Adipose Tissue Aging and Natural Interventions: Potential Roles of Polyphenols and Polysaccharides

Adipose tissue is a metabolically active endocrine organ composed primarily of white adipose tissue (WAT) and brown adipose tissue (BAT). WAT functions not only as the major energy storage depot through triglyceride accumulation and mobilization but also as an endocrine organ that secretes adipokines such as leptin, adiponectin, and resistin, thereby participating in the regulation of systemic metabolic homeostasis [40]. Based on anatomical location, WAT is further classified into visceral adipose tissue (VAT) and subcutaneous adipose tissue (sWAT), which exhibit distinct structural characteristics, metabolic properties, and aging-associated alterations [41]. During aging, VAT becomes increasingly susceptible to inflammatory cell infiltration, excessive lipolysis, and reduced insulin sensitivity, resulting in heightened secretion of pro-inflammatory cytokines and the accumulation of lipotoxic intermediates. These changes significantly increase the risk of insulin resistance, type 2 diabetes, and cardiovascular disease [40,42]. In contrast, sWAT, which exhibits higher insulin sensitivity and stronger metabolic protective capacity in youth, gradually loses its ability for healthy expansion with age due to impaired preadipocyte differentiation, increased fibrosis, and reduced lipid-buffering capacity. These alterations promote ectopic lipid deposition and systemic metabolic dysregulation [43]. Therefore, VAT and sWAT contribute to metabolic dysfunction through distinct mechanisms: VAT via excessive inflammatory activation and lipotoxicity, and sWAT via reduced metabolic flexibility and protective buffering capacity, collectively exacerbating systemic metabolic instability during aging.

BAT, in contrast to WAT, specializes in non-shivering thermogenesis through uncoupling protein 1 (UCP1)-mediated mitochondrial respiratory uncoupling, thereby maintaining body temperature and promoting energy expenditure [40,44]. However, aging leads to a marked decline in BAT activity, mass, and UCP1 expression, accompanied by mitochondrial dysfunction and impaired thermogenic capacity [45]. Additionally, the secretion and bioactivity of batokines, such as FGF21, 12,13-diHOME, and exosomal non-coding RNAs, progressively decrease with age, reducing BAT’s ability to regulate glucose homeostasis, lipid metabolism, and insulin sensitivity [45,46]. Structural aging of BAT also involves decreased vascularization and diminished sympathetic innervation, further limiting its thermogenic responsiveness and metabolic protective capacity [47]. Consequently, BAT aging plays a pivotal role in the progressive decline of systemic energy expenditure and metabolic homeostasis.

Adipose tissue aging is fundamentally characterized by three interrelated pathological hallmarks: oxidative stress, chronic low-grade inflammation, and dysregulated lipid metabolism. Rather than acting independently, these processes are tightly interconnected and collectively form a self-reinforcing degenerative cycle. Oxidative stress not only induces DNA damage but also promotes the secretion of senescence-associated secretory phenotype (SASP) factors, thereby initiating and amplifying inflammatory signaling cascades. The resulting inflammatory milieu further impairs metabolic regulatory pathways, aggravating adipocyte dysfunction, lipid accumulation, and insulin resistance. Meanwhile, excessive lipid deposition and lipotoxicity disrupt mitochondrial integrity and function, generating additional reactive oxygen species (ROS) and further intensifying oxidative stress [48,49]. This reciprocal interplay forms a pathogenic loop that progressively accelerates adipose tissue senescence and systemic metabolic deterioration.

Notably, experimental evidence—such as the observation that antioxidant interventions can simultaneously attenuate inflammation and improve lipid metabolism—supports the existence of crosstalk among these pathways. However, the precise molecular connections, temporal sequence of their interactions, and depot-specific variations remain insufficiently understood. These unresolved questions highlight the need for integrative multi-omics approaches and targeted mechanistic studies to delineate the coordinated regulatory network underlying adipose tissue aging.

