During the process of inflammaging, the plasticity and function of ADSCs are regulated by specific factors. Taha et al. cultured ADSCs treated with TNFα to trigger a strong inflammatory response, and then, deep next-generation mRNA sequencing was performed to evaluate the inflammatory responses of the ADSCs (12). The results showed that the ADSCs exhibited a strong response when exposed to an inflammatory environment. Adipogenesis is also reduced by inflammaging. Liu et al. showed that after the deletion of proinflammatory macrophages in SAT, the differentiation of preadipocytes was upregulated, and the expression of differentiation genes was increased (9). Inflammaging is strongly related to hypoxia (13). Chol et al. found that ADSCs cultured under low-oxygen conditions exhibited a higher proliferative ability, significantly higher basal migration, and reduced lipid production. ADSCs maintain an undifferentiated status in a hypoxic environment, and their potential to differentiate into adipocytes is decreased (14).

Adipose tissue inflammaging, as a consequence of proinflammatory immune cell infiltration, may disrupt the recruitment of new adipocytes, leading to adipocyte hypertrophy (15). Adipocyte hypertrophy is closely related to metabolic diseases. Initially, adipocyte hypertrophy is an adaptive reaction to excessive nutrition, which is beneficial in lean objects as it can protect tissues other than adipose tissue from lipotoxicity. However, in some obese or aging patients, the adipocyte buffering ability may be exceeded, reaching the hypertrophic threshold, leading to ectopic lipid deposition in other tissues (16). Adipocyte hypertrophy further exacerbates adipose tissue hypoxia and inflammation, leading to adipose tissue fibrosis and adipocyte apoptosis.

In aging adipose tissue, the insufficient angiogenic potential, inappropriate ECM remodeling and unresolved inflammation result in adipose tissue fibrosis. An insufficient angiogenic potential leads to hypoxia, which stimulates the transcription of HIF1α (5, 17). On the one hand, the activation of HIF1α inhibits preadipocyte differentiation and initiates adipose tissue fibrosis. On the other hand, HIF1α may induce a change in the cellular redox status, which, in turn, affects enzymes involved in collagen crosslinking and stabilization (18). Fibrosis is characterized by an imbalance in ECM homeostasis, including the balance between ECM production and ECM degradation (19). Studies in aged mice (~30 months of age) demonstrated an increase in WAT collagen staining, indicating more fibrosis in this tissue (20). Two cells play important roles in ECM production, M1-type macrophages and mast cells. Macrophage-inducible C-type lectin (Mincle) production is induced in macrophages through the saturated fatty acid/TLR4/NF-κB pathway and contributes to ECM production. Mast cells can promote fibroblast growth and collagen production by releasing cytokines, chemokines, proteases, etc., eventually leading to ECM production (21, 22). Fibroblasts and macrophages are the primary cell types that mediate collagen internalization and degradation. Studies have shown that an increase in proinflammatory cytokines is linked to the downregulation of metalloproteinase (MMP) expression. MMPs have the ability to cleave ECM components; thus, the increase in proinflammatory cytokines inhibits ECM degradation (21, 22). The size of both VAT and SAT is reduced in aged animals, suggesting that senescence affects lipid processing in adipose tissue, promoting ectopic lipid accumulation.

Inflammaging caused by proinflammatory immune cells largely damages the function of adipose tissue and eventually leads to adipose tissue fibrosis. As the function and composition of VAT and SAT are affected, ectopic lipid storage is promoted (23). When the dietary buffer cannot be addressed by senescent adipose tissue, lipotoxicity mediated by the ectopic deposition of lipids occurs in the liver and skeletal muscle. Lipotoxicity in these tissues increases the ROS levels and activates serine threonine kinases, such as c-jun N-terminal kinase (JNK), IκB kinase (IKK), and protein kinase C (PKC). These events not only disrupt insulin receptor signaling cascades and promote insulin resistance but also are associated with the development of hepatic steatosis and muscle dysfunction and may trigger the development of sarcopenia (24).

