Arachidonic acid in aging: New roles for old players

Graphical abstract

Considering further studies on fatty acids influencing aging, we submit a review describes the role of arachidonic acid metabolism in affecting the aging process and introduces arachidonic acid metabolism through different therapies treat with several aging tissues.

Highlights

• •New perspective for Arachidonic acid (AA) metabolism in aging tissues.
• •A summary concerning AA-associated therapies in aging-related diseases.
• •New strategy for aging diseases.
• •The deficiencies and future development and clinical application of AA metabolism are put forward.

Abstract

Background

Arachidonic acid (AA), one of the most ubiquitous polyunsaturated fatty acids (PUFAs), provides fluidity to mammalian cell membranes. It is derived from linoleic acid (LA) and can be transformed into various bioactive metabolites, including prostaglandins (PGs), thromboxanes (TXs), lipoxins (LXs), hydroxy-eicosatetraenoic acids (HETEs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs), by different pathways. All these processes are involved in AA metabolism. Currently, in the context of an increasingly visible aging world population, several scholars have revealed the essential role of AA metabolism in osteoporosis, chronic obstructive pulmonary disease, and many other aging diseases.

Aim of Review

Although there are some reviews describing the role of AA in some specific diseases, there seems to be no or little information on the role of AA metabolism in aging tissues or organs. This review scrutinizes and highlights the role of AA metabolism in aging and provides a new idea for strategies for treating aging-related diseases.

Key Scientific Concepts of Review

As a member of lipid metabolism, AA metabolism regulates the important lipids that interfere with the aging in several ways. We present a comprehensive review of the role of AA metabolism in aging, with the aim of relieving the extreme suffering of families and the heavy economic burden on society caused by age-related diseases. We also collected and summarized data on anti-aging therapies associated with AA metabolism, with the expectation of identifying a novel and efficient way to protect against aging.

Introduction

Aging is a process that evolves in response to changes in the external environment over time and causes a series of degenerative diseases. According to a 2023 United Nations report on the world population, the number of seniors over 65 years will double worldwide over the next 30 years, reaching 1.6 billion in 2050, comprising more than 16 % of the global population [1]. In this context, aging, accompanied by related diseases, may cause a heavier economic burden and induce severe health impairment soon. Thus, programs exploring aging and anti-aging processes are of prime importance. Factors aggravating aging include stress, tension, injury or infection, reduced immune responses, nutritional imbalances, and metabolic disorders. These factors cause various health problems that accelerate the aging process. Therefore, interfering with these factors and exploring the exact aging mechanisms may help us find appropriate ways to fight aging, although it seems inevitable and irreversible.

Aging mechanisms involve many aspects, such as DNA impairment, gene expression dysfunction, and metabolic disorders. For DNA impairment and expression levels, different endogenous metabolic factors, including excessive reactive oxygen species (ROS) and inflammation, combined with exogenous agents, such as radiation and chemicals, cause DNA damage and may induce shorter telomeres [2]. Interestingly, the boundaries between the different aging mechanisms are not very strict. DNA impairment may also induce other metabolic disorders-related aging mechanisms [3]. Conversely, a high-fat diet can interfere with aging through DNA damage. polyunsaturated fatty acids (PUFAs) are important lipids that interfere with the aging process [4]. Recently, Arachidonic acid, a representative PUFA, has attracted the attention of many scholars, and it has undoubtedly turned out to be a promising target against aging.

AA are essential nutrients for cell survival. All cell types require AA, an omega-6 PUFA, for their membranes' fluidity, flexibility, and functioning. Moreover, AA undoubtedly affects cell sequence and tissue aging. Most AA derivatives are considered inflammatory markers and may lead to platelet dysfunction, DNA impairment, ROS production, and aggravation of aging [5]. Indeed, Different elements of AA metabolism, as fundamental components of the body nutrients, may participate in some aging processes, such as gene expression disorders, inflammation, mitochondrial function, tumorigenesis, telomere attrition, cell senescence, and the release of cytokines, thereby interfering with aging [5] (Fig. 1). Studies on the role of different AA levels in aging progression and changes could help us find a novel view on anti-aging, despite the controversial effects of AA in older adults. To put it in detail, epidemiologic studies among the Japanese suggest higher concentrations of AA with aging [6], but one study was inconsistent with the epidemiologic studies [7]. Considering the controversy between AA and aging, a two-sided effect of AA can also be seen on telomere length, which is related to cell longevity [8]. Herein, we submit a comprehensive review that can explain the exact mechanism of AA metabolism in affecting the aging process and identify appropriate AA-relevant methods against aging.

Fig. 1.

Different elements of AA metabolism meditate aging through many mechanisms. Different elements of AA metabolism: AA, AA substrates, and AA derivatives meditate aging through many mechanisms, such as gene expression disorders, inflammation, mitochondrial function, tumorigenesis, telomere attrition, cell senescence, and the release of cytokines.

AA: Overview

AA is an essential fatty acid (EFA) obtained primarily through dietary supplementation. However, some conversions occur between these EFAs. For example, the small conversion between linoleic acid (LA) and AA reaches between 0.3 % and 0.6 % [9]. n-6 EFAs in the human body originate from linoleic acid (LA, C₁₇H₃₀O₂), whereas n-3 EFAs are derived from alpha-linolenic acid (ALA, C₁₇H₃₀O₂). Delta-6-unsaturase, delta-5-unsaturase, and elongase convert LA and ALA to other bioactive products. LA is primarily responsible for the production of gamma-linolenic acid (GLA, C18H30O2), dihomogamma-linolenic acid (DGLA, C20H34O2), and arachidonic acid (AA, C20H32O2), whereas ALA is converted to eicosapentaenoic acid (EPA, C₂₀H₃₀O₂) or docosahexaenoic acid (DHA, C₂₂H₃₂O₂) by the same set of enzymes (Fig. 2). Generally, AA is obtained directly from food or LA. Scientific and clinical evidence has shown that AA is crucial for the growth of organisms and organ health [10]. It has been demonstrated that the functions of many AA depend on their metabolites. For example, prostaglandins, bioactive molecules, are involved in inflammation and platelet aggregation [11]. In addition, LTD4, a critical derivative, is a potent pro-inflammatory mediator formed from AA. Research has proven that LTD4 significantly impacts cellular senescence in osteoblasts [12] and may induce osteoporosis.

Fig. 2.

Classification of essential fatty acids. Essential fatty acids can be acquired only by daily supplementation and are divided into n-6 unsaturated fatty acids and n-3 unsaturated fatty acids. N-6 unsaturated fatty acid metabolism converts LA into GLA, GLA, DGLA, and AA by delta-6-desaturase and other corresponding enzymes. Similarly, DHA and EPA can be synthesized from ALA, which are n-3 unsaturated fatty acids.

AA is predominantly involved in different theories of aging mechanisms, and it is accepted that glucose-rich diets, shorter telomeres, cellular senescence, chronic inflammation, and ROS contribute to the aging process [13]. Evidence has shown that AA can inhibit various diseases and decrease the lifespan of Caenorhabditis elegans caused by glucose-rich diets [14]. A relatively low AA concentration or glucocorticoid presence stimulates osteoblasts' replication and differentiation, which promotes bone formation. This phenomenon, caused mainly by increased insulin-like growth factor-1 (IGF-1) levels, inhibits osteoporosis [15]. In conclusion, AA may be closely associated with aging via insulin-like signaling pathways. Another relevant theory of aging is the telomere mechanism. Previous studies have demonstrated that excessive consumption of saturated fatty acids induces shorter telomere lengths [16]; however, the connection between AA and telomere length remains controversial. A previous study found that AA significantly shortened telomere length to a large extent [17]. Nevertheless, the evidence suggests that AA is generally positively associated with lymphocyte telomere length [8]. Further research revealed a different rate of AA compared to n-3 nutrients in PUFAs in the above cohort, which may have led to these contradictory results. In other words, a lower ratio of n-6 PUFAs in the body induces longer telomeres [18]. Other relevant evidence suggests that differences in lipid intake may influence the redox-telomere-anti-oncogene axis in telomere maintenance [19]. Cellular senescence is an essential aging process associated with AA. As previously described, AA, which plays an essential role in cellular membrane phospholipid composition, may influence cellular senescence to some extent. Studies have shown that cellular senescence induces the accumulation of phosphatidylcholines, including AA [20]. Another study confirmed that in aging fibroblasts, AA shows a trend of decreasing synthesis and increasing release [21].

In addition, mitochondrial oxidation is an essential factor in the further aggravation of aging [22]. Oxidative stress is mostly accompanied by ROS production, of which AA plays an important role. AA stimulates superoxide synthesis and cellular cytotoxicity [23]. However, a clinical study suggested that serum PUFA produces more ROS in younger people than in older adults. A clinical study also concluded that large amounts of PUFA produced more ROS regardless of age [24].

Regulation of AA metabolism in physiological aging

Modifications of AA substrates in physiological aging

As previously mentioned, LA is a member of AA metabolism and a source of AA. Research on different elements of AA metabolism affecting physiological aging and the connection between members of AA metabolism may help us establish a novel anti-aging mechanism.

LA is the most prevalent PUFA consumed by humans, mainly sourced from vegetable oils and nuts. In addition to providing basic energy, LA can be esterified into various lipids to maintain basic cellular functions. LA is essential for membrane phospholipid synthesis. Under the background of this synthetic function, LA also maintains a suitable level of membrane fluidity, which mediates the exchange of intracellular metabolites and extracellular substances and is extremely important for cellular lifespan. LA is the initial substance involved in n-6 PUFA metabolism, which can be converted into other bioactive n-6 PUFAs such as GLA and AA. Subsequently, AA, as a derivative of LA, can be catalyzed into different bioactive compounds, the most representative of which are eicosanoids. Eicosanoids mainly consist of prostaglandins (PGs) and leukotrienes (LTs) and have been proven active in the normal metabolism of cells and tissues. However, when an organism is confronted with the overproduction of eicosanoids, there is a higher prevalence of chronic diseases such as inflammation and degeneration [25]. Overall, LA is an essential nutrient for cellular development and basic function but can also accelerate physiological aging.

