Adipose tissue aging as a risk factor for metabolic organ abnormalities: mechanistic insights and the role of exercise interventions

Abstract

Aging is widely regarded as an irreversible arrest of cellular growth and proliferation, often accompanied by systemic metabolic organ abnormalities, ultimately reducing quality of life and increasing mortality in the elderly. Multi-organ transcriptomic analyses suggest that adipose tissue is among the earliest organs to respond to aging, characterized by changes in fat content and redistribution of adipose tissue, decline in thermogenic adipose function, reduced proliferation and differentiation capacity of adipose progenitor and stem cells, accumulation of senescent cells, and immunosenescence. These alterations may act synergistically and play a role in abnormalities in metabolic organs including the cardiovascular, liver, skeletal muscle, and brain. Studies have demonstrated that exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities by inhibiting inflammation, reducing the accumulation of ectopic lipids, enhancing the browning of white adipose tissue and thermogenesis in brown adipose tissue, improving lipid metabolism, regulating the secretion of adipokines, and mitigating immunosenescence. This review summarizes the main characteristics of adipose tissue aging, the effects of adipose tissue aging on metabolic organ abnormalities, and the potential mechanisms by which exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities. It provides theoretical support for basic and clinical research on exercise-based prevention and treatment of aging-related diseases.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12944-025-02695-3.

Introduction

With life expectancy continuously rising, population aging has become a critical global issue. According to the United Nations’ World Population Prospects 2024, the proportion of individuals aged 65 and older has increased from 6.00% in 1990 to 10.34% in 2024, and is projected to reach 16.00% by 2050. By the middle of the 21 st century, nearly one-sixth of the global population will be aged 65 or older [1]. The aging population highlights the universal and widespread nature of individual aging, and the associated challenges have become a central social concern [2]. Multi-organ transcriptomic analyses reveal that adipose tissue is among the most vulnerable tissues during aging, with age-associated immune responses initially observed in white adipose tissue (WAT) in both mice and humans [3]. Recent studies confirm that adipose tissue is among the earliest organs to respond to aging and acts as a critical driver of systemic aging [4]. Adipose tissue aging is characterized by a series of hallmark changes, including redistribution of adipose tissue, reduction of brown adipose tissue (BAT) and beige adipocytes, decline in the function of adipose progenitor and stem cells (APSCs), accumulation of senescent cells, and immune dysfunction [5]. Notably, the hallmark changes of adipose tissue aging are interconnected and may synergistically play a role in abnormalities in metabolic organs, including the cardiovascular, liver, skeletal muscle, and brain [6, 7]. It has been confirmed that expression levels of inositol hexakisphosphate kinase 1 (IP6K1), CD11c, tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), protein kinase B (Akt), and AMP-activated protein kinase (AMPK) are significantly upregulated in visceral adipose tissue (VAT) and liver of aged mice, accompanied by downregulation of uncoupling protein 1 (UCP1) expression in subcutaneous adipose tissue (SAT), which leads to increased VAT mass, reduced thermogenic function, macrophage polarization toward the pro-inflammatory M1 phenotype, and metabolic disorders in the liver that trigger liver injury [8]. It has been suggested that adipose tissue aging may be an important risk factor for metabolic organ abnormalities. Several studies have demonstrated that exercise intervention, as an important complement to pharmacological therapy, can ameliorate the effects of adipose tissue aging on metabolic organ abnormalities. Sixteen weeks of aerobic exercise markedly downregulated the expression of P53, P21, IL-6, plasminogen activator inhibitor-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1) in the VAT of aged mice fed a high-fat diet. This intervention attenuated VAT cellular senescence and inflammation, reduced body weight and VAT mass, mitigated adipocyte hypertrophy and insulin resistance, improved cardiac ejection fraction, reduced pathological cardiac hypertrophy, and alleviated hepatic triacylglycerol (TAG) accumulation and fatty liver [9]. However, the underlying mechanisms remain to be fully elucidated. Based on this, this review summarizes the main characteristics of adipose tissue aging, the effects of adipose tissue aging on metabolic organ abnormalities, and the potential mechanisms by which exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities. It provides theoretical support for basic and clinical research on exercise-based prevention and treatment of aging-related diseases.

Main characteristics of adipose tissue aging

Adipose tissue is a highly dynamic organ endowed with extensive endocrine and metabolic regulatory functions, whose structure and function are continually modulated in response to environmental changes and organismal status [10]. However, with aging, the dynamic regulatory capacity of adipose tissue progressively declines, characterized by significant quantitative, structural, and functional changes, leading to negative effects including dysregulation of adipocyte lipid storage and catabolism, abnormal signaling communication, and decreased thermogenesis (Fig. 1) [11]. It has been found that adipose tissue may be one of the earliest organs to respond to aging and serves as a central factor driving organismal aging and the development of age-related diseases [4].