Aging-induced proinflammatory cytokines can directly interfere with the insulin signaling pathway in adipocytes (25). In addition, NLRP3 activated by DAMPs mediates chronic inflammation and insulin resistance. The activation of NLRP3 contributes to a higher expression of IL-1β, and IL-1β is a key cytokine in the etiology of type 2 diabetes. Briefly, IL-1β can affect insulin signaling, reduce glucose transporter type 4 (GLUT4) expression, and have proapoptotic effects on β-cells (mediated by the MAPK and NF-κB signaling pathways) (26).

Adipose tissue can act as an important source of inflammatory mediators, thus promoting systemic inflammaging (27). Chronic inflammation significantly increases the risk of CVD. The proinflammatory cytokines released by inflamed adipose tissue may force perivascular adipose tissue to modify its composition and accelerate atherosclerosis (28). Adipose tissue-derived proinflammatory cytokines, such as IL-1β and TNF, induce the expression of endothelial cell adhesion molecules, which further promote vascular inflammation (29). Exosomes derived from inflamed VAT have been shown to promote the M1 proinflammatory polarization of macrophages and promote atherosclerosis (30).

Cancer can arise at a site of inflammation, and a proinflammatory microenvironment is an essential component of cancer. Chronic inflammation can initiate cancer, promote its progression and support its metastatic diffusion (31). Adipose tissue inflammation may also be the driver of cancer (32).

A central reason for adipose tissue dysfunction and inflammation during aging is the accumulation of senescent cells. Cellular senescence is a basic aging mechanism that results in organ dysfunction and chronic inflammation (33). Upregulated ROS are the main drivers of adipose tissue senescence. Following ROS upregulation, the DNA damage response (DDR) triggers the p53/p21 signaling pathway, followed by the consequent promotion of the senescence phenotype along with exacerbated TNF-α/IL-6 secretion and β-galactosidase activities. Such DNA injury can eventually pave the path for ATM/p53/p21 upregulation (34). Senescent cells can release several proinflammatory cytokines, which are currently considered hallmark components of the SASP (35). These proinflammatory factors continue to accumulate in tissues as the clearance of senescent cells is compromised during aging (4).

Key essential cells within adipose tissue develop the senescence phenotype. Adipose-derived stem cells (ADSCs) gradually lose the ability to replicate before entering cellular senescence, a state characterized by the upregulation of senescence markers, such as p16^INK4a, p21^Waf1 and caveolin-1 (36). p16^INK4a is upregulated through p38 MAPK influence, possibly contributing to cellular senescence. In addition, p53 MAPK is involved in age-related ADSC functional transformation. Its activation impairs mitochondrial function. Mitochondrial activities are essential players in maintaining stem cell pluripotency (37). Additionally, ADSCs expand in dimensions, morphology and structural complexity along with the decreased expression of CD105 during the natural aging process (38). Cellular senescence of preadipocytes can progress to widespread shifts in preadipocyte function, such as reduced proliferation, adipogenesis, and exacerbated production of proinflammatory cytokines and extracellular matrix–modifying proteases (39). Senescent preadipocytes also negatively influence adipogenicity within surrounding progenitors and induce them to senesce (34). Cellular senescence is also linked to downregulated PPARγ and the triggering of downstream targets in endothelial cells, suggesting that capabilities, such as responding to fatty acids and promoting lipid transport, are significantly diminished. Moreover, p53 protein upregulation typically occurs in endothelial cells. Senescent endothelial cells lose the capability to discharge endogenous lipid PPARγ ligands, consequently leading to detrimental influences on the differentiation and function of human adipocytes (34). Adipocyte senescence is also induced by elevated DNA damage (40). In addition to adipocyte senescence, adipocyte death occurs upon obesity or during aging (41, 42). Dying adipocytes can attract macrophages, and these macrophages produce various types of cytokines according to the type of cell death. Apoptotic cells establish the production of anti-inflammatory cytokines, whereas necrotic cells establish proinflammatory cytokine production characterized by the secretion of IL-1 by the macrophage population (43). The NOD-like receptor (NLR) family of pattern recognition receptors (PRRs) can sense obesity- or aging-induced signals, such as damage-associated molecular patterns (DAMPs), originating from stressed adipocytes. In macrophages, the activation of NLR activates the NLRP3 inflammasome (44). The inflammasome consists of a multiprotein intracellular complex that develops as a stress-triggering response, leading to the secretion of the proinflammatory cytokines IL-1β and IL-18 (45). IL-1β upregulates IL-2 and TNFα, generating tissue inflammatory activities by triggering cyclooxygenase-2, consequently generating prostaglandin E2, inducible intercellular adhesion molecules and NO (45).

