Protein aggregation as a paradigm of aging (original) (raw)

Extensive accumulation of misfolded protein aggregates during natural aging and senescence

Frontiers in Aging Neuroscience

Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells, Caenorhabditis elegans, and mouse tissues collected at different times from youth to old age. Our results show a significant accumulation of misfolded protein aggregates in aged samples as compared to young materials. Indeed, aged samples have between 1.3 and 2.5-fold (depending on the biological system) higher amount of insoluble proteins than young ...

Role of Carbonyl Modifications on Aging-Associated Protein Aggregation

Scientific Reports, 2016

Protein aggregation is a common biological phenomenon, observed in different physiological and pathological conditions. Decreased protein solubility and a tendency to aggregate is also observed during physiological aging but the causes are currently unknown. Herein we performed a biophysical separation of aging-related high molecular weight aggregates, isolated from the bone marrow and splenic cells of aging mice and followed by biochemical and mass spectrometric analysis. The analysis indicated that compared to younger mice an increase in protein post-translational carbonylation was observed. The causative role of these modifications in inducing protein misfolding and aggregation was determined by inducing carbonyl stress in young mice, which recapitulated the increased protein aggregation observed in old mice. Altogether our analysis indicates that oxidative stress-related posttranslational modifications accumulate in the aging proteome and are responsible for increased protein aggregation and altered cell proteostasis. Protein aggregation is a general terminology used to describe the association of proteins into larger assemblies following loss of secondary, tertiary or quaternary structure and often loss of biological activity 1. Protein aggregation is a common biological phenomenon associated with the inability of the cell to maintain homeostasis of the proteome (proteostasis) 1. Under physiological conditions, the tendency of de novo synthesized unfolded proteins to aggregate is regulated by several chaperones that aid in their folding 2,3. Soluble aggregation is also commonly observed in ubiquitinated unfolded proteins before proteasome degradation or in damaged proteins before translocation into lysosomes by chaperone-mediated autophagy 4-6. Additionally, temporal changes to cellular homeostasis (temperature, pH, water content and salt/ions concentration) can induce transitory protein unfolding and soluble aggregation 1. During pathological conditions, protein aggregation is a common occurrence giving rise to the group of diseases collectively known as protein conformational diseases. In many degenerative diseases of the CNS, such as Alzheimer's, Parkinson's and Huntington's disease protein aggregation is a common pathological hallmark due to amino acid mutation and changes in the primary structure of the proteins 7-11. Size-wise, aggregates can range considerably, from protein oligomers up to visible cytosolic inclusions, known as the aggresome 12. The sub cellular location of these aggregates can also vary, from perinuclear to peri-endolasmic reticulum (ER) or intra-endosomal. Perinuclear aggregates (aggresomes) co-localize with the microtubule organizing center and mostly contain terminally aggregated proteins 12 , whereas ER-associated aggregates are mostly formed by soluble aggregates of ubiquitinated misfolded proteins 3 and endosomal aggregates are inclusions that co-localize with autophagic markers 13-15. The functional consequences of aggregation are also variable, from up-regulation of autophagy 16 , to cellular apoptosis due to aggregate-related cytotoxicity. Recently, it has been reported that during physiological aging proteostasis gradually becomes compromised and several hundred proteins tend to become more insoluble and aggregate 17,18. A few of these proteins have been shown to have common biochemical and biological properties, such as a primary structure with amino acids stretches often found in proteins associated with neurodegenerative diseases and a secondary structure with

Accumulation of modified proteins and aggregate formation in aging

Experimental gerontology, 2014

Increasing cellular damage during the aging process is considered to be one factor limiting the lifespan of organisms. Besides the DNA and lipids, proteins are frequent targets of non-enzymatic modifications by reactive substances including oxidants and glycating agents. Non-enzymatic protein modifications may alter the protein structure often leading to impaired functionality. Although proteolytic systems ensure the removal of modified proteins, the activity of these proteases was shown to decline during the aging process. The additional age-related increase of reactive compounds as a result of impaired antioxidant systems leads to the accumulation of damaged proteins and the formation of protein aggregates. Both, non-enzymatic modified proteins and protein aggregates impair cellular functions and tissue properties by a variety of mechanisms. This is increasingly important in aging and age-related diseases. In this review, we will give an overview on oxidation and glycation of prot...

Protein homeostasis in models of aging and age-related conformational disease

Protein Metabolism and …, 2010

T he stability of the proteome is crucial to the health of the cell, and contributes significantly to the lifespan of the organism. Aging and many age-related diseases have in common the expression of misfolded and damaged proteins. The chronic expression of damaged proteins during disease can have devastating consequences on protein homeostasis (proteostasis), resulting in disruption of numerous biological processes. This chapter discusses our current understanding of the various contributors to protein misfolding, and the mechanisms by which misfolding, and accompanied aggregation/toxicity, is accelerated by stress and aging. Invertebrate models have been instrumental in studying the processes related to aggregation and toxicity of disease-associated proteins and how dysregulation of proteostasis leads to neurodegenerative diseases of aging.