Adipose tissue is a central regulator of systemic metabolic homeostasis, and its age-related decline contributes to the onset and progression of various chronic diseases. The three core hallmarks of adipose tissue aging—oxidative stress, inflammaging, and dysregulated lipid metabolism—induce profound structural remodeling and functional impairment, which collectively drive metabolic, cardiovascular, neurodegenerative, and musculoskeletal disorders through endocrine, paracrine, and immunometabolic mechanisms [8,9]. The following sections outline the mechanistic contributions of aging adipose depots to major chronic disease categories.

The development of type 2 diabetes (T2D) is closely associated with adipose tissue aging, particularly the functional deterioration of VAT. Aging induces heightened lipolytic activity and attenuated catecholamine responsiveness, leading to excessive release of free fatty acids (FFAs) into circulation. These FFAs accumulate ectopically in the liver and skeletal muscle, where they impair insulin signaling, contribute to mitochondrial dysfunction, and ultimately promote systemic insulin resistance (IR) [73]. Moreover, elevated FFAs enhance hepatic gluconeogenesis and VLDL synthesis, reinforcing a metabolic cycle that links hyperglycemia with lipid dyshomeostasis—an effect consistent with the concepts of lipotoxicity and the dual-cycle hypothesis [74]. Over time, these interactions impair pancreatic β-cell function, reduce insulin secretion, and perpetuate glucose intolerance, thereby accelerating the onset and progression of T2D.

Similarly, aging of cardiac and perivascular adipose tissue plays a direct role in cardiovascular decline. Epicardial adipose tissue (EpAT), a subtype of WAT, exhibits intensified oxidative stress and secretes higher levels of pro-inflammatory adipokines such as leptin and resistin. These mediators interfere with calcium handling and electrical conduction in cardiomyocytes, increasing vulnerability to cardiac arrhythmias [75]. Meanwhile, senescent perivascular adipose tissue (PVAT) loses its vasoprotective, anti-inflammatory phenotype, shifting toward a pro-oxidative state. This change disrupts the nitric oxide (NO)/endothelin-1 (ET-1) balance, impairs endothelial relaxation, and contributes to vascular stiffening, hypertension, and atherosclerosis [76,77]

In the central nervous system, aging adipose tissue contributes to neurodegenerative pathology via inflammatory and metabolic signaling. Cytokines (e.g., TNF-α, IL-6) and adipokines (e.g., leptin, resistin) released from aging VAT can cross the blood–brain barrier and activate microglia, thereby inducing neuroinflammation, oxidative injury, amyloid-β (Aβ) deposition, and tau hyperphosphorylation—hallmark features of Alzheimer’s disease [78,79]. Similar immunometabolic signaling has been implicated in the loss of dopaminergic neurons in Parkinson’s disease, suggesting a shared inflammatory basis across neurodegenerative disorders [80].

Adipose tissue aging also indirectly contributes to osteoarthritis (OA) through adipokine-mediated disruption of joint homeostasis. Circulating leptin and resistin act on chondrocytes and synovial fibroblasts, inducing the expression of matrix metalloproteinases (MMPs) and local inflammatory mediators, which promote cartilage degradation, synovial inflammation, and OA progression [81].

Adipose tissue aging may also contribute to infertility through endocrine, inflammatory, and metabolic mechanisms. Adipose tissue regulates reproductive function by secreting adipokines such as leptin and adiponectin, which influence hypothalamic–pituitary–gonadal axis activity, ovarian steroidogenesis, follicular development, and endometrial receptivity [82]. During aging, adipose tissue senescence is accompanied by chronic low-grade inflammation, altered adipokine secretion, and systemic insulin resistance, all of which may disrupt reproductive hormone homeostasis and impair oocyte quality and ovulatory function [83]. In addition, senescence-associated inflammatory mediators may exacerbate ovarian aging and reduce reproductive capacity [84].