Aging leads to adipocyte hypertrophy, even within a single white adipose tissue (WAT) depot, and the cell diameters of different adipocytes can dramatically vary, ranging from less than 20 µm to 300 μm (46). An increased adipocyte size results in decreased oxygen diffusion. In addition, the blood supply to adipocytes is reduced during aging (5). These two factors generate a hypoxic environment in aged adipose tissue, which has been shown to occur with aging as revealed by immunohistochemistry and direct measurements of the interstitial partial pressure of oxygen (47). Hypoxia may induce a reaction mediated by hypoxia-inducible factors (HIFs) to promote angiogenesis and complement oxygen levels (17). However, as the angiogenic potential of ADSCs declines and the expression of VEGF and the density of blood vessels decrease with aging, compensation from the vasculature becomes inadequate. As a result, the reduced oxygen diffusion is aggravated due to insufficient compensation by the vasculature (48).

The expression of HIFs is usually induced by hypoxia, and HIF isoforms have defined, nonredundant functions concerning adipocyte function. Even though HIF-2α expression within adipocytes is beneficial since it exerts key senescence prophylaxis-related metabolic effects, including enhanced vascularization possibilities (49), HIF-1α could perform opposing functions. HIF-1α triggering did not activate typical VEGFα-vascularization responses; rather, HIF-1α induced a collagen-driven profibrotic response that paved the path for maladaptive adipose tissue remodeling and insulin resistance (49). HIF-1α may also reduce the expression of genes in mitochondrial complex IV such that the reduced mitochondrial activity contributes to adipocyte hypertrophy. A previous study showed that the knockout of HIF-1α improved mitochondrial function and reduced adipocyte hypertrophy in middle-aged mice (5). Studies have shown that cultivating adipose tissue in a hypoxic environment induces alterations in gene expression, including the upregulation of inflammation-related genes (50). Furthermore, evidence suggests that the NF-κB signaling pathway is enhanced in hypoxic adipose tissue (13).

Mechanical stress also induces inflammation in adipose tissue. As adipocyte hypertrophy is facilitated by aging, the pathological expansion of the extracellular matrix (ECM) has also been observed, leading to altered mechanical stress (51). Furthermore, mechanical stress is exerted by enlarged lipid droplets within the cell (52). Although the pathways controlled by mechanical stress in adipocytes have not been elucidated, the NFκB signaling pathway may be influenced by mechanical stress via the RhoA-Rock signaling pathway (53).

As a metabolic syndrome, obesity frequently develops during old age and is a critical factor associated with adipose tissue inflammaging. Typically, obesity is mediated by adipocyte hypertrophy or hyperplasia. Adipocyte hyperplasia is more metabolically friendly than adipocyte hypertrophy. Adipocyte hypertrophy caused by obesity can result in a hypoxic environment, leading to adipose tissue inflammation. Multiple studies have shown that PDGFα⁺CD9^low proadipogenic adipose progenitor cells (APCs) switch to PDGFα⁺CD9^high profibrotic progenitor cells when influenced by inflammation, ultimately promoting adipose tissue fibrosis and reducing adipocyte hyperplasia (54). The increased adipocyte hypertrophy with reduced adipocyte hyperplasia contributes to adipose tissue inflammation through aging (55). However, obesity may further worsen immunosenescence by enabling the activation and differentiation of immune cells passing through the adipose tissue microvasculature. Previous research has shown that adipose tissue dysfunction in obesity enables immunological aging along with excessive inflammatory responses (56).

