Redox Biology 5 (2015) 7179

Contents lists available at ScienceDirect

Redox Biology
journal homepage: www.elsevier.com/locate/redox

Review Article

Redox theory of aging

Dean P. Jones n
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA 30322, USA

art ic l e i nf o

a b s t r a c t

Article history:
Received 16 March 2015
Accepted 19 March 2015

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 exibility 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 genomeexposome interaction that occurs as a consequence of execution of differentiation and exposure memory systems. This includes compromised mitochondrial and bioenergetic
exibility, impaired food utilization and metabolic homeostasis, decreased barrier and defense capabilities and loss of reproductive delity 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.
& 2015 Published by Elsevier B.V.

Keywords:
Redox systems biology
Oxidative stress
Redox signaling

Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Improved understanding of redox circuitry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The redox proteome is an adaptive interface of the genome and exposome. . . .
Increased atmospheric O2 diversied habitats. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Redox mechanisms were harnessed for multicellular differentiation to enhance
Decreased genome adaptability with differentiation and exposure memory. . . .
The redox theory of aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction
Hundreds of philosophers and scientists have addressed the
topics of longevity and aging, and many theories have been
advanced. These have been recently reviewed [1], and I make no
attempt to further summarize these important contributions.

n
Correspondence to: Department of Medicine, Division of Pulmonary, Allergy
and Critical Care Medicine, Emory University, 205P Whitehead Biomedical Research
Building, 615 Michael Street, Atlanta, GA 30322, USA.
E-mail address: [email protected]

http://dx.doi.org/10.1016/j.redox.2015.03.004
2213-2317/& 2015 Published by Elsevier B.V.

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Rather, the present article provides a conceptual review based

upon the emerging concept that redox systems function as a critical interface between the genome and the exposome [2,3].
Relying extensively upon emerging understanding of redox systems biology, acquired epigenetic memory systems, and deductive
reasoning, a simple theory is derived that aging is the decline of
the adaptive interface of the functional genome and exposome
that occurs due to cell and tissue differentiation and cumulative
exposures and responses of an organism. This theory is not limited
to redox processes but has a redox-dependent character due to the
over-riding importance of electron transfer in energy supply,

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D.P. Jones / Redox Biology 5 (2015) 7179

defense, reproduction and molecular dynamics of protein and cell

signaling.
Several years ago, I presented a redox hypothesis of oxidative
stress [4] in which I concluded that oxidative stress is predominantly a process involving 2-electron, non-radical reactions
rather than commonly considered 1-electron, free radical reactions. The central arguments were that (1) experimental measures
showed that non-radical ux substantially exceeds free radical ux
under most oxidative stress conditions, (2) radical scavenger trials
in humans failed to show health benets, and (3) normal cell
functions involving sulfur switches are readily disrupted by nonradical oxidants. The redox hypothesis is thus founded upon the
concept that oxidative stress includes disruption of redox circuitry
[5,6] in addition to the macromolecular damage resulting from an
imbalance of prooxidants and antioxidants [7].
The redox hypothesis of oxidative stress contained four
postulates:
1. All biologic systems contain redox elements [e.g., redox-sensitive cysteines], which function in cell signaling, macromolecular trafcking and physiologic regulation.
2. Organization and coordination of the redox activity of these
elements occurs through redox circuits dependent upon common control nodes (e.g., thioredoxin, GSH).
3. The redox-sensitive elements are spatially and kinetically
insulated so that gated redox circuits can be activated by
translocation/aggregation and/or catalytic mechanisms.
4. Oxidative stress is a disruption of the function of these redox
circuits caused by specic reaction with the redox-sensitive
thiol elements, altered pathways of electron transfer, or interruption of the gating mechanisms controlling the ux through
these pathways.
The current article represents an extension and development of
these concepts into a redox theory of aging. This redox theory is
not exclusively limited to redox reactions but rather emphasizes
the key role of electron transfer in supporting central energy

currencies (ATP, phosphorylation, acetylation, acylation, methylation and ionic gradients across membranes) and providing the free
energy to support metabolism, cell structure, biologic defense
mechanisms and reproduction. Importantly, improved understanding of the integrated nature of redox control and signaling in
complex, multicellular organisms [8] provide a foundation for this
generalized theory.

