Free radicals (freeradicals) are a research hotspot in life science. In 1956, Harman of the United States introduced the concept of freeradicals in radiation chemistry into the biological field. The famous freeradicals theory is proposed. reactive oxygen species (ros) are the most common freeradicals in the body. Free radicals in the human body are mainly oxygen free radicals. Excessive freeradicals induce the oxidation reaction of the body, which can damage the tissues and cells of the body, and then lead to aging. Therefore, Harman proposed the famous freeradicals theory of aging.

Oxidative stress leads to oxidative damage of biomolecules, resulting in the generation of endogenous damage-associatedmolecular patterns (DAMPS) and the release of cytokines.

Cytokines can activate signaling pathways downstream of pattern recognition reptors (PRRS), such as nuclear factor-kB (NF-kB), JAK, ST and MAPK, leading to increased release of cytokines and chemokines, recruitment and activation of more inflammatory cells. It causes systemic chronic inflammatory response. Based on the close relationship between oxidative stress and inflammation and aging.

Dela Fuente et al.

proposed the oxidation-inflammation theory of aging (oxi-inflamm-aging) and believed that oxidative stress leads to inflammatory aging.

Free radicals, inflammation and aging are closely related and complex, which have attracted great attention from scholars. 1. Free radicals and inflammation Free radicals refer to ions, atoms and molecular groups that exist alone and have paired valence electrons. The common feature is that there are unpaired electrons in the outermost electron orbitals, and the main characteristics are active and reactive.

Free radical is an indispensable active element with the nature of double-edged sword in the body, which is both beneficial and harmful to the organism.

Generally, there is a complete set of antioxidant system in organisms, which can remove free radicals, so that the generation and removal of free radicals are in dynamic equilibrium, and maintain the metabolic balance of free radicals.

Under normal circumstances, free radicals play an important role in antibacterial, anti-inflammatory and tumor inhibition.

However, when the body is attacked by some diseases or exogenous substances, the metabolism of free radicals is abnormal, which induces lipid peroxidation and can cause oxidative stress damage to tissues and cells. Highly reactive free radicals, especially ROS free radicals, are produced in the cellular respiratory chain during normal metabolism. In response to oxidative toxicity, cells prevent the formation of ROS or neutralize ROS produced during their metabolism through a variety of antioxidant mechanisms.

When the generation of ROS exceeds the antioxidant clearance capacity of cells, excessive accumulation of ROS causes abnormal inflammatory response. In the stage of immune activation and effector, the elimination of foreign or altered autoantigens is accompanied by an inflammatory state. Oxidation and inflammation are closely related in the process of immune response that maintains body homeostasis. Moderate ROS is conducive to the defense function of the immune system. ROS can not only be used as a chemical weapon to destroy malignant cells and pathogens, but also regulate the expression of antibodies and cytokines during the immune response. Immune cells are more susceptible to oxidative stress damage than other cells because of their fragile structural features.

Oxygen free radicals are effectors of inflammatory responses, and excessive production of oxygen free radicals can induce inflammatory responses through PRRS and non-PRRs pathways.

Free radicals are closely related to chronic inflammatory response. The chronic inflammatory process can lead to enhanced oxidative stress and decreased intracellular antioxidant capacity. Excessive free radicals can act on the membrane lipids of cells, damage the structure and function of proteins, and cause DNA mutations.

Oxidative stress caused by free radicals can increase the production of cytokines through different mechanisms. Oxygen-containing derivatives act as second messengers to activate the transcription factors NF-KB and activator protein 1 (AP-1), and oxidation of the reduced coenzyme H (NADPH) oxidase complex on the cell membrane generates ROS to amplify the oxidative stress response. Thus, the activation of inflammatory cells is further stimulated, thus forming a spiral vicious cycle between oxidative stress and inflammatory response.

Inflammatory state is closely related to oxidative stress state, and NF-KB is the key to link inflammation and oxidative stress.