Exogenous and endogenous fatty acids and exogenous lipopolysaccharide (LPS) are capable of inducing inflammation in adipose tissue through the activation of toll-like receptors (TLRs) expressed in both adipocytes and macrophages (57). Gut-derived LPS binds TLR4, while free fatty acids (FFAs) can activate inflammatory signaling through either TLR4 or TLR2 (58).

Immunosenescence, which results in a defective immune response to pathogens and is often coupled with excessive inflammatory activities, is also found in aging adipose tissue. In particular, VAT shows immune cell activation and inflammation compared to other tissues (59). The abnormal activation of immune cells was first detected in WAT depots in middle age and is considered a hallmark of aging (32). In old age, the adipose immune system shifts toward being more unregulated. At this age, various resident regulatory cell populations are dwindling and substituted by inflammatory cells due to phenotypic switching in resident adipose immune cells or the infiltration of inflammatory immune cells from the periphery (60). Prior studies have mainly focused on macrophages, ILCs and eosinophils in adipose tissue. Among these cell types, M2-like macrophages tend to be lost in aged adipose tissue (61). Moreover, there are differential age-related changes between SAT and VAT. For example, the number of eosinophils is substantially reduced in elderly VAT but remains unaffected in SAT (62). Other changes in immune cells are also discussed in this review ( Figure 1 ).

Over the past two decades, the JAK/STAT signaling pathway has been shown to play vital roles in the regulation of lipid metabolism, glucose metabolism, and adipokine secretion in adipose tissue (158). While early research mainly focused on the role of JAK/STAT signaling in adipogenesis, subsequent studies further demonstrated a role in mediating inflammation in adipose tissue (159). The JAK/STAT signaling pathway mediates the activation of peripheral blood B cells and promotes the activation and proliferation of ILC1s in adipose tissue (83). Adipocytes also express several receptors for JAK/STAT-activating cytokines and hormones, including immune cytokines acting in a paracrine manner to induce JAK/STAT signaling in adipocytes (160). For example, IFN-γ can induce JAK1/STAT1 signaling in human adipocytes and promote inflammation and insulin resistance (161). STAT proteins heterodimerize with phosphorylated IRFs to activate the expression of inflammatory gene signatures (162). Ligands, including IL-6 and platelet-derived growth factor receptors (PDGFRs), also signal through the JAK/STAT signaling pathway (163). Oncostatin M (OSM) is a cytokine expressed in immune cells in adipose tissue, while its receptor OSMR is expressed on adipocytes (164). The loss of OSMR expression is accompanied by decreased STAT5 phosphorylation in adipocytes and a reduction in the expression of proinflammatory cytokines and chemokines (165). Recent studies have reported crosstalk between the JAK/STAT and TGFβ signaling pathways. Transient inflammation caused by lipolysis leads to the upregulation of IL-6 and activation of JAK/STAT3 signaling in adipose progenitors, alleviating the inhibitory effect of TGFβ on adipogenic lineage commitment and thermogenic beige adipocyte differentiation (166).

