Oxidative stress, frailty and cognitive decline

Abstract

The causes of frailty are complex and must be accepted as multidimensional based on the interplay of genetic, biological, physical, psychological, social and environmental factors, although inflammation and oxidative stress are two factors that play an important role in the development of symptoms with those fragile states.

Objective

To establish the relationship between oxidative stress, frailty and decline cognitive.

Methods

A review of the literature and data abstraction from papers are showing the relationship between a) oxidative stress and frailty, b) oxidative stress and decline cognitive.

Results

The papers reviewed showed that we can establish a relationship between the progress of neurodegenerative disorders and increased oxidative stress. Also found in frailty, that oxidative stress plays an important role as one of the starting points for the appearance of permanent inflammatory states.

Conclusions

Although the literature indicates the relationship between oxidative stress, frailty and decline cognitive, more studies are needed in this regard, especially interventions that asses whether increased intake of antioxidants in older frailty may improve the progress of disease and slow cognitive decline.

Introduction

In the last decades has been an increasing interest with respect to the research of the biological and environmental factors affecting the quality of human aging. This is primarily due to the social burden connected to the extraordinary increase of the elder population, which implies an increase of the subjects which are not autonomous and are affected by invalidating pathologies 1, 2, 3.

The concept of frailty began to emerge as a medically distinct, clinically recognizable syndrome some years ago based on the clinical experience of geriatricians 4, 5, 6, 7. This has become a fascinating concept despite difficulties in providing an exact definition of the term.

The term “frailty” is commonly used in different ways under different circumstances but mainly to describe a physical and functional decline which may occur as a consequence of certain diseases, but most intriguingly also in the absence of identifiable specific disease (8). The emerging concept of “frailty” as a syndrome related to the decline of the homeostatic capacity is strongly favoring the research in this field 9, 10. In particular, the definition of frailty given by Fried and coworkers (4), where frailty is defined as a wasting syndrome correlated to the lost of homeostasis and increased vulnerability to stressor which leads to a significant increase of the age-related decline of different physiological systems and then to disability, comorbidity, and death risk (4), seems particularly promising as it leaves the field open to future research to develop therapies that compensate for this loss or slow of homeostasis.

Cognitive function is a predictor of frailty in older (11). In a recent study (12) 820 subjects were evaluated for cognitive function and frailty status during a 3-year follow-up and found that the risk of developing Alzheimer's disease was 2.5 times higher when frailty was present at baseline. Other authors (13) found that the risk of becoming cognitively impaired for frail subjects was 1.3 times higher than of not frail subjects over a 10-year period. Also, the decline in cognition over time was more severe in frail subject compared to non-frail and pre-frail.

The causes of frailty are complex and must be accepted as multidimensional based on the interplay of genetic, biological, physical, psychological, social and environmental factors 9, 14.

In this regard we will see how oxidative stress is a common factor in the frailty and cognitive decline.

Oxidative stress, inflammation and frailty

The primary biologic mechanism that causes frailty in older persons has never been adequately explained. There is increasing interest in the role of oxidative stress and inflammation in ageing processes and the development of frailty, thus, according to recent views, oxidative stress may be the driving force of this condition (15).

Inflammation and frailty

During aging, a reduction in sex steroids, growth hormone, and vitamin D levels are associated with increases in the baseline levels of inflammatory proteins (16). Inflammation also arises in response to the continuous antigenic load from subclinical infections, atherosclerosis and other chronic diseases (Fig 1). This creates a condition of chronic inflammation, or “inflammaging”, which has been associated with many detrimental effects and may contribute significantly to the increase in morbidity and mortality of old age and could contribute to the wasting state of frailty syndrome 17, 18.

Figure 1.

Physiology of frailty (19)

Systemic inflammation could contribute to the wasting state of frailty syndrome through its catabolic effects, as seen in many inflammatory diseases (19). Recent studies showed the role of inflammation activation in the development of frail state (18).

In cross-sectional association studies performed in at least three different populations, significant positive relationships were identified between frailty and the inflammatory cytokine IL-6 and C-reactive protein. However, the inflammatory triggers in frailty are still unknown.

Interleukin-6 (IL-6) has been termed the ‘‘cytokine for geriatricians’’ (20). In older people, higher circulating levels of IL-6 are associated with poor physical performance and muscle weakness (21) and predict the onset of disability (22). Older patients thus defined as frail exhibit evidence of increased inflammation, with higher levels of C-reactive protein (CRP) (23) and IL-6 (24). TNF-α and other inflammatory signals increase IL-6 production which in turn stimulates production of CRP.

