Dysfunction and toxicity of damaged proteins in the etiology of aging and age-related degenerative and malignant diseases

Abstract

Health can be defined as a harmony, or homeostasis, of the activities of thousands of different proteins, whereas aging and diseases result from their disharmony manifested at the levels of cells and tissues. Such disharmony is caused primarily by dysfunction and toxicity of misfolded proteins damaged by oxidation. This is an overview of key data that inspired new concepts allowing interpretation and integration of the scientific literature on aging and age-related diseases. These concepts suggest strategies for prevention and attenuation of age-related degenerative and malignant diseases mimicking the life of super-centenarians.

Figure 1

Protein oxidation and misfolding cause age-related diseases. The misfolded or mutant protein is more sensitive to the attack of reactive oxygen species (ROS) and will be oxidised. Two competing processes will come into play, either the misfolding is reversible by the intervention of chaperones and the protein will be folded to its native conformation and keep its function (green arrows); or the oxidative modification (carbonylation) will fix the misfolded conformation by precluding the refolding by chaperones (red arrows). From there, the oxidised and misfolded proteins can follow different paths: 1) the protein is immediately degraded by proteases; 2) the protein avoids degradation and remains in its dysfunctional monomeric state that leads to disease (cancer for example); 3) the protein can form multimeric structures (oligomers and aggregates) that are toxic to the cell and will eventually lead to neurodegenerative diseases, among others. The presence of aggregates causes an immunogenic inflammatory reaction that triggers the onset of age-related diseases.

Figure 2

Key molecular and cellular processes affecting the onset of aging and age-related diseases (eg, carcinomas). “Initiation” and “Promotion” are two key mechanistic phases in the onset of age-related diseases. Oxidative proteome damage by reactive oxygen species (ROS) displays diverse reversible phenotypic effects, including generation of stable genetic and epigenetic alterations (“Initiation” by DNA change) kept in phenotypic silence by cellular parabiosis (phenotypic suppression). “Promotion” is typically a chronic inflammation that interrupts cellular parabiosis (see text) leading to phenotypic expression, ie, the onset of disease. DNA damage merely synergises generation of (epi)mutations since protein damage alone is more mutagenic than DNA damage (2,4). Lasting promotion via chronic inflammation activates initiated morbid phenotypes, ranging from malignant growth to cell death. Red colored processes produce, or are affected by, ROS and stimulate initiation and/or promotion of pathological phenotypes, whereas green and blue belong to tissue homeostasis. High adenosine triphosphate and low ROS levels increase proteome quality and promote health and longevity (see text). Figure reproduced from (3).