Abstract
Ageing is considered as a snowballing phenotype of the accumulation of damaged dysfunctional or toxic proteins and silent mutations (polymorphisms) that sensitize relevant proteins to oxidative damage as inborn predispositions to age-related diseases.Ageing is not a disease, but it causes (or shares common cause with) age-related diseases as suggested by similar slopes of age-related increase in the incidence of diseases and death. Studies of robust and more standard species revealed that dysfunctional oxidatively damaged proteins are the root cause of radiation-induced morbidity and mortality. Oxidized proteins accumulate with age and cause reversible ageing-like phenotypes with some irreversible consequences (e.g. mutations). Here, we observe in yeast that aggregation rate of damaged proteins follows the Gompertz law of mortality and review arguments for a causal relationship between oxidative protein damage, ageing and disease. Aerobes evolved proteomes remarkably resistant to oxidative damage, but imperfectly folded proteins become sensitive to oxidation. We show that α-synuclein mutations that predispose to early-onset Parkinson's disease bestow an increased intrinsic sensitivity of α-synuclein to in vitro oxidation. Considering how initially silent protein polymorphism becomes phenotypic while causing age-related diseases and how protein damage leads to genome alterations inspires a vision of predictive diagnostic, prognostic, prevention and treatment of degenerative diseases.
Highlights
While powerful technologies led to a rapid growth of a descriptive molecular cell biology and to the development of new drugs, the benefit to human health remains dismal to modest
We conclude that oxidative protein damage is a likely common cause of ageing and age-related diseases (ARD) emerging via a common mechanism with ‘snowballing’ phenotypic consequences
We further propose that ARD can emerge as phenotypes of damage to particular diseaserelated proteins sensitized to oxidation by subtle structural alterations caused by silent mutations
Summary
While powerful technologies led to a rapid growth of a descriptive molecular cell biology and to the development of new drugs, the benefit to human health remains dismal to modest. The fact that addition of standard antioxidants to growth medium allows for survival and aerobic growth of obligate anaerobes [4] shows that ROS activity kills non-adapted cells This cytotoxic property of ROS was adopted in apoptotic cell death (review [3]) and bacterial killing by the specialized cells of the immune system [5]. We argue that the root cause of ageing is simple (i.e. the accumulating oxidative proteome damage) with functional ( phenotypic) consequences increasing with time in intensity and complexity This concept, which was put forward by Stadtman and colleagues [8], is further refined and supported by data reviewed or displayed in this paper showing that:. The identification of such mutational polymorphisms would break new ground in the area of predictive diagnostics of predispo- 2 sitions to ARD and inspire the design of interventions, at the level of proteins, for their delay or even reversion
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