senescence-associated secretory phenotype (SASP), occur in the brain as well, and previous work has found that removing these cells leads to cognitive benefits [5].
However, these researchers hold that such previous work did not adequately distinguish between cognitively impaired and intact mice. Therefore, they performed an experiment of their own, attempting to more thoroughly document the relationship between brain senescence and cognitive decline.
Teaching old mice new tricks
For their first experiment, the researchers used their PhenoTyper system to assess the capabilities of their mice. In this experiment, mice were taught for 50 hours that they must enter the leftmost hole of a three-hole setup in order to receive food pellets; for another 40 hours, however, they had to use the rightmost hole instead (“reversal learning”).
In learning the initial hole, young (6 months) mice and old (22 to 24 months) mice performed similarly well. However, in the reversal learning task, there was an immense amount of difference between the two groups; the older mice’s performance was bimodal, with some older mice completely failing to unlearn what they had learned.
These dramatic differences within the aged group were not related to the total distance moved by the mice, nor were they related to changes in circadian rhythms (this test was performed during the dark hours in which mice are most active). They also only applied to male mice; female mice did not have a similarly sharp stratification.
The researchers then examined the differences between these stratified groups. They found substantial and stark differences in both morphology and in biochemistry. Microglial activity was greatly increased in the impaired group, while the intact group was indistinguishable in this area from younger mice. Some biomarkers of reactive gliosis were moderately increased in the intact group, but all of them were far more elevated in the impaired group. These researchers, therefore, hold that they have found a distinct phenotype of neurological impairment.
This was linked to biomarkers of cellular senescence. Interestingly, the p16 senescence biomarker, which was significantly more elevated in intact older mice compared to young mice, was only slightly more elevated in the impaired group. p21 was nearly the same in both older groups and elevated compared to younger mice. However, other biomarkers were significantly different. The interleukin IL-6 was notably upregulated only in the impaired group, as was the key senescence marker SA-β-gal.
Senolytics appear to help
The researchers then administered the well-known senolytic combination of dasatinib and quercetin (D+Q) to 22-month-old mice and performed cognitive tests at 24 months. Nearly all the older animals given the senolytic were considered cognitively intact mice, with very few failing the reversal learning task. Their senescent cell biomarkers were similarly reduced to those of intact mice, with IL-6 reaching approximately the level of young mice; similar beneifits were found in microglial morphology and biochemistry. Once again, these findings only applied to males.
The researchers surmise that such sex-related differences may also apply to human beings. Additionally, this work applies specifically to ‘normal’ cognitive decline that may not be directly related to proteostasis diseases such as Alzheimer’s. However, if a relevant human population can be identified, a senolytic or senomorphic regimen may allow them to retain their cognitive abilities.
Literature
[1] Marron, M. M., Wojczynski, M. K., Minster, R. L., Boudreau, R. M., Sebastiani, P., Cosentino, S., … & Long Life Family Study. (2019). Heterogeneity of healthy aging: comparing long-lived families across five healthy aging phenotypes of blood pressure, memory, pulmonary function, grip strength, and metabolism. Geroscience, 41, 383-393.
[2] Baier, M. P., Nagaraja, R. Y., Yarbrough, H. P., Owen, D. B., Masingale, A. M., Ranjit, R., … & Logan, S. (2022). Selective ablation of Sod2 in astrocytes induces sex-specific effects on cognitive function, d-serine availability, and astrogliosis. Journal of Neuroscience, 42(31), 5992-6006.
[3] Logan, S., Baier, M. P., Owen, D. B., Peasari, J., Jones, K. L., Ranjit, R., … & Sonntag, W. E. (2023). Cognitive heterogeneity reveals molecular signatures of age-related impairment. PNAS nexus, 2(4), pgad101.
[4] Sochocka, M., Diniz, B. S., & Leszek, J. (2017). Inflammatory response in the CNS: friend or foe?. Molecular neurobiology, 54, 8071-8089.
[5] Ogrodnik, M., Evans, S. A., Fielder, E., Victorelli, S., Kruger, P., Salmonowicz, H., … & Jurk, D. (2021). Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice. Aging cell, 20(2), e13296.