As a substrate of AA, it is reasonable to assume that restricted intake of LA reduces AA in the serum. Interestingly, research on the intake of high doses of LA in Western individuals does not support this hypothesis [9]. Further tracer kinetic studies revealed that the LA to AA conversion rate ranged between 0.3 % and 0.6 %, and AA transformation into LA seemed to offset this transition [9]. Evidence also suggests that the risk of some chronic metabolic diseases, typically diabetes and atherosclerosis, increases with the excessive consumption of LA-rich foods. These harmful outcomes are mainly due to LA metabolism, which transforms LA into AA and subsequently synthesizes other bioactive substances. However, a few recent studies have presented contrasting views. For example. Evidence suggests that diverse LA intake has almost no effect on regulating AA levels [26], and more LA accumulates in the plasma, reducing the risk of diabetes by 43 % compared to a lower amount [27]. High-dose LA intake seems to alter AA levels in the human body, but no substantial evidence exists that LA can affect aging. In summary, further steps must be taken to explore the relationship between LA and aging.

However, the release of AA largely originates from cellular phospholipids, in which phospholipase A2 (PLA2) catalyzes the hydrolysis of ester bonds at the sn − 2 position [28]. PLA2 can be divided into two types: secreted PLA2 (sPLA2) and membrane-bound PLA2 (Ma-PLA2). sPLA2 is mainly expressed in certain cell types, including immune and epithelial cells [29], and is involved in inflammatory pathological injury, whereas Ma-PLA2 controls AA metabolism. Ma-PLA2 can be activated to release AA by various stimuli such as Toll-like receptors, hormones, and Ca²⁺. In inflammation, which participates in most aging processes, PLA2 undoubtedly represents activity in aging diseases. However, further studies are required to confirm these findings. Phospholipase C (PLC) and PLD also promote AA release from membrane phospholipids [30]. PLC converts phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol [31]. The binding of IP3 to its receptors induces Ca²⁺ release, which triggers AA release by Ma-PLA.

Regulation of AA in physiological aging

Given that AA is closely related to the aging process, it is unclear whether dietary intake influences AA levels in serum. Previous studies have reported an inaccurate correlation between AA intake and serum phospholipid levels. Some researchers have suggested that AA intake increases serum phospholipids [32], while other scholars have reported a negative relationship between AA intake and the amount of AA in plasma phospholipids through a survey of Japanese people [33]. Moreover, studies have also indicated that the intake of AA is not significantly related to AA levels in plasma phospholipids [34]. In summary, the relationship between AA and plasma phospholipids remains largely unknown.

Studies have shown that AA has anti-inflammatory effects, and oral AA increases plasma LXA4 levels [35]. LXA4 inhibits the recruitment, chemotaxis, adhesion, and transit of immunocytes and the synthesis of pro-inflammatory cytokines, which promote the regression of inflammation and play a braking role in vitro and in vivo after injury or cell damage. Herein, AA supplementation augmented LXA4 formation rather than PGE2 during inflammation, thus providing an anti-inflammatory effect [36] in aging. Intravenous AA is considered safe and has no complications [37], and oral supplementation of AA in the range of 1000 mg/day to 2000 mg/day is harmless [38]. In addition, AA levels in all blood lipid fractions, especially erythrocyte plasma phospholipids, are affected by the amount of EPA and DHA intake [39], indicating that n-3 nutrients can also influence AA levels in the human body. When a high dose of n-3 linoleate is ingested together with a relatively low content of n-6 linoleate, indiscriminate enzymes eventually catalyze the production of more n-6 nutrients than n-3 nutrients in tissues [40]. Beyond common understanding, this phenomenon is also a potential proof of the precise relationship between other dietary fatty acids and AA. The proper ratio of these dietary fatty acids has been studied to develop innovative therapies. Regarding the dynamic conversion between EFAs and other PUFAs in human tissues, an LA intake of 0.3 to 0.5 % of dietary energy meets the basic needs of the body for EFAs and maintains tissue levels of arachidonate above 50 % of PUFAs [41]. In a deficiency of n-3 nutrient intake, a tiny supplement of the essential n-6 nutrient, which consists of approximately 0.5 % of the daily energy intake, can result in more than 50 % n-6PUFA level in the PUFA balance and eventually cause damage to health [42]. Therefore, the therapeutic intake of n-6 nutrients is difficult to manage. Fortunately, competing n-3 nutrients induce a lower n-6 value in the tissue PUFA balance, below 50 %, making this an achievable therapy [42]. Studies have brought us a new perspective that we may restructure a proper diet to extend life span.

Modifications of AA derivatives in physiological aging

The effect of AA on physiological aging is not only due to itself but also because of its derivatives. Three main pathways that AA can be catalyzed. The synthesis of different AA derivatives largely depends on different stimulus factors, such as inflammation and metabolic disorders.

The first enzymes that metabolize AA are cyclooxygenases (COXs), which produce prostanoids, including PGs and thromboxane. These processes are initially derived from the action of phospholipases, which induce the release of lipids from the cellular membrane and subsequent metabolism, in which COX enzymes transform relevant lipids into PGG2 and PGH2. PG synthases then catalyze the conversion of PGH2 into bioactive PGs. COX enzymes are classified into two distinct isoforms. COX-1, an integral membrane protein primarily located in the endoplasmic reticulum, synthesizes physiological PGs and regulates the physiological activity of normal cells [43]. In contrast, COX-2, an inducible enzyme, is activated by various internal changes or external stimuli and produces effective prostanoids in many aging-related diseases [43], [44]. Nevertheless, the discrimination between the two COX enzymes is not well defined because both enzymes have similar capabilities for producing homeostatic prostanoids and promoting prostanoid release during inflammation. The role of COX enzymes in inflammation provides novel insights into anti-inflammatory therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) have proven effective in alleviating inflammation and painful episodes [45]. Meanwhile, suppression of COX expression may induce side effects. For example, aspirin, a nonselective COX inhibitor, may cause gastrointestinal reactions and even gastric ulcers in severe cases. The rational utilization of COX-related drugs may provide a more suitable therapeutic strategy for derivatives metabolized by the COX enzyme in diverse diseases. Evidence has shown that aspirin can suppress thromboembolic diseases by inhibiting blood clotting, and PGI2 analogs have been used in systematic therapies for pulmonary hypertension owing to their vasodilatory function [46].

As stated above, COX enzymes are responsible for PGH2 and PGG2 synthesis. These enzymes are differentially expressed at sites of inflammation and determine the amount and category of prostanoids produced [47]. In addition to the COX enzymes described above, there is another COX isoenzyme called COX-3, which has been reported as a splice variant of COX-1 [48]. COX-3 is mainly present in the canine brain and in rats, and there is no evidence that it exists in the human body, although it has been identified as a producer of PGH2 [49]. PGs, as major products of the COX pathway, PGs bind to G protein-coupled receptors on membranes and consequently exert their effects. However, different PGs can exert dissimilar or opposing effects. PGE2 is a pro-inflammatory factor that aggravates the pathogenesis of various diseases such as arthritis and osteoporosis. By binding to EP1 ∼ 4 receptors, PGE2 also participates in hypertension, atherosclerosis, diabetes, and tumorigenesis[50]. Conversely, PGI2 inhibits the release of inflammatory mediators and dilates vessels, which are known to be positive in some cardiovascular diseases[50]. PGD2 is a powerful endogenous sleep promoter that regulates sleep. Besides, PGD2 also has a tracheal systolic effect that induces bronchial hyperresponsiveness in asthma and suppresses ovarian cancer [51]. Research into PGD2 may benefit the treatment of insomnia, asthma, and ovarian cancer, while PGF2α acts primarily in the kidney and heart muscle and promotes pain. Additionally, PGF receptor agonists are widely used to treat glaucoma by reducing intraocular pressure [52]. TXA2, synthesized by PGH2, is a potent vasoconstrictor that causes platelet aggregation. This reflection is effective until the point of injury or inflammation. However, TXA2 is unstable in serum and is rapidly converted to inert TXB2 in 30 s. The balance between TXA2 and TXB2 mediates vasoconstriction and platelet aggregation [53].

The lipoxygenase (LOX) pathway is the second most well-studied pathway involved in AA metabolism. LTs are the predominant products synthesized by LOX enzymes. Since LTs mediate the occurrence and progression of allergic diseases, antagonists, such as zileuton, which suppresses the expression of 5-LOX and LTs, have been developed to treat asthma and seasonal allergies [54]. In addition to LTs, several other important metabolites are produced via the LOX pathway. LOX enzymes insert oxygen into the AA molecules to form four hydroperoxyeicosatetraenoic acids (HPETEs): 5- HPETE, 8-HPETE, 12-HPETE, and 15-HPETE. HPETEs can be transformed into hydroxy-eicosatetraenoic acids (HETEs) or into other bioactive molecules, including lipoxins (LXs) and hepoxilins using peroxidases. Notably, HETEs were converted to epoxyeicosatrienoic acids (EETs) under specific conditions (Fig. 3).

Fig. 3.

AA metabolism. All stimuli, such as Ca²⁺, activate AA release from cell phospholipids by catalysis of PLA 2 or PLC/D. Afterward, AA was converted to the corresponding derivatives by diverse pathways. The COX pathway transforms AA into PGs and thromboxane, mediating inflammation and blood coagulation. AA can also promote the synthesis of HETEs, EETs, lipoxins, and LTs, which LTs have been proven essential in asthma and other allergic diseases. Besides, AA produced EETs, HETES, and DHETs by the CYP pathway. Indeed. The synthetic pathway of AA metabolism depends on the stimulus and is mainly thought to be a reaction to microenvironment changes.

According to diverse studies on LOX enzymes, 5-LOX may be the best-studied enzyme that can subsequently form leukotriene A4 (LTA4). Subsequently, LTA4 forms various LTs, including LTB4, LTC4, LTD4 and LTE4 [55]. Initially, it was believed that 5-LOX acted on the cell membrane; however, subsequent studies claimed that phosphorylation could transfer 5-LOX to the nuclear envelope [56]. There is a consensus that the production of LTs mainly occurs in the nuclear membrane. 5-HPETE is further hydrolyzed by LTA4 hydrolase to generate LTB4 [56]. LTA4 hydrolase is a cytosolic protein that exhibits both LTA4 hydrolase and zinc-dependent peptidase activities. Although the biological role of LTA4 hydrolase remains unknown, it limits pulmonary inflammation by degrading the chemotactic peptide PGP (proline-glycine-proline) [57]. Interestingly, LTA4 hydrolase generates a chemotactic lipid mediator, whereas LTB4 simultaneously promotes inflammation. 12-LOXs and 15-LOXs produce LXs and dihydroxyeicosatetraenoic acids (diHETEs), affecting ischemic cerebrovascular disease and diabetes [58]. In fact, 12-LOX can transform 5-HETE into 5S,12S,14R, and 15S-diHETE, producing more platelets for blood coagulation [59]. In addition, 5-LOX and 12-LOX have been reported to enhance LX synthesis. Neutrophils develop LTA4 through 5-LOX, which then becomes LXA4 or LXB4 through 12-LOX in platelets [60].