Oxidative stress and frailty

Excessive and unopposed oxidative stress may be the core mechanism leading to age-associated frailty (25). Oxidative damage accumulates with age and causes an accumulation of genetic, muscle and lipid damage sufficient to impair cellular and organ function (26) (Fig. 2)

Figure 2.

A schematic summary of proposed mechanisms by which ROS and oxidative stress could contribute to the process of aging (26)

Recent evidence also supports a link between oxidative damage and frailty in older people. Protein carbonylation, an indirect measure of ROS muscle damage, was associated with low grip strength in the Women's Health and Ageing Study 1 (27). Furthermore, in two recent studies, a close relationship was found between frailty status and markers of oxidative stress 28, 29.

A variety of exogenous and endogenous factors can stimulate an increase in ROS production at the cellular level. ROS can stimulate signal transduction pathways, resulting in changes in gene expression that can modulate numerous responses that impact on cellular function and survival. In addition to activating intracellular signaling pathways, elevations in ROS can produce oxidative damage at molecular levels (DNA, proteins, lipids), if repair processes are insufficient. One result is organelle damage, which can directly affect key cellular responses. In both scenarios-the modulation of expression of various stress-response genes and the intracellular damage to macromolecules-there are subsequent responses at cellular levels (e.g., inflammation, proliferation, apoptosis, necrosis) that can stimulate additional ROS generation from endogenous sources. ROS-induced changes at cellular levels can also lead to an integrated array of systemic responses that can impact, with the passage of time, on aging processes, as well as organ dysfunction, frailty, and age-related diseases (26).

Reactive oxygen species (ROS) also are of critical importance in skeletal muscle damage and sarcopenia 30, 31.

Moreover, reactive oxygen species, especially hydrogen peroxide (H₂O₂), are noted to play important roles in regulation of various intracellular signal transduction pathways (28). There is evidence suggesting that H2O2 could act as an inducer of apoptosis and, through regulating nuclear factor (NF)-ϰB, is implicated in inflammation 32, 33. Indeed, H₂O₂, produced in the mitochondria by several enzymatic systems, has been proposed as key regulator of widespread aging mechanisms, including impaired protein turnover, telomere shortening, increased somatic mutations, cell death and proliferation (34).

Body composition change is thought to be another major player in the development of frailty. Age-dependent increase in visceral abdominal fat and decrease in subcutaneous fat have been repeatedly observed in numerous studies.

The visceral fat is known to be metabolically active, and could cause many metabolic and physiological alterations through endocrine as well as paracrine activities (35). In particular, IL-6 and other cytokines could be secreted by adipose tissue and enter the circulation, which, as previously described, play important role in frailty (18). Additionally, it is known that increasing abdominal fat is closely associated with insulin resistance, which has been shown to precede the development of frailty (35).

Thus, central obesity is a key factor of frailty through several different pathways including generating inflammation (36) and oxidative stress (37) as well as releasing free fatty acids into the circulation (38).

Mild cognitive impairment and oxidative stress

Ageing in humans is accompanied by stereotypical structural and neurophysiological changes in the brain and variable degrees of cognitive decline. Studies have revealed that separate brain regions that interact to subserve higher-order cognitive functions show less-coordinated activation with ageing, suggesting a global loss of integrative function. These observations suggest that the higher-order systems biology of the brain is significantly altered by normal ageing in the absence of disease (39).

Recent emphasis in adult dementing disorders has been on early detection with the hope of early treatment to slow disease progression. Mild cognitive impairment (MCI) is generally considered to be the transitional zone between normal aging and early dementing disorders, especially Alzheimer disease (AD) (40).

Decrements in motor function and decrements in memory are two main behavioral parameters that are altered in senescence in both humans and animals. Age related deficits in motor performance are thought to be result of alterations in the striate dopamine (DA) system as the striatum shows marked neurodegenerative changes with age. In contrast to neurodegenerative diseases, the cognitive decline in normal aging may not be associated with a significant loss of neurons (41).

Oxidative stress (OS) is thought to be a contributing factor to the decrements in cognitive and/or motor performance seen in aging. The brain may be particularly vulnerable to the deleterious effects of oxidative damage because it is relatively deficient in free radicals protective antioxidant compounds, utilizes high amounts of oxygen, contains high concentrations of iron and easily peroxidizable fatty acids, and the essentially nonregenerative nature of nervous tissue (42).