In summary, adipose tissue aging is not merely a localized degenerative process but a systemic pathogenic driver that, through amplified oxidative stress, chronic inflammation, and metabolic dysregulation, contributes to the development of T2D, cardiovascular disease, neurodegenerative disorders, osteoarthritis and infertility (Figure 1). From a clinical perspective, interventions targeting adipose tissue–specific aging mechanisms—such as restoring adipokine balance, enhancing antioxidant capacity, and suppressing inflammatory signaling—may offer promising strategies to delay systemic aging and prevent multiple chronic diseases, highlighting their potential in translational medicine.

Polyphenolic compounds are widely recognized for their strong antioxidant properties and have shown considerable potential in delaying adipose tissue aging. Their antioxidant actions can be broadly categorized into two mechanisms: direct chemical scavenging of ROS and activation of endogenous antioxidant defense systems by modulating key intracellular antioxidant signaling pathways. Rather than relying solely on redox chemical reactions, polyphenols exert more sustained and biologically relevant effects by modulating major antioxidant signaling pathways, particularly the Keap1–Nrf2 and SIRT1 signaling axes. The Keap1–Nrf2 pathway is a central regulatory system of oxidative stress resistance. Under oxidative stimulation or activation by polyphenols, Nrf2 dissociates from Keap1, translocates into the nucleus, and induces the transcription of antioxidant genes such as SOD, CAT, and HO-1, thereby enhancing cellular resilience to oxidative damage [96]. SIRT1, a key NAD⁺-dependent deacetylase, not only activates Nrf2 through deacetylation but also improves mitochondrial function, promotes mitophagy, and suppresses SASP-associated inflammation, thus helping maintain redox homeostasis at both cellular and tissue levels.

Representative polyphenolic compounds further illustrate these antioxidant effects in adipose tissue. For example, quercetin markedly increases the expression of SOD, CAT, and HO-1, reduces ROS and MDA accumulation, and attenuates senescence in both preadipocytes and mature adipocytes [96]. EGCG enhances antioxidant enzyme activity and improves mitochondrial biogenesis and function, thereby delaying adipose tissue degeneration [115]. Similarly, resveratrol facilitates ROS clearance and improves mitochondrial homeostasis, while curcumin promotes antioxidant enzyme activity and alleviates age-related oxidative damage in adipose tissue [104,110].

Although the antioxidant effects of polyphenols are largely attributed to these classical signaling pathways, their regulatory specificity, metabolic stability, and depot-selective actions across different adipose tissues remain insufficiently understood. The pleiotropic and multi-target nature of polyphenols indicates that their benefits are unlikely to arise from a single signaling cascade, but rather from coordinated modulation of multiple interconnected pathways [116]. Future studies should therefore incorporate multi-omics technologies, systems pharmacology, and molecular interaction profiling to systematically compare different polyphenols, identify critical network nodes (such as Nrf2, AMPK, and SIRT1), and elucidate their synergistic mechanisms in regulating adipose tissue redox homeostasis. These insights will be essential for developing polyphenol-based therapeutic strategies targeting oxidative stress in adipose tissue aging.

Polyphenolic compounds exert anti-inflammatory effects through their phenolic hydroxyl groups, which can form hydrogen bonds or π–π interactions with key sites of inflammatory signaling molecules, thereby interfering with the activity and binding processes of inflammation-related enzymes and receptors [117]. At the molecular level, these compounds attenuate proinflammatory signaling primarily by inhibiting NF-κB, MAPK, and JAK/STAT pathways, reducing the transcription and secretion of TNF-α, IL-1β, and IL-6 [118]. NF-κB is particularly important in inflammaging due to its dual role in regulating both inflammatory responses and cellular senescence. Under basal conditions, NF-κB remains inactive in the cytoplasm through binding to IκBα. Upon exposure to inflammatory or aging-related stimuli, IκBα undergoes phosphorylation and proteasomal degradation, enabling NF-κB nuclear translocation and transcriptional activation of a wide range of proinflammatory genes, including SASP factors [119,120]. Polyphenols such as curcumin and resveratrol inhibit this process by suppressing IκBα degradation, blocking NF-κB nuclear translocation, and downregulating TNF-α, IL-6, and IL-1β expression, thereby alleviating adipose tissue inflammation and cellular senescence [106,112]. Anthocyanins have also been shown to reduce adipocyte inflammation by inhibiting NF-κB signaling and reduce IL-6 expression, while improving insulin sensitivity through enhanced PI3K/Akt activation and GLUT-1 expression [113]. Quercetin has also been shown to improve adipose tissue structure, reduce adipocyte hypertrophy, and decrease the expression of proinflammatory factors such as Cd11b and Cd68 in mice fed a high-fat diet, thereby exerting tissue-specific anti-inflammatory effects [98].