The cytochrome P (CYP) pathway is an essential AA metabolic pathway influencing physiological aging. There are many classifications of CYP enzyme families, among which those closely related to AA metabolism invariably have the activity of ω-hydroxylase and epoxygenase activities [61]. However, the products of these enzymes are often present in diverse and mixed forms. CYP enzymes help produce HETEs, among which 20-HETEs are the best-studied metabolites for their pro-inflammatory properties and role in improving vascular health [62]. In contrast, CYP2J and CYP2C belong to the CYP enzyme family, have epoxygenase activity, and can convert AA into different types of EETs, such as 5,6-EET and 11,12-EET. Bioactive EETs are primarily detected in the liver, heart, and vasculature. In the context of the vasodilative effect of EETs in organisms, EETs reduce vasotension to address several cardiovascular diseases, including atherosclerosis and deep venous thrombosis [63]. In addition to their protective effect on the vascular system, EETs mediate the induction and progression of cancer. The related mechanisms involve many aspects. The initial mechanism refers to EETs indefinitely promoting stem cell proliferation and the invasion of other human tissues. EETs promote angiogenesis and cause capillary inflammation and apoptosis of endothelial cells, thereby accelerating tumor cell metastasis. CYP-derived AA metabolites are known to aggravate tumor development [64].

In addition, the CYP-HETE pathway is also important for human health. 20-HETE and 19-HETE are the major metabolites of AA, and their effects are mediated by the CYP-HETE pathway. Scholars have found 20-HETE contributes to vascular dysfunction and ultimately influences cognitive impairment and dementia [65]. Moreover. Genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies [65]. Another study suggested that the CYP/20-HETE/GPR75 axis may be a potential target for the treatment of hypertension and obesity/metabolic syndrome [66]. In addition, targeting the identified pathological axis CYP4A/20-HETE/AMPK may have clinical potential for predicting and alleviating peripheral nerve injury in patients with type 2 diabetes mellitus [67].

19-HETE is another indispensable product of AA metabolism in the CYP-HETE pathway and is mainly synthesized by the CYP2C19 and CYP2E1 pathways [68]. It has been reported that 19-HETE is strongly correlated with cardiovascular events and can act as a prognostic marker for patients with acute coronary syndrome [68]. In the heart, 19-HETE is the major subterminal HETE formed in the cardiac tissue of rat, which not only plays a protective role in cardiac hypertrophy but also participates in the pathogenesis of chronic kidney diseases [69].

The upregulation of CYP gene transcription often involves the activation of various cytosolic or nuclear receptors, including the aromatic hydrocarbon receptor (AHR), the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the peroxisome proliferator-activated receptor (PPAR) [70]. Activation of these transcriptional factors induce an increase in the CYP pathway and ultimately causes age-related modifications [71]. For example, CAR agonists, including phenobarbital and artemisinin, can cause transcriptional activation of CYP2C9, CYP2C8, and CYP2C19 [72]. Another receptor, PXR, has been shown to mediate the induction of CYP2C genes by drugs such as rifampicin, artemisinin, and hyperforin, all of which act as ligands for PXR [73]. Dexamethasone, a glucocorticoid mimic drug, activates the CYP2C promoters in HepG2 cells via the glucocorticoid receptor (GR)[74]. While FXR is a bile acid-activated nuclear receptor that regulates bile acid metabolism, suppressing bile acid synthesis and stimulating enterohepatic bile acidcirculation by inhibition of CYP7A1 [75]. FXR can also reportedly inhibit CAR/PXR activation in certain gene promoters [76], A recent report also proves that FXR can induce the activation of CYP2C and CYP4 [77].

The family of mixed-function monooxygenases encoded by the CYP gene contains more than 6000 enzymes [78]. CYPs metabolize a wide range of metabolites, particularly lipophilic compounds with typical fatty acid symbols. CYP expression varies among tissues and developmental periods, and studies have shown that in addition to the liver and cardiovascular tissues mentioned previously, CYP can also be detected in the kidney, pancreas, and neural tissues. This expression is regulated endogenously by hormones, growth factors, and transcription factors and exogenously by environmental changes[79].

In addition, endocannabinoids, which are essential AA derivatives, play an important role in the aging process and have attracted much attention in recent years. The endocannabinoid system (ECS) of the body is comprised of the G-protein-coupled cannabinoid receptor type 1 (CB1), cannabinoid receptor type 2 (CB2), anandamide and 2-arachidonoylglycerol (2-AG) [80]. Anandamide is biosynthesized from arachidonic acid by N-acylphosphatidyl ethanolamines (NAPE)-specific phospholipase D (NAPE-PLD), while 2-AG is biosynthesized by diacylglycerol lipase alpha and diacylglycerol lipase beta. The degrading enzymes for anandamide and 2-AG are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In general, CB receptors are endogenously activated by anandamide and 2-AG, inactivated through membrane transporter-facilitated reuptake, and degraded by an intracellular FAAH for AEA or MAGL for 2-AG. This ECS has been shown to modulate behaviors and physiological processes, such as food intake, the circadian rhythm, learning and memory, motivation, and pain perception [81]. In addition, cannabinoids also promote different cell death mechanisms as their anti-proliferative cancer actions [82]. There exists another report suggests that endocannabinoid system also may help control and reduce pain in osteoarthritis [83].

AA metabolism in aging-related diseases

In the context of the preliminary knowledge regarding the roles of AA metabolism in aging mechanisms, AA metabolism undoubtedly participates in various aging tissues. Compelling evidence has shown that AA metabolites formed by different metabolic pathways influence the occurrence and development of osteoporosis, Alzheimer's disease (AD), tumors, nonalcoholic fatty liver disease (NAFLD), and other aging diseases. Consequently, we will detail how AA metabolism influences different aging tissues and sicknesses.

AA in musculoskeletal aging

Muscle and bone aging are important causes of reduced quality of life and increased susceptibility to other age-related diseases in older players [84]. Smoking habits, unbalanced diet, and lack of exercise are all contributing factors that cause accelerated bone density deterioration and severe osteoporotic fragility fractures. Osteoporosis is a major disease associated with bone aging. Increasing age adversely affects bone and muscle densities, which can significantly impair independence as people age.

Active bone resorption and inhibition of bone synthesis are the main manifestations of osteoporosis's imbalance in bone metabolism. The cells mainly involved in this process include osteoblasts and osteoclasts. Mesenchymal stem cells (MSCs) give rise to osteoblasts. MSC precursors can differentiate into lipogenic cells and competitively inhibit the formation of osteoblasts during normal aging or in response to inflammatory stimuli. Therefore, studies on MSC differentiation toward osteogenesis have important anti-aging implications. Transcription factors, such as, Wnt/β-catenin, runt-related transcription factor 2 (Runx2), and osterix, mainly promote MSC differentiation toward osteogenesis, whereas PPAR-γ and CCAAT/enhancer-binding proteins (C/EBPs) are important regulators of adipogenesis [85]. Another regulator of bone homeostasis is the osteoclasts, which are generated primarily by hematopoietic stem cell differentiation. The differentiation of hematopoietic stem cells into osteoclasts is mainly regulated by macrophage colony-stimulating factor (M−CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) located in osteoclasts [86]. There is an exciting connection between osteoclasts and osteoblasts because osteoblasts undertake the majority of RANKL generation. Primary human osteoblasts and osteoblast-like cells proliferate less when exposed to 3–20 mmol/L AA [87].

Various factors and extracellular signaling pathways are involved in the transactivation of Wnt and PPAR-γ signaling, which can trigger adipogenesis or osteoblast genesis switching, respectively [88]. The AA metabolite PGE2 is considered a PPAR ligand [89]. Reports have proven that Fatty acids, including AA, can bind to PPAR-α and PPAR-γ [90]. Researchers also found a continuous increase in the expression of the adipogenic gene PPARγ2 when human bone MSCs were exposed to a certain level of AA [91]. In addition, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a specific biologically active substance, activates the PPAR pathway to promote adipocyte production and inhibits osteoblastogenesis through Wnt/β-catenin and other signaling pathways [92]. Further studies showed that additional treatment of bone MSCs with AA suppressed the expression of alkaline phosphatase and RUNX2, preferentially initiated during osteogenic differentiation but barely affected the expression of other late-initiating genes, such as osteocalcin. Furthermore, the same authors found that in addition to AA alone, combining high concentrations of AA with EPA or DHA significantly increased PPAR gene expression in MSCs, suggesting that high concentrations of fatty acids promote lipogenesis to some extent [93]. The adipogenic pathway competitively inhibits the conversion of MSCs to osteoblasts, and fatty acids may affect this inhibition to AA, PGE2, and 15d-PGJ2, upregulating a PPARγ-dependent pathway. Moreover, sclerostin, an inhibitor of bone morphogenetic proteins, inhibits the Wnt-β pathway, inhibiting osteogenesis. Related studies have demonstrated decreased sclerostin expression under mechanical loading and that PGE2 is involved in this process [94]. When osteoblasts are exposed to an environment in which the concentration of AA reaches 75 mmol/L, there is a transient decrease in cell adhesion, causing them to become sluggish in response to external stimuli, thus affecting the function of osteoblasts [95].