Reprint of "accumulation of modified proteins and aggregate formation in aging

Experimental gerontology, 2014

Increasing cellular damage during the aging process is considered to be one factor limiting the lifespan of organisms. Besides the DNA and lipids, proteins are frequent targets of non-enzymatic modifications by reactive substances including oxidants and glycating agents. Non-enzymatic protein modifications may alter the protein structure often leading to impaired functionality. Although proteolytic systems ensure the removal of modified proteins, the activity of these proteases was shown to decline during the aging process. The additional age-related increase of reactive compounds as a result of impaired antioxidant systems leads to the accumulation of damaged proteins and the formation of protein aggregates. Both, non-enzymatic modified proteins and protein aggregates impair cellular functions and tissue properties by a variety of mechanisms. This is increasingly important in aging and age-related diseases. In this review, we will give an overview on oxidation and glycation of prot...

Asymmetric segregation of protein aggregates is associated with cellular aging and rejuvenation

Proceedings of The National Academy of Sciences, 2008

Aging, defined as a decrease in reproduction rate with age, is a fundamental characteristic of all living organisms down to bacteria. Yet we know little about the causal molecular mechanisms of aging within the in vivo context of a wild-type organism. One of the prominent markers of aging is protein aggregation, associated with cellular degeneracy in many age-related diseases, although its in vivo dynamics and effect are poorly understood. We followed the appearance and inheritance of spontaneous protein aggregation within lineages of Escherichia coli grown under nonstressed conditions using time-lapse microscopy and a fluorescently tagged chaperone (IbpA) involved in aggregate processing. The fluorescent marker is shown to faithfully identify in vivo the localization of aggregated proteins, revealing their accumulation upon cell division in cells with older poles. This accretion is associated with >30% of the loss of reproductive ability (aging) in these cells relative to the new-pole progeny, devoid of parental inclusion bodies, that exhibit rejuvenation. This suggests an asymmetric strategy whereby dividing cells segregate damage at the expense of aging individuals, resulting in the perpetuation of the population.

The Biology of Proteostasis in Aging and Disease

Loss of protein homeostasis (proteostasis) is a common feature of aging and disease that is characterized by the appearance of nonnative protein aggregates in various tissues. Protein aggregation is routinely suppressed by the proteostasis network (PN), a collection of macromolecular machines that operate in diverse ways to maintain proteome integrity across subcellular compartments and between tissues to ensure a healthy life span. Here, we review the composition, function, and organizational properties of the PN in the context of individual cells and entire organisms and discuss the mechanisms by which disruption of the PN, and related stress response pathways, contributes to the initiation and progression of disease. We explore emerging evidence that disease susceptibility arises from early changes in the composition and activity of the PN and propose that a more complete understanding of the temporal and spatial properties of the PN will enhance our ability to develop effective treatments for protein conformational diseases.

Protein Structure and Function in Aging and Age-Related Diseases

2020

Aging is not a disease, but a complex process driven by diverse molecular pathways and biochemical events. It is usually seen as the reason of progressive loss of physiological functions that ultimately lead to death. Every species is associated with an average life expectancy, and therefore it is plausible to think that aging is programmed in our genes. Genes exert their effects by gene expression that is coupled with protein synthesis. Proteins are most abundant and structurally diverse, perform wide variety of roles, and in part maintain functional stability and homeostasis of cells. Protein misfolding, aggregation, or an alteration in protein–protein/nucleic acid/lipid interactions and modifications has the potential to disturb many metabolic pathways. During aging such alterations are accelerated and accumulations of altered proteins are correlated with age- and disease-related pathologies. Therefore, it is critical to identify and understand proteomic spectrum and its function...

What is the role of protein aggregation in neurodegeneration?

Nature Reviews Molecular Cell Biology, 2005

Neurodegenerative diseases typically involve deposits of inclusion bodies that contain abnormal aggregated proteins. Therefore, it has been suggested that protein aggregation is pathogenic. However, several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response. Aggregation is a complex multi-step process of protein conformational change and accretion. The early species in this process might be most toxic, perhaps through the exposure of buried moieties such as main chain NH and CO groups that could serve as hydrogen bond donors or acceptors in abnormal interactions with other cellular proteins. This model implies that the pathogenesis of diverse neurodegenerative diseases arises by common mechanisms, and might yield common therapeutic targets.

Proteostasis collapse is a driver of cell aging and death

Proceedings of the National Academy of Sciences

What molecular processes drive cell aging and death? Here, we model how proteostasis—i.e., the folding, chaperoning, and maintenance of protein function—collapses with age from slowed translation and cumulative oxidative damage. Irreparably damaged proteins accumulate with age, increasingly distracting the chaperones from folding the healthy proteins the cell needs. The tipping point to death occurs when replenishing good proteins no longer keeps up with depletion from misfolding, aggregation, and damage. The model agrees with experiments in the worm Caenorhabditis elegans that show the following: Life span shortens nonlinearly with increased temperature or added oxidant concentration, and life span increases in mutants having more chaperones or proteasomes. It predicts observed increases in cellular oxidative damage with age and provides a mechanism for the Gompertz-like rise in mortality observed in humans and other organisms. Overall, the model shows how the instability of protei...