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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60:1378-1385 (2005)
© 2005 The Gerontological Society of America

REVIEW ARTICLE

Oxidative Aging and Insulin Receptor Signaling

Wulf Dröge

Division of Redox Physiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.

Address correspondence to Dr. Wulf Dröge, Professor of Immunology, Senior Vice-President, Research & Development, Immunotec Research Ltd., 300 Joseph Carrier, Vaudreuil-Dorion, Quebec, J7V 5V5, Canada.


   Abstract
Top
 Abstract
Decrease in Insulin Receptor...
 Modulation of Insulin Receptor...
 Life-Span Extension by Calorie...
 Effect of Cysteine...
 References
 
The life span of nematodes, fruit flies, and mice can be significantly increased (and aging-related changes decreased) by mutations affecting insulin receptor signaling. This effect involves several cellular functions which are negatively regulated by the insulin receptor and thus typically expressed under fasting conditions. This involvement raises the question of whether the insulin-independent basal receptor kinase activity in the postabsorptive state can be decreased without compromising the physiologically important response to insulin in the postprandial state. Recent studies have shown that (a) the basal human insulin receptor kinase activity is increased under oxidative conditions in the absence of insulin and (b) insulin signaling in the fasted state can be decreased by cysteine supplementation. Cysteine supplementation has also been shown to improve certain aging-related parameters, suggesting that the average dietary cysteine consumption in Western countries may be suboptimal. These findings provide a conceptual framework that extends the "free radical theory of aging."

THAT aging research eventually became a respectable topic on the agenda of medical science and pharmaceutical companies may be mainly credited to the discovery by Cynthia Kenyon and colleagues who showed that the life span of a little worm (Caenorhabditis elegans) was increased 2.5-fold and more by mutating a single gene (1). Although speculations about a similar extension of the human life span or even immortality may be unrealistic, the study of Kenyon and similar studies of others may provide clues on how to improve the quality of life in old age by methods other than genetic manipulation. Importantly, it was noted that mutant strains of worms, flies, and mice with increased life span often showed an increased resistance to oxidative stress (Table 1) (2–9), suggesting that oxidative stress and aging are mechanistically linked. Moreover, mutant animals with an extended life span often turned out to have a mutation in the signaling pathway of the insulin receptor or related receptors (Table 2) (reviewed in 10,11). More recently, mutations of the insulin receptor in Drosophila were also shown to ameliorate the age-related decline in cardiac performance (12), implying that this signaling cascade determines the aging-related deterioration of organ performance at least in the fruit fly.


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  		Table 1. Genetic Evidence Linking Oxidative Stress to Life Span.

 

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  		Table 2. Genetic Evidence Linking a Decrease in Insulin Receptor Signaling to an Increase in Life Span.

 

   DECREASE IN INSULIN RECEPTOR SIGNALING FACILITATES THE OPTIMAL ACTIVATION OF AUTOPHAGY, SIR2/SIRT1, AND FOXO TRANSCRIPTION FACTORS
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 Decrease in Insulin Receptor...
Modulation of Insulin Receptor...
 Life-Span Extension by Calorie...
 Effect of Cysteine...
 References
 
Mechanisms Involved in Life-Span Extension in Mutant Strains of Worms, Flies, and Mice
The insulin receptor signaling cascade is schematically illustrated in Figure 1F (see 13–19). An increase in the life span of the nematode C. elegans was achieved by mutations in daf-2, which encodes an insulin receptor autolog (1,14), or by mutations in age-1 and pdk-1, which encode a phosphatidylinsositol-3 kinase (PI3K) and phosphoinositide-dependent protein kinase 1 (PDK1), respectively (15,16). A mutation in daf-18, the phosphatase and tensin homolog on chromosome 10 (PTEN), was found to suppress the life-span extension of daf-2 and age-1 mutants (17,18). Further downstream, the target of rapamycin (TOR) was found to have a negative effect on life span (19). Among other functions, TOR downregulates the activity of the autophagic and lysosomal protein catabolism (reviewed in 20,21). In the daf-2 (e1370) mutant of C. elegans, autophagy was shown to be essential for life-span extension (22). By removing damaged mitochondria and other organelles, autophagy plays an important role in the maintenance of cellular integrity, notably in the postmitotic tissues. At times of limited amino acid availability, autophagy is critical for the maintenance of amino acid homeostasis and cell survival (reviewed in 20). In addition, TOR activity enhances (and autophagy suppresses) tumor formation (23,24). TOR/mTOR also downregulates the expression of proteins of the sirtuin family, which includes Sir2p in yeast, the worm autolog sir2.1, and mammalian SIRT1 (reviewed in 25). By deacetylating proteins, the Sir2 family regulates a set of pathways which all have an impact on aging. Recently, SIRT1 was shown to play a role in glucose homeostasis in mice by inducing gluconeogenic genes in the liver (26).