Multiple lines of evidence suggest that progressive oxidative damage is a conserved, central mechanism of age-related functional decline. Gene expression studies of whole-organism ageing in worms and flies and brain-specific ageing in mice, rats, chimpanzees and humans reveal that all six organisms show an age-dependent upregulation of oxidative stress-response genes. Moreover, genes that mediate oxidative stress responses and DNA damage repair constitute the largest class of genes upregulated in the ageing human prefrontal cortex. Age related memory impairment is correlated with a decrease in brain and plasma antioxidants (43). Dietary antioxidants can suppress many age-related gene expression changes in the mouse brain and can reduce cognitive decline and prevent oxidative damage to the brain in ageing rats 39, 44, 45, 46.

Mitochondria are the major source of free radicals in cells and DNA and protein may be more easily oxidized than in the nucleus (47).

Several studies of MCI show significant elevations of DNA damage in peripheral leukocytes (48), isoprostanes (49) and elevated levels of oxidized base adduct in MCI compared with age matched control subjects that are similar to levels observed in late stage AD subjects, which suggests that oxidative damage to nDNA and particularly mtDNA occurs early in the course of AD and may contribute to the pathology of neurodegeneration (50). An increase in protein carbonyl levels has been demonstrated for various brain regions including the hippocampus 51, 52, and levels significantly higher of 8,12-isoiPF2 α-VI in cerebrospinal fluid, plasma, and urine of subjects with MCI compared with cognitively normal elderly subjects (49).

Mutated mitochondrial DNA may code for abnormal cytochromes and may cause infidelity of the electron transport chain associated with increased superoxide radical production and a vicious cycle of progressively increasing oxidative stress (53). Mitochondrial dysfunction and mitochondria derived ROS have been implicated in both normal brain aging and neurodegenerative diseases (54).

Several authors suggested the possibility that the increase in oxidative stress may result, at least partly, from a relative decrease in antioxidant enzyme activities 55, 56. A decline in the activities of Mn as CuZn superoxide dismutase isoenzymes and catalase has been found in the brain, heart, liver and kidney of aging mice (57).

ROS production regulated NAD(P)H oxidase, isoenzymes is known to play a role in main redox-sensitive signalling pathways, any increase in ROS levels and/or any oxidative shift in the thiol-disulfide redox status may cause a shift in numerous physiological processes, eg the age related increased in the steady state level of interleukin 6 (IL-6) mRNA and IL-6 production in the brain (58). Oxidative conditions cause not only structural damage but also changes in the ser points of redox sensitive signalig processes including the insulin receptor signalling pathway. In the absence of insulin, the otherwise low insulin receptor signalling is strongly enhanced by oxidative conditions. Autophagic proteolysis and sirtuin activity, in turn, are down regulated by the insulin signalling pathway, and impaired autophagic activity has been associated with neurodegeneration (59).

Diet, mild cognitive impairment and frailty

Several authors 60, 61 suggests that the combinations of antioxidants anti-inflammatory polyphenolics found in fruits and vegetables may show efficacy in aging because these compounds may be responsible for putative multitude of beneficial on healt. Higher adherence to the Mediterranean diet (MeDi) (a diet characterized by high intake of fish, vegetables, legumes, fruits, cereals, and unsaturated fatty acids [mostly in the form of olive oil], low intake of dairy products, meat, and saturated fatty acids, and a regular but moderate intake of alcohol is associated with lower risk of future development of MCI and that patients with MCI and higher MeDi adherence would have a lower risk of developing future AD (61).

The protective effect of the MeDi for MCI may be mediated via inflammatory pathways. Links between MCI and higher inflammatory states have been demonstrated. Higher adherence to the MeDi is in general associated with significant reductions in a series of other inflammatory markers including white blood cell counts and others.

Conclusion

Intracellular ROS production is increased with exposure to many environmental stress conditions. While increased oxidative stress and other factors trigger an array of alterations at molecular levels that contribute to aging, genetic factors, as well as lifestyle, can accelerate or reverse the aging process by either sensitizing or preventing and repairing the defects. As the molecular and cellular defects accumulate during the life span of an organism, the resulting perturbation in redox balance and the endogenous generation of ROS will further influence the regulation of a number of physiological functions (e.g., metabolism and stress tolerance) and, ultimately, accelerate the aging process.

Frailty and cognitive decline are associated with oxidative stress and inflammatory states. More studies are needed in this regard, especially interventions that asses whether increased intake of antioxidants in older frailty may improve the progress of disease and slow cognitive decline.