Frailty as a Manifestation of Oxidative Stress
Oxidative stress is the name given to the presence of an overly large number of oxidative molecules in cells and tissues, a state that results in damage to protein machinery and degraded function as chemical reactions take place at a faster pace than altered proteins can be replaced. Oxidative stress is a feature of aging, resulting from mitochondrial dysfunction and processes related to chronic inflammation, among other issues. This open access paper discusses oxidative stress in connection with age-related frailty, but is non-committal on where in the chain of cause and consequence, from root causes to final manifestations of aging, oxidative stress is to be found. This is a problem in the field: without some view on which causes result in which consequences in aging, how to steer the research community towards the exploration of effective therapies, those that address causes rather than patching over consequences?
The free radical theory of aging connected oxidative stress with the aging process and aging-related diseases. Although this theory failed to completely explain the aging process, the prominent role of oxidative damage in the decline of function coursing with aging in different tissues is widely accepted. An imbalance between pro-oxidant and antioxidant species would result in oxidative molecular and cellular damage. However, despite their well-known deleterious role, it is now recognized that reactive oxygen species (ROS) are key physiological signaling molecules with regulatory functions. Physiological elevation of ROS generates responses that contribute to cellular hormesis while unmodulated excessive amount of ROS is what results in oxidative damage of molecular and cellular structures. In fact, adequate ROS signaling induces endogenous defense mechanisms and mitohormesis and would explain some contradictory adverse clinical outcomes obtained with antioxidant supplementation.
Oxidative stress has been proven to be associated with age-related diseases. In fact, oxidative stress is related to unsuccessful aging outcome rather than to the aging process by itself. This led us to hypothesize that, as a common background, oxidant injury contributes to functional decline in different tissues and organs and, depending on resilience of these systems, specific clinical alterations are manifested. For instance, specific isolated age-related exhaustion of functional reserve in brain would lead to cognitive impairment while dysfunctional kidney could result in chronic kidney disease, dysfunctional cardiovascular system in cardiovascular disease or dysfunctional lung in chronic obstructive pulmonary disease. In contrast, frailty status would involve a multisystemic failure that results in a condition prone to disability and mortality.
Although the association of frailty and sarcopenia is consistent, the fact that sarcopenia is absent in a significant proportion of frail subjects suggests that frailty and sarcopenia are related but distinct phenotypes of aging. We might consider sarcopenia as a clinical manifestation related to skeletal muscle dysfunction where oxidative stress seems to play a key role. This does not mean that the frailty phenotype in the absence of sarcopenia is unrelated to oxidative stress. In fact, aging-related diseases that could contribute to frailty development share oxidative stress as a common factor in their pathophysiological background. In this sense, there is substantial evidence of the important role played by ROS in the context of unsuccessful aging in organs and systems outside skeletal muscle, including vascular system, kidney, lung, metabolism, and nervous system.
It is important to highlight that aging-related diseases that favor the manifestation of frailty phenotype should not be considered isolated entities but interconnected clinical manifestations with multidirectional relationships and common pathophysiological environments such as oxidative damage. Thus, oxidative stress-related multisystem dysfunction could result in the performance deficit associated to frailty phenotype either including or not sarcopenia phenotype. Mitochondrial dysfunction related to oxidative stress is a key event in this process that affects skeletal muscle but also other tissues promoting the development of age-related diseases and frailty.
'cause or consequenes' OR 'circular reference where consequences are the cause' in a positive feedback loop? If the latter is the case, then looking for definitive most basic cause will never yield a definitive cause. If this is it, then stopping this circular reference loop at any point of this spiral may yield as good result as finding "non existing" cause.