Wnt signaling plays pivotal roles in modulating the adipose tissue microenvironment. Wnt signals can alter important steps of insulin utilization within cells, leading to the progression of insulin resistance (167). The binding of Wnt ligands to their receptors activates the Wnt pathway and causes adipose tissue inflammation, obesity, and glucose homeostasis. Wnt signaling can be further divided into canonical and noncanonical Wnt signaling. Noncanonical Wnt ligands, such as Wnt5a, are expressed in adipocytes at high levels when the diet consists of fatty substances, which contributes to obesity-associated inflammation (168). Wnt5a can also activate JNK and promote insulin resistance (169). The Wnt signaling pathway is activated in cDC1s, leading to the production of the anti-inflammatory cytokine IL-10 (80). However, TLR signaling acts in conjunction with the Wnt signaling pathway to amplify the release of proinflammatory cytokines in macrophage-induced inflammation (72). PI3K signaling is also closely related to chronic inflammation and insulin resistance. Inflammation or other stress stimuli block the PI3K signaling pathway downstream of the insulin receptor through the activation of several serine/threonine kinases, contributing to insulin resistance in adipocytes (170). PI3K signaling and its downstream effectors, including protein kinase B (AKT), help preserve beneficial macrophage subpopulations (75). However, the PI3K/AKT-mediated anti-inflammatory effects are inhibited in aging adipose tissue DCs (171). PI3Kγ can promote neutrophil infiltration.

The NF-κB and JNK signaling pathways are two central mediators of the inflammatory response in adipose inflammation. Specific dietary saturated fatty acids induce the expression of MCP-1 and SAA in adipocytes through the activation of the NF-κB and ROS pathways (172). The activation of NF-κB signaling increases the expression of TNF-α, IL-6 and MCP-1, leading to serine phosphorylation of IRS-1, thus blocking insulin signaling downstream of insulin receptors (26). The transcription of NF-κB is mainly controlled by the phosphorylation of inhibitor of NF-κB (IκB) by the upstream IκB kinase (IKK). Canonical IKKs, including IKKα and IKKβ, phosphorylate IκB and other subunits of NF-κB to induce the expression of NF-κB target genes. IKKα phosphorylates IRS-1 and, thus, induces insulin resistance (153). Panahi et al. found that IKKβ deficiency in adipocytes prevents the expression of proinflammatory cytokines, such as IL-6 and TNF-α, induced by free fatty acids. In contrast, the activation of IKKβ inhibits the expression of anti-inflammatory cytokines, such as adiponectin and leptin (173). In addition to canonical IKKα and IKKβ, two noncanonical IKKs, IKKϵ and tank-binding kinase 1 (TBK1), play roles in adipocyte biology (174). Proinflammatory cytokines, such as TNF-α, activate TBK1, which attenuates adipose tissue inflammation by repressing the atypical NF-κB pathway. In this pathway, NF-κB-inducing kinase (NIF) phosphorylates Ser176 to activate IKKα, which, in turn, activates the RelB (NF-κB2) precursor p100, inducing its maturation. This pathway induces the expression of target genes, such as CCL2, and promotes infiltration by macrophages. TBK1 can further inhibit the metabolic regulator AMPK, thus promoting inflammation (175). Moreover, NFκB activation in adipose tissue neutrophils is important for its expression of IL-1β (82). Activated NFκB also promotes the activation of ILC2s and a type 2 immune response (128). DR3, a recently defined receptor expressed on ILC2s, can also induce and activate ILC2s through NFκB pathways (176).

The following two distinct MAPK signaling pathways play important roles in adipocyte inflammation: the p38 pathway and the JNK pathway. JNK signaling is activated in adipocytes in obese humans and mice and promotes insulin resistance through the phosphorylation of IRS, thereby decreasing PI3K/PKB signaling downstream of insulin receptors (153). The activation of JNK can further activate the transcriptional regulator AP-1 and induce the expression of inflammatory genes, such as IL-6 and TNF, inhibiting insulin signaling and causing insulin resistance (25). In contrast to JNK, p38α activity is reduced in obese mice, with concurrent activation of other p38 isoforms, including p38g and p38d (177). The p38 pathway is activated in adipose tissue immune cells, such as macrophages, to promote the production of inflammatory cytokines and the recruitment of monocytes, leading to adipose tissue inflammation (178). Activated p38MAPK signaling in mast cells can also contribute to metabolic dysfunction in SAT (179). The p38 pathway is also implicated in adipocytes as the inhibition of p38 in adipocytes results in a decreased secretion of TNF-α-induced IL-6 (180). JNK plays a role in lipolysis induced by TNF-α, while the role of p38 in this process needs further elucidation (181). When MAPK signaling is activated in DCs, the expression of MHC-II and cellular maturation are increased (81).

