Adaptive homeostasis and the free radical theory of ageing

Abstract

The Free Radical Theory of Ageing, was first proposed by Denham Harman in the mid-1950's, based largely on work conducted by Rebeca Gerschman and Daniel Gilbert. At its core, the Free Radical Theory of Ageing posits that free radical and related oxidants, from the environment and internal metabolism, cause damage to cellular constituents that, over time, result in an accumulation of structural and functional problems. Several variations on the original concept have been advanced over the past six decades, including the suggestion of a central role for mitochondria-derived reactive species, and the proposal of an age-related decline in the effectiveness of protein, lipid, and DNA repair systems. Such innovations have helped the Free Radical Theory of Aging to achieve widespread popularity. Nevertheless, an ever-growing number of apparent 'exceptions' to the Theory have seriously undermined its acceptance. In part, we suggest, this has resulted from a rather simplistic experimental approach of knocking-out, knocking-down, knocking-in, or overexpressing antioxidant-related genes to determine effects on lifespan. In some cases such experiments have yielded results that appear to support the Free Radical Theory of Aging, but there are just as many published papers that appear to contradict the Theory. We suggest that free radicals and related oxidants are but one subset of stressors with which all life forms must cope over their lifespans. Adaptive Homeostasis is the mechanism by which organisms dynamically expand or contract the homeostatic range of stress defense and repair systems, employing a veritable armory of signal transduction pathways (such as the Keap1-Nrf2 system) to generate a complex profile of inducible and enzymatic protection that best fits the particular need. Viewed as a component of Adaptive Homeostasis, the Free Radical Theory of Aging appears both viable and robust.

Keywords: Ageing; Nrf2; Oxidative stress; Proteasome; Protein oxidation and aggregation; Signal transduction pathways; Stress adaptation.

Figure 1. Assessment of the Stress Response

In studies assessing the ability of an organism to withstand an oxidative stress it is important to perturb the homeostatic set-point. (A) Stress resistance is commonly measured to assess tolerance. Biological models (yeast, mammalian cell culture, nematode worms, and fruit flies) are treated with a semi-lethal, high concentration of an oxidant to assess survivability or other markers of stress tolerance. One of the limitations of this approach is the overwhelming biological assault to the system, leading to extensive oxidative damage. Assessment of the adaptive stress response, enables an organism to first activate multiple protective pathways prior to being challenged with a semi-toxic concentration. (B) The adaptive response is induced in multiple biological systems (yeast, mammalian cell culture, nematode worms, and fruit flies) and is carried out by treating the organism with a non-damaging, signaling concentration of an oxidant to stimulate stress-inducible pathways (including those transcriptionally regulated by Nrf2). Once pathways are activated and upregulated, the organism is then challenged with a semi-lethal dose of an oxidant, and subsequently survival and other markers of stress activation are measured.

Figure 2. Age-Dependent Decline of the Adaptive Stress Response

Early passage cells and young organisms are capable of rapidly and transiently upregulating the adaptive homeostatic response. In turn, keeping damage accumulation, such as protein aggregates, limited and cellular maintenance. However, with age, the inducibility of the adaptive response declines, which is accompanied with a parallel rise in protein aggregation, sluggish cellular signaling and basal rise in inflammation (‘inflammaging’).

Figure 3. Chronic Up- or Downregulation of Target Protein Does Not Extend Lifespan

Chronic up- or downregulation of multiple stress-responsive proteins have shown little consistent impact upon lifespan across multiple biological models. Forced overexpression (OE) or suppression (RNAi), chronically throughout the lifespan, may limit the ability of transient modulation of target protein to appropriately respond to a stimulus. Instead, by continually upregulating or downregulating a target protein, creates a new physiological set-point, and may limit the dynamic stress-responsive capability within the cellular environment. Thus, many efforts for chronic changes in stress-responsive proteins have shown no impact upon lifespan.