Previous studies have demonstrated that AA and DHA tend to inhibit the differentiation of RAW cells into osteoclasts via the RANKL pathway, in which AA showed a strong inhibitory effect on osteoclastogenesis, whereas DHA had a more substantial effect [93]. The osteoprotegerin (OPG)/RANKL pathway is an important signaling pathway that can effectively regulate osteoclast activity and promote bone resorption and reconstruction. PGE2 significantly affected the OPG/RANKL pathway. There is also compelling evidence that PGE2 regulates osteoclast activity and production in a postmenopausal mouse model of osteoporosis, where n-3 fatty acid-rich Antarctic krill oil inhibits PGE2 expression and inhibits PGE2 binding to related receptors, such as EP4, to inhibit the OPG/RANKL pathway. In addition to PGE2, AA decreases the expression of the OPG/RANKL pathway in MSCs, inhibiting osteoclasts from hematopoietic stem cells [91]. Therefore, excessive AA intake may increase serum PGE2 levels, thereby enhancing bone resorption and osteolysis via the OPG/RANKL pathway. However, in vitro, low concentrations of PGE2 (10^-11 to 10^-9M) indiscriminately promote the growth and proliferation of different human bone cells to benefit bone formation, while it is inhibitory for osteogenesis through the cAMP messenger pathway at high concentrations (10^-7 M) [96]. In addition to the amount of PGE2, different cell types and dissimilar manners of differentiation of the intervening source cells may also contribute to the differential effects of PGE2 on osteoblasts. Interestingly, osteoclasts also secrete various growth factors into the endoenvironment, and these growth factors stimulate osteoblast production and expression in an endocrine or paracrine manner, ultimately promoting osteogenesis. Overall, a stable homeostatic balance of the bone can be achieved through the expression and interaction of osteoblasts and osteoclasts, in which AA metabolism is involved. IGF-1, which regulates glucose metabolism, is an important growth factor associated with aging. IGF-1 can bind to IGF-binding proteins, resulting in osteogenesis [97]. PGE2 stimulates the IGF-1-mediated osteogenic signaling pathway. Moreover. Considering that different PUFAs have diverse effects on PGE2, in vitro studies have confirmed that PUFAs regulate bone cell differentiation through the PGE2/IGF-1 pathway [98].

AA also favors osteoclastic activity by reducing the expression of OPG, which is a protective factor in bone homeostasis and suppresses the expression of the RANKL gene in osteoblasts to promote the generation of adipocytes, thereby reducing the production of osteoblasts. Several studies have suggested that long-chain PUFAs are critical in bone homeostasis [99]. Patel et al. reported lower amounts of AA in aged male C57BL/6 mice than in young male mice [100]. We believe that AA may aggravate the aging process of bone (Fig. 4). However, previous studies have shown that men who consume more AA-rich foods are less likely to develop hip fractures [101]. Further studies are required to elucidate the role of AA in osteoporosis.

Fig. 4.

The mechanism of AA metabolism interferes with the process of osteoporosis. AA and its metabolite mediate the synthesis and function of osteoblasts and osteoclasts to interfere with osteoporosis. AA and PGE2 generally induce MSCs to convert to adipocytes through PPAR-γ and C/EBPs and suppress osteoblast synthesis. In addition, there is evidence that AA and DHA also inhibit the synthesis of osteoclasts.

Inflammatory degeneration is the pathological basis of arthritis. Arthritis can be divided into non-erosive arthritis, represented by lupus erythematosus; erosive arthritis, represented by rheumatoid arthritis (RA), degenerative arthritis, represented by osteoarthritis; and metabolic arthritis, represented by gouty arthritis. RA is the most common form of arthritis, and its preliminary pathological basis is inflammatory cell infiltration [102]. AA metabolism plays a role in the inflammatory process, and it is reasonable to assume that AA also plays a role in arthritis. In AA metabolism, the COX pathway of AA metabolism induces a series of inflammatory responses that promote arthritis development. In this context, NSAIDS, which inhibit COX enzymes, are approved as first-line drugs for newly diagnosed cases of RA. Recent research on COX enzyme drugs has focused on COX-2 inhibition, as COX-2 inhibiting drugs tend to have fewer and less severe side effects and the same anti-inflammatory and analgesic efficacy [103]. Prostaglandin E synthase-1 has been shown to have an upward tendency in osteoarthritis and release more PGE2 [104]. MMPs, disintegrin, and metalloproteinase with thrombospondin motifs (ADAMTS) are primarily involved in cartilage degeneration [105]. In detail, extra AA reduced the amount of MMP-3 but surprisingly increased ADAMTS-5 and PGE2 secretion [106]. Overall, it is difficult to determine whether AA has a positive or negative role in arthritis. Nevertheless, research on AA derivatives could contribute to novel ideas for treating arthritis. LTB4 is derived from the 5-LOX pathway, and the LTB4 receptor has two subtypes: BLT1 and BLT2. In several RA mouse models, BLT1 is crucial in inflammatory arthritis [107]. Recent studies have shown that BLT recruits neutrophils to the joints, thereby inducing elevated levels of inflammatory mediators such as IL-1 and TNFα, causing joint pain and impaired mobility. These inflammatory mediators increase related inflammatory chemokines, such as CXCL1 and CXCL5, which bind to their corresponding receptors and accelerate the recruitment of neutrophils to the joints. Moreover, compelling evidence has shown that CP105696, a BLT1 inhibitor, significantly reduces the onset and delays arthritis progression in mice [107b]. Taken together, LOX enzymes and BLT1 may be promising therapeutic targets for the treatment of arthritis.

Notably, many biobased materials demonstrate strong bone repair functions and are important for the treatment of diseases such as osteoporosis and osteoarthritis. The combination of AA metabolism and functional materials may provide new opportunities for the treatment of aging diseases. in the future [108].

Intervertebral disc degeneration (IVDD) is an important cause of aging-related degenerative spinal diseases, such as lumbar disc herniation. Overexertion or injury to the back during aging may lead to progressive changes in intervertebral disc degeneration, which gradually causes the loss of normal spinal structure and dysfunction, ultimately resulting in pain and disability. Therefore, it is important to explore the exact mechanism underlying IVDD and how AA influences IVDD. IVDD occurs when the homeostatic balance of the disc environment is lost, and a predominantly catabolic and hypoxic microenvironment is present [109]. As mentioned previously, AA is positively associated with ROS production [23] and may induce microenvironment changes. We speculated that AA may inhibit IVDD by promoting ROS production. In addition, obvious alterations in AA metabolism have been reported in herniated human nucleus pulposus cells but not in normal human nucleus pulposus cells [110]. Among a set of AA derivatives, EET, synthesized by CYP450 enzymes, has a protective effect by inhibiting the apoptosis of nucleus pulposus cells and maintaining the elasticity of the disc to suppress the development of degenerative disc disease. From a molecular perspective, nuclear factor-kappa (NF-κB), a specific protein complex, promotes disc degeneration and largely shortens the life span of nucleus pulposus cells. EETs inhibit the NF-κB pathway to resist disc degeneration [111]. AA metabolites produced by the COX pathway also influence IVDD. By inhibiting the inflammatory derivatives of the COX pathway in AA metabolism, it also relieves the pain caused by disc degeneration and even retards the progression of degeneration [112]. Exploring AA metabolism in IVDD has revealed a novel target to fight against it and other degenerative diseases.

AA in nervous tissue aging

The nervous system is the earliest, most sensitive, and most complex system in the body where aging occurs. During nervous tissue aging, a decrease in neuronal cells together with the proliferation of glial cells induces a decline in nervous system function, which is associated with neuroinflammation and leads to neurodegenerative diseases such as AD and Parkinson's disease (PD). AA and DHA in neuronal membrane phospholipids work together to maintain normal physiological functions and regulate inflammation in the brain [113]. A high dose of AA competitively inhibits DHA expression in the brain, which has a strong inhibitory effect on neuroinflammation and contributes to the transmission of information from neurons in the brain [113a]. Deficiencies of PUFAs in daily intake lead to oxidative damage to neurons and generate excess ROS, promoting further apoptosis of neuronal cells, including neurons, microglia, and astrocytes, as described in reports on cognitive development [114], AD, and PD [115]. Furthermore, aging rat tissues contain more AA phospholipids than younger rat tissues [116]. AA and its metabolic derivatives have been proven to participate in neuroinflammation during aging, whereas DHA has an anti-inflammatory effect [117]. However, early studies revealed that AA tends to decrease with aging in the cerebellum, and it has been reported that AA maintains the fluidity of the hippocampal cell membrane and has a protective effect against brain aging [118]. Thus, AA may be a promising target for the treatment of amnesia. The paradox of AA influencing neurons may be due to the different aging stages. We speculate that increasing AA levels cause neuroinflammation during the early aging stage. Subsequently, neuroinflammation constantly depletes AA in the brain, and in late aging, AA is not replenished in time; the AA continues to decline and eventually shows a decreased inclination in aged tissues. In previous studies, either esterified or free AA have been found to decrease in the late stages of human and rat brain aging, providing potential support for our speculation [119].

High concentrations of AA in erythrocytes are thought to impair human cognitive function, although the underlying mechanisms have not been fully investigated [120]. However, LA, a precursor of AA, has been reported to alleviate some chronic diseases [121] that are often accompanied by cognitive impairment. To determine how AA affects cognition, a prospective cohort study of older adults in Puerto Rico suggested that AA is detrimental to normal cognitive function in older adults, and the next two years of follow-up revealed that AA increased the risk of cognitive impairment in 26 % of older adults [122]. Chronic inflammation has been implicated as a basis for cognitive dysfunction, but previous studies have found that dietary AA intake causes little or no chronic inflammation in the circulation; therefore, cognitive dysfunction might not be caused by dietary AA consumption. Rather, a study exploring the correlation between PUFA intake in midlife and cognitive performance 13 years later in French adults claimed that the negative role of AA in cognition might be related to the higher number of double bonds in AA, making it more vulnerable to lipid peroxidation [117b]. However, the effect of AA intake on cognition remains unclear. Nevertheless, several age-related neurological diseases, such as AD and PD, have been reported to be associated with AA.

