Loss of Proteostasis

    From Longevity Wiki
    Endogenous and exogenous stress causes the unfolding of proteins (or impairs proper folding during protein synthesis). Unfolded proteins are usually refolded by heat-shock proteins (HSP) or targeted to destruction by the ubiquitin-proteasome or lysosomal (autophagic) pathways. The autophagic pathways include recognition of unfolded proteins by the chaperone Hsc70 and their subsequent import into lysosomes (chaperone-mediated autophagy) or sequestration of damaged proteins and organelles in autophagosomes that later fuse with lysosomes (macroautophagy). Failure to refold or degrade unfolded proteins can lead to their accumulation and aggregation, resulting in proteotoxic effects.[1]

    Loss of Proteostasis is one of the primary hallmarks of aging, signifying the decline in the cell's ability to regulate protein balance. Proteostasis encompasses all aspects of protein metabolism, including the synthesis, folding, trafficking, and degradation of proteins. Efficient proteostasis is vital for maintaining cellular function and homeostasis, as proteins are integral components of all cellular processes. However, as organisms age, the proteostasis network becomes less efficient, leading to the accumulation of damaged and misfolded proteins, which can form toxic aggregates and disrupt cellular functions.

    The Proteostasis Network[edit | edit source]

    The proteostasis network includes several key mechanisms and pathways:

    • Protein Synthesis: Ribosomes are responsible for translating mRNA into polypeptide chains, which must then fold into functional three-dimensional structures.
    • Molecular Chaperones: These proteins assist in the proper folding of other proteins, preventing misfolding and aggregation.
    • Protein Folding Mechanisms: Proper folding is crucial for protein function. Misfolded proteins can lead to the formation of toxic aggregates.
    • Protein Degradation Systems: Two main systems, the ubiquitin-proteasome system and the autophagy-lysosome pathway, are responsible for degrading and recycling damaged or unnecessary proteins.
    • Protein Trafficking: Proteins must often be transported to specific locations within or outside the cell to function correctly.

    Implications of Loss of Proteostasis[edit | edit source]

    The failure to maintain proteostasis has profound implications:

    • Age-related Diseases: Many neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease, are associated with the accumulation of misfolded protein aggregates, a direct consequence of impaired proteostasis.
    • Cellular Stress Response: Impaired proteostasis leads to cellular stress and the activation of various stress response pathways, which can have additional deleterious effects on cell function.
    • Inflammation: The accumulation of misfolded proteins can trigger inflammatory responses, contributing to tissue damage and age-related pathologies.
    • Reduced Cellular Function: Accumulation of damaged proteins can disrupt cellular functions, leading to reduced cellular performance and viability.

    Molecular Chaperones and Heat Shock Proteins[edit | edit source]

    Molecular chaperones and heat shock proteins play a critical role in maintaining proteostasis. They recognize and bind to misfolded or unfolded proteins, preventing their aggregation and assisting in proper refolding or directing them to degradation pathways. These proteins are particularly important during cellular stress, where the risk of protein misfolding is increased. However, the expression and functionality of chaperones decline with age, contributing to the loss of proteostasis.

    The Role of Autophagy in Proteostasis[edit | edit source]

    Autophagy, specifically macroautophagy, is a cellular degradation pathway that plays a significant role in removing damaged organelles and protein aggregates. During autophagy, cellular components are sequestered into autophagosomes, which then fuse with lysosomes for degradation. Impaired autophagy is a common feature in aged cells and is associated with the accumulation of protein aggregates and dysfunctional organelles.

    The Ubiquitin-Proteasome System[edit | edit source]

    The ubiquitin-proteasome system is another crucial component of the proteostasis network, responsible for the targeted degradation of proteins. Proteins marked for degradation are tagged with ubiquitin molecules and directed to the proteasome, where they are broken down into amino acids. Dysregulation or decline in the efficiency of the ubiquitin-proteasome system is observed in aging and is associated with the accumulation of damaged or misfolded proteins.

    Therapeutic Interventions[edit | edit source]

    Given the central role of proteostasis in aging and disease, strategies to enhance proteostasis are of considerable interest. Potential approaches include boosting the expression or activity of molecular chaperones, enhancing autophagy, and improving the efficiency of the ubiquitin-proteasome system. Such interventions could help prevent or mitigate the effects of protein aggregation diseases and extend healthy lifespan.

    See Also[edit | edit source]

    1. López-Otín C et al.: The hallmarks of aging. Cell 2013. (PMID 23746838) [PubMed] [DOI] [Full text] Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.