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  		Figure 1. Insulin receptor signaling pathways that influence life span. Binding of insulin leads to autophosphorylation and activation of the insulin receptor kinase (IRK) domain and recruitment of insulin-receptor substrate (IRS-1). As a consequence, phosphatidylinositol-3 kinase (PI3K) converts phosphatidylinositol(4,5)diphosphate [PI(4,5)P2] into phosphatidylinositol(3,4,5)triphosphate [PI(3,4,5)P3]. This in turn binds and activates phosphoinositide-dependent protein kinase-1 (PDK1), which in turn phosphorylates the serine/threonine kinase Akt1. Akt1 is activated by binding to PI(3,4,5)P3 at the cell membrane and by phosphorylation at Thr308 and Ser473. Akt inhibits tuberous sclerosis complex 1 and 2 (Tsc1/2) and activates the target of rapamycin (TOR, FRAP, or mTOR in mammals) which controls a number of physiological functions including protein synthesis, cell size, proliferation, and differentiation programs (12). In addition, Akt1 is an inhibitor of several functions, including autophagy, SIRT1, and forkhead box (FOXO) transcription factor activity. Insulin receptor signaling activity is downregulated by protein tyrosine phosphatase 1B (PTB1B), which dephosphorylates the IRK domain, and by the phosphatase and tensin homolog on chromosome 10 (PTEN) and SH2-domain-containing inositol phosphatase (SHIP2) both of which dephosphorylate PI(3,4,5)P3. Hydrogen peroxide enhances the autophosphorylation of IRK and inhibits the activity of the phosphatases as illustrated by the dashed lines

 
Last but not least, the insulin receptor Akt signaling pathway also downregulates the activity of certain FOXO (forkhead box) transcription factors (27–29). The ability of daf-2 mutations to increase life span was shown to depend on the activity of the FOXO family transcription factor DAF-16 (reviewed in 30). DAF-16 and its mammalian counterparts activate the transcription of certain stress-related genes (31; reviewed in 32). In addition, FOXO transcription factors are key players in metabolic processes (29,33–35). FOXO1 and FOXO3 were shown to induce the expression of proteins involved in the proteasomal pathway of proteolysis (36–38). In contrast to the role of autophagy as a mechanism involved in the removal of defective organelles, the FOXO-dependent stimulation of the proteasomal pathway accounts for the turnover of damaged long-lived myofibrillar proteins which are not degraded through the autophagic/lysosomal pathway (39). In fruit flies (Drosophila), overexpression of dFOXO was shown to prevent the age-related decline in cardiac performance (12).

Taken together, these genetic and biochemical studies strongly suggest that downregulating the insulin receptor signaling cascade is needed for optimal activation of several independent mechanisms which all have an impact on the speed of aging. Two of these mechanisms appear to be involved in the intracellular degradation (turnover) of damaged cellular constituents and may thereby maintain the integrity of postmitotic tissues. During starvation these mechanisms may also play an important role in the control of amino acid and glucose homeostasis, respectively. A relatively high basal insulin receptor signaling activity in the fasted state is expected to increase the glucose uptake in adipose tissues and to compromise gluconeogenesis in the liver, thus causing a relatively strong decrease in plasma glucose levels in the postabsorptive period. The resulting hypoglycemic response involves increases in glucagon, epinephrine, and/or glucocorticoids, i.e., hormones which have potential catabolic effects on muscle tissues.

