Figure 2.

Loss of proteome stability during ageing impacts on genome (and metabolome) integrity, resulting in disease prone cells/organisms. Young biological systems are characterized by low levels of damaged biomolecules due to highly active proteostatic pathways and stress responses (e.g., the Nrf2 pathway). This period of life is characterized by genome stability as a result of precise duplication and effective repair pathways (blue arrows in left panel denote balanced cross-talk among shown pathways and regulatory modules). On the other hand, the age-related collapse of proteostatic modules functionality and/or expression levels (red arrows; upper right panel), along with increased oxidative stress and the accumulation of non-functional polypeptides and/or protein aggregates (black arrows; upper right panel), compromises proteome integrity leading to significantly reduced chances of survival/health due to metabolic alterations and/or genomic instability (caused by ineffective DNA maintenance and/or repair). Eventually, a vicious circle (red arrows; lower right panel) may be formed where a mildly unstable genome accelerates proteome instability (and consequently metabolic alterations) due to synthesis of mutated polypeptides, which progressively increase the attrition of protein machines. This vicious circle gradually results in an increasingly stressful cellular landscape that favors the appearance of age-related diseases (e.g., cancer).