Abstract
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.
Highlights
Aging is accompanied by a wide range of symptoms that reduce health span, such as cardiovascular dysfunction, osteoporosis, neurodegeneration and cancer, among other diseases
Since several reports indicate the presence of senescent glial cells in old brains [13], we considered that glial cells could become senescent and promote paracrine neuronal senescence; we allowed the proliferation of glial cells during the culture of primary cortical cells
Every senescent marker we looked at in primary culture of senescent neurons was confirmed in old rat brains (25 months old), validating this in vitro neuronal senescence model
Summary
Aging is accompanied by a wide range of symptoms that reduce health span, such as cardiovascular dysfunction, osteoporosis, neurodegeneration and cancer, among other diseases. Amelioration of those symptoms has been achieved after pharmacological interventions using a novel class of drugs termed senolytics. These compounds clear senescent cells that accumulate late in life both in normal tissues and especially in those affected by age-related pathologies [1]. The most important activity of senescent cells is the secretion of a set of molecules, known as the senescence-associated secretory phenotype (SASP) that, depending on the physiological context, can be either beneficial or harmful. SASP molecules have an autocrine role, fostering the senescent phenotype, and a paracrine role inducing senescence in surrounding cells [5], inflammation and tumorigenesis [6, 7]
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