Aging has long been thought to be an irreversible process associated with a decline in tissue homeostasis, repair and regeneration potential. The brain is particularly vulnerable to the effects of aging, since it is an organ with limited regenerative capacity, which can have detrimental consequences on cognitive processes leading to devastating neurodegenerative diseases. Given the increased life expectancy in our current society, the number of people likely to be affected by an age-related debilitating disease has increased. Therefore, the identification of specific mechanisms underlying neural stem cell aging and the possibility to restore tissue functions in order to delay aging, and improve healthspan, are crucial.

The regenerative potential of the brain lies upon the ability of its neural stem cells (NSCs) to continuously give rise to new neurons, a process called neurogenesis that is central to memory formation, cognition, mood states, as well as brain homeostasis and repair upon injury. NSCs live primarily in two neurogenic niches, the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus, and they exist mainly in two states: either quiescent (qNSCs) or activated (aNSCs). Quiescent NSCs (EGFR-), are the main reservoir for future regenerative needs of the brain, and they are non-dividing, or extremely slowly dividing. Upon extrinsic cues they become aNSCs (EGFR+) and start self-renewing, proliferating and differentiating into new neurons. Therefore, aNSCs are the main drivers of neurogenesis. However, as the organism ages, NSCs decline in number but also in their capacity to self-renew and differentiate, thus depriving the brain from its regenerative capacity. Intrinsically, aged NSCs exhibit defects in their cell cycle, damaged telomeres, defects in their intrinsic metabolic processes and accumulation of protein aggregates and damaged proteins, which prevent activation and self-renewal. It is still unclear what exactly drives NSC aging, as this field is only beginning to be explored, but it has been shown that systemic and niche/paracrine niche signals negatively regulate regeneration of aged NSCs.

We previously showed that young blood can rejuvenate the regenerative capacities of NSCs, whereas old blood accelerates NSC aging.

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Our current projects focus on understanding the mechanisms underlying NSC aging and identifying molecules and pathways in order to reverse these processes.

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