AD is the most common neurodegenerative disease; however, its exact cause and pathogenic mechanisms remain unclear. Brain neuroinflammation plays an essential role in AD. Neuroinflammation is a complex and dynamic damaging process. Activation of microglia and astrocytes often represents the onset of inflammation in the brain, and these two cells tend to promote amyloid-β (Aβ) peptide to become abundant or even deposited to damage neurons and eventually lead to the development of AD. Increased AA content has been observed in neuroinflammation and contributes to AD pathogenesis [123]. Several studies have found that cognitive dysfunction due to abnormal processing of amyloid precursor proteins in AD mouse models can be alleviated by consuming an AA-rich diet, which also means that AA contributes to reducing Aβ deposition in the brain [124]. Conversely, one similar study presented the contrary result that AA-rich diets produced more Aβ and caused more Aβ deposition [125]. This contrasting phenomenon may be due to the AA intake being approximately ten times higher in later studies. We can infer that within a certain concentration range, elevated AA levels in specific brain regions contribute to neuronal function and improve cognition, and once a specific concentration is exceeded, high AA levels accelerate AD development. Early studies showed that AA, a potent activator of NADPH oxidase, can stimulate ROS generation in rat brain astrocytes [126], which may provide protective evidence that AA stimulates neuroinflammation to promote AD. However, specific concentrations of AA in different brain regions that aggravate AD may differ and require further investigation. In addition, studies have indicated that PGE2, which is closely associated with inflammation, can regulate neuroinflammation through various transmitters to modulate AD [127]. Among LOXs, 5-LOX converts AA into 5-HETE and LTA4. Suppression of 5-LOX has been reported to ameliorate Tau and Aβ-related mechanisms in AD mouse models [128], but 5-LOX was overexpressed in the brains of AD patients in only one study [129]. In addition, endocannabinoids, which contain AA in their chemical structure, have been shown to influence AD through CB2 receptors. Although cannabinoids affect the level of Aβ deposition in the brain, they seem to have little effect on the cognitive function of patients [130]. Studies targeting neuroendocrine cells have also found that AA promotes the release of vesicles [131], although we found that a decrease in phospholipids containing AA occurred in the human hippocampus [132]. The exact mechanism by which AA mediates synaptic function remains unclear, although it may be related to the balance between the correct AA content and the microenvironment. However, evidence shows that AA mediates long-term plasticity (LTP) of synapses and participates in neurodegenerative diseases (Fig. 5).

Fig. 5.

The mechanism of AA metabolism interferes with the process of nervous tissue aging. Astrocytes and microglial cells influence neuronal function and may be related to neuroinflammation. High doses of AA stimulate astrocytes to generate ROS, while the binding of PGE2 and its receptors induces inflammatory effects by activating microglial cells. AA also promotes Aβ levels and thus interferes with synaptic plasticity.

The pathogenesis of PD is complex, and the specific role of AA in PD has not been investigated. Under neuronal pathological conditions, the protein α-synuclein is folded into β-sheets instead of-helical oligomers. Previous studies have reported that AA induces α-helices, thereby triggering less neuron impairment [133]. Nevertheless, converse reports suggest that PD patients had higher AA brain levels [134]. Finally, a meta-analysis concluded that AA intake increases PD risk [135]. The relationship between AA metabolism and PD progression seems complex. However, compelling evidence has shown that AA and its related derivatives mediate neurons mainly through the endocrine system. Endocannabinoids such as anandamide and 2-arachidonoylglycerol are important regulators of synaptic functions [136]. AA metabolites bind to cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), which are mainly located in neurons, astrocytes and microglia [137]. Indeed, in experimental models of PD, mRNA encoding CB1 and CB1 receptor-mediated signaling are enhanced [138]. Monoacylglycerol lipase (MAGL), a serine hydrolase, has been studied for its role in hydrolyzing endocannabinoid 2-arachidonoylglycerol (2-AG) [139]. MAGL inhibitors have been shown to downregulate CB1 receptors in specific brain regions and cause mild physical dependence after chronic treatment at high doses [140]. In addition, the neuroprotective effects of MAGL inactivation are mainly due to a reduction in AA and pro-inflammatory PGs [141]. EETs can be synthesized by LOX and CYP450 epoxygenases from AA [142]. EETs have been found to play a protective role in peripheral tissues, and this neuroprotection may help several inflammatory neuropathies, such as AD and PD [143].

AA in cardiac aging and heart failure

Cardiovascular aging is accompanied by cellular senescence, primarily characterized by irreversible cell cycle stasis induced by stressors such as aging, DNA damage, or elevated levels of ROS. The senescence of different types of cardiac cells may induce several cardiovascular diseases, including atherosclerosis, cardiomyopathy, and arrhythmias. The AA metabolic pathway affects the physiological function of the heart through the flow of AA metabolites among the cardiac myocytes, endothelial cells, and vascular smooth muscle cells.

Numerous pharmacological studies have shown that the selective inhibition of COX-2 may contribute to myocardial dysfunction, whereas nonselective inhibition of COX may prevent it [144]. One possible explanation for this phenomenon is that suppressing COX-2 reduces the amount of prostacyclin (PGI2) without reducing the production of TXA2, which promotes blood clotting [145]. Conversely, our information suggests that COX-2 may protect against heart damage under certain circumstances [146]. COX-2 mRNA levels are rapidly elevated during the early phase of myocardial ischemic preconditioning in rabbits, and the elevation of COX-2 similarly increases the expression of PGE2 and 6-keto-PGF1a after myocardial ischemia–reperfusion for 24 h [147]. During ischemic preconditioning, COX-2 appears to be upregulated via the PKC, Src-PTK, and NF-κB pathways, in which NO produced by iNOS in the heart is indispensable. Selective inhibitors such as NS-398 or celecoxib abolish the cardioprotective effect of ischemic preconditioning, suggesting that PGE2 and PGI2 may participate in this process [148]. Hence, the COX pathway of AA metabolism is vital in cardiac aging, and various AA metabolites mediate the function and sequence of heart cells. For example, PGF2a stimulates multiple signaling pathways in cardiomyocytes, such as the JNK1 and c-Jun pathways, to regulate myocardial function, although some activated kinases do not affect heart hypertrophy [149]. Mice lacking PGI2 receptors are susceptible to hypertension, which promotes myocardial hypertrophy and heart failure [150]. AA metabolites produced via the COX pathway have different, and even opposite, effects on cardiac aging.

The onset and progression of cellular senescence in the heart are responsible for the course and severity of cardiac disease. Atherogenesis and the progression of atherosclerosis are influenced by AA and its derivatives [151]. Sun et al. found that AA metabolism is a major metabolic pathway responsible for cardiovascular aging [152]. A previous prospective study showed that arterial stiffness was independently associated with an increased AA/LA ratio and a decreased EPA/AA ratio [153]. The best-characterized oxylipins concerning cardiovascular disease are derived from n-6 fatty acid AA, which generally increases inflammation, hypertension, and platelet aggregation [154].

LOX enzymes are widely found in rat hearts [155]. Myocardial ischemia activates the LOX pathway in rat myocytes, causing leukocyte aggregation in injured areas [156]. Different LOX products have varying effects. For instance, HETEs, a series of derivatives of the LOX pathway, contribute to basic myocardial function. Instead, derivatives of 12-LOX promote cardiac fibrosis and hypertrophy [157]. The CYP family has also been detected in the human heart, and research has suggested that cardiac hypertrophy and heart failure generally increase the expression of CYP enzymes [158]. Notably, CYP inhibitors have been reported to decrease myocardial ischemia/reperfusion damage, mainly due to less generation of ROS [159]. Endogenous EETs are beneficial in I/R injury [160]. Conversely, increased levels of HETEs during ischemia by CYP4 family members may contribute to ischemic injury by constricting blood vessels and increasing the production of ROS [161].

AA in skin aging

The skin, the largest organ in the human body, covers a wide area. Skin aging has recently been reported to be a systemic trigger of whole-body aging [162]. The skin is a physical barrier that is permanently exposed to environmental agents. The factors that cause skin aging are divided into two categories: normal intrinsic aging and extrinsic environmental factors, such as air pollution, smoking, poor nutrition, and ultraviolet rays. Both sides can cause skin cell aging, which is the main way to induce skin aging. During skin cell aging, fibroblast senescence is associated with COX-2 activity, which is enhanced by exogenous AA intake [163]. The synthesis of AA decreases with age owing to the decreased activity of desaturating/elongating enzyme systems [164] and is accompanied by the replicative aging of human fibroblasts [165]. However, other authors have observed increased AA release in the growth medium with the cellular aging of human fibroblasts [166]. Eventually, Lorenzini et al. summarized that the total amount of AA synthesized is reduced while the amount released is increased, indicating that AA hardly inhibits fibroblast proliferation during senescence [21]. In other words, AA is a general marker of fibroblast senescence but not a cause. However, skin changes in response to environmental stimulation may be mediated by the cutaneous neuroendocrine system; the skin locally expresses elements of the hypothalamic–pituitary–adrenal (HPA) axis, and dietary AA seem to suppress age-related HPA axis responsiveness [167]. According to the studies mentioned above, a decrease in AA is accompanied by AA release during skin aging. Dietary AA suppresses rather than aggravates skin aging.

Inhibition of collagen expression by PGE2, a derivative of AA, is one of the mechanisms responsible for skin aging [168]. In addition, PGE2 is an inflammatory cytokine that may enhance skin aging by stimulating inflammatory processes. Other AA derivatives that have not been reported to affect skin aging require further investigation.

AA in cancer

The predisposing factors for cancer development are highly complex and regulated to varying degrees by both intrinsic and extrinsic factors. Intrinsic factors, including chromosome abnormalities, immune imbalance, and lipid metabolism disorders, especially AA-derived lipid mediator disorders, may induce cancer progression [169]. In addition, extrinsic factors such as smoking, ultraviolet radiation, and chemical carcinogens induce various types of cancers, such as skin and pulmonary cancer.

COX catalyzes AA into PGs and thromboxanes (TXs) to exert various effects. COX-1 is a constitutive enzyme expressed in almost all cells in the body, whereas COX-2 can be induced by various stimuli to produce various metabolites that accelerate the pathophysiological process of cancer [170]. The knockdown of COX-2 or inhibition of COX enzyme expression with drugs suppresses the infiltration and growth of tumors [171]. Thus, COX-2 may be a potential novel cancer prevention and therapeutic target. PGE2, a derivative of the COX pathway, and its four EP receptors are strongly associated with tumor processes. Although the effects of EP1 on tumors have not been conclusively demonstrated, EP2, EP3, and EP4 have been shown to promote tumorigenesis [172]. Prostaglandin synthase and prostaglandin D (2) synthase have been reported to inhibit cancer development, while the carcinogenic effect of thromboxane synthase has been demonstrated in various cancers [173]. FP receptors and their pro-tumor-promoting enzymes, including PGF, have been identified as therapeutic targets for cancer [174]. TXA is also an anticancer target for treating several cancers [175].