The final signaling pathway we aim to discuss here is the AMPK pathway, an important anti-inflammatory signaling pathway in adipose tissue. AMPK signaling can inhibit the synthesis of proinflammatory cytokines, including IL-6 and IL-8, in adipocytes, while a deficiency in AMPK leads to an increased production of proinflammatory cytokines. The knockdown of AMPKα1 in 3T3-L1 adipocytes leads to an increase in the mRNA levels of the proinflammatory cytokines TNF-α, IL-1β and MCP-1 in response to FA treatment (182). In a recent study, the following more detailed mechanism was elucidated: AMPK might block a proinflammatory IL-6 trans-signaling mechanism involving IL-6/soluble IL-6R that can stimulate JAK, thus influencing the JAK/STAT3 signaling pathway in adipocytes. Furthermore, AMPK can block IL-1β-stimulated IRAK-4, thus influencing the JNK signaling pathway in adipocytes. Moreover, AMPK can block TNF-α-stimulated IKKβ, thus influencing the NF-κB signaling pathway in adipocytes (183). Thus, AMPK plays a critical role as a master regulator of inflammation by regulating several inflammatory pathways (82). In addition, AMPK can promote M2-type macrophage polarization (61) and compromise the function of ILC2s by interacting with the NFκB pathway (184) ( Figure 5 ).

Caloric restriction (CR) without malnutrition has been the foundation of aging for decades (196). A reduction in food intake prolongs the lifespan and delays the onset of age-related diseases in diverse species. The life-prolonging effect of CR is due to changes in many physiological processes, and the biology of AT is closely related (197). As we previously mentioned, hypoxia, mechanical stress and obesity caused by adipocyte hypertrophy are factors contributing to adipose tissue inflammaging. Research has found that the surgical removal of VAT in rats offered approximately 20% of the effect of CR on longevity, preventing insulin resistance and glucose intolerance of aging (189). A reduction in the fat mass, specifically visceral fat, may be a possible underlying mechanism of the antiaging effect of CR (190). However, a recent study has shown that 30% CR alone without fasting or circadian alignment accounts for a 10% extension of the lifespan; however, a daily fasting interval and circadian alignment of feeding act together to extend the lifespan by 35% in male C57BL/6J mice, with improvements in inflammation and immune and metabolic function (198), which are consistent with the results of other recent studies in C57BL/6J male mice (199). Moreover, researchers have found that CR and fasting have overlapping effects on gene expression by performing transcriptomic profiling of inguinal white adipose tissue (iWAT), where CR and fasting altered many Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including PPAR, insulin, TGF-β and AMPK signaling and various metabolic pathways (198–201). Many molecules have been discovered to function in regulating the lifespan by dietary restriction; among these, SIRT1, an NAD-dependent deacetylase that participates in cell cycle regulation, is the best established longevity determinant. Studies have shown that SIRT1 mediates the effect of CR on longevity by suppressing lipid accumulation and enhancing adipocyte lipolysis (202, 203). SIRT1 also participates in the regulation of other signaling pathways related to aging. The transactivation of PPARγ, which is essential for proper adipose tissue development and function, is repressed in WAT by SIRT1 (204). Previous studies suggested that experimental Pparg2-deficient mouse models with a lower expression of PPARγ in WAT exhibited a reduction in the lifespan (205). In addition, a new study identified reduced expression of platelet-activating factor acetylhydrolase (PLA2G7) in adipose tissue from people undergoing CR for 2 years by using gene expression profiles, and PLA2G7-deficient mice showed decreased age-related inflammation, lower NLRP3 inflammasome activation, and improved adipose tissue metabolism. These findings demonstrate that PLA2G7 may become an immunometabolic regulator of CR and could potentially be used to lower inflammation and extend the lifespan (206). Moreover, the pathologic expansion of adipose tissue leads to the excessive production of FFA, thereby stimulating TLR4 signaling through the TLR4-NFkB pathway, resulting in the release of proinflammatory cytokines. A study suggested that the expression of three major proinflammatory cytokines (IL-6, MCP1 and TNF-α) in adipose tissue is significantly reduced in old TLR4-KO mice compared to old wild-type mice, showing that TLR4-deficient mice are protected from adipose tissue inflammation during aging (207). Thus, the manipulation of the TLR4 pathway might have great therapeutic potential in aging. The possible molecular pathways described above link caloric restriction to life extension in mammals, providing new insight into the targets of anti-aging treatments.