AP-1 is involved in the regulation of a wide range of physiological processes including cell proliferation, apoptosis, survival and differentiation.

ROS and the balance of intracellular REDOX states, especially sulfhydryl groups, can directly affect AP-1 activity.

The expression of AP-1 gene can also be regulated by cytokines.

NF-KB is a very special transcription factor that can be activated by a variety of pathological factors.

It is involved in the regulation of many inflammatory factor gene expression and is an essential factor for the transcription of a variety of pro-inflammatory genes.

At the same time, NF-KB also plays an important role in regulating the expression of many enzymes (such as iNOS and COX-2) genes involved in the amplification and persistence of inflammatory response (i.e., cascade effect).

The moderate activation of NF-KB is of great significance for the body to resist the harm of various factors, but at the same time, due to the excessive activation of NF-KB can induce the expression of cytokines such as IL-1β, adhesion molecules, immune receptors, inflammation-related enzymes, thus forming a vicious circle of inflammatory response.

Oxygen free radicals can accelerate macrophage migration and cause the release of inflammatory and profibrotic cytokines, which further stimulate ROS production.

Excessive ROS can promote the expression of pro-inflammatory cytokines by activating the redox-sensitive transcription factors NF-KB and AP-1, which further up-regulate the expression of gene products related to inflammation such as VCAM-1, ICAM-1 and MCP-1, and aggravate the inflammatory response.

Therefore, it is likely that oxidative stress-induced cytokine production will further increase the intensity of oxidative stress, thus forming a vicious cycle.

The relationship between oxidative stress and tumor necrosis factor-α (TNF-α) is very complex.

TNF-α can induce the production of oxygen free radicals, promote the "oxidative burst" of neutrophils, produce ROS mediators such as oxygen free radicals and cause tissue damage, while ROS can also increase the level of TNF-α.

TNF-α can activate the transcription and expression of inflammatory mediators mediated by the NF-KB pathway, induce the expression of a variety of inflammatory mediators in vascular endothelial cells and mesangial cells through the NF-KB pathway, and form an autocrine enhanced circuit, thereby aggravating the degree of inflammatory injury and promoting the occurrence and development of inflammation.

Oxidative stress and inflammation caused by free radicals interact with each other by regulating transcriptional levels, forming a vicious cycle of free radical-oxidative stress-inflammation-oxidative stress-free radicals.

Oxidative stress is a concomitant phenomenon in the process of inflammation, which aggravates the inflammatory response through oxidation, and inflammation promotes oxidation through inflammatory mediators.

2. Free radicals and aging Under normal circumstances, the production and scavenging of free radicals in cells are in a dynamic balance. With the increase of age, this balance is gradually destroyed, and the concentration of free radicals exceeds the "threshold". It can damage organelles, cell membranes and other structures, leading to oxidative stress injury of organisms, and eventually aging and death.

Therefore, Harman proposed the theory of free radical aging, which can be summarized as the intensification of the contradiction between excessive ROS production by mitochondria and weakened defense ability of ROS, ultimately leading to aging. In 1994, Barja et al. showed that the less ROS produced per unit oxygen consumption, the longer life span. The use of drugs or nutrients, calorie restriction (CR), and exercise are effective measures to delay aging, which can increase antioxidant capacity and reduce ROS production, becoming a strong support for the theory of free radical aging.

The theory of free radical aging basically reflects the universal law of biological aging, but the new research evidence has posed a serious challenge to this theory. Harman believed that the lower the cell metabolic rate, the more ROS produced, causing senescence, but RIStoe et al. found that CR delayed senescence by inducing mitochondrial metabolic rate and increasing ROS production when studying the model organism of aging, nematode. SeSSO et al., after 8 years of randomized investigation, concluded that: The antioxidants vitamin C and vitamin E are not effective in preventing cardiovascular disease, and vitamin E even increases the risk of ischemic stroke. The free radical theory seems to be in doubt.