Improved understanding of redox circuitry

The logic of development of the redox theory of aging depends
upon recognition that the third postulate of the redox hypothesis
[4] probably applies to a relatively limited subset of redox switches
that function in redox signaling [8]. Insulated pathways with
gating mechanisms, as discussed in consideration of redox systems
biology [9], may be relatively rare. Instead, a much larger number
of redox switches exist that support redox sensing to coordinate
and integrate functional networks [8,10,11]. These redox sensors
exist in dynamic steady state, with Cys in multiple proteins in
functional networks sharing similar redox character [10]. They
have promiscuous reactivities, with multiple targets and switchable specicities. For example, most protein thiols are oxidizable
by hydrogen peroxide and some are reduced by either thioredoxin
or glutathione systems [12]. Furthermore, inhibition of thioredoxin
reductase activity does not invariably result in thioredoxin oxidation [13], implying alternate reductant system for thioredoxin.
Additionally, electron ow from thioredoxin reductase switches
between targets due to the relative abundances of the targets [14].
Many thioredoxin-like proteins exist [15], but their reactivities and
specicities are largely uncharacterized. These and many other
observations show that protein redox systems are not highly
insulated but rather part of a redox network with many possible
electron pathways determined by relative abundance and reactivity of the elements.
Available evidence indicates that these redox systems are
organized within interacting metabolomics and proteomics

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.

D.P. Jones / Redox Biology 5 (2015) 7179

networks (Fig. 1). Little effort has been made to organize the large
number of characterized redox enzyme reactions into a metabolomics network structure, but the redox proteomic structure has
been outlined as a bilateral hierarchical structure dependent upon
reductant hubs and oxidant hubs [16]. Scale-free hierarchical
structures are inherently stable [17,18], and readily accommodate
redox control of 214,000 Cys encoded in the human genome [16].
Thus, an overall biological redox system can be viewed as (1) a
series of electron donors maintaining the NAD and NADP redox
couples, (2) the terminal electron acceptor, O2, maintaining H2O2
and other oxidants, and (3) intermediary redox modules maintaining redox organizational structure of cell functions. In analogy
to the hierarchy of gene regulation, this hierarchy provides a framework to map the redox circuitry of cells [16]. Important recent
advances include clarication of oxidative redox regulons, now
including peroxiredoxins [19,20], glutathione S-transferases
[21,22] for thiols and a range of methionine redox functions [23].
This redox system interacts with other post-translational modications such as nitrosylation, persuldation and acylation, to
provide a multidimensional epiproteome control structure [2].

The redox proteome is an adaptive interface of the genome and

exposome
Logical argument 1. Redox modications of the proteome provide a
system to sense, avoid and defend against environmental oxidants
and other toxic chemicals.

73

the exposome. The exposome was dened by Wild [24] as a conceptual grid of cumulative lifelong exposures to complement the
genome in understanding human disease [24,25]. The concept
includes infections, behavioral exposures, diet, nutrition and
microbiome [26], and has been further developed for environmental health sciences [27,28], including epigenetic changes and
mutations [29].
The redox proteome sits as a rst defense against xenobiotic
stresses and thus represents an adaptive interface of the genome
and exposome [3] (Fig. 2). Relatively stable protein modications,
such as those from reactive lipid modications of protein, extend
the reversible oxidations of Cys or Met to provide sustained stress
signals [30,31]. An understanding of this exposure memory helps
clarify the role of redox systems in evolution of complex structures. Multiple exposure memory systems support organismic
development and adaptation to diet and environment. Reversible
oxidation of metabolites and amino acids in proteins are most
responsive, but slow and non-reversible proteomic changes also
provide exposure memory. Even longer lasting epigenetic changes,
linked to the redox systems by transmethylation of methionine,
can sustain exposure memory over a lifespan, and higher cognitive
function similarly serves as a long-term interface between genome
and environment. Importantly, this series of exposure memory
systems provides a way to think about the incessant progression
from conception to death and the meaning of aging and longevity.

Observations concerning the redox proteome considerably

impact concepts of aging when considered within the context of

Fig 2. The redox metabolome and redox proteome serve as an adaptive interface for genomeexposome 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#me
diaviewer/File:Industrial-pollution.JPG.

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D.P. Jones / Redox Biology 5 (2015) 7179

Increased atmospheric O2 diversied habitats

Logical argument 2. Increased atmospheric O2 supported redoxdriven speciation and evolution of complexity in metazoans
Atmospheric O2 increased substantially about 900 million years
ago. By this time, archebacteria, eubacteria and single cell eukaryotes had evolved biologic solutions to the challenges of life, i.e.,
mechanisms to acquire and maintain bioenergetics, sustain organized metabolism and structure, defend against environmental
threats and reproduce. These systems included Cys and Met in the
proteome, functioning under relatively low (o1%) O2 atmosphere.
Increase to 21% O2 resulted in increased production of H2O2 by
reaction of O2 with thiols and other redox elements in living systems. This provided driving force for mechanisms to avoid exposure to O2 and to eliminate H2O2. At the same time, more efcient
ATP production by mitochondria provided driving force to seek
and maintain O2 exposure. Thus, the O2 atmosphere created forces
for speciation to avoid O2, to tolerate O2 and to maximize O2
supply. The reversible oxidation of Cys and Met residues within
proteins were harnessed to sense and support these adaptations.
Viewed as an adaptive interface of the genome and proteome,
the redox proteome therefore provides an underlying logic to
current functions of redox switches in differentiation and