Accumulating evidence confirms that polyphenols such as curcumin [121,122], RES [123,124], anthocyanins [125], and quercetin [96] not only suppress adipose tissue inflammation but also exert broader anti-aging effects in liver, brain, and skeletal muscle, supporting their regulatory role in systemic inflammaging. However, current studies predominantly focus on classical inflammatory pathways, particularly NF-κB, and often overlook broader signaling network interactions, immune cell–adipocyte crosstalk, and depot-specific regulatory differences. Moreover, inflammaging is driven by self-amplifying feedback loops involving immune cell recruitment, SASP propagation, and adipocyte–macrophage interactions, suggesting that targeting a single mediator may be insufficient to disrupt the inflammatory cascade. Future research should therefore focus on identifying key inflammatory amplification nodes, particularly the crosstalk between senescent adipocytes and immune cells, and elucidating how specific polyphenols modulate these networks in a depot- and cell-type–selective manner. Such mechanistic insights will be essential for designing precise, multi-target intervention strategies to mitigate adipose inflammaging.

Age-related adipose tissue dysfunction is characterized by impaired lipolysis, excessive lipid accumulation, reduced fatty acid oxidation, and diminished thermogenic capacity, collectively contributing to insulin resistance and metabolic deterioration [108]. Polyphenolic compounds modulate these pathological alterations through multi-target regulation of lipid metabolism, adipogenic transcription networks, thermogenic signaling, and adipokine secretion.

A major mechanism involves the suppression of adipogenesis and lipid storage. Resveratrol inhibits lipid accumulation and differentiation of 3T3-L1 preadipocytes via AMPK activation, leading to the downregulation of lipogenic regulators such as FAS, SREBP-1c, and PPARγ [107,108]. Similarly, EGCG reduces adipocyte differentiation by inhibiting PPARγ and C/EBPα transcriptional activity and further alleviates lipid accumulation by modulating autophagy-related pathways [100,101,102,103]. These findings suggest that polyphenols reshape the transcriptional landscape of adipocytes, shifting their phenotype away from excessive lipid deposition

Polyphenols also promote lipolysis and enhance the browning and thermogenic conversion of white adipose tissue. Quercetin activates the β3-adrenergic receptor–PKA–AMPK–PGC1-α axis, upregulating UCP1 expression and facilitating the formation of beige adipocytes, which enhances energy expenditure and prevents age-associated adiposity [98,99]. EGCG similarly promotes beige adipocyte formation and improves mitochondrial thermogenic function, thereby counteracting age-related thermogenic decline [126,127].

In addition to metabolic reprogramming, polyphenols help restore endocrine function in aging adipose tissue. Resveratrol reduces leptin secretion while increasing adiponectin levels, thereby improving insulin sensitivity and supporting systemic metabolic homeostasis [114]. Chlorogenic acid enhances adiponectin sensitivity by activating the AMPK pathway, thereby promoting glucose uptake and fatty acid oxidation in skeletal muscle and contributing to the maintenance of metabolic balance [109].

In summary, polyphenols do not merely suppress adipogenesis but instead reprogram adipose tissue from an energy-storing to an energy-expending phenotype through coordinated regulation of AMPK, PPARγ, PGC1α, and UCP1. This multi-pathway modulation offers mechanistic support for their application in mitigating adipose tissue aging and preventing metabolic disorders such as obesity and type 2 diabetes. Future research should focus on identifying tissue-selective regulatory effects and structural determinants of different polyphenols to guide their precise pharmacological use.