Excessive activation of protein catabolism by FOXO1 and FOXO3, however, was shown to be involved in cancer cachexia (36–38), and autophagy can ultimately lead to cell death (40–42). Ideally, autophagy and FOXO activity should therefore be delicately balanced to ensure the optimal turnover of damaged organelles and other cellular structures in all postmitotic tissues while avoiding a net loss of body protein and muscle mass over long periods of time. The genetic studies in C. elegans, Drosophila, and mice suggest that these two aspects are not well balanced in the normal (wild-type) animals, at least under the conditions tested.


   MODULATION OF INSULIN RECEPTOR SIGNALING IN HUMANS
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 Decrease in Insulin Receptor...
 Modulation of Insulin Receptor...
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Chances to Extend the Human Life Span: Impeding Insulin Receptor Signaling Has To Be Restricted to the Fasted State
In view of the role of SIRT1 and autophagy in the control of glucose and amino acid homeostasis, respectively, in fasting conditions, and in view of the role of autophagy and FOXO-dependent ubiquitin ligases in the turnover of damaged mitochondria and contractile proteins, respectively (see above), it is reasonable to assume that a well balanced downregulation of the insulin receptor signaling cascade may also be required to maintain the integrity of postmitotic tissues in humans. However, in view of the positive role of insulin in metabolic regulation and the negative consequences of insulin receptor dysfunction (see, e.g., 43,44), it is reasonable to assume that the persistent impairment of insulin receptor function by genetic or other means may not be the method of choice for humans and may not even be the optimal method for life extension in worms, flies, and mice.

As the response to insulin is needed to ensure glucose clearance and to stimulate protein synthesis after food intake, insulin receptor signaling must be sufficiently strong in the postprandial (fed) state. In healthy human persons, downregulation of insulin receptor signaling is therefore only found in the postabsorptive (fasted) state (reviewed in 20), implying that optimal induction of SIRT1 activity, autophagy, and FOXO1 and FOXO3 transcription factor activity is largely restricted to this state. This conclusion is in agreement with the putative role of these activities in the maintenance of glucose and amino acid homeostasis during the fasted state as mentioned above. Any attempt to further downregulate insulin receptor signaling in humans must be restricted to the fasted state, i.e., it must involve the "basal" insulin receptor activity. A series of recent reports have shown that the insulin-independent "basal activity" of the insulin receptor is weak (but clearly detectable) and subject to regulation by the redox status.

Basal Insulin Receptor Kinase Activity Is Increased Under Conditions of Oxidative Stress
The basal insulin receptor tyrosine kinase activity is strongly increased by small concentrations of hydrogen peroxide (i.e., 60 µM), or by an oxidative shift in the intracellular thiol/disulfide redox status (Figure 2) (45,46). Hydrogen peroxide enhances the kinase activity in the presence of otherwise inhibitory physiologically relevant concentrations of ADP (i.e., 70 µM). In skeletal muscle tissue, cytoplasmic ADP is rapidly converted into adenosine triphosphatase (ATP) by cytoplasmic creatine kinase in combination with relatively high concentrations of phosphocreatine. ADP-mediated inhibition and oxidative enhancement of insulin receptor kinase activity are therefore expected to be particularly strong in cells with little creatine and creatine kinase activity, such as adipose tissue. That mice with fat-specific insulin receptor knockout showed an increased life span (47) suggests that the insulin reactivity of this tissue is particularly relevant for longevity. The physiological relevance of the interrelated effects of oxidative stress and ADP has been underscored by the results of a clinical study of nondiabetic obese persons (48). This study indicated that basal insulin receptor signaling was decreased in patients supplemented with N-acetylcysteine (NAC). The homeostasis model assessment/insulin resistance (HOMA-R) index (which is determined by the fasting plasma glucose and fasting plasma insulin concentrations and which, therefore, is an inverse indicator of the basal insulin receptor signaling activity in the postabsorptive period) was increased in the group treated with NAC plus placebo but decreased in the group treated with NAC plus creatine (Figure 3) (48). The results of these molecular studies and the complementary clinical study therefore suggested that any oxidative stress or oxidative shift in the glutathione redox status may be associated with an increase in the insulin-independent basal activity of the insulin receptor kinase in the absence of insulin.



