scholarly journals Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in Caenorhabditis elegans

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Chaolie Huang ◽  
Sara Wagner-Valladolid ◽  
Amberley D Stephens ◽  
Raimund Jung ◽  
Chetan Poudel ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Aging Process ◽  
Amyloid Fibrils ◽  
Functional Decline ◽  
Molecular Feature ◽  
C Elegans ◽  
Age Dependent ◽  
Dependent Protein ◽  
Tissue Aging ◽  
Different Tissues

Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life.

scholarly journals Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans

2018 ◽  
Author(s):  
C. Huang ◽  
S. Wagner-Valladolid ◽  
A.D. Stephens ◽  
R. Jung ◽  
C. Poudel ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Functional Decline ◽  
C Elegans ◽  
Amyloid Aggregates ◽  
Age Dependent ◽  
Dependent Protein ◽  
Specific Proteins ◽  
Protein Instability ◽  
Tissue Aging

AbstractReduced protein homeostasis and increased protein instability is a common feature of aging. Yet it remains unclear whether protein instability is a cause of aging. In neurodegenerative diseases and amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological solid aggregates in a variety of tissues. More recently, widespread protein aggregation has been described during normal aging, in the absence of disease processes. Until now, an extensive characterization of the nature of age-dependent protein aggregation and its consequences for aging has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and contain amyloid-like structures similar to disease-associated protein aggregates. Moreover, we demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these finding reveal that the formation of amyloid aggregates is a generic problem of aging and likely to be an important target for strategies designed to maintain physiological functions in later stages of life.

scholarly journals PIP3-binding proteins promote age-dependent protein aggregation and limit survival in C. elegans

Oncotarget ◽  
2016 ◽  
Vol 7 (31) ◽  
pp. 48870-48886 ◽  
Author(s):  
Srinivas Ayyadevara ◽  
Meenakshisundaram Balasubramaniam ◽  
Jay Johnson ◽  
Ramani Alla ◽  
Samuel G. Mackintosh ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Binding Proteins ◽  
C Elegans ◽  
Age Dependent ◽  
Dependent Protein

scholarly journals New Insights into Chronological Mobility of Retrotransposons In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Amr. R. Ghanam ◽  
Jun Cao ◽  
Xuan Ouyang ◽  
Xiaoyuan Song
Keyword(s):  
Aging Process ◽  
Therapeutic Interventions ◽  
Chronological Aging ◽  
Mouse Tissues ◽  
Biological Compounds ◽  
Physiological Homeostasis ◽  
Tissue Aging ◽  
Cell Expression ◽  
Different Tissues

Tissue aging is the gradual decline of physiological homeostasis accompanied with accumulation of senescent cells, decreased clearance of unwanted biological compounds, and depletion of stem cells. Senescent cells were cell cycle arrested in response to various stimuli and identified using distinct phenotypes and changes in gene expression. Senescent cells that accumulate with aging can compromise normal tissue function and inhibit or stop repair and regeneration. Selective removal of senescent cells can slow the aging process and inhibits age-associated diseases leading to extended lifespans in mice and thus provides a possibility for developing antiaging therapy. To monitor the appearance of senescent cells in vivo and target them, a clearer understanding of senescent cell expression markers is needed. We investigated the age-associated expression of three molecular hallmarks of aging: SA-β-gal, P16INK4a, and retrotransposable elements (RTEs), in different mouse tissues during chronological aging. Our data showed that the expression of these markers is variable with aging in the different tissues. P16INK4a showed consistent increases with age in most tissues, while expression of RTEs was variable among different tissues examined. These data suggest that biological changes occurring with physiological aging may be useful in choosing the appropriate timing of therapeutic interventions to slow the aging process or keep more susceptible organs healthier in the aging process.

scholarly journals Drosophila p38 MAPK Interacts with BAG-3/starvin to Regulate Age-dependent Protein Homeostasis

2019 ◽  
Author(s):  
Sarah M. Ryan ◽  
Michael Almassey ◽  
Amelia M. Burch ◽  
Gia Ngo ◽  
Julia M. Martin ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
P38 Mapk ◽  
Protein Aggregates ◽  
Protein Homeostasis ◽  
Selective Autophagy ◽  
Age Related ◽  
Age Dependent ◽  
Dependent Protein ◽  
Locomotor Behaviors ◽  
The Relationship

