Original ContributionDifferential inflammatory responses in aging and disease: TNF-α and IL-6 as possible biomarkers
Introduction
Large health care expenditures for a growing elderly population have both stimulated scientific inquiry and heightened public awareness regarding aging-related issues. As a result, many theories have been developed to explain why we age. In the 1950 s, Harman proposed the “free radical theory” of aging, postulating that damage to cellular macromolecules via free radical production in aerobic organisms is a major determinant of life span [1].
Generally, increased oxidative/nitrosative stress describes a condition in which cellular antioxidant defenses are inadequate to completely inactivate reactive oxygen species (ROS)1 and reactive nitrogen species (RNS). Oxidative/nitrosative stress can be caused by excessive ROS/RNS, loss of antioxidant defenses, or both. A major consequence of oxidative/nitrosative stress is damage to nucleic acid bases, lipids, and proteins, which can severely compromise cellular viability and induce a variety of cellular responses through the generation of secondary reactive species, ultimately leading to cell death via necrosis or apoptosis [2]. Substantial evidence suggests that ROS and RNS actively participate in normal aging and have an effect on the onset and progression of age-related diseases [3].
The ability of cells to use oxygen requires adequate cellular oxygen uptake, so abnormal cellular processes can alter cellular oxygen use. Hypoglycemia, for example, can impair the cell's ability to process oxygen and causes hypoxia. In fact, oxyhemoglobin saturation (HbSaO2) can fall to extremely low levels quickly and unexpectedly in association with episodic hypoxemia and is often accompanied by marked changes in heart rate, blood pressure, and respiratory rate [4]. Several high-incidence diseases, including heart failure, chronic obstructive pulmonary disease, and ictus, include hypoxemic incidents among their symptoms. In all instances, this hypoxemic process leads to cellular hypoxia that, in turn, stimulates the generation of ROS [5]. An imbalance between the production and the destruction of ROS, resulting in an increase in ROS, gives rise to oxidative stress, which can inflict direct damage on macromolecules, such as lipids, nucleic acids, and proteins [6]. Previous studies from our laboratory provide evidence that hypoxia-induced ROS cause significant damage to macromolecules in diverse cell types [5].
A modern version of Harman's free radical theory of aging is the “mitochondrial theory of aging,” in which mitochondria are incorporated as critical components that regulate aging. This updated version postulates that electrons from the mitochondrial electron transport chain (ETC) produce ROS, which damage components of the ETC and mitochondrial DNA, leading to a cyclic increase in intracellular ROS levels and a decline in mitochondrial function [7].
An additional theory that has gained increasing attention in recent years is the “molecular inflammatory theory of aging,” which postulates that the activation of redox-sensitive transcription factors by age-related oxidative stress up-regulates the expression of proinflammatory genes [8]. Proinflammatory molecules, such as cytokines, lead to inflammation in various tissues and organs [9]. Cytokines are intercellular signaling proteins that exert pro- and anti-inflammatory activities by binding to specific receptors and stimulating the hepatic production of acute-phase proteins as part of a systemic response that accompanies the local inflammatory response. Cytokines are released at the site of inflammation where they facilitate the influx of lymphocytes, neutrophils, monocytes, and other cells that participate in the clearance of antigens and facilitate healing [10].
The first two cytokines in the inflammatory cascade are tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β), which are produced locally and are considered proinflammatory cytokines. TNF-α and IL-1β stimulate the production of interleukin 6 (IL-6), which has been classified as both a proinflammatory and an anti-inflammatory cytokine. IL-6 inhibits the production of TNF-α and IL-1β, stimulates the release of soluble TNF-α receptors (sTNF-R) [11], and seems to be the primary inducer of hepatocyte-derived acute-phase proteins, many of which have anti-inflammatory properties [12]. C-reactive protein has a role in the induction of anti-inflammatory cytokines in circulating monocytes and in the suppression of proinflammatory cytokines in tissue macrophages [13]. TNF-α and IL-1β represent classic proinflammatory cytokines, whereas sTNF-R and interleukin 10 are anti-inflammatory cytokines [10].
Systemic low-grade inflammation is defined by a two- to threefold increase in the plasma concentration of cytokines and acute-phase proteins [14]. The molecular and physiological significance of systemic low-grade inflammation in chronic disease is not yet fully understood [10]; however, it is associated with age-related diseases including atherosclerosis [15], metabolic syndrome [16], type 2 diabetes mellitus [17], Alzheimer disease [18], and vascular dementia [19].
Although aging is a well-defined process with a familiar set of characteristics, its basis remains poorly understood owing in large part to the difficulty in dissociating normal aging effects from those brought about by age-associated diseases [9]. Likewise, data about the roles of cytokines in aging are conflicting, and most of them are derived from in vitro studies. In vivo studies are necessary to improve the understanding of the roles of inflammatory proteins in the differential responses to aging and age-related pathologies. This study is based on the various hypotheses that relate oxidative stress with aging and the inflammatory response. This is an in vivo study with the aim of defining the effects of aging on the main cytokines TNF-α and IL-6, as well as the effects of acute processes such as hypoxemia on the expression of these cytokines. The ultimate goal of this study is to identify possible differential biomarkers of aging with and without hypoxic episodes.
