Aging-associated Aberrant Mitochondrial Redox Signaling, Physical Activity, and Sarcopenia.

Aging-related alteration of mitochondrial morphology, impairment in metabolic capacity, bioenergetics, and biogenesis are closely associated with loss of muscle mass and function. Mitochondrial Reactive Oxygen Species (ROS) stimulate muscular redox signaling mechanisms. Bioenergetic integrity of mitochondria and redox signaling dynamics deteriorates in aged skeletal muscle. Mitochondrial bioenergetic impairment leads to excessive ROS levels and induces the generation of defective mitochondria. Higher ROS levels may induce senescence or apoptosis. It is not a resolved issue that mitochondrial dysfunction is either the sole reason or a consequence of muscle loss (or both). However, Increasing evidence emphasizes that dysregulated mitochondrial redox signaling has a central role in age-related muscle loss. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox signaling pathways with the expression of antioxidant genes. As the aberrant redox signaling mechanisms in aging skeletal muscle become clearer, new natural and synthetic Nrf2-modulating substances and integrated daily physical activity alternatives are coming into view for preventing muscle loss in the elderly. A comprehensive understanding of the relationship between redox signaling pathways and age-related sarcopenia can help us to prevent sarcopenia and its frailty effects with an optimized exercise program as an innovative non-pharmacological therapeutic approach. A further aspect is necessary to consider both individualized physical training options and alternative Nrf2 signaling modulators. Ameliorating the redox signaling with physical activity and pharmacological interventions may help to prevent sarcopenia and its frailty effects.

Redox signaling and modulation in ageing.

In spite of considerable progress that has been reached in understanding how reactive oxygen species (ROS) interact with its cellular targets, several important challenges regarding regulatory effects of redox signaling mechanisms remain to be addressed enough in aging and age-related disorders. Redox signaling is precisely regulated in different tissues and subcellular locations. It modulates the homeostatic balance of many regulatory facilities such as cell cycle, circadian rhythms, adapting the external environments, etc. The newly proposed term "adaptive redox homeostasis" describes the transient increase in ROS buffering capacity in response to amplified ROS formation rate within a physiological range. Redox-dependent second messengers are generated in subcellular locations according to a specific set of rules and regulations. Their appearance depends on cellular needs in response to variations in external and internal stimulus. The intensity and magnitude of ROS signaling determines its downstream effects. This issue includes review and research papers in the context of redox signaling mechanisms and related redox-regulatory interventions, aiming to guide for understanding the degenerative processes of biological ageing and alleviating possible prevention approaches for age-related complications.

Mitochondria-associated cellular senescence mechanisms: Biochemical and pharmacological perspectives.

Initially, endosymbiotic relation of mitochondria and other cellular compartments had been continued mutually. However, that evolutionary adaptation impaired because of the deterioration of endosymbiotic crosstalk due to aging and several pathological consequences in cellular redox status are seen, such as deterioration in redox integrity of mitochondria, interfered inter-organelle redox signaling and inefficient antioxidant response element mediated gene expression. Although the dysfunction of mitochondria is known to be a classical pattern of senescence, it is unresolved that why dysfunctional mitochondria is the core of senescence-associated secretory phenotype (SASP). Redox impairment and SASP-related disease development are generally together with weaken immunity. Impaired mitochondrial redox integrity and its ineffectiveness in immunity control render elders to be more prone to age-related diseases. As senotherapeutic agents, senolytics remove senescent cells whilst senomorphics/senostatics inhibits the secretion of SASP. Senotherapeutics and the novel approaches for ameliorating SASP-related unfavorable effects are recently thought to be promising ways as mitochondria-targeted gerotherapeutic options.

Redox signaling in impaired cascades of wound healing: promising approach.

In the aging communities, wound healing management is a quite remarkable problem especially in elderly individuals. The optimal level of healing of wounds developed spontaneously or due to surgery is of critical importance in order to prevent the negative effects that may occur due to delayed healing (for example, organ or system damage caused by infections that may develop in the wound area). The deteriorated subcellular redox signaling is considered to be as the main factor in the chronicity of wounds. The pivotal role of mitochondria in redox regulation reveals the importance of modulation of redox signaling pathways in senescent cells. Secretory factors released upon the acquisition of senescence-associated secretory phenotype (SASP) function in a paracrine manner to disseminate impaired tissue redox status by affecting the redox metabolome of nearby cells, which could promote age-related pro-inflammatory pathologies. Evaluating the wound-site redox regulation in impaired redox signaling pathways may help prevent the formation of chronic wounds and the development of long-term complications of the wounds, especially in the elderly. Using the redox modulatory pharmacologically active substances targeting the senescent cells in chronic wound areas hopefully opens a new avenue in wound management. As the signaling mechanisms of wound healing and its relationship with advanced age become more clearly understood, many promising therapeutic approaches and redox modulator substances are coming into clinical view for the management of chronic wounds.

Significance of Intercellular adhesion molecule-1 Lys496Glu gene polimorphism on plasma redox status regulation in laryngeal carcinoma.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a surface glycoprotein important for tumor invasion and angiogenesis. The present research is conducted to investigate whether specific gene polymorphism of ICAM-1 K469E (rs5498) and plasma redox status could be associated with laryngeal cancer (LC) development. Since there is no clear evidence which investigates the relationship between ICAM-1 polymorphism and ROS-mediated plasma protein oxidation in LC, our study is the first significant contribution for investigating the relationship. METHODS: The study covered patients with primary LC and their age-matched healthy control subjects. Evaluation of ICAM-1 K469E (rs5498) gene polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. Plasma redox status was assessed with spectrophotometric methods. RESULTS: In the current paper, we found that LC patients with GG genotype had a decreasing trend for the plasma oxidative damage biomarker levels when compared with all allele genotypes (AA and AG). CONCLUSION: We concluded that G allele of the ICAM-1 K469E gene plays a significant role in the optimal regulation of plasma redox homeostasis in patients with LC.