SummaryAs organisms age, they often accumulate protein aggregates that are thought to be toxic, potentially leading to age-related diseases. This accumulation of protein aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of genetic factors have been linked to longevity, but how these factors also contribute to protein homeostasis is not completely understood. In order to understand the relationship between aging and protein aggregation, we tested how a gene that regulates lifespan and age-dependent locomotor behaviors, p38 MAPK (p38Kb), influences protein homeostasis as an organism ages. We find that p38Kb regulates age-dependent protein aggregation through an interaction with the Chaperone-Assisted Selective Autophagy complex. Furthermore, we have identified Lamin as an age-dependent target of p38Kb and the Chaperone-Assisted Selective Autophagy complex.

scholarly journals A genetic screen identifies processes that couple oocyte maturation to proteostasis in the immortal C. elegans germ lineage

2020 ◽  
Author(s):  
Madhuja Samaddar ◽  
Jérôme Goudeau ◽  
Melissa Sanchez ◽  
David H. Hall ◽  
K. Adam Bohnert ◽  
...  
Keyword(s):  
Oocyte Maturation ◽  
Cell Biology ◽  
Cell Lineage ◽  
Genetic Screen ◽  
Protein Aggregate ◽  
C Elegans ◽  
Age Dependent ◽  
Dependent Protein ◽  
Atp Generation ◽  
And Function

AbstractSomatic cells age and die, but the germ-cell lineage is immortal. In C. elegans, oocyte-maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen for knockdowns that interfere with aggregate clearance. Oocyte-maturation signals are known to trigger protein-aggregate removal via lysosome acidification, and our findings suggest that lysosomes are acidified as a consequence of changes in ER morphology and function that permit assembly of the lysosomal V-ATPase. Once lysosomes are acidified, our genetic findings support the model that they remove aggregates by microautophagy. We also define two functions for mitochondria in this proteostasis renewal, both of which appear to be independent of mitochondrial ATP generation. Finally, many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and the maintenance of the soma.

scholarly journals Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation

2017 ◽  
Vol 9 ◽  
Author(s):  
Nicole Groh ◽  
Anika Bühler ◽  
Chaolie Huang ◽  
Ka Wan Li ◽  
Pim van Nierop ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Amyloid Β ◽  
Age Dependent ◽  
Dependent Protein

scholarly journals Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yanan Sun ◽  
Meijiao Li ◽  
Dongfeng Zhao ◽  
Xin Li ◽  
Chonglin Yang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Food Intake ◽  
Aging Process ◽  
Lifespan Extension ◽  
C Elegans ◽  
Cathepsin Proteases ◽  
Age Dependent ◽  
Genes Encoding ◽  
Degradation Activity ◽  
Lifespan Regulation

Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans. We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2, eat-2 and isp-1, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2, eat-2 and isp-1 worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension.

scholarly journals A transcriptome based aging clock near the theoretical limit of accuracy

2020 ◽  
Author(s):  
David H. Meyer ◽  
Björn Schumacher
Keyword(s):  
Aging Process ◽  
Biological Age ◽  
Therapeutic Interventions ◽  
Epigenetic Alterations ◽  
Theoretical Limit ◽  
C Elegans ◽  
Age Dependent ◽  
Affect Gene Expression ◽  
Age Prediction

Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such as Caenorhabditis elegans and it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy. Here, we devised an approach that uses temporal scaling and binarization of C. elegans transcriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this transcriptome clock can also be applied to human age prediction with high accuracy. This transcriptome aging clock could therefore find wide application in genetic, environmental and therapeutic interventions in the aging process.

scholarly journals Clonal expansion of mitochondrial DNA deletions is a private mechanism of ageing in long-lived animals

2018 ◽  
Author(s):  
Lakshmi Narayanan Lakshmanan ◽  
Zhuangli Yee ◽  
Li Fang Ng ◽  
Rudiyanto Gunawan ◽  
Barry Halliwell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dna ◽  
Functional Decline ◽  
Computational Modelling ◽  
Clonal Expansion ◽  
Mtdna Mutation ◽  
C Elegans ◽  
Mtdna Deletions ◽  
Age Dependent ◽  
And Function

SummaryDisruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of ageing (López-Otín et al. 2013). Human ageing is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle ageing is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions co-localize with sites of fiber-breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age-dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans ageing. Here we report identification of 266 novel mtDNA deletions in ageing nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (1) mtDNA deletions in nematode is extremely rare, (2) there is no significant age-dependent increase in mtDNA deletions and (3) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age-dependent functional decline commonly observed in C. elegans. Computational modelling of mtDNA dynamics in C. elegans indicates that the lifespan of short-lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of ageing predominantly relevant in long-lived animals such as humans and rhesus monkey and possibly in rodents.

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