Deep Sleep, Cognition, Body Weight, Body Temperature, and Behavioral Distress Responses to New Onset Psychosocial Stressors are Blunted with Age in Male F344 Rats

Complaints associated with aging, including cognitive deficits and sleep loss, are highly prevalent and negatively impact quality of life. Further, with increased age, humans are also more likely to experience new-onset psychosocial stressors, such as divorce, loss of a spouse, and social isolation. Stress has detrimental consequences that in many ways parallel the effects of aging on sleep and cognition. The long-standing stress/ glucocorticoid hypotheses of brain aging posit that stress exposure exacerbates aging symptoms, and extensive prior studies have shown that early life stress exposure does worsen phenotypic aging symptoms. However, despite its prevalence in aged humans, little basic research has investigated the response of aged subjects to new-onset psychosocial stress. Prior work in our lab showed aged rodents to be hyporesponsive to a new-onset acute psychosocial stress. Here, we assess the age-course of this acute response, as well as evaluate the consequences of chronic psychosocial stress exposure in aged animals. Our lab tested two hypotheses. First, we hypothesized that mid-aged animals will have an intermediate response between young and aged to acute psychosocial stress. Second, we hypothesized that aged animals’ will continue to be hyporesponsive during a chronic psychosocial stress. We focused on mid-aged animals for our first study because this age-point serves as the transition period from young to aged and could hold some key information about the transition from healthy to unhealthy brain aging. We used restraints to induce stress, the Morris water maze to test cognitive function, and telemetry devices to characterize sleep architecture and body temperature. We showed that, among age-related acute stress hyposensitive findings (deep sleep loss, hyperthermia, and cognitive deficit), mid-aged animals were hyporesponsive to sleep, but not body temperature or maze performance. This suggests that the failure to manifest a sleep response to stress precedes cognitive and body temperature related stress insensitivity. In our second study, we investigated the influence of new-onset chronic psychosocial stress (three hours per day, four days per week for one month) in young and aged rodents. Aged animals were hyporesponsive to multiple common indicators of stress including distress during the restraint, weight loss, and cognitive deficits, all of which were easily detectable in young animals. These results suggest that the age-related blunting of the stress response is sustained from acute to chronic exposures. While the hyporesponsiveness may seem advantageous in the aged, a failed response could also be maladaptive, reducing a subject’s ability to compensate for a changing environment. Together, this work supports prior observations that stress exposure makes young animals more aged like. Aged animals also showed a more limited response to stress, suggesting that age itself may act as an occluding stressor. Finally, this work points to deep sleep promoting interventions as potential therapeutic strategies for managing age-related changes in stress response

Transcriptional Signatures of Brain Aging and Alzheimer\u27s Disease: What Are Our Rodent Models Telling Us?

Aging is the biggest risk factor for idiopathic Alzheimer’s disease (AD). Recently, the National Institutes of Health released AD research recommendations that include: appreciating normal brain aging, expanding data-driven research, using open-access resources, and evaluating experimental reproducibility. Transcriptome data sets for aging and AD in humans and animal models are available in NIH-curated, publically accessible databases. However, little work has been done to test for concordance among those molecular signatures. Here, we test the hypothesis that brain transcriptional profiles from animal models recapitulate those observed in the human condition. Raw transcriptional profile data from twenty-nine studies were analyzed to produce p-values and fold changes for young vs. aged or control vs. AD conditions. Concordance across profiles was assessed at three levels: (1) # of significant genes observed vs. # expected by chance; (2) proportion of significant genes showing directional agreement; (3) correlation among studies for magnitude of effect among significant genes. The highest concordance was found within subjects across brain regions. Normal brain aging was concordant across studies, brain regions, and species, despite profound differences in chronological aging among humans, rats and mice. Human studies of idiopathic AD were concordant across brain structures and studies, but were not concordant with the transcriptional profiles of transgenic AD mouse models. Further, the five transgenic AD mouse models that were assessed were not concordant with one another. These results suggest that normal brain aging is similar in humans and research animals, and that different transgenic AD model mice may reflect selected aspects of AD pathology