Senescent cells cause harm to surrounding tissue when they linger over time, evading the usual fate of self-destruction or destruction by the immune system. They secrete inflammatory and other signals that rouse the immune system into a state of chronic inflammation, destructively remodel nearby tissue, and encourage other cells to become senescent. The presence of senescent cells is a significant cause of aging and age-related disease, as demonstrated by studies in which senolytic therapies are used to selectively remove some portion of the burden of senescent cell in old tissues.
Researchers here show that long-lived non-dividing cells in the brain also become senescent, and that a faltering of the cell maintenance processes of autophagy is important in this process. One of the reasons why autophagy declines with age, particularly in long-lived cells, is the build up of hardy metabolic waste products that clutter the recycling structures called lysosomes, making them inefficient and bloated. More effort should be devoted towards building therapies capable of breaking down the waste products that our biochemistry struggles with.
Senescent cells accumulate in various tissues and organs with aging altering surrounding tissue due to an active secretome, and at least in mice their elimination extends healthy lifespan and ameliorates several chronic diseases. Whether all cell types senesce, including post-mitotic cells, has been poorly described mainly because cellular senescence was defined as a permanent cell cycle arrest. Nevertheless, neurons with features of senescence have been described in old rodent and human brains.
In this study we characterized an in vitro model useful to study the molecular basis of senescence of primary rat cortical cells that recapitulates senescent features described in brain aging. We found that in long-term cultures, rat primary cortical neurons displayed features of cellular senescence before glial cells did, and developed a functional senescence-associated secretory phenotype able to induce paracrine premature senescence of mouse embryonic fibroblasts but proliferation of rat glial cells.
Functional autophagy seems to prevent neuronal senescence, as we observed an autophagic flux reduction in senescent neurons both in vitro and in vivo, and autophagy impairment induced cortical cell senescence while autophagy stimulation inhibited it. Our findings suggest that aging-associated dysfunctional autophagy contributes to senescence transition also in neuronal cells.