Melatonin-related signaling pathways and their regulatory effects in aging organisms.

Melatonin is a tryptophan-derived ancestral molecule evolved in bacteria. According to the endosymbiotic theory, eukaryotic cells received mitochondria, plastids, and other organelles from bacteria by internalization. After the endosymbiosis, bacteria evolved into organelles and retained their ability of producing melatonin. Melatonin is a small, evolutionarily conserved indole with multiple receptor-mediated, receptor-dependent, and independent actions. Melatonin's initial function was likely a radical scavenger in bacteria that's why there was high intensity of free radicals on primitive atmosphere in the ancient times, and hormetic functions of melatonin, which are effecting through the level of gene expression via prooxidant and antioxidant redox pathways, are developed in throughout the eukaryotic evolution. In the earlier stages of life, endosymbiotic events between mitochondria and other downstream organelles continue with mutual benefits. However, this interaction gradually deteriorates as a result of the imperfection of both mitochondrial and extramitochondrial endosymbiotic crosstalk with the advancing age of eukaryotic organisms. Throughout the aging process melatonin levels tend to reduce and as a manifestation of this, many symptoms in organisms' homeostasis, such as deterioration in adjustment of cellular clocks, are commonly seen. In addition, due to deterioration in mitochondrial integrity and functions, immunity decreases, and lower levels of melatonin renders older individuals to be more susceptible to impaired redox modulation and age-related diseases. Our aim in this paper is to focus on the several redox modulation mechanisms in which melatonin signaling has a central role, to discuss melatonin's gerontological aspects and to provide new research ideas with researchers.

Mitochondria-targeted senotherapeutic interventions.

Healthy aging is the art of balancing a delicate scale. On one side of the scale, there are the factors that make life difficult with aging, and on the other side are the products of human effort against these factors. The most important factors that make the life difficult with aging are age-related disorders. Developing senotherapeutic strategies may bring effective solutions for the sufferers of age-related disorders. Mitochondrial dysfunction comes first in elucidating the pathogenesis of age-related disorders and presenting appropriate treatment options. Although it has been widely accepted that mitochondrial dysfunction is a common characteristic of cellular senescence, it still remains unclear why dysfunctional mitochondria occupy a central position in the development senescence-associated secretory phenotype (SASP) related to age-related disorders. Mitochondrial dysfunction and SASP-related disease progression are closely interlinked to weaken immunity which is a common phenomenon in aging. A group of substances known as senotherapeutics targeted to senescent cells can be classified into two main groups: senolytics (kill senescent cells) and senomorphics/senostatics (suppress their SASP secretions) in order to extend health lifespan and potentially lifespan. As mitochondria are also closely related to the survival of senescent cells, using either mitochondria-targeted senolytic or redox modulator senomorphic strategies may help us to solve the complex problems with the detrimental consequences of cellular senescence. Killing of senescent cells and/or ameliorate their SASP-related negative effects are currently considered to be effective mitochondria-directed gerotherapeutic approaches for fighting against age-related disorders.

Early-adulthood caloric restriction is beneficial to improve renal redox status as future anti-aging strategy in rats.

AIMS: Caloric restriction (CR) is an experimental approach proposed to alleviate age-related oxidative damage. In the present study, we investigated the consequences of CR on renal redox homeostasis in rats at a specific time frame in early-adulthood.. METHODS: Three groups of male Sprague-Dawley rats; young control at 6-month-old, 2-year-old subjected to 40% CR between 18th-24th months of age, and their non-CR controls were sacrificed, and numerous redox status biomarkers including protein oxidation, glycation, lipid peroxidation, glycation end products, thiol groups, and superoxide dismutase were assayed. It was also ensured that CR rats and their non-CR corresponding rats had similar body weights at the end of the study to decrease the confounding effects of different body weights on redox homeostasis and caloric restriction. RESULTS: After CR, the detrimental effects of the protein oxidation, glycation, and lipid peroxidation were significantly improved in the renal tissue CR rats when compared to their non-CR control group. However, there were no significant difference in thiol fractions between younger controls and both of the elderly groups. CONCLUSION: Detrimental consequences of renal senescence on redox homeostasis are significantly improved via CR especially applied in early-adulthood.

Novel biomarkers for the evaluation of aging-induced proteinopathies.

Proteinopathies are characterized by aging related accumulation of misfolded protein aggregates. Irreversible covalent modifications of aging proteins may significantly affect the native three dimentional conformation of proteins, alter their function and lead to accumulation of misfolded protein as dysfunctional aggregates. Protein misfolding and accumulation of aberrant proteins are known to be associated with aging-induced proteinopathies such as amyloid ß and tau proteins in Alzheimer's disease, α-synuclein in Parkinson's disease and islet amyloid polypeptides in Type 2 diabetes mellitus. Protein oxidation processes such as S-nitrosylation, dityrosine formation and some of the newly elucidated processes such as carbamylation and citrullination recently drew the attention of researchers in the field of Gerontology. Studying over these processes and illuminating their relations between proteinopathies may help to diagnose early and even to treat age related disorders. Therefore, we have chosen to concentrate on aging-induced proteinopathic nature of these novel protein modifications in this review.