Redox theory of aging

Abstract

Metazoan genomes encode exposure memory systems to enhance survival and reproductive potential by providing mechanisms for an individual to adjust during lifespan to environmental resources and challenges. These systems are inherently redox networks, arising during evolution of complex systems with O2 as a major determinant of bioenergetics, metabolic and structural organization, defense, and reproduction. The network structure decreases flexibility from conception onward due to differentiation and cumulative responses to environment (exposome). The redox theory of aging is that aging is a decline in plasticity of genome-exposome interaction that occurs as a consequence of execution of differentiation and exposure memory systems. This includes compromised mitochondrial and bioenergetic flexibility, impaired food utilization and metabolic homeostasis, decreased barrier and defense capabilities and loss of reproductive fidelity and fecundity. This theory accounts for hallmarks of aging, including failure to maintain oxidative or xenobiotic defenses, mitochondrial integrity, proteostasis, barrier structures, DNA repair, telomeres, immune function, metabolic regulation and regenerative capacity.

Keywords: Oxidative stress; Redox signaling; Redox systems biology.

Graphical abstract

Fig 1

Redox biology of metazoans. Metazoans depend upon redox processes to support energetics, metabolic and structural organization, separation from and defense against external environment, and reproduction. The overall redox structure is a complex network including small molecules, measured by redox metabolomics, and proteins, measured by redox proteomics. Metal ions derived from the environment are a major variable not explicitly shown, but impact both the redox metabolome and redox proteome by interfering with essential metal ion functions and catalyzing non-enzymatic reactions. The enzymology of redox reactions has been studied in detail and organized by the Enzyme Commission in terms of electron donors and electron acceptors in enzyme-catalyzed reactions (see http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/). No systematic consideration of the redox metabolome is currently available. The elements of the redox proteome are mostly known, but systematic knowledge of spatial and temporal distributions is not available. Redox systems biology provides an initial framework for development, but quantitative data for abundance and kinetics are limited. Ultimately, this knowledge is needed to understand and develop strategies to improve healthy longevity.

Fig 2

The redox metabolome and redox proteome serve as an adaptive interface for genome–exposome interaction. The exposome includes essential nutrients, other chemicals from food, products of the microbiome, food supplements and drugs, commercial products and environmental chemicals. Based upon Jones et al. 2012, Go and Jones 2013 and Go and Jones 2014. “Industrial-pollution” by John Tarantino, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Industrial-pollution.JPG#mediaviewer/File:Industrial-pollution.JPG.

Fig 3

Co-evolution of thiol systems with biological complexity. Life is thought to have evolved under relatively reducing conditions, with a substantial increase in atmospheric O₂ only after efficient photosynthetic organisms were present. Miseta and Czutora (2000) showed that the percentage of Cys encoded in genomes increased from about 0.5% to >2% in association with evolution of complexity. Redox-sensitive Cys are common in the proteome, are redox sensitive and are extensively conserved with evolution, consistent with roles in redox sensing, redox processing and redox signaling. Viewed as a redox interface between the genome and exposome, the O₂ environment provided a driving force for evolution while the redox sensing, processing and signaling capabilities enabled speciation with diverse mechanisms to improve energy utilization, metabolic organization, defenses against environmental threats and reproduction.

Fig 4

Molecular memory systems. An interacting series of molecular memory systems enable an individual genome to learn from the exposome, improve health, survival and reproduction of the individual and progeny. Execution of developmental and exposure memory systems decreases flexibility of the molecular systems of the organism.

Fig 5

Multifractal analysis distinguishes healthy from unhealthy metabolic profiles. A. Plots of the partition function f(a) of wavelet transformed plasma metabolomics analysis shows greater regularity in intensive care unit (ICU) patients (blue) compared to healthy individuals (red). B. Individual receiving diet deficient in the essential amino acid, methionine (−SAA, blue) showed greater regularity than receiving the same diet with adequate methionine (+SAA, Red). Data from Park et al. .

Fig 6

Redox theory accounts for hallmarks of aging. The hallmarks of aging as summarized by López-Otín et al. , occur as a consequence of the developmental and exposure memory systems encoded in the genome. Execution of the developmental programs and responses to dietary and other environmental exposures alter the DNA methylation and epigenetic marks controlling gene expression. Developmental programs, dietary and environmental exposures determine function of proteostasis systems involving protein synthesis, epiproteomic modifications and degradation. Lifelong responses to dietary excesses and insufficiencies, in the context of early imprinted responses to diet and exposures, deregulate nutrient sensing and utilization. Memory systems for food availability, quality and utilization cause mitochondrial dysfunction. Differentiation programs, cumulative lifelong exposures and execution of response programs lead to cellular senescence. Telomere shortening is a differentiation and exposure memory system for complex organisms. Stem cell exhaustion is a consequence of the evolved differentiation and exposure memory system. Altered intercellular communication is a consequence of execution of differentiation programs and cumulative responses of the adaptive memory system. Genomic instability appears likely to be a failure of the differentiation and exposure memory systems but may also reflect execution of genetic mechanisms or transposon-dependent functions that are not currently understood. Photo credits: Newborn Josey, Holly Jones photography; surgery aboard the USNS Comfort, public domain; fruits and vegetables, Jack Dykinga; smokestacks, Alfred Palmer.