Aging, stress and neuroplasticity

The effort to understand brain aging and discover treatments to postpone aging-related cognitive decline has long intrigued society. However, one of the substantial obstacles in aging research is finding and employing appropriate model systems that can effectively replicate the natural aging process of the human brain. This doctoral thesis aimed to broaden our knowledge and comprehension of promising models for studying human neuronal aging. To accomplish this, the thesis is divided into two sections: I. The first section explored potential neuronal aging models in vitro. A. This involved comparing induced pluripotent stem cell (iPSC)-derived neurons (iPSCsNs) with directly converted neurons (iNs) from aged human fibroblasts (HFs) of the same aged individuals. B. Additionally, this thesis endeavored to create a stress-induced aging model. II. The second section focused on examining the effect of childhood adversities (CAs) on biological alteration in adulthood to detect an accelerated aging-associated phenotype. C. This thesis studied the correlation between cellular aging and biological stress, as well as D. the interplay between brain-derived neurotrophic factor (BDNF), stress, and sleep in a high-risk sample of young adults with a history of residential youth care placements.
I. In the first section, this thesis demonstrates that aged iPSCsNs exhibit an aging phenotype like that of aged iNs from the same donors in terms of mitochondrial functional properties, including a rise in mitochondrial reactive oxygen species (ROS), destabilizing of the respiratory chain, and dysfunction in the mitochondrial quality control system. However, aged iPSCsNs differed in terms of transcriptomic level and glycolytic activity compared to aged iNs. Based on these findings, aged iPSCsNs demonstrated rejuvenation in transcriptomic and glycolytic levels but unexpectedly maintained aging-associated impairment on mitochondrial properties linked to their cells of origin. Thereby contradicting the common assumption of a complete rejuvenation process. However, the aged iNs represent an overall model of neuronal aging to study other aging features beyond mitochondrial impairments. Although aged iNs exhibited promising results in studying aging, their poor efficiency in reprogramming and conversion impedes their usefulness. Given that stress has been identified as a significant contributor to aging, a stress approach to mimic an aging-associated phenotype in young iNs could be a potential approach to establish a fast and easy-to-use “aged” neuronal in vitro model. Our research presents those subjecting iNs obtained from young donors to rotenone exposure led to a more pronounced aging-associated phenotype on the mitochondrial level than exposure to the human stress hormone cortisol. However, we observed that neither of these acute stress approaches had any adverse impact on the morphology of the mitochondrial network. The thesis presented an innovative strategy for utilizing the sensitive iNs model system as a potential replacement model for in vivo aged iNs.
II. In that context, young people exposed to elevated stress levels may display an accelerated biological aging phenotype in early adulthood. It is essential to bridge the substantial gap in our understanding of the biological alteration on adversity's long-term effects, which still need to be overcome. The investigation of the association between biological stress responses and cellular aging has proven challenging due to the need for biological measures of chronic psychological stress in humans. This thesis represented that HCC (a parameter of chronic HPA activation) and LTL (an aging index) showed a strong negative correlation in a high-risk group with a history of placement in residential youth care. HCC as a tool could help us explore and understand the effects of chronic stress on biological changes related to aging. In our study in this high-risk population, we further discovered that each participant's sleep quality played an essential role in the relationship between CTQ (index of CAs) and BDNF concentration. Even though we did not find a direct correlation between various stress-related psychological factors (such as CTQ or well-being), biological indicators of stress (HCC), or sleep (PSQI) with BDNF concentration, our research did show that CTQ was associated with BDNF concentration levels in individuals who had healthy sleep patterns. However, this association was not observed in individuals who suffered from sleep disturbances. These findings highlight the importance of getting enough sleep to manage stress effectively.
The broad implication of the results of this thesis proposed that either aged iNs or iPSCsNs have their benefits and disadvantages, and depending on the application, one in vitro neuron model of human aging is more favorable than the other. Moreover, stress approaches on young iNs could be an alternative avenue to generate "aged" neurons. Exposure of rotenone on young iNs especially proposes a large-scale replacement model for in vivo aged iNs. In the second part of this thesis, our investigation suggested that HCC might be a valuable method for assessing chronic stress activation in the setting of cellular aging. Our discovery of a negative relationship between HCC and LTL supported this. Lastly, this thesis emphasized the matter of sleep in evaluating CAs on the long-term effect of BDNF.