Found at Fisetin Research and Reports
Abstract
Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity. Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone). Iron accumulation in senescent cells was driven by impaired ferritinophagy, a lysosomal process that promotes ferritin degradation and ferroptosis. Lysosomal dysfunction in senescent cells was confirmed through several markers, including the build-up of microtubule-associated protein light chain 3 (LC3-II) in autophagosomes. Impaired ferritin degradation explains the iron accumulation phenotype of senescent cells, whereby iron is effectively trapped in ferritin creating a perceived cellular deficiency. Accordingly, senescent cells were highly resistant to ferroptosis. Promoting ferritin degradation by using the autophagy activator rapamycin averted the iron accumulation phenotype of senescent cells, preventing the increase of TfR1, ferritin and intracellular iron, but failed to re-sensitize these cells to ferroptosis. Finally, the enrichment of senescent cells in mouse ageing hepatic tissue was found to accompany iron accumulation, an elevation in ferritin and mirrored our observations using cultured senescent cells.
Cellular senescence refers to cells that have undergone irreversible growth arrest through replicative exhaustion, or in response to a variety of pro-oncogenic cellular stresses (e.g. oncogenes, oxidants, and radiation) [1], [2]. Irrespective of the stimulus, senescence safeguards against the unrestricted growth of damaged cells and promotes cellular clearance through eliciting the immune system. However, senescent cells accumulate with age and contribute to chronic diseases and age-related dysfunctions, in part, through the pro-inflammatory factors (e.g. cytokines & chemokines) they secrete (senescence-associated secretory phenotype; SASP) [1], [2]. Senescent cells and SASP have been linked with chronic inflammation that is often observed during ageing in tissues in the absence of obvious infection [2]. The clearance of senescent cells in mice, using a novel transgene (INK-ATTAC) that allows for selective apoptosis of p16-positive senescent cells in vivo, improved healthspan by attenuating age-related pathologies both prophylactically and as treatment [3], [4]. Removal of p16-positive senescent cells in ageing mice delayed tumourigenesis and attenuated age-related deterioration of several organs, including kidney, heart and adipose tissue, without adverse side effects [3]. Furthermore, a median lifespan extension was observed, indicating that p16-positive senescent cells negatively impact longevity [3].
Senolytic (anti-senescence) treatment is also sought-after for cancer therapy, as current chemotherapeutics (e.g. DNA damaging agents) can cause cancer cells to become senescent [5], [6], [7], [8]. Senescent cells are linked with cancer drug resistance and recurrence [9], [10]. A novel senolytic agent (FOXO4-p53 interfering peptide) has shown promise in mice, promoting apoptosis of doxorubicin-induced senescent cells, neutralizing doxorubicin-induced toxicity and improving overall healthspan [6]. Together, these studies demonstrate tangible health benefits for targeting senescent cells and thereby identify senescent cells as being integral to many age-related pathologies and dysfunctions.
Several reports have described dysfunctional iron homeostasis with ageing, either systemically [11], [12], or in specific organ systems affected by age-related pathologies [13], [14], [15]. Age-dependent accumulation of iron in various tissues has been reported to occur separately to the enrichment of senescent cells [11], [12], [16], [17], [18], [19]. Diseases associated with the accumulation of senescent cells, such as neurodegenerative disorders (e.g. Alzheimer's and Parkinson's) [20], [21], [22], osteoarthritis [23], [24] and idiopathic pulmonary fibrosis [25], also exhibit iron dyshomeostasis where often iron burden correlates with disease severity [14], [15], [26], [27], [28], [29], [30], [31], [32], [33], [34]. Iron accumulation occurs in replicative senescent fibroblasts in vitro [35] and the iron storage protein ferritin is enriched in ageing tissues [36], [37]. Since excess iron can be toxic through redox activity, iron burden has been hypothesized to cause cellular damage or to promote ferroptosis. However, the relationship between senescent cells and iron dyshomeostasis in ageing, or in age-related pathologies, is unclear. We therefore investigated whether altered iron homeostasis is a characteristic of senescent cells using mammalian cell culture models and aged wild-type (wt) C57BL/6 mice. The aim was to determine if the senescence phenotype is intrinsically linked with changes to cellular iron homeostasis and related cell death pathways.
Edited by Engadin, 14 May 2019 - 06:03 PM.