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  		Figure 2. Stimulation of the insulin-independent basal insulin receptor kinase (IRK) activity by hydrogen peroxide or a shift in glutathione redox status. A, Phosphorylation of recombinant IRK proteins and myelin basic protein (MBP) substrate. The recombinant IRK protein was incubated at 30°C for 20 minutes with or without 60 µM hydrogen peroxide (HP), then for 30 minutes with MBP and 1 mM adenosine triphosphatase (ATP), and finally for 20 minutes with 32P-ATP and MBP. B, Chinese hamster ovary (CHO)-HIR cells were cultured with 50 µM HP, 80 µM 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea (PC, a specific inhibitor of glutathione reductase), or no additives (Co). The insulin receptor was purified by immunoprecipitation and assayed for autophosphorylation (ß-IR) or substrate phosphorylation (MBP) either by 32P-incorporation or phosphotyrosine antibody ({alpha}-pY). C, Mean ± SEM of the relative autophosphorylation from four different experiments (data taken from 45)

 


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  		Figure 3. Effect of N-acetylcysteine (NAC) with or without creatine (C) on basal insulin reactivity. The homeostasis model assessment/insulin resistance (HOMA-R) index was used as a widely accepted measure of basal insulin reactivity (48). It was calculated by the formula: HOMA-R = fasting plasma glucose (mg dl–1) x fasting plasma insulin concentration (mU ml–1) x 405–1. Data show the absolute changes (mean ± SEM) in the HOMA-R index between baseline and terminal examination in the four treatment groups: Pc/Pn = placebocreatine + placeboNAC, C/Pn = creatine + placeboNAC, PC/NAC = placebocreatine + NAC, and C/NAC = creatine + NAC (data taken from 48)

 
This basal activity of the insulin receptor signaling cascade is further enhanced by hydrogen peroxide through the inhibition of the protein tyrosine phosphatase (PTP) 1B and the lipid phosphatases PTEN and SH2-domain-containing inositol phosphatase 2 (SHIP2) (see Figure 1). PTP1B dephosphorylates the insulin receptor during internalization and recycling (49), whereas PTEN and SHIP dephosphorylate PI(3,4,5)P3. Both types of phosphatases are inactivated by oxidation of a redox-sensitive cysteine residue (50–54). Work from several laboratories has shown that autophosphorylation of the insulin receptor is facilitated by hydrogen peroxide and enhanced by procedures that decrease intracellular levels of glutathione (55–60).

Prolonged exposure to hydrogen peroxide, however, strongly inhibits insulin action (61–65), suggesting that insulin signaling is enhanced only by moderate oxidative conditions but inhibited by excessive exposure to hydrogen peroxide. In diabetes, hyperglycemia leads to glucose oxidation and oxidative degradation of glycated proteins, which result in the production of reactive oxygen species (ROS) (reviewed in 66). As hyperglycemia was found to be ameliorated in diabetic patients by certain antioxidants, such as {alpha}-lipoic acid and NAC (66,67), it has been suggested that oxidative inhibition of insulin signaling accounts at least in part for the decrease in insulin responsiveness seen in this clinical condition. These findings do not preclude, however, that administration of antioxidants to nondiabetic persons decreases insulin reactivity due to the enhancing effect of moderate oxidative conditions on insulin receptor activity.


   LIFE-SPAN EXTENSION BY CALORIE RESTRICTION
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 Decrease in Insulin Receptor...
 Modulation of Insulin Receptor...
 Life-Span Extension by Calorie...
Effect of Cysteine...
 References
 
A reduction in the amount of daily dietary calories (calorie restriction) is presently the only intervention proven to cause life-span extension in a variety of species including mammals (reviewed in 68,69). In yeast (Saccharomyces cerevisiae) and fruit flies (Drosophila), Sir2 was shown to be directly involved in the life-span-extending effect of calorie restriction (70,71). This makes sense in view of the role of SIRT1 in the maintenance of glucose homeostasis (26). Sir2 and its biochemical pathway thus appear to link the life-extending mechanism of calorie restriction with the life-extending effects of mutations in the insulin receptor signaling cascade. Among other effects, calorie restriction causes also a decrease in body fat mass and (in the steady-state) levels of oxidative stress (69). The latter effect is reversed by exogenous administration of insulin (72). Paradoxically, calorically restricted animals showed a markedly enhanced response to insulin. This paradox may be explained by the fact that oxidative conditions may be associated with an increased basal insulin receptor signaling activity, whereas the response to insulin is relatively decreased (see, e.g., 73).


