Proteins can become modified by a large number of reactions involving reactive oxygen species. Among these reactions, carbonylation has attracted a great deal of attention due to its irreversible and ...unrepairable nature. Carbonylated proteins are marked for proteolysis by the proteasome and the Lon protease but can escape degradation and form high‐molecular‐weight aggregates that accumulate with age. Such carbonylated aggregates can become cytotoxic and have been associated with a large number of age‐related disorders, including Parkinson's disease, Alzheimer's disease, and cancer. This review focuses on the generation of and defence against protein carbonyls and speculates on the potential role of carbonylation in protein quality control, cellular deterioration, and senescence.
Type 2 diabetes and attendant cardiovascular morbidity are becoming major health concerns globally. Obesity-related type 2 diabetes is rapidly rising in prevalence, probably largely because of ...increased longevity and sedentary lifestyles. Insulin resistance and type 2 diabetes are associated with increased coronary heart disease, but the severity of glycaemia during the diabetic phase can only to a minor extent explain the increased risk. Increased levels of the acute-phase inflammatory marker, C-reactive protein (CRP), are related to insulin resistance and the metabolic syndrome, suggesting a role for chronic low-grade inflammation. CRP levels might predict the development of type 2 diabetes.
Subodh Verma and associates (Circulation 2004; 109: 2058–67) recently showed that CRP attenuates the survival, differentiation, and function of endothelial progenitor cells, partly by CRP reducing expression of endothelial nitric-oxide synthase. Rosiglitazone, a peroxisome-proliferator-activator receptor γ agonist, inhibits the negative effects of CRP on endothelial progenitor cells. The results are consistent with the suggestion that CRP directly promotes atherosclerotic processes and endothelial cell inflammation. CRP might thus directly trigger the development of a proinflammatory and proatherosclerotic state, leading to atherothrombosis.
Cell-surface CRP receptors and signalling pathways need to be characterised. From such study might come novel drugs that will defer proinflammatory reactions leading to insulin resistance and atherothrombosis.
Yeast cytokinesis entails a rejuvenation process by which the aged mother cell generates daughter cells enjoying full replicative potential. Here we show that this process includes a precipitous ...reduction in the levels of reactive oxygen species in the progeny immediately after completion of cytokinesis. The reduction in hydrogen peroxide is the result of a Sir2p and actin cytoskeleton-dependent segregation of the cytosolic catalase Ctt1p such that the daughter cell receives a higher load of undamaged and active Ctt1p than the progenitor cell. Such spatial quality control provides the daughter cells with a superior capacity to combat external oxidative stress and delays self-inflicted oxidative damage to their cellular proteins.
Spatial Protein Quality Control (sPQC) sequesters misfolded proteins into specific, organelle-associated inclusions within the cell to control their toxicity. To approach the role of sPQC in cellular ...fitness, neurodegenerative diseases and aging, we report on the construction of Hsp100-based systems in budding yeast cells, which can artificially target protein aggregates to non-canonical locations. We demonstrate that aggregates of mutant huntingtin (mHtt), the disease-causing agent of Huntington's disease can be artificially targeted to daughter cells as well as to eisosomes and endosomes with this approach. We find that the artificial removal of mHtt inclusions from mother cells protects them from cell death suggesting that even large mHtt inclusions may be cytotoxic, a trait that has been widely debated. In contrast, removing inclusions of endogenous age-associated misfolded proteins does not significantly affect the lifespan of mother cells. We demonstrate also that this approach is able to manipulate mHtt inclusion formation in human cells and has the potential to be useful as an alternative, complementary approach to study the role of sPQC, for example in aging and neurodegenerative disease.
The aim of this study was to investigate temporal trends in survival and subsequent cardiovascular events in a nationwide myocardial infarction population with and without diabetes.