Section snippets
Subjects
We collected blood samples from three experimental groups of volunteers: a group of healthy and normoxic, middle-aged subjects (middle-aged group, n = 41) and two groups of individuals older than 75 years. The group of older subjects consisted of two subgroups, one group of normoxic subjects with HbSaO2 over 95% (no-hypoxia group, n = 41) and one group with HbSaO2 lower than 95% (hypoxia group, n = 41). The control middle-aged group contained individuals between 18 and 40 years of age (mean age 26
Results
Protein carbonyls are usually formed by various oxidative mechanisms and have been used as a marker of oxidative stress in human tissues. Here, we show that PD plasma levels were significantly higher in older subjects than in middle-aged persons (P ≤ 0.05). When we compared the elderly group with a low HbSaO2 (hypoxia) to an elderly group with physiological HbSaO2 (no hypoxia), we observed a significant increase in protein oxidative damage (P ≤ 0.05; Fig. 1).
TAA is a measurable parameter that
Discussion
Aging is an inherently complex process that is regulated at multiple levels, including genetic, molecular, cellular, organic, and systemic. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward ROS as one of the primary determinants of aging [9]. We studied the relationship between oxidative stress, inflammation, and aging and the association between these phenomena and age-related disorders such as hypoxia. Our results support the importance
Acknowledgments
The authors thank the personnel of the Hospital Universitario Central de Asturias and the Centro de Transfusión y Banco de Tejidos del Principado de Asturias for their excellent work. We also thank the Hospital Monte Naranco and the Consejería de Salud Pública del Principado de Asturias. We are part of the INPROTEOLYS group and the National Net RETICEF for Aging study. This work was partly supported by Grants FISS-06-RD06/0013/0011 from the Instituto Carlos III and INIA-RTA2007-00087-C02-02
References (48)
Use of biomarkers of oxidative stress in research studies
J. Nutr.
(2004)- et al.
Age-related inflammatory cytokines and disease
Immunol. Allergy Clin. N. Am.
(2003) - et al.
Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF
Blood
(1990) - et al.
IL-6 and APPs: anti-inflammatory and immunosuppressive mediators
Immunol. Today
(1997) - et al.
Plasma cytokine profiles in elderly humans
Mech. Ageing Dev.
(2003) - et al.
Elevated circulating tumor necrosis factor levels in Alzheimer's disease
Neurosci. Lett.
(1991) - et al.
Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study
Lancet
(1997) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal. Biochem.
(1976)- et al.
Determination of carbonyl content in oxidatively modified proteins
Meth. Enzymol.
(1990) - et al.
The hydrophilic and lipophilic contribution to total antioxidant activity
Food Chem.
(2001)
Effects of δ-aminolevulinic acid and melatonin in the Harderian gland of female Syrian hamsters
Free Radic. Biol. Med.
Melatonin protects against delta-aminolevulinic acid-induced oxidative damage in male Syrian hamster Harderian glands
Int. J. Biochem. Cell Biol.
Cytokine production and lymphocyte subpopulations in aged humans: an assessment during nocturnal sleep
Mech. Ageing Dev.
Relation between markers of systemic vascular inflammation and smoking in women
Am. J. Cardiol.
Role of frailty in patients with cardiovascular disease
Am. J. Cardiol.
Inflammation markers predicting frailty and mortality in the elderly
Exp. Mol. Pathol.
Elevated levels of tumor necrosis factor alpha and mortality in centenarians
Am. J. Med.
Possible association of psoriasis and reduced bone mineral density due to increased TNF-alpha and IL-6 concentrations
Med. Hypotheses
Aging: a theory based on free radical and radiation chemistry
J. Gerontol.
Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice
J. Pineal Res.
Oxidants, oxidative stress and the biology of ageing
Nature
Hazards of hypoxemia: how to protect your patient from low oxygen levels
Nursing
Antioxidant activity in Spalax ehrenbergi: a possible adaptation to underground stress
J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol.
A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine
Annu. Rev. Genet.
Cited by (126)
TNF is a critical cytokine in age-related dry eye disease
2023, Ocular SurfaceAnti-aging effects of the pistachio extract on mesenchymal stem cells proliferation and telomerase activity
2023, Archives of Gerontology and GeriatricsSexual dimorphism in spatial learning and brain metabolism after exposure to a western diet and early life stress in rats
2022, Physiology and BehaviorCitation Excerpt :The difference between the initial and final absorbance value at 730 nm is used as an index of antioxidant activity. Finally, the results are transformed into the equivalent of Trolox, which is a vitamin E analogous, in mg Trolox / mL, which produce the same antioxidant effect as the brain sample to be studied [49, 50]. We determined the lipid peroxidation (LP) levels or lipoperoxidation levels, a process that leads to the production of lipid peroxides and their derivatives such as malonyl dialdehyde (MDA) and 4-hydroxynonenal (4-HNE) that provide a convenient lipid peroxidation index.
New cannabidiol (CBD) derivatives: Synthesis, anti-inflammatory activity, and molecular docking
2022, Phytochemistry LettersAdipose-derived exosomes block muscular stem cell proliferation in aged mouse by delivering miRNA Let-7d-3p that targets transcription factor HMGA2
2022, Journal of Biological Chemistry