Over the past decade, the search for strategies that can achieve the beneficial effects of CR without reducing calorie intake has undergone considerable expansion (208). The accumulation of senescent cells (SnCs) is one of the hallmarks of aging, which leads to tissue and organismal aging, and the selective elimination of SnCs in animal models extends the health span (209). Therefore, pharmacological interventions targeting SnCs, also known as senotherapeutics, might be a potential strategy for longevity and the prevention of age-related diseases. Senolytics, drugs that specifically kill SnCs, have shown efficacy against atherosclerosis (210), osteoarthritis (211) and other age-related diseases (212–214). The first senolytics reported by Zhu et al. in 2015 were a drug combination of dasatinib (D), a protein tyrosine kinase inhibitor, and quercetin (Q), a plant flavonoid. By using a transcriptome analysis of senescent and nonsenescent human preadipocytes, the authors revealed that SnCs protect themselves from apoptosis through senescent cell antiapoptotic pathways (SCAPs), including ephrin receptors, BCL-2/BCL-XL family members, P13K/AKT, HIF-1α, etc. (213). In vivo, the D + Q combination reduced the senescent cell burden in fat tissue by targeting SCAPs with the benefit of reduced frailty and an extended healthspan (194, 213). To date, D + Q treatment has been tested in several human clinical trials; for example, a clinical trial of D + Q in individuals with diabetic kidney disease found that the D + Q treatment alleviated adipose tissue and the skin senescent cell burden, decreased the resulting adipose tissue macrophage accumulation, enhanced the adipocyte progenitor replicative potential, and reduced key circulating SASP factors (215).