development. Miseta and Csutora [32] showed that the cysteine

proteome co-evolved with the evolution of complexity. Despite
selection against cysteine in the proteome, cysteine content
increased with phylogenetic complexity from 0.5% in prokaryotes
to 42% in mammals. The methionine proteome and other reactive
centers, like those of the NADPH oxidases, thioredoxins, peroxiredoxins and selenoenzymes, similarly coevolved. Evolution of
adaptive redox mechanisms yielded selective advantage for complex organisms to tolerate diverse and unique environments.
A conceptual framework for this co-evolution is provided in
Fig. 3. Already at the time of evolution of O2 in the atmosphere,
unicellular organisms had mechanisms to manage energetics,
maintain molecular order (metabolic and structural organization),
defend again predation and hostile environmental factors, and
reproduce. Increased atmospheric O2 created different habitats
and opportunity for organisms with oxidant sensing and detoxication, oxidative DNA damage repair systems and more efcient
mitochondrial energy production.

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 efcient photosynthetic organisms were present. Miseta and Czutora (2000) showed that the percentage of Cys encoded in genomes increased from
about 0.5% to 42% 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.

D.P. Jones / Redox Biology 5 (2015) 7179

Redox mechanisms were harnessed for multicellular differentiation to enhance adaptability

Logical argument 3. Evolution of multicellularity utilized available
redox mechanisms to support spatiotemporal signaling and molecular
memory systems.
Love et al. [33] showed a spatial and temporal sequence of
oxidation occurs during wound healing following tadpole tail
amputation. Knoeer et al. [34] showed that sequential changes in
oxidant generation were directly linked to specic protein Cys
oxidation in Caenorhabditis elegans development. These ndings
provide evidence that redox signaling of adaptation to environment were co-opted for spatiotemporal signaling in multicellular
organism differentiation and development.
Building upon these concepts, the molecular logic of multicellularity unfolds as a memory system to maintain differentiated
phenotypes of cells, which provides the genome a competitive
advantage in survival and reproduction by having components
with more specialized functions. Differentiated epiproteomic,
lipidomic, glycomic and epigenetic systems provide molecular
memory (Fig. 4) for genomeexposome interactions. Each is
directly or indirectly redox-dependent; all require high-energy
metabolites like ATP. The epiproteome is directly modied by
oxidation and reaction with oxidized lipid products; epigenetic
systems include oxidative demethylases and redox-dependent
deacetylases; the systems are linked by the methionine/cysteine
metabolism and other components of the redox metabolome.
Species gained selective advantage during evolution as memory
systems enhanced individual competitiveness for nutrient acquisition, management of O2 supply, defense against predators, and
reproduction.

75

Decreased genome adaptability with differentiation and exposure memory

Logical argument 4. Molecular memories of differentiation and
environmental exposures decrease genomic exibility to accommodate future environmental challenges.
Fractal dynamics [35] have been used to show that irregularity
and unpredictability are features of health and that decreased
variability and adaptability are associated with disease [36,37].
Ivanov et al. [38,39] used fractal analysis of the human heartbeat
to show that a higher Hurst Exponent (H), indicative of greater
regularity, was associated with disease, while normal heartbeat
exhibited more chaotic behavior and lower H value. Such concepts
have been extended to study Parkinson's disease [40], sleep apnea
[41], and sudden cardiac death [42]. In our own studies, healthy
individuals responding to malnutrition induced by a diet decient
in essential amino acid had increased H in wavelet-transformed
plasma metabolomic data [43], indicating decreased metabolic
exibility (Fig. 5). Patients in an Intensive Care Unit (ICU) also
showed higher H, indicating greater regularity compared to healthy individuals, and those who recovered from the ICU had values
return toward those of healthy individuals [43]. Results show that
adaptability in biologic systems reects health and implies that
loss of exibility is critical in aging and longevity.
Methods are not yet available to evaluate fractal dynamics of
the functional genome during lifespan. DNA methylation and
epigenetic marks in gametes and fertilized ovum may reect a
basal state for the exposure memory system with high exibility to
adapt to the environment during differentiation, development and
maturation. Alternatively, these mechanisms may reect exposures of parents or earlier generations. In both cases, execution of
differentiation and development programs would decrease exibility within cells and tissues over the lifespan.

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 exibility of the molecular systems of the organism.

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D.P. Jones / Redox Biology 5 (2015) 7179

Fig 5. Multifractal analysis distinguishes healthy from unhealthy metabolic proles. 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 decient 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. [43].

