Proteodynamics and aging of eukaryotic cells

Immune system aging and the aging-related diseases in the COVID-19 era

“…Changed activity of calpains in the immune cells of the elderly is an illustration of a broader issue of improper protein manufacturing, maturation, posttranslational modifications, misfolding, aggregation, inefficient removal (by autophagy) etc., which goes under the common heading of modified proteodynamics in aged cells, immune and otherwise [ 90 , 91 ].…”

“…Maintenance of functional proteomes and their more or less immediate functions for a long time (for some memory T cells approaching the length of the lifespan) requires vast amounts of metabolic energy (ATP), in the resting lymphocytes provided mainly by oxidative phosphorylation (OXPHOS), while the activated cells tend to rely on glycolysis (Warburg effect) [ 91 , 92 ]. It is recognized for more than 4 decades already that aging has a profound effect on mammalian mitochondria, including reduced output of ATP, increased production of ROS (and, consequently, increased oxidative stress) and numerous mutations in mitochondrial (mt)DNA, likely contributing to mentioned dysfunction.…”

Proteolysis dysfunction in the process of aging and age-related diseases

“…Thus, the dynamic balance between the production of functional proteins (including their translation, posttranslational modifications, multi-order folding leading to functional proteome), maintenance of the proteome and detection/degradation of dysfunctional, misfolded, or aggregated proteins is failing with time. Altogether the mentioned processes of protein synthesis, folding and maintenance, and finally degradation are described as proteostasis network (PN) or proteodynamics ( Balch et al, 2008 ; Hipp et al, 2019 ; Jayaraj et al, 2020 ; Witkowski et al, 2021 ). One needs to bear in mind that this cellular protein homeostasis machinery is also a network of proteins performing quality control of other cellular proteins and, as such, is prone to similar aging-related changes.…”

“…Exposure of the cells to reactive oxygen species (ROS) results in elevated amounts of oxidized proteins and an increased risk for protein aggregation at the same time. Also, other aging-related processes, including accumulation of SNPs and somatic mutations, decreased fidelity of transcription and translation, and changes in posttranslational protein modification will add to the rising proportion of misfolded and aggregated proteins in aging cells ( Witkowski et al, 2021 ). Irreversible accumulation of modified (e.g., misfolded, oxidized, or improperly cleaved) proteins contributes to the development of aging-related diseases that include neurodegenerative disorders such as Parkinson’s disease or Alzheimer’s disease ( Ho et al, 2020 ; Pathak et al, 2021 ), metabolic disorders ( Sooparb et al, 2004 ; Kimura et al, 2015 ) or even cancer ( Fulop et al, 2013 ; Chavez-Dominguez et al, 2020 ).…”

Immunosenescence and COVID-19

“…Finally, clearing of dysfunctional, used-up or aggregated intracellular proteins (proteostasis) is greatly impaired in old immune cells due to changes in autophagy, mitophagy, activities of the enzymes in lysosomes and proteasomes, reduced activities of modulatory proteases (calpains) coupled with rising amounts of these proteins due to faults in transcription and translation ( Witkowski et al, 2021a , Witkowski et al, 2018 ). These phenomena also impair the functions of immune cells in elderly, again affecting adversely their antiviral capabilities.…”