Chemistry and biology of aging and age-related diseases

author: Miroslav Radman, Mediterranean Institute for Life Sciences (MedILS)
published: Dec. 9, 2017,   recorded: November 2017,   views: 738


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Proteins carry on, directly or indirectly, all life activities and are subject to oxidative damage. Ever since the increase in atmospheric oxygen from about 1 to 21%, accompanied by the shift from anaerobic to aerobic life, proteins were under strong selective pressure to evolve oxidation-resistant structures resulting in remarkable resistance of most proteins to damage inflicted by reactive oxygen species (ROS). However, this intrinsic resistance is fragile: subtle biosynthetic and folding errors, as well as “silent” missense mutations (polymorphisms) lead to the loss of oxidation resistance, with latent phenotypic consequences (e.g., disease predisposition) (1). There is a competitive antagonism between protein misfolding and oxidation: misfolded proteins either refold by chaperons and become oxidation-resistant, or they undergo oxidation that precludes refolding. We found evidence that functional degeneracy of cells (akin to ageing) and their death result primarily from proteome failure due to oxidative protein damage inflicted by radiation or aging (1-3). Persistence of DNA damage is the consequences of damage to repair proteome that appears as the primary cause of cell death (1-4). Before cell death, phenotypic (functional) deficiencies can be demonstrated that are proportional to protein damage and reversible upon their decrease (1). Since the dedicated proteins carry all DNA transactions, e.g., repair, replication and gene expression, we show that selective non-lethal proteome damage results also in high increase in mutation rates (1). Thus, because the selective proteome damage mimics key aging phenotypes, we posit that aging itself is the progressive complex phenotype of the accumulating proteome damage (1,4). I shall present data suggesting that protein carbonylation is not only a biomarker of human aging - increasing exponentially with age like the incidence of diseases and death (5) - but the most likely root cause of aging and of all age-related diseases. Finally, the correlations between body mass, metabolism, longevity and disease latency will be interpreted by variations in ROS and phenotypic suppression of cell defects (tissue homeostasis).

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