   EFFECT OF CYSTEINE SUPPLEMENTATION ON FUNCTIONAL PARAMETERS RELEVANT TO AGING
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 Decrease in Insulin Receptor...
 Modulation of Insulin Receptor...
 Life-Span Extension by Calorie...
 Effect of Cysteine...
References
 
As downregulation of insulin receptor signaling in humans must be restricted to the fasted state, and the insulin-independent basal insulin receptor tyrosine kinase activity is increased under (moderately) oxidative conditions, the following section deals with clinical trials on the effect of cysteine supplementation on functional parameters relevant to aging.

Most Important Sources of Cysteine
Cysteine has been termed a "semi-essential" amino acid, as humans can synthesize cysteine from methionine only to a limited extent. When cysteine and methionine are taken together, an adult person in Western countries consumes, on average, protein equivalent to 2-4 grams of cysteine per day (74). Several recent clinical investigations have shown that cysteine supplementation in addition to the normal protein diet has several positive effects, implying that the normal dietary intake of cysteine may be suboptimal although the average intake of calories in Western countries is generally considered superoptimal.

As cysteine is unstable, and cystine is poorly soluble in water and poorly absorbed, most clinical studies on cysteine supplementation have used either the synthetic cysteine derivative NAC, or a cysteine-rich undenatured whey protein isolate. Table 3 summarizes some of the more important results obtained with these two cysteine delivery systems. In view of the role of insulin signaling in the age-related decline in cardiac performance in the fruit fly (12), it may be important to note that whey protein supplementation has been shown to increase the intracellular glutathione concentration in heart muscle tissue of mice (75,76). A dietary supplement containing NAC was also shown to abolish the age-related cognitive decline in transgenic mice, expressing elevated free radical processes (77). NAC, either with or without creatine, has been shown to modulate both basal and postprandrial insulin responsiveness (48). This study also suggested that the addition of creatine can be used to achieve different effects of NAC on fat tissue and skeletal muscle tissue as expected in view of the difference in creatine content.


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  		Table 3. Key Results From Clinical Studies.

 
Muscle Function as a Measure (Surrogate Parameter) of Aging and Frailty
Aging in humans is a complex process involving the generalized impairment of physiological functions, a decreased ability to respond to a wide range of stress, the increased risk of age-associated diseases, and the increased likelihood of death (78). The loss of skeletal muscle function can be measured with good precision and reproducibility and was shown to be strongly correlated with the age-related increase in the probability of death (79,80). This loss of function is therefore one of the best single surrogate parameters of aging. Loss of skeletal muscle mass and muscle function (wasting) is a common finding in old age and typically associated with compromised physical and social functions, loss of independence, and psychological stress. Eventually, the wasting process leads to organ failure (81), and is therefore often considered to be a cause of death.

Physical exercise has been shown to improve skeletal muscle strength and functional performance but is not always effective in old age (82–86). In a placebo-controlled, double-blind study of frail elderly patients, it was found that treatment with NAC doubled the increase in knee extensor strength during a 6-week program of physical exercise and slowed the subsequent decline during a 6-week follow-up period (Figure 4) (87). Similarly, treatment with a cysteine-rich, undenatured whey protein isolate significantly increased peak power and 30-s work capacity in a whole-leg isokinetic cycle test when compared with placebo-treated controls in a randomized double-blind study of young healthy persons (88). Moreover, treatment with NAC was found to ameliorate the loss of body cell mass in cancer patients; this finding also reflects a loss of skeletal muscle mass (89). These positive effects of cysteine supplementation were in line with studies of both elderly persons and cancer patients, showing that the aging- and disease-related decrease in body cell mass is significantly correlated with the age-related oxidative shift in the plasma thiol/disulfide redox status (89). More extensive studies will be needed to define optimal guidelines with respect to doses and time schedules. Future studies will have to show how much postabsorptive protein catabolism we need to optimally balance the healthy turnover of damaged cellular constituents with the long-term maintenance of the body's protein mass.



