A study published in Aging and Disease has shown how exposure to old serum causes hippocampal progenitor cells (HPCs), which form new neurons, to die.
Drawing and testing serum from living people
To begin their study, the researchers examined a middle-aged to old (MATO) cohort ranging in age from 52 to 89. This cohort consists of cognitively healthy individuals that were recruited as the control group in a different study. The researchers found that their chronological age was inversely correlated with brain volume as measured in multiple areas, including the hippocampus and the dentate gyrus.
When their serum was tested in vitro on a sample of HPCs, the researchers found weak correlations between neuroblast numbers and donor brain volume as well as DNA damage and donor brain volume.
The researchers also drew samples from younger people (average age of 27) and older people (average age of 77), then examined the effects of young and old serum on another cellular culture.
After determining the optimal amount of serum for testing, they found that a marker of apoptosis (cellular death), CC3, was approximately doubled in the cells that had received old serum. Additionally, the researchers found that cells cultured in older serum from people with very mild cognitive decline were found to have more immature neurons.
Reporting negative results
In this study, the researchers did something that is seldom shown in these sorts of studies: they reported many results that did not show statistical significance. For example, the proliferation marker Ki67 was not associated with old or young serum, as was expected from the results of parabiosis studies. Instead, the researchers investigated further, and found that this was most likely due to the use of antihypertensives; older people who took hypertensives were found to have significantly more Ki67 than those that did not.
Things like gender, education, and statin use were not shown to have very much effect on cellular readouts, and even chronological age within the old cohort was not shown to have a statistically significant effect. The researchers state that epidemological factors, natural variances that are expected in human studies, are responsible for the strong variance in the cellular readouts of cells exposed to their serum.
Changes to gene expression
Interestingly, most of the well-known aging-associated genes did not change their expression when cells were exposed to old serum. These included genes related to nutrient sensing, cellular senescence, intercellular communication, and inflammation. Telomerase seemed to be affected, but not to the level of statistical significance. The proteostasis-related enzyme UCHL1, which increases in aging mice, was shown to increase.
The expression of another gene, PARP1, was shown to decrease. While PARP1 serves a protective role in moderate amounts, it increases with age, and this accumulation is associated with age-related cognitive decline [1].
The researchers identified three more potentially important genes affected by the administration of old serum. TMEM149 is largely unexplored but is associated with chronological age, and it was increased with old serum, as is ENDOG. RFN126 decreased in response to old serum, and it is also related to proteostasis, cleaning up mislocated and misfolded proteins [2,3].
Conclusion
The researchers share the most critical point taken from their study as follows:
Importantly, we show that although key in vitro readouts following the cellular assay correlate with in vivo phenotypes such as hippocampal volumes and cognitive performance, they do not show association to chronological age. This supports the notion that a lifetime of contributing factors causes increased divergence between chronological and (neuro)biological age which leads to greater heterogeneity in older populations. Our findings support the here-described serum assay as a potential biomarker for neurobiological age, making it a valuble tool for studies investigating ageing and age-related conditions as well as lifestyle factors such as diet and exercise.
There is another question that can be taken from this study’s results, one that the researchers did not explore: Does antihypertensive medication have a positive impact on neurogenesis, as was suggested by the Ki67 results? If there is a positive association between antihypertensive medication and the development of new brain cells, one which is not simply attributable to the amelioration of the negative effects of hypertension, this may be a line of research worth exploring.
Literature
[1] Mao, K., & Zhang, G. (2021). The role of PARP1 in neurodegenerative diseases and aging. The FEBS Journal.
[2] Rodrigo-Brenni, M. C., Gutierrez, E., & Hegde, R. S. (2014). Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Molecular cell, 55(2), 227-237.
[3] Hu, X., Wang, L., Wang, Y., Ji, J., Li, J., Wang, Z., … & Zhang, Z. R. (2020). RNF126-mediated reubiquitination is required for proteasomal degradation of p97-extracted membrane proteins. Molecular Cell, 79(2), 320-331.