However, in 2011, an authoritative journal reported that low concentrations of ROS can induce many protective mechanisms. For example, the activation of cellular redox-sensitive elements and related signaling pathways can stably, comprehensively, and effectively improve the body's antioxidant capacity, and ultimately eliminate disease and prolong life. "Thus, in general, antioxidants are antioxidative at low concentrations and pro-oxidative at high concentrations." 3. Inflammation and aging With aging, there is a pro-inflammatory status (pro-inflammatory status) in the body. Franceschi et al. first named this phenomenon as inflammatory senescence. inflammaging, inflamm-ageing and inflammageing appeared in later literature. Xia Shijin et al. first translated "inflamm-aging" into the Chinese term "inflammatory aging", and took the lead in carrying out a series of studies on the mechanism and intervention of inflammatory aging in China. Inflammatory senescence is closely related to a variety of geriatric diseases. The changes of pro-inflammatory factors and anti-inflammatory factors in the elderly eventually result in excessive pro-inflammatory response and imbalance of inflammatory homeostasis, leading to inflammatory aging. Salviolii et al. showed that pro-inflammatory cytokines play an important role in the inflammatory aging of the body caused by chronic inflammation.

Elevated serum levels of interleukin-6 (IL-6) and TNF-a in the elderly are associated with disease, disability, and mortality.

A large number of population-based studies have shown that serum IL-6 level can be used as a reliable marker for the decline of functional disability in the elderly and as a predictor of inflammatory aging in the elderly.

Experiments in healthy older adults have shown that aging is associated with a hyperinflammatory state due to elevated circulating levels of proinflammatory mediators, including IL-1, IL-6, TNF-α, and prostaglandin E2 (PGE2).

Aging and inflammation are closely related events, so some scholars have suggested that chronic inflammation can be used as a biomarker of aging. Recent studies have found that the hypothalamus is the main site of overall inflammation in mice, and the key molecules of inflammation such as IKK-β and NF-KB are significantly activated.

Proinflammatory cytokines can induce cellular senescence. Proinflammatory cytokines (such as TNF-α, IFN-β, IFN-γ, etc.) induce epithelial cell senescence by generating ROS and activating ATM/ P53/P21 (WAF1 / CIP1) signaling pathway.

The chemokine receptor CXCR2 induces fibroblast senescence through the P53 pathway, and DNA damage activates Nf-κb signaling pathways to produce proinflammatory cytokines (IL-1, IL-6, IL-8, etc.), thereby arresting the cell cycle and inducing and maintaining the cell senescence phenotype.

CD4+ Th1 cells secreting TNF and IFN-γ can inhibit the growth of aggressive β-cell tumors by inducing cell senescence and up-regulating the expression of senescence marker protein p16.

NF-KB is a molecular switch for inflammatory signaling pathways. Studies have found that longevity gene SIRT1 can bind to the REL /p16 subunit of NF-KB, deacetylate K310 and inhibit the transcriptional activity of NF-KB.

NF-KB can regulate aging, and SIRT1 can interfere aging by regulating NF-KB. SIRT6, a deacetylase, plays a key role in regulating the secretion of TNF-α and can significantly increase the life span of male mice.

These results suggest that intervention of inflammation is of great significance for delaying aging. 4. The relationship among free radicals, inflammation and aging In short, free radicals can lead to the imbalance of inflammation homeostasis, which in turn leads to the excessive production of free radicals. The imbalance of free radical homeostasis can lead to aging, which in turn leads to the destruction of free radical metabolic balance. There is an imbalance of inflammatory homeostasis in the aging process, and inflammation can lead to aging.

Free radicals ⇌ inflammation ⇌ aging ⇌ free radicals cause and effect, the relationship is complex. Nf-κb, TOR, RIG-I, JNK, NOTCh, Sirtuins, TGF-β, Wnt, Ras, and In-sulin /IGF-1 signaling pathways can regulate inflammation and aging.

These regulatory signaling pathways may be the hub of the link between free radicals, inflammation, and aging, which needs to be further studied.