Early environmental exposures similarly impact DNA methylation, ribosomal RNA, histone marks, epiproteomic signatures and
mitochondrial heteroplasmy. These have a trade-off in improving
short-term tness and reproductive potential with the consequence of long-term decrease in adaptability. Hysteresis introduces variability in the rate and magnitude of effects. Most critically for aging, the differentiation and exposure memory system
ultimately limits tolerance to environmental variation and results
in failure of energetics, maintenance of molecular order, defenses
against xenobiotics and infection and reproductive capability.

The redox theory of aging

Logical argument 5. Aging is a decline in plasticity of genome
exposome interaction that occurs as a consequence of execution of
differentiation and exposure memory systems.
From this logical development, one reaches the conclusion that
aging is loss of adaptability due to cumulative network responses
supporting genomeexposome interaction. The differentiation and
adaptive structures allow an individual genome to be molded by
exposures throughout life, enhancing tness for the environment
and improving opportunity for success in reproduction. By evolving mechanisms to protect against infectious agents, remember
food sources, discriminate good and bad food, avoid dangers, etc.,
multicellular organisms gained survival advantage.
This exposure memory system, utilizing mechanisms in parallel
with developmental programs, also has a cost, and this cost has a
central role in aging. Execution of organogenesis programs
decreases exibility of the genome for other programs. Execution
of programs in response to exposures decreases exibility to
respond to other exposures. The redox networks controlling

cellular energetics, molecular order, organismic defense and

reproduction serve to maximize exibility and adaptability to
environment. At the same time, such responses limit future
adaptability.
Perhaps more critically for aging and longevity, the networks
are interconnected in function. The inter-conversion of redoxderived bioenergetics with metabolic control means that failure of
the former is accompanied by compensation and ultimate failure
of the latter. The inter-conversion of redox-dependent metabolism
and defense mechanisms means that failure of metabolism also
results in failure of defense against toxic exposures and infectious
organisms. The glutathione redox system becomes oxidized with
age; the immune system loses response, the brain accumulates
protein aggregates, the lungs and kidneys decline in function,
blood vessels lose exibility and the heart begins to fail. This interdependence of energetics, molecular order and defense means
that with natural aging, all systems age, even if experimental
measures are too insensitive to detect the changes. Death is the
eventual collapse of the networks supporting genomeexposome
interaction.

Summary and perspective

The logical arguments derived from consideration of accumulating knowledge of the redox proteome and the redox interface of
the genome and exposome is that aging is a cumulative failure of
the adaptive structures supporting genomeexposome interaction.
The integrated redox networks essential for bioenergetics, metabolic and structural organization, defense, and reproduction, ultimately fail due to exhausted differentiation programs and environmental challenge(s) that cannot be accommodated. The

D.P. Jones / Redox Biology 5 (2015) 7179

77

Fig 6. Redox theory accounts for hallmarks of aging. The hallmarks of aging as summarized by Lpez-Otn et al. [1], 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 modications and degradation. Lifelong responses to dietary excesses and insufciencies, 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 reect 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.

exposure memory system allows an individual life history of

exposures to determine tolerance to exposures, thereby decreasing
or increasing individual lifespan due to respective inappropriate or
benecial exposures.
The theory accommodates hallmarks of aging (Fig. 6), such as
those involving oxidative stress, mitochondrial dysfunction,
growth factor signaling and nutrient regulation, failure of proteostasis, telomere shortening, cellular senescence and stem cell
exhaustion, epigenetics, barrier failure, intercellular communication, immune system dysfunction, and reproductive exhaustion
[1]. Other mechanisms may also be accommodated, such as
mitochondrial heteroplasmy to provide a mechanism for cells to
change respiratory function during lifespan to adjust to different

foods [44]. Similarly, retrotransposable elements, and other poorly

understood elements within the genome, could also serve adaptive or maladaptive functions during lifespan [45,46]. On the other
hand, some characteristics, such as genomic instability, may
represent failure of repair systems and/or failure of the adaptive
memory systems.
Key challenges exist to formulate appropriate testable
hypotheses for function of redox networks due to the complexity
of the systems. Evolution resulted in redundant and shared functions. Populations evolve, not individuals. Genetic diversity exists
in populations, providing individuals with different adaptability
and tolerance to exposures, i.e., a dened exposome is not likely to
affect each genome equivalently. Because individuals differ in

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D.P. Jones / Redox Biology 5 (2015) 7179

genome and response to exposome, no experiment is precisely

reproducible. Furthermore, no experiment is precisely replicable
within an individual because subsequent challenges may not elicit
the same response as an initial challenge. None-the-less, clones
with controlled sequences of variation in early exposures and later
lifetime challenges may prove useful to directly test the theory
that aging and longevity are determined by the differentiation and
exposure memory systems for genomeexposome interaction.

Acknowledgements
The author gratefully acknowledges critical input from Dr.
Young-Mi Go concerning the redox proteome and genomeexposome interactions. Research support provided by NIH Grants
AG038746, ES023485, HL113451, ES009047 and ES019776.

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