Oxidative stress and mitochondrial dysfunction are fundamental drivers of adipose tissue aging, and natural polysaccharides mitigate these processes through multiple structural- and signaling-dependent mechanisms. Unlike polyphenols, polysaccharides do not rely on phenolic hydroxyl groups; instead, their antioxidant activities are largely influenced by molecular characteristics such as spatial conformation, molecular weight, degree of branching, and monosaccharide composition. These properties allow polysaccharides to interact with reactive species and transition-metal ions, thereby modulating redox balance at both chemical and cellular levels. Several polysaccharides derived from fungi and plants have demonstrated the ability to directly scavenge superoxide and hydroxyl radicals, stabilize mitochondrial membrane potential, and suppress lipid peroxidation, ultimately preserving mitochondrial integrity and redox homeostasis [128,145,146]. For instance, sulfated fucoidan derivatives chelate Fe²⁺ and Cu²⁺ ions, thereby suppressing hydroxyl radical formation via inhibition of the Fenton reaction and reducing mitochondrial oxidative injury [128]. Similarly, low-methylated pectate forms metal-coordination complexes through its sugar–aldehyde structures, significantly inhibiting lipid peroxidation and protecting mitochondrial function [129]. In addition to direct redox modulation, polysaccharides enhance endogenous antioxidant capacity through activation of the Keap1–Nrf2 signaling pathway. GLP activates the Nrf2/HO-1 axis, increases SOD and GSH-Px expression, and reduces malondialdehyde (MDA) accumulation [130]. PBRP effectively separates Nrf2 from Keap1, enhancing the activity of antioxidant enzymes such as HO-1, SOD, GSH-Px, and CAT. Additionally, these polysaccharides reduce MDA production by activating the Keap1/Nrf2/HO-1 signaling pathway, demonstrating anti-aging effects [35,132]. The acidic polysaccharide ABM-A from Agaricus blazei regulates both Keap1–Nrf2/ARE and MAPK pathways, reducing ROS and lipid peroxidation product MDA levels while enhancing antioxidant enzyme activity, thereby exhibiting significant anti-aging effects in D-galactose–induced aging models [133].

In summary, natural polysaccharides attenuate oxidative stress in adipose tissue through three complementary mechanisms: direct free radical scavenging, metal chelation to inhibit Fenton-driven ROS formation, and activation of endogenous antioxidant signaling pathways—particularly the Keap1–Nrf2/HO-1 axis. The consistent involvement of Nrf2 activation across multiple models suggests that Nrf2 and its downstream effectors may serve as key mechanistic biomarkers for evaluating the anti-aging efficacy of polysaccharides.

Chronic low-grade inflammation driven by SASP factors is a major hallmark of adipose tissue aging and a critical contributor to inflammaging [31,147]. Natural polysaccharides mitigate this process not merely through direct cytokine suppression, but through structure-dependent immunomodulation. Their biological activities are closely associated with molecular weight, monosaccharide composition, sulfation or acetylation levels, and glycosidic bond complexity, which together determine their binding affinity to pattern recognition receptors (PRRs) such as TLR2/4, Dectin-1, and the mannose receptor (MR). These interactions enable polysaccharides to modulate immune–adipocyte crosstalk, influence macrophage polarization, and reshape the adipose immune microenvironment [148,149,150].