The LOX pathway in AA metabolism also affects tumorigenesis. 5-LOX is the best-studied isoform of the LOX family in cancer. LTB4 produced by the 5-LOX enzyme has been detected in several tumors and leukemias [176]. The main mechanism by which 5-LOX and LTB4 initiate cancer development involves interfering with cellular functions and altering the extracellular microenvironment [177]. Considering the translational link between LTA4 and LTB4, it is speculated that agonists of LTA4 promote tumorigenesis and inhibitors inhibit tumor growth, which was later confirmed by previous studies [178]. It has been proved that 12-LOX exhibits protumorigenic properties in many cancers. Several inhibitors of 12-LOX have been investigated as chemopreventive agents [179], whereas 2-HETE and 15-HETE, produced by 15-LOX, are considered tumor inhibitors [180]. Cytoskeletal leukocyte receptor 1 promotes tumor growth, whereas cytoskeletal leukocyte receptor 2 prevents tumor cell proliferation [181]. In addition, EETs and HETEs produced by the CYP pathway exert protumorigenic effects in breast cancer and other tumors [182]. During cancer suppression, the metabolites produced by LOX and COX tend to have an interactive relationship. For example, LXA4 can suppress the activity of COX-2 and 5-LOX in Kaposi sarcoma tumor cells [183]. Overall, AA metabolism is an important target for cancer treatment.

AA metabolism may also be used in biomaterials to fight cancer, and rational intervention in AA metabolism to deliver targeted drugs may be an innovative option for cancer therapy. In fact, several researchers have found potential applications of biomaterials in the treatment of some specific cancers[184].

AA in obesity

Obesity in aged men is related to changes in body weight and composition due to alterations in energy intake and total energy expenditure. Increased visceral adiposity in elderly individuals is mainly due to a defect in free fatty acid mobilization, which produces more ROS and induces chronic low-grade inflammation. This has been recognized as the major underlying mechanism of obesity-related pathologies. Interestingly, obesity reduces lifespan and affects cellular and molecular processes resembling aging [185]. Increasing evidence indicates that increased activity of the Δ6 desaturase enzyme and decreased activity ofΔ5 desaturase may accelerate obesity [186].

As a PGI2 precursor, AA potently stimulates adipogenesis [187]. However, another report showed no significant differences in plasma AA levels between obese and healthy individuals. This finding is inconsistent with studies examining the AA content of adipose tissue, which almost unanimously found that increased AA levels in adipose tissue correlated with obesity [188]. This discrepancy may be explained by the hypothesis that expanded adipocytes can remove specific amounts of AA, but once the blood level reaches a certain concentration, AA in the blood cannot be removed in time [189]. Additionally, chronic inflammation in obese individuals leads to increased AA utilization, and more active AA metabolism may explain the lack of change in AA levels in obese individuals. In addition, plasma lipid levels were only relevant for detecting lipid intake during the previous few weeks [190]. Therefore, AA may play a pathogenic role in the development of obesity, despite its plasma levels.

Plasma n-3 PUFAs have been found to negatively correlate with obesity, whereas adipose tissue AAs positively correlate with obesity a), [191]. Evidence has also indicated that LA and AA regulate the conversion of white adipocytes to brite adipocytes through a prostaglandin/calcium-mediated pathway, which means that n-6 PFUA can prevent the “browning” process that contributes to obesity, a feature of adipocyte aging [192]. Moreover, aged rats had higher total lipid contents than young rats and lower AA contents in the major salivary glands [193]. All evidence suggests that a high dose of AA is responsible for obesity and that AA may cause more age-associated metabolic disorders to shorten the human lifespan (Fig. 6).

Fig. 6.

AA metabolism in aging-related disorders. EETs meditate the release of glucagon and insulin to influence blood glucose. LA/AA suppresses the synthesis of brown adipocytes to aggravate obesity. Declines in AA, EETs, and LXA4 increased blood vessel pressure and impaired the elasticity of blood vessels, eventually causing hypertension.

AA in diabetes and hypertension

There is a strong link between AA, LXA4, and EETs in current studies on AA metabolism in blood pressure and diabetes. Studies have shown that defects in the activities of enzymes involved in AA metabolism cause deficiencies in AA, LXA4, and EETs, increasing vascular pressure and decreasing vascular elasticity, leading to hypertension [194]. In type 2 diabetes mellitus, there is low-grade systemic inflammation, as evidenced by increased circulating concentrations of IL-6, TNF-α, and arachidonic acid, which work by inhibiting these inflammatory mediators [195]. Furthermore, patients with type 2 diabetes mellitus have low plasma phospholipid levels of AA and LXA4, which may increase the plasma and tissue levels of TNF-α and IL-6 due to a lack of negative feedback control exerted by PUFAs and LXA4 on proinflammatory cytokines. Low plasma and tissue concentrations of PUFAs can result in low secretion of adiponectin. Low plasma and tissue concentrations of polyunsaturated fatty acids (PUFAs) can result in low secretion of adiponectin, which can aggravate insulin resistance and enhance the occurrence of type 2 diabetes mellitus [196]. Based on this evidence, a rational combination of AA (and possibly other PUFAs), low-dose aspirin (to enhance the formation of LXA4), and other cofactors, such as vitamin C, folic acid, niacinamide, B12, and magnesium, could be employed to prevent hypertension and diabetes mellitus.

AA can produce two types of eicosanoids through the CYP pathway: EETs, including the four isomers 5,6-EETs,8,9- EETs,11,12-EETs,14,15-EETs, are metabolized by CYP epoxygenase, and HETEs are metabolized by CYP w-hydroxylase. CYP2J is abundantly expressed in islet cells, especially in glucagon-secreting alpha cells. EETs promote insulin secretion, possibly related to their regulatory role in Ca²⁺ inward flow. This suggests that EETs may play an important physiological role in the excitation-secretion coupling process in pancreatic islet cells. This suggests that EETs may play an important physiological role in the excitation-secretion coupling process in islet cells [197]. All evidence suggests that EETs mediate islet function and that islets can produce EETs (Fig. 6).

Few studies have been conducted on 20-HETE, diabetic islet function, and insulin resistance, mainly focusing on altered diabetic vascular activity and diabetic nephropathy. HET0016, a selective 20-HETE inhibitor, improves carotid mesenteric and renal artery activities in streptozotocin-induced diabetic rats [198].

AA in other aging tissues

With aging, the kidneys' structure undergoes age-related changes that further deteriorate kidney function. They cannot compensate for normal physiological functions, particularly under severe circumstances, and can induce a range of kidney diseases, including renal cysts, nephrosclerosis, and kidney failure. Increased PUFAs levels may be a compensatory response to kidney aging rather than a cause [199]. AA-derived eicosanoids are essential regulators of renal function. Long-term AA intake has been proven to ameliorate chronic inflammation-induced kidney damage but does not affect kidney function in aged rats [200].

The treatment and prognosis of aged livers following liver disease are often poor [201]. Han et al. show that the AA metabolic pathway participates in the aging of the liver [202]. Besides, AA also promotes hepatic steatosis, eventually causing fatty liver disease [203]. AA modulates the gut microbiota to affect the inflammatory response in the hypothalamus, adipose tissue, and liver and regulates lipid and glucose homeostasis. AA supplementation may induce fatty liver disease. Collectively, AA interacts with the gut, brain, adipose, and liver tissues [204].

The senescence of blood cells such as erythrocytes, leukocytes, platelets, neutrophils, and lymphocytes accompanies the aging of the blood system. Older adults have lower levels of AA in erythrocytes and lymphocytes than young people, but aging does not affect the fatty acid composition of neutrophil phospholipids [39], [205]. AA may contribute to age-related decline in blood cell function, which may cause atherosclerosis, a common geriatric disease [206].

Pulmonary fibrosis is an age-related disease with fewer appropriate therapies to achieve a perfect outcome. Several studies have shown that AA metabolites are involved in the pathogenesis of various fibrosis types. AA metabolism in the lung was disturbed during pulmonary fibrosis. In mice, bleomycin-induced epithelial senescence and extracellular matrix deposition can be alleviated by modulating COX-2/CYP metabolism, reducing pulmonary fibrosis [207].

Senile cataract is caused by lens opacity in the aging eyes, which affects vision. The lens fatty acids increased steadily during their lifespan, and the ratio of unsaturated to saturated fatty acids was maintained within a narrow range. However, the predominant changes observed in cataractous lenses are a rapid decrease in AA and high nervonic acid content [208]. Mendelian randomization research revealed that circulating LA alleviated macular degeneration, whereas AA aggravated degenerative risk [209].

PUFAs, including AA, increase hepatic superoxide dismutase and cardiac superoxide dismutase (SOD) activity and inhibit testicular telomerase activity and expression, possibly detrimental to cell longevity. The expression of 15-LOX2 causes hyperplasia and senescence in mouse prostate cells, demonstrating the harmful effects of some AA derivatives. [210].

Potential of AA inhibitors as anti-aging drugs

In the context of a relatively comprehensive understanding of AA metabolism during aging, we hope to use AA to find appropriate therapies for sick circumstances. Although a low dose of AA in the brain has been proven to have a protective effect on astrocytes, AA can inhibit the development of cerebral ischemic diseases [211]. However, most anti-aging drugs exhibit curative effects through the inhibition of AA. Besides, capacity of AA to induce paw or ear edema has been regarded as an acute or chronic skin inflammation model that some extractives from plants or drugs can reverse; therefore, AA injection is usually used to evaluate the anti-inflammatory ability of the active ingredients of some plants or drugs [212]. For example, the ethanol extract from Murdannia loriformis (Hassk.) Rolla Rao et Kammathy was found to be helpful in AA-induced paw edema in rats [212a]. It has also been reported that garden rue inhibits the arachidonic acid pathway to alleviate paw edema in rats [213].

The COX pathway and LOX pathway largely mediate the inflammatory effects of AA. Eicosanoids are a series of AA derivatives containing PGs, TXs, LTs, and lipoxins, which are rapidly altered under inflammatory conditions. Exploring suitable ways to deal with such inflammatory substances offers an opportunity to fight aging-related diseases or disorders. Some therapies, including Food and Drug Administration (FDA)-approved drugs, Chinese traditional medicines, and natural products, have proven to be efficient in treating age-related diseases (Table 1).

Table 1.

AA-associated drugs in aging-related diseases.