In addition, SnCs can lead to extensive microenvironment dysfunction and cause damage to surrounding cells and tissues due to their proinflammatory SASP (216). Senomorphics, another class of senotherapeutics, is known for modulating the phenotypes of SnCs by interfering with inflammaging, senescence-related signaling pathways, and SASP without inducing apoptosis (217). Resveratrol, a plant-derived polyphenol, is the most potent of the natural SIRT1 activators, and several studies have reported that it can extend the lifespan of various organisms (218–221). In addition to the features of SIRT1 mentioned above, SIRT1 exerts anti-inflammatory activity by inhibiting NF-κB, a key regulator of the immune response and inflammaging (222, 223). Research involving rhesus monkeys fed a high-fat, high-sugar diet suggested that resveratrol improves adipose insulin signaling and reduces the inflammatory response in WAT with increased SIRT 1 expression and decreased NF-κB activation (224). Moreover, SASP in SnCs is regulated by the JAK/STAT pathway, and using the JAK inhibitor roxolitinib in aged mice for 10 weeks reduced both adipose tissue and systemic inflammation and enhanced physical function (225). Metformin, originally approved for the treatment of type 2 diabetes, has been found to have therapeutic effects on age-related diseases, such as insulin resistance, obesity and cardiovascular diseases (226). Numerous studies have proven that metformin is effective in inhibiting cellular senescence and SASPs and preventing age-associated dysfunctions in many model organisms. Metformin modulates aging-related protein synthesis by regulating AMPK/mTOR signaling and enhancing autophagy to increase aging-related protein degradation (227). A recent study demonstrated that metformin reduced cell cycle progression and mTOR signaling and decreased the secretion of most proinflammatory SASP cytokines in mature human adipocytes, exerting anti-inflammatory effects on adipose tissue function (228). Rapamycin, a specific mTOR inhibitor, has been regarded as one of the most well-established senomorphics that reduce cell senescence, suppress SASPs and extend the lifespan. A study focusing on the effects of rapamycin on inflammation in gonadal white adipose tissue (gWAT) of HET3 mice revealed that rapamycin led to a 56% increase in CD45+ leukocytes in gWAT, where the majority of these are ATMs. Interestingly, rapamycin led to an increase in M1 type ATMs, suggesting that rapamycin may achieve life-span extension partially through adipose tissue inflammation (229). L-carnitine, an inhibitor of the JNK/p53 pathway that can prevent apoptosis, has been found to attenuate aging adipose tissue dysfunction by reducing the expression of SASP factors in the WAT of aged (> 18 months old) rats (230).

Since immune cells play a key role as sources and integrators of inflammatory signals, the regulation of immune cell phenotypes could be a target for intervention to limit ‘inflammaging’ and restore repair capacity in older organisms. Heterochronic parabiosis, a model system in which two animals of different ages are joined to share a common circulatory system, represents an important milestone in aging biology (231). Various circulatory factors have been identified as mediators of the prorejuvenation and proaging systemic effects of heterochronic parabiosis. A recent study demonstrated that transferring eosinophils from young mice reduces WAT and systemic low-grade inflammation, with lower levels of inflammatory factors (such as IL-6, CCL2 and IL-1β), resulting in the restoration of adipose immune homeostasis and widespread rejuvenating consequences for the aging host (125). Another study suggested that adoptive NK-cell infusion reduces senescent markers (p16 and p21) and decreases the SASP phenotype in human adipose tissue (232). Therefore, immune therapy could be a promising strategy for intervention in aging in the future.

The JAK/STAT pathway is of great importance in regulating cytokine production and has been investigated as a therapeutic target for many diseases (233–236). Studies have found that the JAK pathway is more highly activated in fat tissue from old than young animals and senescent than nonsenescent cells, and 2 months of administration of ruxolitinib, a specific JAK1/2 inhibitor, reduced systemic inflammation, enhanced physical capacity, preserved fat tissue homeostasis, and improved metabolic function in 22– to 24-month-old mice (237, 238).

As we previously discussed, the p38MAPK pathway also plays a vital role in adipose tissue inflammaging. Studies have proven that the l-arginine-metabolizing enzyme arginase-II (Arg-II) promotes IL-6 production in aging adipose tissues through the p38MAPK pathway. There is more macrophage accumulation in visceral adipose tissues in old WT mice than Arg-II knockout mice. The treatment of aging adipose tissues in WT mice with the specific p38mapk inhibitor SB203580 reduces IL-6 secretion, suggesting that targeting Arg-II or inhibiting p38mapk could be beneficial in reducing age-associated adipose tissue inflammation (239).

In addition, studies have shown that Rolipram is a selective phosphodiesterase 4 (PDE4) inhibitor that activates the AMPK-SIRT6 pathway to reduce adipose deposition and inflammation in aged mice, suggesting that targeting the AMPK-SIRT6 pathway and selective PDE4 inhibitors may be useful agents for the treatment of age-related metabolic dysfunction and diseases (240).

In summary, adipose tissue aging is of great value for studying the basic mechanisms of aging and is an effective therapeutic target for developing new strategies to combat aging and age-related disease ( Table 3 ).