Senescence in Post-Mitotic Cells: A Driver of Aging?

Abstract

Significance: Cell senescence was originally defined by an acute loss of replicative capacity and thus believed to be restricted to proliferation-competent cells. More recently, senescence has been recognized as a cellular stress and damage response encompassing multiple pathways or senescence domains, namely DNA damage response, cell cycle arrest, senescence-associated secretory phenotype, senescence-associated mitochondrial dysfunction, autophagy/mitophagy dysfunction, nutrient and stress signaling, and epigenetic reprogramming. Each of these domains is activated during senescence, and all appear to interact with each other. Cell senescence has been identified as an important driver of mammalian aging. Recent Advances: Activation of all these senescence domains has now also been observed in a wide range of post-mitotic cells, suggesting that senescence as a stress response can occur in nondividing cells temporally uncoupled from cell cycle arrest. Here, we review recent evidence for post-mitotic cell senescence and speculate about its possible relevance for mammalian aging. Critical Issues: Although a majority of senescence domains has been found to be activated in a range of post-mitotic cells during aging, independent confirmation of these results is still lacking for most of them. Future Directions: To define whether post-mitotic senescence plays a significant role as a driver of aging phenotypes in tissues such as brain, muscle, heart, and others. Antioxid. Redox Signal. 34, 308-323.

Keywords: aging; post-mitotic; senescence.

FIG. 1.

Phenotypes (“building blocks”) of the senescent state and observable markers associated with it. Although all phenotypes are tightly interrelated (not shown), individual phenotypes might be more or less strongly activated in individual senescent cells depending on contexts including senescence inducer, cell type, tissue environment, and others. For each phenotype, there are multiple markers that enable assessment of its involvement in a given senescent state. CI, complex I of the mitochondrial electron transport chain; DDF, DNA damage foci; DDR, DNA damage response; ROS, reactive oxygen species; SADS, senescence-associated distension of satellites; SAHF, senescence-associated heterochromatin foci; SAMD, senescence-associated mitochondrial dysfunction; SASP, senescence-associated secretory phenotype; SCARS, DNA segments with chromatin alterations reinforcing senescence; TAF, telomere-associated foci; TL, telomere length. Color images are available online.

FIG. 2.

Senescence markers measured in neurons. (A) Purkinje neurons (labeled by calbindin, purple) in an old (32 months) mouse frequently stain positive for IL-6 (green) (60). (B) Senescence markers observed and senescence phenotypes inferred in neurons (60, 98, 104). IL, interleukin. Color images are available online.

FIG. 3.

Senescence markers measured in cardiomyocytes. (A) Mouse cardiomyocytes (labelled with Troponin C, white) show co-localization of telomeres (red) and γH2AX-positive DDF (green) (4). Cardiomyocyte nuclei are labelled with dotted lines. (B) Senescence markers observed and senescence phenotypes inferred in cardiomyocytes (4). Color images are available online.

FIG. 4.

Senescence markers measured in skeletal muscle myofibers. (A) Gastrocnemius muscle from a 32-month-old mouse. Blue: DAPI, red: p21, green: autofluorescence (28). White arrows indicate p21-positive centrally located nuclei. (B) Senescence markers observed and senescence phenotypes inferred in skeletal myofibers (28). Color images are available online.

FIG. 5.

Senescence markers measured in osteocytes. (A) SADS (arrows) in an osteocyte freshly isolated from bone marrow of old (24 months) mice (38). (B) Senescence markers observed and senescence phenotypes inferred in osteocytes (38). Color images are available online.

FIG. 6.

Senescence markers measured in post-mitotic cochlear cells. (A) Basal region of cochlear explant stained with myosin 7A (red, outer hair cell [OHC] and inner hair cell [IHC]) and with neurofilament 200 (green, auditory nerve fibers, nf) (6). (B) Senescence markers observed and senescence phenotypes inferred in cochlear cells (6). Color images are available online.