An Introduction to the Redox Theory of Aging

There are a lot of theories of aging. Simply outlining the numerous categories of theory and offering a few comments as to which of the better known theories are currently well supported, dead, or disputed is a fairly detailed undertaking. It is hard to avoid delving into the history of the field when explaining how the research community ended up where it is today in terms of the various camps. There are evolutionary theories that seek to explain how aging came about, there are damage accumulation theories of aging, programmed aging theories that see aging as an evolved program of individual self-destruction, and any number of single-mechanism theories based on one or more researchers generalizing their narrow area of familiarity out to the whole body. Usually overgeneralizing, to be truthful: aging is a complex mix of at least initially independent causes, not one single mechanism.

The diversity of theories is really a reflection of just how much yet remains uncertain in the study of human biochemistry. In the sciences you will find theories proliferating wildly wherever there are few definitive answers due to the sheer complexity of the systems under examination. Inventive exploration and theorizing continues until some faction can prove themselves correct and everyone else wrong beyond any reasonable doubt. My expectation is that damage accumulation theories are mostly correct, that the SENS proposals contain a fair digest of which damage is fundamental and important rather than secondary or unimportant, and proof beyond any reasonable doubt will be provided in animal studies that test various SENS or SENS-like implementations of rejuvenation treatments. Large degrees of healthy life extension in the laboratory will prove the point faster and more cost-effectively than any research programs aiming to find and catalog all of the relevant mechanisms involved. This process is well underway for relevant areas in stem cell research, and has of late just begun for the clearance of senescent cells. Repair of other important forms of damage is yet to be earnestly tested: removal of various forms of metabolic waste, for example, such as amyloids and lipofuscin.

It has long been noted in parts of the aging research community that the activity of most of the researchers involved bears some resemblance to the tale of the blind men and the elephant. Each feels but a part of the whole, and that is their conception of the beast. Modern medical life science, even just a small field within the whole, is so complex and vast that researchers specialize in tiny slices of it, having only a superficial familiarity at best with everything else. It is often the case that when these researchers apply their knowledge to aging in isolation, without networking extensively, they propose theories that only cover a fraction of the biochemistry that the broader aging research community has identified as being relevant and involved in aging.

Redox theory of aging

Hundreds of philosophers and scientists have addressed the topics of longevity and aging, and many theories have been advanced. These have been recently reviewed, and I make no attempt to further summarize these important contributions. 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. 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, defense, reproduction and molecular dynamics of protein and cell signaling.

Several years ago, I presented a redox hypothesis of oxidative stress 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 flux substantially exceeds free radical flux under most oxidative stress conditions, (2) radical scavenger trials in humans failed to show health benefits, and (3) normal cell functions involving sulfur switches are readily disrupted by non-radical oxidants. The redox hypothesis is thus founded upon the concept that oxidative stress includes disruption of redox circuitry in addition to the macromolecular damage resulting from an imbalance of prooxidants and antioxidants.

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 trafficking 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 specific reaction with the redox-sensitive thiol elements, altered pathways of electron transfer, or interruption of the gating mechanisms controlling the flux 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 provide a foundation for this generalized theory.

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