Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.
The hippocampus is essential for learning and memory,but it also plays an important role in regulating emotional behavior,as hippocampal excitability and plasticity affect anxiety and fear.Brain synaptic plasticity may be regulated by tissue inhibitor of matrix metalloproteinase 1(TIMP1),a known protein inhibitor of extracellular matrix(ECM),and the expression of TIMP1 in the hippocampus can be induced by neuronal excitation and various stimuli.However,the involvement of Timp1 in fear learning,anxiety,and hippocampal synaptic function remains to be established.Our study of Timp1 function in vivo revealed that Timp1 knockout mice exhibit anxiety-like behavior but normal fear learning.Electrophysiological results suggested that Timp1 knockout mice showed hyperactivity in the ventral CA1 region,but the basic synaptic transmission and plasticity were normal in the Schaffer collateral pathway.Taken together,our results suggest that deletion of Timp1 in vivo leads to the occurrence of anxiety behaviors,but that Timp1 is not crucial for fear learning.
