gut-brain-aging axis

GUT-BRAIN-AGING AXIS : MICROBIOTA SUPPORTS DASATINIB AND QUERCETIN DIMINUTION OF SENESCENCE BURDEN AND ALLEVIATION OF AGE-RELATED COGNITIVE DECLINE 

Keywords: aging, senescence, gut microbiota, senolytic drugs, inflammation

The main scientific goal of our project is to assess the implications of the gut-brain axis in aged rodents following senolytic drug administration. Senotherapy, or the use of senolytic drugs to fight aging and age-related conditions, is a promising and blooming field that paved the road for rejuvenating therapies. Such approach aimed at reducing the organismal senescence burden which conditions healthspan and lifespan. Senolytic drugs directly target senescent cells but may also exerts pleiotrophic effects that would support their mechanism of action. Among others, additional effects from senolytic might impact the host microbiome. The gut microbiome can both influence the central nervous system homeostasis and exerts a profound effect on systemic immune response. The interplay of the microbiome, cognition, senescence and inflammation in the context of aging has been an underlook field of research that is nowadays gaining a lot of interest. This project aims to shed-light on the dynamic changes in the gut-brain axis and inflammaging following Dasatinib and Quercetin combination of senolytics in naturally aged rodent. 

In review - soon to be published:

COMBINATION OF DASATINIB AND QUERCETIN IMPROVES COGNITIVE ABILITIES IN AGED WISTAR RATS, ALLEVIATES INFLAMMATION AND CHANGES HIPPOCAMPAL SYNAPTIC PLASTICITY AND HISTONE H3 METHYLATION PROFILE. 

Introduction: Neurons and other glial cells have the potential to acquire senescent characteristics that could lead to defect in neuronal plasticity and alteration of cognition which negatively impact quality-of-life of elders. Eliminating senescent cells that accumulates with age, using senolytics drugs, has proven to be effective in alleviating symptoms of aged-related diseases.

Hypothesis: Combination of Dasatinib and Quercetin senolytics (D+Q) might prevent cognitive decline observed in aged rats.

Objectives: Quantify systemic inflammation level since inflammaging is a key component of unhealthy aging. Assess synaptic plasticity in hippocampal structures that are principally involved in memory processing, spatial processing and navigation. Investigation epigenetic and senescence hallmarks to shed light on relevant molecular pathway affected by D+Q treatment.

Methods: Young (3-month-old) and naturally aged male Wistar rats (18-/22-month-old) were treated with D+Q for eight weeks and tested in the active allothetic place avoidance task. Arterious blood was collected to assess cytokines level. Fresh hippocampal slices were stained with Dil to analyze dendritic spine morphology. Epigenetic and senescence markers were quantified from fixed hippocampal slices or lysates.

Results: We confirmed the cognitive decline of aged rats compare to younger animals. We observed in aged but not young rats treated with D+Q a reduction in systemic inflammation and an alleviation of aged-related learning deficits and memory impairments associated with changes in synaptic plasticity and epigenetic but not senescence markers. Furthermore, D+Q treatment retains long lasting effects up to six weeks after treatment.

Conclusion: Our study brings new insights on the effects of D+Q senolytics in alleviating age-associated cognitive dysfunctions.