Inhibitors	Targets	Disease	Function	Reference
Drugs approved by FDA
Indomethacin	COX	Pain; Renal failure	Pain↓; IL-6↓; IL-10 ↓	[222]
NSAIDS（Ibuprofen、Nimesulide、Meloxicam、Carprofen, Aspirin）	COX	Pain; Inflammatory diseases; Acute Kidney Injury	Pain↓; IL-1β ↓	[223]
Valproic acid, carbamazepine, lithium, lamotrigine, Olanzapine	COX	Bipolar disorder	sPLA2↓; Astrocyte apoptosis↓	[224]
Salicylazosulfapyridine（SASP）	COX/LOX	Inflammatory bowel disease; rheumatoid arthritis	LTs↓; PGs↓; LTs↓; HETEs↓	[225]
Zallustat, Prilosec and Monilustat	COX/LOX	Asthma	LTs↓	[226]
Sulfadiazole	CYP450	Stargardt disease, senile macular degeneration	Cell apoptosis↓	[227]
Fexofenadine	TNF-α, AA	Inflammatory arthritis	Pain↓; Inflammation↓	[228]
Melbine	MAGL	AD, diabetes	Neuronal death↓;	[229]
Dapsone	LOX	Skin aging	LTA4↓	[230]
Zileuton	5-LOX	Asthma	LTs↓	[231]
Diclofenac acid	COX	Renal cancer	PGE2↓	[232]
Aconiti Radix Cocta	COX	Rheumatoid Arthritis	pain↓; IL-1β↓	[233]
Olanzapine	COX	Schizophrenia, bipolar disorder	PGE2↓; AA↓	[234]
Drugs not approved by FDA but proved efficient
Licofelone	5-LOX/COX	Glomerulonephritis	IL-18↓; PGE2 ↓	[235]
Clozapine	COX	Bipolar disorder	cPLA2↓; PGE2 ↓	[234]
PVPA（[N-isopropyl-N-(5-((3-(5-(N-isopropylheptanamido)pentyl)-2-(pivaloylimino)-2,3-dihydrobenzo[d]thiazol-4-yl)oxy)pentyl)heptanamide]）	CYP450	Hypertension, kidney injury in cyclosporine-treated rats	14,15-EET analog; Proteinuria↓; ROS↓	[236]
Traditional Chinese medicine
Morinda officinalis	COX-2/5-LOX	Osteoporosis, joint disease	LTA4H↓; bone absorption↓	[237]
FuFang Zhenzhu TiaoZhi	COX-2/5-LOX	Osteoporosis, liver aging disease	TNF-α、IL-6↓; delay normal liver aging	[221]
Huanglian Jiedu decoction	COX-2/5-LOX	Cerebral ischemia	Apoptosis↓; excitatory toxicity↓; regulation of oxygen balance, and maintenance of essential cell functions	[238]
Achyranthes bidentata	COX/LOX	Osteoarthritis	PGE2, COX-2, IL-1β↓	[239]
Aconiti Radix Cocta	COX	Rheumatoid Arthritis	COX-1 and COX-2 in the synovial tissues↓; IL-1β and IL-17↓	[233]
Anemarrhenae Rhizoma flavonoids	5-LOX/COX-2	benign prostatic hyperplasia	PGD2, PGE2, PGF2α, PGH2 and TXB2↓; 5-HETE, 8-HETE, 11-HETE, 12-HETE, 15-HETE, and LTB4↓	[240]
BHUx	5-LOX, 15-LOX/COX	atherosclerosis	Low-density lipoprotein-cholesterol oxidations↓; eicosanoids↓	[241]
Danqi pill	COX/5-LOX	coronary heart disease	PPARα↑; PLA2, COX-2, NF-κB, LTB4↓	[242]
Glycyrrhiza Uralensis-Salvia miltiorrhiza	COX-2	NAFLD, hepatic fibrosis	AA↓; PGs↓	[243]
Huzhen Tongfeng Formula	COX/5-LOX	Gouty Arthritis	5-LO,mPGES-1, and XO, IL-1β, IL-6, TNF-α, COX-1,COX-2, PGE2, LTB4 and NO↓; Inflammation↓	[244]
Jian Pi Tiao Gan Yin	LA metabolism, ALA metabolism, glycerophospholipid metabolism, AA metabolism, and pyrimidine metabolism	Obesity	Total cholesterol↓; triglyceride↓; low-density lipoprotein cholesterol ↓; high-density lipoprotein cholesterol↑	[245]
Kaixinsan	LA metabolism, AA metabolism, and sphingolipid metabolism	AD	PGF2α and LTA4↓; Inflammation↓	[246]
Qishenyiqi	LOX, RAAS pathway	Acute myocardial infarction, myocardial fibrosis	Alleviated ventricular remodeling progression; NF-κB, JAK1/STAT3 and Akt ↓, Inflammation↓	[247]
Qishen granules	PLA2, COXs and LOXs, TNF-α-NF-κB and IL-6-JAK2-STAT3 pathway	Coronary heart disease, including acute myocardial infarction	Inhibited release of cytokines, improved cardiac functions, and altered pathological changes	[248]
Quzhi decoction	CYP3A4, PLA2G4A, COX-1, COX-2, TYR, and ALOX	Osteoarthritis	Pain↓; Inflammation↓	[249]
Shengmai Yin formula	15-LOX, CYP450 1A2, CYP2E1	Chronic heart failure	Improved the disorder of energy metabolism by regulating CYP2E1, improved inflammation by regulating CYP1A2, through LA metabolism pathway caused cardioprotective effect.	[250]
Yangyinqingfei Decoction	5-COX1/LOX/CYP2U, CYP4A, CYP4F	Diphtheria and lung injury	IL-6, malondialdehyde and TNF-α↓; SOD and 20-HETE in serum↓	[251]
Zishen pill	COX/LOX	Benign prostatic hyperplasia	Diminished the altered histology and the hyperplasia; 15-HETE,12-HETE,8-HETE,5-HETE, AA, TXA2, PGs and LTB4↓	[252]
Huo Luo Xiao Ling Dan	COX/LOX	rheumatoid arthritis	12-HETE, 15HETE, 8-HETE, LTB4, PGE2, PGI2, PGD2, PGF2α, TXB2↓	[253]
Schisandra chinensis	LA metabolism, ALA metabolism, and AA metabolism	AD	Aβ deposition↓;	[254]
Ling-Gui-Zhu-Gan Decoction	glycerophospholipid metabolism and AA metabolism（mainly LOX）	heart failure	AA↓;5-HPETE↓; 15-HETE and uric acid↓	[255]

Western medicine

Various drugs have been proven valid for different aging-related diseases, and the FDA authorizes some of them for their potent efficacy and relatively mild complications. For example, NSAIDs are widely used to treat inflammation and pain owing to their inhibitory effects on COX. In particular, selective COX2 inhibitors, such as nimesulide, meloxicam, and celecoxib, cause fewer gastrointestinal complications than nonselective COX inhibitors. This suggests that different target drugs may have superior efficacy and decreased toxicity [214]. Zileuton, an inhibitor of 5-LOX, was approved by the FDA for the treatment of asthma in 1996 [215]. Zileuton has shown a synergistic effect with celecoxib, downregulating the activity of 5-LOX and COX-2 enzymes [216].

Apart from FDA-authorized drugs, some drugs have also been demonstrated to be efficient but have not been approved by the FDA. For instance, clozapine (CLZ), a tricyclic dibenzodiazepine, is not FDA-approved but has been reported to be effective in acute bipolar disorder mania [217], rapid cycling, and in patients with refractory bipolar disorder [218]. Similarly, chronic clozapine (10 mg/kg/day) injection for 30 days increased brain activity and the mRNA and protein levels of DHA-selective calcium-independent PLA2 type VIA and BDNF in rats. In addition, chronic clozapine injection decreased COX activity and the concentration of PGE2 [219]. Hence, understanding the diverse mechanisms of anti-aging drugs could provide better brand targets for treating diseases.

Traditional Chinese medicine

In light of Western medicine's shortcomings in treating age-related diseases, doctors seek traditional Chinese medicine to fill this gap. Therefore, using Chinese medicine as a complementary method for patient therapy is becoming increasingly popular in many countries. Notably, traditional Chinese medicine is used as an adjunct therapy to Western medicine in patients who require significantly lower doses than those who use Western medicine, as recommended [220]. Traditional Chinese medicine (TCM) has advantages in the treatment of diseases. Searching for the exact AA metabolism in the process of traditional Chinese medicine interference with diseases may also benefit therapies in the future. For example, FuFang Zhenzhu Tiao Zhi (FTZ) is an effective hepatoprotective agent. FTZ mainly regulates LT changes in blood according to metabolomics. Following FTZ treatment, the levels of LTs were downregulated along with those of other inflammatory substances such as TNF-α and IL-6. All these indications suggest that FTZ, which appears to be a promising agent against normal liver aging, may mediate chronic inflammation via AA metabolism [221]. Traditional Chinese medicine should be recognized as an essential part of the anti-aging process (Table 1). Combining medications will help identify more appropriate treatments for aging.

Natural products

Generally, natural products have better safety profiles than synthetic molecules. In this context, research on AA pathway inhibitory natural products has gained momentum in developing novel therapeutic agents [44]. Natural products were the earliest source of drugs and are being actively researched as alternatives because some medicines have inevitable side effects. Several natural products are AA inhibitors and possess therapeutic potential against many aging-related diseases (Table 2). A reasonable mix of active elements in natural products may help obtain new medicines with superior efficacy and fewer complications (Table 2). Natural products associated with AA also benefit from aging.

Table 2.

Natural products associated with AA benefit aging diseases.

