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In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed “senescence”. For nearly 60 years, the cell biology fields of neuroscience and senescence ran in parallel, each separately defining phenotypes and uncovering molecular mediators to explain the 1960s observations of their founding mothers and fathers, respectively. During this time neuroscientists have consistently observed the remarkable ability of neurons to survive. Despite residing in environments of chronic inflammation and degeneration, as occurs in numerous neurodegenerative diseases, often times the neurons with highest levels of pathology resist death. Similarly, cellular senescence (hereon referred to simply as “senescence”) now is recognized as a complex stress response that culminates with a change in cell fate. Instead of reacting to cellular/DNA damage by proliferation or apoptosis, senescent cells survive in a stable cell cycle arrest. Senescent cells simultaneously contribute to chronic tissue degeneration by secreting deleterious molecules that negatively impact surrounding cells. These fields have finally collided. Neuroscientists have begun applying concepts of senescence to the brain, including post-mitotic cells. This initially presented conceptual challenges to senescence cell biologists. Nonetheless, efforts to understand senescence in the context of brain aging and neurodegenerative disease and injury emerged and are advancing the field. The present review uses pre-defined criteria to evaluate evidence for post-mitotic brain cell senescence. A closer interaction between neuro and senescent cell biologists has potential to advance both disciplines and explain fundamental questions that have plagued their fields for decades.

Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.

In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve crosssection were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of~18.5 (p genome-wide~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including Gpnmb, Tyrp1, Cdh11, Pou6f2, and Cacna2d1. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes-CDC42 binding protein kinase beta (Cdc42bpb); eukaryotic translation initiation factor 5 (Eif5); BCL2-associated athanogene 5 (Bag5); apoptogenic 1, mitochondrial (Apopt1); kinesin light chain 1 (Klc1); X-ray repair cross complementing 3 (Xrcc3); protein phosphatase 1, regulatory subunit 13B (Ppp1r13b); and transmembrane protein 179 (Tmem179)-passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.

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IntroductionChanges in dynamic metabolic processes during lung development is not well known, particularly during the saccular and alveolar stages. Lungs of infants prematurely born during either stage have underdeveloped alveolar sacs with arrested growth and frequently require oxygen supplementation, which can result in lung disease of prematurity (bronchopulmonary dysplasia, BPD). Oxidation‐reduction (redox) processes are important in both lung development and pathogenesis; however, clinical studies attempting to limit BPD pathogenesis targeting redox processes have not been promising. In this study, metabolomics were utilized to identify alternative metabolic perturbations during the two lung development stages in an established murine model of hyperoxia‐induced BPD.MethodsPostnatal day (PN) 3 mice from pairs of pregnant dam mice were pooled, randomized, and left at normoxia (room air, 21% O2) or exposed to hyperoxia (85% O2) in a tight‐sealed, plexiglass chamber until PN 15. Nursing dams were rotated every 24 hours to limit oxygen toxicity. Lungs were isolated from mice on PN 1, 3, 5, 7, 10, and 15 within two minutes then snap frozen in liquid nitrogen. Following methanol extraction, metabolites were detected by liquid chromatography‐mass spectrometry. Statistics including partial least squares – discriminant analysis (PLS‐DA) and Variable Importance in Projection (VIP), i.e. a quantitative measure of discriminating metabolites, were performed using Python 2.7/3.0 and R.ResultsA series of analysis were performed to validate, identify, and characterize both significant metabolites and their involved pathways. Samples could be separated by both time and oxygen‐level using PLS‐DA. Enrichment analysis of metabolites with VIP ≥ 1 indicated that both the methionine‐homocysteine degradation cycle (p ≤ 1e‐4) and downstream of it, polyamine synthesis was perturbed (p ≤ 1e‐4). Components of both the arginine and glutathione metabolism pathways were also significantly enriched (p ≤ 1e‐4). Metabolites specifically found in the prior enrichment analysis (e.g., cystathione in glutathione metabolism, spermine, spermidine in polyamine synthesis) were significantly elevated in hyperoxic lung tissues on PN 5, 7, and 10 (one way ANOVA, p ≤ 1e‐2). Metabolites with a fold change of ≥ 1.3 from only day 5 lung tissues were significantly enriched for methylhistidine metabolism (p ≤ 1e‐5).ConclusionSignificant alterations of redox process such as glutathione or arginine metabolism were found which corroborate current studies in lung development and BPD. Yet other metabolic processes such as methionine‐homocysteine degradation and polyamine synthesis were discovered. Deregulation of the recycling of homocysteine into methionine and how it is further metabolized into polyamines is common in other pathogenesis. Further examination to intervene the deregulation in BPD pathogenesis may be attractive.Support or Funding InformationNIH Grant to MAS (R21 HD090227) and fellowship to DL (T32 HL091816‐09)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.