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

Höhn, Annika; Weber, Daniela; Jung, Tobias; Ott, Christiane; Hugo, Martín; Kochlik, Bastian; Kehm, Richard; König, Jeannette; Grune, Tilman; Castro, José Pedro

doi:10.1016/j.redox.2016.12.001

Cited by 267 publications

(209 citation statements)

References 328 publications

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“…Gradual build up of senescent cardiomyocytes occurs during ageing and in various cardiac diseases 158 . Experimental evidence from ageing mice demonstrates that twice weekly killing of senescent cells for 6 months, by activating a drug inducible 'suicide' protein in senescent cells, decreases cardiac surface expression of the senescence marker β galactosidase, decreases cardio myocyte size, and improves cardiac stress toler ance at age 18 months, without improving cardiac mass or dimensions 159 .…”

Section: Cellular Senescencementioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

132

111

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Section: Cellular Senescencementioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

132

111

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“…whether they will refold into their original conformation or whether they will be removed from the cell (Kaushik & Cuervo, ; Anthony, ; Hohn et al . ). When a protein is targeted for degradation, chaperones often dictate which proteolytic pathway these unfolded, misfolded or oxidised proteins will follow.…”

Section: Introductionmentioning

confidence: 97%

Role of nerve–muscle interactions and reactive oxygen species in regulation of muscle proteostasis with ageing

Vasilaki

Richardson

Remmen

et al. 2017

The Journal of Physiology

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Skeletal muscle ageing is characterised by atrophy, a deficit in specific force generation, increased susceptibility to injury, and incomplete recovery after severe damage. The hypothesis that increased generation of reactive oxygen species (ROS) in vivo plays a key role in the ageing process has been extensively studied, but remains controversial. Skeletal muscle generates ROS at rest and during exercise. ROS can cause oxidative damage particularly to proteins. Indeed, products of oxidative damage accumulate in skeletal muscle during ageing and the ability of muscle cells to respond to increased ROS becomes defective. The aim of this review is to examine the evidence that ROS manipulation in peripheral nerves and/or muscle modifies mechanisms of proteostasis in skeletal muscle and plays a key role in initiating sarcopenia.

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“…Proteome oxidation caused by reactive oxygen species (ROS) is a primary determinant of 35 cellular sensitivity to desiccation and irradiation (1,2) and is involved in the progression of agerelated human diseases, including neurodegeneration and cancer (3). ROS toxicity is a common antibiotic mechanism (4) and presents challenges in biotechnology including metabolic engineering (5-7) and synthetic systems involving the high expression of fluorescent proteins (8).…”

Section: Main Textmentioning

confidence: 99%