At the signaling level, polysaccharides modulate major inflammatory pathways, including TLR4/NF-κB, AMPK/mTOR, SIRT1/NF-κB, and Nrf2/HO-1, thereby downregulating pro-inflammatory mediators (TNF-α, IL-6, IL-1β) and upregulating anti-inflammatory factors (IL-10 and adiponectin). In HFD-induced adipose inflammation, fucoidan markedly reduces TNF-α, IL-1β, and IL-6 expression, suppresses macrophage infiltration (Cd68, Emr1), while enhancing Adipoq and IL-10, indicative of restored adipose tissue homeostasis [134]. Similarly, LYTP inhibits the M1 marker Cd11c and promotes M2 markers Arg1 and Cd206, facilitating immune microenvironment remodeling toward an anti-inflammatory phenotype [136]. HSP further attenuates adipose tissue inflammation by reducing macrophage activation and indirectly modifying gut microbiota composition, including an increase in Parabacteroides goldsteinii [138]. Beyond adipose tissue, polysaccharides also demonstrate systemic anti-inflammatory and anti-aging effects via shared signaling pathways. LBP attenuates hippocampal TNF-α and IL-6 by inhibiting TLR4/NF-κB signaling in OVX-induced aging models, improving neurological function [139]. AMP co-activates AMPK/SIRT1/NF-κB and Nrf2/HO-1 pathways, reducing ROS accumulation and inflammatory stress during brain aging [144]. Moreover, Astragalus polysaccharides activate AMPK/mTOR-mediated autophagy, thereby reversing hepatic and adipose aging phenotypes in naturally aged mice [141,142].

Overall, natural polysaccharides alleviate adipose inflammaging not only through inhibition of inflammatory mediators but also by reprogramming the adipose immune–metabolic microenvironment through macrophage polarization, PRR-mediated signaling modulation, gut microbiota interactions, and autophagy regulation. These findings highlight the unique advantage of polysaccharides in coordinating multi-layered inflammatory regulation through both immunological and metabolic pathways. Future studies should focus on elucidating structure–activity relationships and identifying key receptor-mediated signaling hubs to support the precise application of polysaccharides in delaying adipose tissue aging and preventing chronic metabolic diseases.

Age-related adipose dysfunction is closely associated with disturbances in lipid metabolic networks, including enhanced lipogenesis, impaired lipolysis, reduced fatty acid oxidation, and ectopic lipid deposition in non-adipose organs such as the liver. These metabolic abnormalities accelerate insulin resistance, chronic inflammation, and structural degeneration of adipose tissue [131]. Accumulating studies indicate that polysaccharides regulate lipid metabolism through coordinated actions on adipogenesis, lipid catabolism, and mitochondrial fatty acid oxidation.

At the transcriptional level, they inhibit adipogenic programs by downregulating core lipogenic regulators. In 3T3-L1 adipocytes, LBP markedly reduces the expression of PPARγ, C/EBPα, FAS, and LPL, thereby suppressing lipid droplet accumulation and early adipocyte differentiation [140]. In vivo, fucoidan decreases SREBP-1c and FASN expression in HFD-fed mice, alleviating adipocyte hypertrophy and lipid deposition [135]. Polysaccharides from Ganoderma lucidum spores similarly suppress SREBP-1c and FASN expression in MAFLD models, reducing hepatic lipid load and improving systemic metabolic parameters [144]. In parallel with the inhibition of lipogenesis, polysaccharides enhance cellular energy metabolism by activating AMPK-centered signaling pathways. AMPK functions as a metabolic sensor that suppresses ACC activity, relieves inhibition of CPT1, and promotes mitochondrial fatty acid β-oxidation. Its activation also upregulates PGC-1α and PPARα, further strengthening oxidative catabolism. GLP significantly increases AMPK phosphorylation in HFD mice, accompanied by enhanced ACC phosphorylation, reduced lipid synthesis, and improved hepatic and adipose lipid profiles, ultimately ameliorating insulin resistance [131]. Similarly, LYTP activates AMPK and induces the expression of fatty acid oxidation–related genes, thereby reversing hepatic lipid accumulation and metabolic abnormalities in db/db mice [137].

In summary, natural polysaccharides modulate lipid metabolism through multilayered regulatory actions that include suppressing adipogenic transcriptional programs, inhibiting lipid synthesis, activating the AMPK metabolic hub, and promoting fatty acid oxidation. This combined suppression at the source and enhancement of catabolism framework provides an integrated approach for alleviating lipid metabolic dysfunction in aging adipose tissue. These mechanistic insights underscore the therapeutic relevance of polysaccharides in restoring adipose metabolic resilience and mitigating age-related metabolic disorders.