Oxidative stress and ageing, is ageing a cysteine deficiency syndrome? [2005] (Abstract & Conclusions)
Wulf Dröge*
Division of Redox Physiology and Aging Research, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
* w_droege@web.de
Oxidative stress and ageing: is ageing a cysteine deficiency syndrome
http://journals.royalsociety.org/content/l70078673710x66k/fulltext.html
Published online 3 November 2005
Abstract
Reactive oxygen species (ROS) are constantly produced in biological tissues and play a role in various signalling pathways. Abnormally high ROS concentrations cause oxidative stress associated with tissue damage and dysregulation of physiological signals. There is growing evidence that oxidative stress increases with age. It has also been shown that the life span of worms, flies and mice can be significantly increased by mutations which impede the insulin receptor signalling cascade. Molecular studies revealed that the insulin-independent basal activity of the insulin receptor is increased by ROS and downregulated by certain antioxidants. Complementary clinical studies confirmed that supplementation of the glutathione precursor cysteine decreases insulin responsiveness in the fasted state. In several clinical trials, cysteine supplementation improved skeletal muscle functions, decreased the body fat/lean body mass ratio, decreased plasma levels of the inflammatory cytokine tumour necrosis factor (TNF- ), improved immune functions, and increased plasma albumin levels. As all these parameters degenerate with age, these findings suggest: (i) that loss of youth, health and quality of life may be partly explained by a deficit in cysteine and (ii) that the dietary consumption of cysteine is generally suboptimal and everybody is likely to have a cysteine deficiency sooner or later.
Keywords: cysteine in vivo; redox status; muscle functions; immune functions; inflammatory cytokines; insulin signalling
1. Introduction
The popularity of antioxidative vitamins as dietary supplements may illustrate the growing public awareness that oxidative stress and oxygen radicals are important hazards to our health and play a major role in the ageing process. This review provides a critical evaluation of the evidence for a role of oxygen radicals and oxidative conditions in the ageing process and of the available options for therapeutic intervention.
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5. Conclusions
(a) Redox signalling and oxidative stress
Superoxide radicals and hydrogen peroxide play an important role as regulatory mediators in physiological signalling processes. Oxidative stress occurs if either the production of ROS is abnormally increased or the antioxidant concentration is decreased. Oxidative stress can lead to tissue damage and to the dysregulation of redox-sensitive signalling pathways.
At least some of the critical redox-responsive signalling proteins contain redox-sensitive cysteine moieties which activate or inactivate their regulatory function upon oxidation into a mixed disulfide. This conversion into disulfide formation is typically mediated by ROS as the signalling molecules proper, but inherently, it is also facilitated by an oxidative shift in the thiol/disulfide redox status of the microenvironment. An oxidative shift in redox status may thus also lead to dysregulation.
(b) Multiple benefits of cysteine supplementation
Several lines of evidence indicate that oxidative stress increases with age. These changes include a decrease in glutathione levels and/or a shift in redox status. To ameliorate oxidative stress and to improve the oxidant/antioxidant balance, antioxidative vitamins E, C and -carotene (provitamin A) are widely used as dietary supplements. Surprisingly little attention has been given to the dietary intake of cysteine which is needed for the biosynthesis of glutathione, the quantitatively most important antioxidant and radical scavenger. Recent clinical studies have actually shown that cysteine supplementation on top of the normal protein diet has clear benefits with respect to several parameters relevant to ageing, suggesting that the age-related decrease in glutathione plays indeed a causative role in various ageing related degenerative processes. For the sake of brevity, this review has mainly focused on skeletal muscle functions, body fat, immunological reactivity, circulating TNF- levels, and plasma albumin concentrations (see table 1). Cysteine supplementation has shown significant effects on all of these parameters in several independent studies.
As the quality of life in old age is severely compromised by the loss of skeletal muscle function, and given that muscle function can be quantitatively measured with good precision and reproducibility, loss of muscle function is taken as the best surrogate parameter of ageing. Cysteine supplementation mediated a significant increase in skeletal muscle functions in two independent placebo-controlled trials.
TNF- is one of the hormone-like factors (cytokines) implicated in the loss of muscle mass and muscle function under catabolic conditions. In addition, high plasma TNF- levels have been associated with a number of ageing-related degenerative processes. Cysteine supplementation was found to prevent the increase in plasma TNF- concentration after physical exercise in two independent trials.