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  		Figure 4. Effect of N-acetylcysteine on muscular performance and tumor necrosis factor-{alpha} (TNF-{alpha}) level during a program of physical exercise. Data indicate the relative increase (%) in knee extension strength and plasma TNF-{alpha} level during a 6-week treatment and exercise program (t), and during the total 12- to 13-week observation period (o). Filled circles: placebo group; open squares: N-acetylcysteine-treated group (data taken from 87)

 
Body Fat Mass
With any standard diet it is practically impossible even for healthy persons to maintain muscle mass without gaining weight and body fat. If the diet is adjusted to maintain a constant body weight, the skeletal muscle mass will start to decline sooner or later, and body fat will increase accordingly. In view of this problem, it was encouraging to see that supplementation with either NAC (48,90) or a cysteine-rich undenatured whey protein isolate (88) caused a significant decrease in the ratio of body fat versus body cell mass. Similarly, treatment of rats with whey protein during a 5-week exercise program caused an increase in lean body mass and a decrease in relative fat mass when compared with rats fed a control diet (91).

Circulating Tumor Necrosis Factor-{alpha} Level
Cytokines such as tumor necrosis factor-{alpha} (TNF-{alpha}) are proteins with a hormone-like function. Aging is associated with increased circulating levels of certain inflammatory cytokines (including TNF-{alpha}) and was therefore interpreted by some authors as a low-grade inflammatory condition (92,93). High plasma TNF-{alpha} levels were found to be correlated with morbidity (94,95), mortality (93), Alzheimer's disease, atherosclerosis (94,96), and low muscle mass and muscle strength in elderly persons (97). In mouse muscles and myotubes, TNF-{alpha} in combination with interferon-{gamma} (IFN-{gamma}) was shown to strongly reduce the expression of myosin (98). In centenarians, a high plasma concentration of TNF-{alpha} was found to be associated with dementia (94). TNF-{alpha} and the TNF-{alpha}–inducible transcription factor nuclear factor {kappa}B (NF-{kappa}B) have also been implicated in the development of inflammation-associated cancer (99,100). It was therefore alarming to see that the plasma TNF-{alpha} level in frail elderly persons was significantly increased during a 6-week program of physical exercise, i.e., a program that was actually intended to improve their condition (87). The increase in TNF-{alpha} level was completely prevented, however, by cysteine supplementation (Figure 4). A similar increase in plasma TNF-{alpha} concentration was also seen after physical exercise in healthy young persons (101). Again, the increase in TNF-{alpha} was completely abolished by treatment with NAC in combination with the antioxidant vitamins A, C, and E.

Superoxide anion or low micromolar concentrations of hydrogen peroxide have been found to stimulate lymphokine production in activated T cells (102). Subsequent studies have shown that at least two transcription factors involved in cytokine production, i.e., NF-{kappa}B and activator protein-1, are activated under oxidative conditions (103,104; reviewed in 105). Several different redox-responsive mechanisms lead to the stimulation of mitogen-activated protein kinases, Jun N-terminal kinase, p38 or, to a lesser extent, extracellular signal-regulated kinase-1 and -2, which ultimately activate mitogen-activated protein kinase-dependent transcription factors (reviewed in 105). Transcription factors of the activator protein-1 family are largely responsible for the upregulation of plasminogen activator inhibitor-1, which plays an important role in the pathogenesis of type 2 diabetes mellitus and associated cardiovascular complications (106–109). The expression of the cytokine TNF-{alpha} was shown to be induced by the transcription factor NF-{kappa}B and accordingly increased under oxidative conditions (reviewed in 105). The upregulation of TNF-{alpha} synthesis in human dendritic cells by oxidative stress (hydrogen peroxide) is one example (110). That NAC suppresses NF-{kappa}B activation has been documented in patients with sepsis (111).

