Aging and Innate immune system resilience in TBI

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Traumatic brain injury (TBI) is a leading cause of neurological complications including chronic memory deficits such as dementia. Older TBI patients are at a higher risk for worsening of outcomes than their younger counterparts (Chou et al., 2018; Early et al., 2020; Morganti et al., 2016; Ritzel et al., 2019), despite the higher risk and worse outcomes, there are no targeted therapies targeted for this susceptible population, and only a few publications looking at therapeutics for this vulnerable population. This is compounded by data suggesting that older subjects may show less responsiveness to therapeutic interventions (Tajiri et al., 2014) which may indicate that aged individuals will require optimized treatments that differ from young. We have identified a therapy exosomes from human adipose derived stem cells (hASC exo) (Patel et al., 2018) that have a therapeutic window up to at least 48 hours post injury in young rodents (see preliminary data). The extended therapeutic window of hASC exo would be a major advancement over most current experimental therapeutics, with a treatment window of only hours and not days. To move this promising therapy forward we must address critical gaps in our knowledge regarding hASC exo’s mechanism of action, and effectiveness of the intervention in diverse age populations. Our hypothesis is that a major action of these hASC exosomes is to modulate the secondary immune response to injury by interacting with the immune system. It is already well established that in aged rodents aged there is an exaggerated response of innate immune cells to the injury. Our preliminary data demonstrates the efficacy of hASC exo to improve behavior and reduce inflammatory markers following CCI is modified in aged rodents . Thus, an unanswered question is how aging impacts the response to treatment, and specifically treatment with hASC exosomes.