Elderly subjects and patients with practically all types of catabolic conditions typically show a conspicuous decrease in the plasma albumin level, and albumin plays an important role in the maintenance of the oncoosmotic pressure of blood that is needed to avoid oedema. Cysteine supplementation has been shown to increase the mean plasma albumin level in two independent clinical studies.
The best documented effects of cysteine supplementation on immunological functions in humans have been found in patients infected with a virus such as HIV and HBV. As both types of virus infection are typically associated with compromised immune functions and an exceptionally strong decrease in lymphocyte glutathione levels, it remains to be determined whether the immune enhancing activity of cysteine supplementation may be limited to these types of stress conditions.
Taken together, the association between oxidative stress resistance and life span in a series of animal studies (see §3a), the beneficial effects of cysteine supplementation on various parameters relevant to the ageing process (§4), and the age-related changes in the cysteine and glutathione status (§2b) strongly support the hypothesis that these oxidative changes may contribute to the ageing process. At least some of the effects of cysteine supplementation are best explained by the interpretation that this treatment ameliorates the age-related oxidative stress and the resulting dysregulation of redox-sensitive signalling cascades (§1). The redox-sensitive insulin receptor signalling cascade (§3b)is just one prominent example.
(c) Balanced modulation of the insulin receptor signalling cascade
A large body of evidence suggests that silencing of the insulin receptor signalling cascade is needed for optimal activation of SIRT1 activity, autophagy, and FOXO transcription factor activity, i.e. a diverse set of activities that were all found to have an impact on life span at least in mutant strains of worms, flies and mice. A well-balanced cysteine supplementation accompanied by a delicately balanced supply of creatine and guided by occasional measurements of fasting glucose levels and glucose tolerance tests appears to be a method suitable for humans to decrease insulin receptor signalling in the fasted state without compromising the clearance of glucose and other nutrients in the postprandial state.
Whether downregulation of insulin receptor signalling accounts for some of the beneficial effects cysteine supplementation described above remains to be shown. At least some of the beneficial effects are obviously based on redox mechanisms which do not involve insulin receptor signalling.
(d) The concept of cysteine as a 'paravitamin'
It is now becoming increasingly clear that cysteine and its derivatives play a role similar to that of vitamins. Unlike vitamins, cysteine serves as a building unit of proteins and as a source of energy. But like the antioxidative vitamins, cysteine and its derivatives play a role in the oxidant/antioxidant balance and indirectly in the regulation of metabolic processes. One may, therefore, define cysteine or a cysteine-delivering substance as a 'paravitamin', i.e. a substance resembling a vitamin.
A deficit of any particular vitamin gives rise to typical symptoms which are reversed by supplementation of that vitamin. The various beneficial effects of cysteine supplementation on top of the normal diet suggest by analogy: (i) that there is an ageing-related deficit in body cysteine and glutathione reservoirs and (ii) that a deficit in cysteine leads to a decrease in muscle function, a decrease in immune function, a decrease in plasma albumin concentration, and an increase in TNF- concentration. As all these changes are hallmarks of the ageing process, it is concluded that the age-related decrease in body cysteine and/or glutathione level may be a major driving force for multiple ageing-related degenerative processes.
(e) Everybody is likely to experience a cysteine deficiency sooner or later
As everybody beyond the fifth decade of life will experience sooner or later a decrease in muscle function, a decrease in immune function, a decrease in plasma albumin concentration, and/or an increase in TNF- concentration, it is hypothesized that practically everybody experiences sooner or later an ageing-related deficit in the body cysteine and glutathione reservoirs that warrants cysteine supplementation. This hypothesis implies that ageing may be postponed and frailty be avoided to some extent by supplementation of the 'paravitamin' cysteine. It is emphasized, however, that several details still require more systematic investigation. Although substantial negative side effects have not been observed in previous studies on cysteine supplementation, it is felt that the treatment protocols ought to be further improved to achieve maximum safety and efficacy over long periods of time. Properly done, cysteine supplementation can reasonably be expected to improve the quality of life in old age. With the availability of novel cysteine delivery systems with minimum amounts of calories, which are superior to any of the naturally available cysteine sources, it is conceivable that even the maximum human life span may be increased beyond the previous limit.
Acknowledgements
The dedicated assistance of Mrs I. Fryson in the preparation of the manuscript is gratefully acknowledged.
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One contribution of 18 to a Theme Issue 'Reactive oxygen species in health and disease'.
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