Conclusions
A large body of evidence suggests that a decrease in insulin receptor signaling facilitates the optimal activation of SIRT1 activity, autophagy, and FOXO transcription factors. These activities were all found to have a strong impact on life span at least in worms, fruit flies, and mice. SIRT1 was also implicated in the life-span-extending effect of calorie restriction. Autophagy and certain FOXO transcription factors play a role in the maintenance of cellular integrity by facilitating the proteolytic removal of damaged long-lived cellular constituents and by ensuring amino acid homeostasis under conditions of amino acid starvation. SIRT1 was implicated in the control of glucose homeostasis under conditions of starvation. This is likely to apply also to humans. A more adequate adjustment of the insulin receptor signaling activity may therefore be warranted.

Whereas genetic manipulation of the insulin receptor signaling pathway or massive calorie restriction may not be viable options for the treatment of humans, the redox-based downregulation of the insulin-independent basal insulin receptor kinase activity may be a promising alternative. Cysteine is the biosynthetic precursor of the quantitatively most important antioxidant and radical scavenger glutathione. Cysteine supplementation in addition to the normal protein diet has shown clear benefits with respect to several parameters relevant to aging. For the sake of brevity, this review has mainly dealt with effects on skeletal muscle functions, body fat, and TNF-{alpha} levels. Cysteine supplementation has shown significant effects on each of these parameters in at least two independent studies. These effects suggest that (a) seemingly healthy persons may have a previously unnoticed deficiency of cysteine, and (b) a deficiency of cysteine leads to a decrease in muscle function and an increase in TNF-{alpha} concentration. These changes are among the hallmarks of aging. Novel cysteine derivatives and cysteine-enriched dietary supplements with minimum amounts of calories are now becoming available. As these are superior to any of the naturally available cysteine sources, the maximum human life span may possibly be increased beyond the previous limit.

The available evidence suggests that a well balanced increase in the dietary cysteine supply may allow us to decrease basal insulin receptor signaling without compromising postprandial glucose clearance to an unacceptable extent. Cysteine supplementation should be accompanied by a delicately balanced supply of creatine (either in the form of meat or dietary creatine supplements) to selectively enhance the insulin response of skeletal muscle tissue relative to insulin signaling in fat cells. Occasional measurements of fasting glucose levels and glucose tolerance tests may be performed to ensure the adequate doses of creatine and cysteine. Even a moderate decrease in basal insulin receptor signaling and a corresponding moderate increase in the postabsorptive plasma glucose concentration to about 95 mg/dL may have the advantage of providing the central nervous system at all times with a good supply of glucose to avoid hypoglycemic reactions involving glucagon, epinephrine, and cortisol, all of which are known to induce skeletal muscle catabolism. More systematic studies of these points are warranted.

The redox sensitivity of the basal insulin receptor kinase activity suggests a linkage between the free radical theory of aging (112) and the impact of insulin receptor signaling on longevity. It is reasonable to assume that cysteine supplementation ameliorates the well documented age-related increase in oxidative stress and the resulting dysregulation of redox-sensitive signaling cascades (113,114). It is tentatively assumed that the downregulation of basal insulin receptor signaling accounts at least to some extent for the effect of cysteine supplementation on the skeletal muscle tissue by facilitating the optimal induction of autophagy, SIRT1, and FOXO transcription factor activities in this postmitotic tissue. However, indirect effects involving signaling cascades in adipocytes, liver, central nervous system, or other cells and tissues cannot be excluded. Downregulation of TNF-{alpha} indicates that cysteine supplementation modulates more redox-sensitive signaling pathways than just the insulin receptor-dependent cascade.

Taken together, the genetic studies on longevity, the biochemical studies on the redox regulation of the insulin receptor kinase activity, and the clinical studies on cysteine supplementation provide a conceptual framework that may serve as a guideline for further studies. Obviously, there are still gaps that need to be filled.


   Acknowledgments
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The dedicated assistance of Mrs. I. Fryson in the preparation of the manuscript is gratefully acknowledged.


   Footnotes
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Decision Editor: James R. Smith, PhD

Received February 3, 2005

Accepted May 20, 2005


   References
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