Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy

Area of Science:

• Neuroscience
• Cell Biology
• Aging Research

Background:

• Cellular senescence, characterized by a permanent cell cycle arrest and active secretome, accumulates with age.
• Senescent cells impact tissue function and are linked to chronic diseases and reduced lifespan.
• While senescence is known in many cell types, its occurrence in post-mitotic cells like neurons is less understood.

Purpose of the Study:

• To characterize an in vitro model for studying neuronal senescence in primary rat cortical cells.
• To investigate the role of autophagy in neuronal senescence.
• To explore the potential of targeting autophagy for age-related neuronal dysfunction.

Main Methods:

• Establishment of long-term cultures of primary rat cortical cells.
• Analysis of senescence markers and the senescence-associated secretory phenotype (SASP) in neurons and glial cells.
• Assessment of autophagic flux in senescent and non-senescent neurons in vitro and in vivo.
• Manipulation of autophagy levels (impairment and stimulation) to observe effects on cortical cell senescence.

Main Results:

• Rat primary cortical neurons exhibited senescence features before glial cells in long-term cultures.
• Senescent neurons displayed a functional SASP, inducing premature senescence in fibroblasts and proliferation in glial cells.
• A reduction in autophagic flux was observed in senescent neurons both in vitro and in vivo.
• Impaired autophagy promoted cortical cell senescence, whereas autophagy stimulation inhibited it.

Conclusions:

• Dysfunctional autophagy is implicated in the transition to senescence in neuronal cells.
• Autophagy plays a protective role against neuronal senescence.
• Aging-associated autophagy decline may contribute to senescence in the brain.