Macroautophagy is impaired in old murine brain tissue as well as in senescent human fibroblasts

Ott, Christiane; König, Jeannette; Höhn, Annika; Jung, Tobias; Grune, Tilman

doi:10.1016/j.redox.2016.10.015

Cited by 72 publications

(59 citation statements)

References 45 publications

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“…As EP2 signaling contributes to senescence in fibroblasts [72], and EP2 deletion reduces oxidative damage and severity of Alzheimer's disease [73], which suggests EP2 signaling as a potential link between defective autophagy and senescence/aging. Recently, it was shown, that in aged dermal fibroblasts and brain tissue the autophagic activity was declined [74], underlining the potential impact of autophagy and lipid mediators in age associated diseases.…”

Section: Discussionmentioning

confidence: 99%

Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo

et al. 2017

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Autophagy allows cells fundamental adaptations to metabolic needs and to stress. Using autophagic bulk degradation cells can clear crosslinked macromolecules and damaged organelles that arise under redox stress. Accumulation of such debris results in cellular dysfunction and is observed in aged tissue and senescent cells. Conversely, promising anti-aging strategies aim at inhibiting the mTOR pathway and thereby activating autophagy, to counteract aging associated damage. We have inactivated autophagy related 7 (Atg7), an essential autophagy gene, in murine keratinocytes (KC) and have found in an earlier study that this resulted in increased baseline oxidative stress and reduced capacity to degrade crosslinked proteins after oxidative ultraviolet stress. To investigate whether autophagy deficiency would promote cellular aging, we studied how Atg7 deficient (KO) and Atg7 bearing cells (WT) would respond to stress induced by paraquat (PQ), an oxidant drug commonly used to induce cellular senescence.Atg7 deficient KC displayed increased prostanoid signaling and a pro- mitotic gene expression signature as compared to the WT. After exposure to PQ, both WT and KO cells showed an inflammatory and stress-related transcriptomic response. However, the Atg7 deficient cells additionally showed drastic DNA damage- and cell cycle arrest signaling. Indeed, DNA fragmentation and –oxidation were strongly increased in the stressed Atg7 deficient cells upon PQ stress but also after oxidizing ultraviolet A irradiation. Damage associated phosphorylated histone H2AX (γH2AX) foci were increased in the nuclei, whereas expression of the nuclear lamina protein lamin B1 was strongly decreased. Similarly, in both, PQ treated mouse tail skin explants and in UVA irradiated mouse tail skin, we found a strong increase in γH2AX positive nuclei within the basal layer of Atg7 deficient epidermis.Atg7 deficiency significantly affected expression of lipid metabolic genes. Therefore we performed lipid profiling of keratinocytes which demonstrated a major dysregulation of cellular lipid metabolism. We found accumulation of autophagy agonisitic free fatty acids, whereas triglyceride levels were strongly decreased. Together, our data show that in absence of Atg7/autophagy the resistance of keratinocytes to intrinsic and environmental oxidative stress was severely impaired and resulted in DNA damage, cell cycle arrest and a disturbed lipid phenotype, all typical for premature cell aging.

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Section: Discussionmentioning

confidence: 99%

Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo

et al. 2017

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“…8). Furthermore, it was reported that mTORC1 activity is enhanced in aged tissue and linked to mitochondrial dysfunction independent of growth factor signaling [177], [178]. ALP-related proteins, demonstrating reduced MA in aging are summarized in Table 1.…”

Section: Proteostasis In Agingmentioning

confidence: 99%

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

et al. 2017

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Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies) by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset.

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“…Many of these alterations may arise, at least in part, from deterioration of basal autophagy and/or impairment of correct autophagy flux induction during cellular stress [2], although data assessing the role of autophagy in brain physiological aging is only beginning to emerge. In the human aged brain, a downregulation of autophagy genes including ATG-5, ATG-7, and BECN-1 has been observed [30], and brains of aged rodents exhibit increased MTORC1 activity together with a decline of ATG protein levels [31,32], suggesting decreased autophagic function. Similarly, mice carrying neural lineage-specific deletions of ATG-5 [27] and ATG-7 [28] show spontaneous and accelerated neurodegeneration.…”

Section: Autophagy In the Central Nervous System (Cns)mentioning

confidence: 99%

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Plaza-Zabala

Sierra-Torre

Sierra

2017

IJMS

260

209

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Abstract:Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer's, Parkinson's, and Huntington's diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence.

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Macroautophagy is impaired in old murine brain tissue as well as in senescent human fibroblasts

Cited by 72 publications

References 45 publications

Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo

Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

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