Inhibitors	Targets	Disease	Function	Reference
Natural products
Capsaicin	COX/5-LOX	Inflammatory diseases; pain	5-HETE, PGE2↓; Pain↓	[256]
Gingerdione, Shogaol	COX/5-LOX; TLR4	Cancer; inflammatory diseases	TLR4; PGE2; Pain↓	[256], [257]
Daphnetin	COX/5-LOX	Rheumatic joint diseases	LTB4, ROS↓	[258]
(−) Epicatechin	5-LOX	Inflammatory disease	Inhibit both dioxygenase and LTA4 synthase activities of human 5-LOX	[259]
Esculetin	5-LOX	Inflammatory diseases; pain	5-HETE, PGE2↓	[258]
Forsythiaside	5-LOX	Asthma and allergic diseases	noncompetitive inhibition of 5-HETE formation.	[260]
Fraxetin	5-LOX	Rheumatic joint diseases; rheumatic heart valve disease	LTB4↓	[258]
Helenalin	5-LOX	Inflammatory diseases, cancer	5-HETE, LTs↓	[261]
11α,13-Dihydrohelenalin acetate	5-LOX	Inflammatory diseases, cancer	5-HETE, LTs↓	[261]
β-Hydroxyacteoside	5-LOX	Rheumatic joint diseases	5-HETE, LTB4↓	[260]
Marchantin A	COX/5-LOX	Rheumatic joint diseases	5-HETE, ROS↓	[262]
Marchantin B	COX/5-LOX
Marchantin D	5-LOX
Marchantin E	COX/5-LOX
Paleatin B	COX/5-LOX
Isoriccardin C	COX/5-LOX
Perrottetin D	COX/5-LOX
Radulanin H	COX/5-LOX
4-Methylesculetin	5-LOX	Rheumatic joint diseases; rheumatic heart valve disease	LTB4, ROS↓	[258]
Panaxynol	5-LOX	Asthma and allergic diseases	Noncompetitive inhibition of 5-HETE formation.	[260]
Apigenin	COX	Prostate cancer, oral cancer, gastric cancer	Inhibit tumorigenesis, tumor growth, and metastasis; COX-2, NF-κB↓	[263]
Anthocyan	COX	Skin cancer, liver cancer	Suppressed skin damage in mice; abrogate hepatocarcinogenesis in rats; ERK 1/2, JNK1/2, p38, NO↓	[264]
Baicalein	12-LOX	Pancreatic cancer, lung cancer, breast cancer, liver cancer	Cancer cells↓; Bcl-2↓	[265]
Berberine	COX-2	Colorectal cancer, skin cancer, breast cancer, oral cancer	Induce apoptosis in cancer cells; PGE2↓	[266]
Curcumin	COX-2	Pancreas cancer, breast cancer, colon cancer, lung cancer, cervix cancer, liver cancer, blood cancer, skin cancer	Cell survival↓; apoptosis in cancer cells↑	[267]
Diallyl sulfide	COX-2	Colon cancer, skin cancer	PI3K, ERK1/2, JNK1/2, p38, NF-κB ↓	[268]
Ellagic acid	COX-2	Pancreas cancer	NF-κB, Vimentin↓; E-cadherin↑	[269]
Epigallocatechin-3-gallate	COX-2	Skin cancer, liver cancer, prostate cancer	Bcl-2↓; IGF-1↓; phospho-ERKs 1 and 2↓; iNOS↓	[270]
Eugenol	COX-2	Colon cancer, skin cancer	Proliferation of human colon cancer cells↓; skin damage↓	[271]
Fisetin	COX-2	Colon cancer	Wnt/EGFR/NF-κB-signaling pathways↓, PGE2↓	[272]
Garcinol	COX/5-LOX	Colon cancer	LTB4↓; PGE2↓	[273]
Genistein	COX-2	Liver cancer	Migration hepatocellular carcinoma cell ↓; Inflammation↓	[274]
6-Gingerol	5-LOX	Colon cancer	LTA4 hydrolase↓	[275]
Guggulsterone	COX-2	Esophagus cancer, blood cancer	Esophageal adenocarcinoma cells↓; leukemic cells↓; PGE2↓	[276]
Indole-3-carbinol	COX-2	Blood cancer	MMP-9↓; Bcl-2↓; IL-1β↓; NF-Κb↓; cyclin D1↓; survivin↓; TRAF1↓	[277]
Lycopene	COX-2	Colon cancer	PGE2; phospho-ERKs 1 and 2↓	[278]
Nordihydroguaiaretic acid	12-LOX	Prostate cancer	12-LOX, vascular endothelial growth factor, AKT, PI3K↓	[279]
C-phycocyanin	COX-2	Liver cancer	Inhibited MDR1-mediated drug resistance in HepG2 cells	[280]
Quercetin	COX	Colon cancer	Inflammation↓； inducible nitric oxide synthase in early stages↓	[281]
Resveratrol	COX-2	Breast cancer, liver cancer, prostate cancer	PGE2, NF-κB↓	[282]
Sulforaphane	COX-2	Oral cancer, Bladder cancer	COX-2, MMP2, MMP9, ZEB1, Snail↓	[283];
Silibinin	COX	Colon cancer	ERK1/2, p-Akt, VEGF, NOS↓	[284]
Thymoquinone	COX-2	Bile duct cancer	Cell proliferation↓; PI3K, Akt, NF-κB, p65, Bcl-2, VEGF↓	[285]
Triptolide	COX-2/5-LOX	Pancreatic cancer, colon cancer	Cell proliferation↓; apoptosis in human pancreatic cancer cells↑	[286];
Ursolic acid	COX-2	Colon Cancer, prostate cancer	Cell proliferation↓; apoptosis in cancer cells↑	[287]
Wogonin	COX-2	Osteosarcoma	Tumor growth and metastasis and tumor-associated macrophages numbers↓	[288]
Sagittaria sagittifolia polysaccharide	COX/LOX	NAFLD	Interfered AA metabolism via Nrf2/HO-1 signaling pathway	[289]
Geniposide	Glycerophospholipid, arginine, proline, and AA metabolism	Liver fibrosis	Methane dicarboxylic aldehyde levels in liver↓;the apoptosis of hepatocytes↓;cleaved-Caspase 3, cleaved-Caspase 9, Bcl-2 Associated X ↓;IL-6, IL-1β,TNF α↓; Bcl↑PGs and LTs↓;	[290]
Other active compounds extracted from plants associated with AA
Radix Paeoniae Rubra	COX-2	Chronic pelvic inflammation disease	Inflammatory biomarker↓	[291]
Baicalein	12/15-LOX	Renal injury	12-HETE↓; IL-6↓	[292]
The methanolic extract of Cyathula prostrata	5-LOX	Inflammation and pain	Histamine, serotonin, and kinin↓; 5-LOX derivatives↓	[293]
Hordeum vulgare L	COX/LOX	Various inflammatory and cardiovascular diseases	SOD and glutathione peroxidase activity↑; COX and LOX↓; inflammation↓	[294]
Panax notoginseng saponins	Tricarboxylic acid cycle, energy metabolism, and AA metabolism	Cardiotoxicity of periplocin	Cardiotoxicity biomarkers↓	[295]

Dietary supplement

Daily dietary supplementation also affects human health. The n-3 PUFAs are mainly derived from fish and animal oils, whereas the n-6 PUFAs are mainly derived from vegetable oils [296]. Fish oil also has potential health benefits [297]. Fish oil has been used as a nutrient for disease prevention and control for several years. DHA and EPA, n-3 PUFAs, are the main components of fish oil. Considering the competitive relationship between EPA and AA, EPA can also inhibit the generation of AA inflammatory derivatives such as PGs [298], which can induce inflammation and eventually promote skin aging. In addition, fish oils have been proven beneficial in treating arthritis, asthma, PD, osteoporosis, diabetes, cardiovascular events, cancer, and depression [299]. An appropriate n-6 PUFA: n-3 PUFA ratio benefits our health, and the WHO suggests that an n-6: n-3 ratio (lower than 10) of daily food consumption can be achieved using certain edible sources.

Conclusions

Aging is a highly complex process that occurs through various mechanisms regulated by the environment and genes. In many cases, aging is considered a persistent chronic inflammation, and a continuous increase in inflammatory molecules in the body may accelerate aging. Exercise, a proper diet, maintaining a good mind, and an excellent circadian rhythm help fight aging and diseases. We recommend that individuals consume more n-3 nutrients to achieve a healthy nutritional intake balance and significantly delay the onset of aging.

However, AA metabolism does not always promote chronic inflammation in mice. AA and its metabolite LX4 have been reported to prevent diabetes[35]. In addition, the consumption of AA-rich foods can lower blood cholesterol levels and boost LX4 production [36], [151], which may promote basic health. It is also interesting to note that desaturase-deficient mice lacking PGE2 can not fight inflammation in the intestine due to intestinal crypts [300]. PGE2 is essential for maintaining basic health, and PGE2 deficiency can aggravate intestinal infections. Thus, as discussed above, PGE2, as an inflammatory molecule, is not always harmful to human health but depends on local concentration and specific location. In AA metabolism, in addition to the classical COX pathway, HETEs produced by the LOX pathway and ETEs produced by the CYP pathway have different roles in aging because of their different mechanisms. Research on these metabolites and drug development can help us fight many aging diseases, such as osteoporosis, diabetes, and AD. Normal cellular senescence and metabolic and endocrine dysfunction are important catalytic factors in many aging-related diseases. The currently marketed drugs targeting AA metabolism are often AA metabolic inhibitors, which suggests that research targeting some AA anti-aging products may improve the internal and external cellular environment and promote normal apoptosis and the generation of new healthy cells.

Understanding AA metabolism, dissecting the products of different pathways of AA metabolism, and rationalizing multiple drugs can help improve the efficacy of treating aging-related diseases and effectively reduce the adverse effects caused by drugs.

Compliance with ethics requirements

Our article does not contain any studies with human or animal subjects.

Credit author statement

All authors have read and approved the final review manuscript. Dechun Geng, Huilin Yang and Jiaxiang Bai conceived the article. Chen Qian wrote the first version of the manuscript. Yusen Qiao and Qing Wang made the outline and formatted the figures. Haixiang Xiao, Zhixiang Lin and Ze Xu formatted tables. Mingzhou Wu, Wenyu Xia and Linlin Zhang checked the English. Jiaxiang Bai oversaw and directed the entire work. Chen Qian, Qing Wang and Yusen Qiao contributed equally to this work.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Chen Qian is a young research scholar at Department of Orthopedics, The First Affiliated Hospital of Soochow University. He has participated in a number of medical research projects, promoted the writing of project declaration and facilitated the process of article writing. At present, his main research content is Cellular senescence and aging.

Jiaxiang Bai is a postdoctoral fellow at the University of Science and Technology of China (USTC), and an attending physician and assistant researcher in the Department of Orthopaedics at the First Affiliated Hospital of USTC. His current research interests focus on the construction of osteoinductive bone implant materials and bone homeostasis studies.

Dechun Geng is a full professor at The First Affiliated Hospital of Soochow University. Currently, he is the Principal Investigator of Joint Degeneration and Injury Laboratory in Institute of Orthopaedics at Soochow University. His scientific interests are focused on osteoimmunology in bone metabolic diseases and engineering implants for enhanced osseointegration.