Between 2006 and ...2020, we identified 2527 individuals with type 1 diabetes, 48 321 individuals with type 2 diabetes and 243 170 individuals without diabetes with first myocardial infarction in national health care registries. Outcomes were trends in all-cause death after 30 and 365 days, cardiovascular death and major adverse cardiovascular events (ie, nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, and heart failure hospitalization). Pseudo-observations were used to estimate the mortality risk, with 95% CIs, using linear regression, adjusted for age and sex. Individuals with type 1 diabetes were younger (62±12.2 years) and more often women (43.6%) compared with individuals with type 2 diabetes (75±10.8 years; women, 38.1%), and individuals without diabetes (73±13.2 years; women, 38.4%). Early death decreased in people without diabetes from 23.1% to 17.5%, (annual change -0.48% 95% CI, -0.52% to -0.44%) and in people with type 2 diabetes from 22.6% to 19.3% (annual change, -0.33% 95% CI, -0.43% to -0.24%), with no such significant trend in people with type 1 diabetes from 23.8% to 21.7% (annual change, -0.18% 95% CI, -0.53% to 0.17%). Similar trends were observed with regard to 1-year death, cardiovascular death, and major adverse cardiovascular events.
During the past 15 years, the trend in survival and major adverse cardiovascular events in people with first myocardial infarction without diabetes and with type 2 diabetes have improved significantly. In contrast, a similar improvement was not seen in people with type 1 diabetes.
Interconnectivity and feedback control are hallmarks of biological systems. This includes communication between organelles, which allows them to function and adapt to changing cellular environments. ...While the specific mechanisms for all communications remain opaque, unraveling the wiring of organelle networks is critical to understand how biological systems are built and why they might collapse, as occurs in aging. A comprehensive understanding of all the routes involved in inter-organelle communication is still lacking, but important themes are beginning to emerge, primarily in budding yeast. These routes are reviewed here in the context of sub-system proteostasis and complex adaptive systems theory.
The communication between cellular organelles is important for basic cellular function. Mapping the wiring between organelle networks can reveal how and when a collapse in communication may occur, such as aging.
Metacaspases are ancestral homologs of caspases that can either promote cell death or confer cytoprotection. Furthermore, yeast (Saccharomyces cerevisiae) metacaspase Mca1 possesses dual biochemical ...activity: proteolytic activity causing cell death and cytoprotective, co-chaperone-like activity retarding replicative aging. The molecular mechanism favoring one activity of Mca1 over another remains elusive. Here, we show that this mechanism involves calmodulin binding to the N-terminal pro-domain of Mca1, which prevents its proteolytic activation and promotes co-chaperone-like activity, thus switching from pro-cell death to anti-aging function. The longevity-promoting effect of Mca1 requires the Hsp40 co-chaperone Sis1, which is necessary for Mca1 recruitment to protein aggregates and their clearance. In contrast, proteolytically active Mca1 cleaves Sis1 both in vitro and in vivo, further clarifying molecular mechanism behind a dual role of Mca1 as a cell-death protease versus gerontogene.
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•Metacaspase Mca1 executes cell death and cleaves the Hsp40 co-chaperone Sis1•Calmodulin inhibits proteolytic activity of Mca1 by binding to its N terminus•This binding promotes co-chaperone-like activity of Mca1 in Sis1-dependent PQC and longevity
Eisele-Bürger et al. report that the dual role of yeast metacaspase Mca1 as a pro- and anti-death factor involves calmodulin binding to its N terminus. This binding inhibits proteolytic activity of Mca1 essential for cell death while enabling its co-chaperone-like activity in Hsp40-dependent proteostasis and longevity.
Protein carbonylation is an irreversible oxidative process leading to a loss of function of the modified proteins, and in
a variety of model systems, including worms, flies, and mammals, carbonyl ...levels gradually increase with age. In contrast,
we report here that in Arabidopsis thaliana an initial increase in protein oxidation during the first 20 days of the life cycle of the plant is followed by a drastic
reduction in protein carbonyls prior to bolting and flower development. Protein carbonylation prior to the transition to flowering
targets specific proteins such as Hsp70, ATP synthases, the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase
(Rubisco), and proteins involved in light harvesting/energy transfer and the C2 oxidative photosynthetic carbon cycle. The
precipitous fall in protein carbonyl levels is due to the specific reduction in the levels of oxidized proteins rather than
an overall loss of chlorophyll and Rubisco associated with the senescence syndrome. The results are discussed in light of
contemporary theories of aging in animals.
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