Fig. 1.

Main characteristics of adipose tissue aging. APSC, adipose progenitor and stem cell; SASP, senescence-associated secretory phenotype

Changes in fat content and redistribution of adipose tissue

Throughout aging, significant alterations occur in both total fat content and adipose tissue distribution. Body composition assessments indicate that total body fat content may begin to accumulate during middle age in both healthy and unhealthy older adults [12]. The gradual decline in overall fat content observed in older adults during aging may be closely associated with their health status [13]. Studies have shown that the volume of suborbital fat is higher in individuals aged 50 years and older, while fat density is significantly lower than in those aged 18–29 years [14]. Fat volume refers to the total volume occupied by adipose tissue in the body [15], and increased fat volume is strongly associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease [16]. Fat density is typically defined as the radiographic attenuation value of adipose tissue measured by imaging, reflecting the integrated characteristics of its lipid and water content, cellular density, and blood perfusion [17]. Lower fat density is typically associated with diminished mitochondrial activity, reduced blood perfusion, and elevated inflammatory markers, indicating impaired metabolic function of adipose tissue [18]. Another body composition change involves the redistribution of adipose tissue to different fat depots, characterized by increased VAT and decreased SAT [19, 20]. Studies have confirmed that VAT accumulation is closely associated with atherosclerosis, type 2 diabetes mellitus, obesity, sleep deprivation, hypertension, insulin resistance, and glucose metabolism disorders and even leads to a shortened life expectancy, suggesting that abnormal VAT accumulation may be a key driver in the pathological progression of various metabolic diseases [21–24]. The probable mechanism involves VAT promoting the upregulation of β-adrenergic receptor (β-AR) expression and downregulation of α-AR expression, thereby enhancing lipoprotein hydrolysis and increasing serum free fatty acid (FFA) levels [25]. Notably, although VAT tends to increase during normal aging, both VAT and SAT decline at very advanced ages (e.g., 80 years and older), indicating that changes in adipose tissue distribution with age are nonlinear, characterized by a general decline beyond a certain age [26]. Additionally, abundant inflammatory cytokines secreted by VAT enter the portal vein via venous return, exposing the liver to elevated FFA and TAG, which reduces hepatic insulin sensitivity [25]. Another study confirmed that increased SAT mass confers metaboloprotective effects and is inversely associated with glucose intolerance, insulin resistance, and type 2 diabetes [27, 28]. SAT serves as the primary fat storage depot, efficiently buffering excess energy and preventing the accumulation of FFA in the bloodstream [29]. Under normal physiological conditions, SAT exhibits low levels of pro-inflammatory cytokines and secretes elevated levels of adiponectin (APN), thereby enhancing insulin sensitivity and glucose metabolism [30]. However, age-related changes impair SAT function and reduce its plasticity, promoting the redistribution of excess lipids to other fat depots, triggering excessive inflammatory cytokine release, and exacerbating lipotoxicity, insulin resistance, and metabolic disorders [31]. Compared to VAT, SAT displays shorter baseline telomere length, which induces premature aging of SAT cells, resulting in impaired lipid storage and synthesis capacity and accelerating the progression of age-related metabolic syndrome [32, 33]. Therefore, age-related aging can drive changes in fat content and redistribution of adipose tissue, exacerbating dysregulation of metabolic homeostasis.

Decline in thermogenic adipose function

Thermogenic adipose tissue exhibits a distinct cellular structure and function, directly converting chemical energy into heat without producing adenosine triphosphate (ATP), thereby dissipating excess energy via non-shivering thermogenesis [34]. BAT and beige adipose tissue constitute the primary types of thermogenic adipose tissue, and upregulation of UCP1 expression promotes energy expenditure, thereby counteracting glycolipid metabolism disorders and obesity development [34, 35]. Meanwhile, peroxisome proliferator activated receptor γ (PPARγ) secreted by BAT maintains metabolic homeostasis in adipose tissue by promoting adipocyte differentiation, enhancing insulin sensitivity, suppressing pro-inflammatory cytokine expression, and improving glucolipid metabolism [36, 37]. In contrast, unlike the readily inducible browning of WAT in mice, human WAT demonstrates a relatively limited browning capacity, and the recruitment and activation of brown and beige adipocytes remain contentious in clinical studies [38]. With age-related aging, the number, volume and activity of BAT and beige adipocytes in aged mice decreased, UCP1 expression is down-regulated, and the capacity for adipose tissue browning in response to cold exposure or β3-AR activation is diminished, resulting in impaired energy expenditure and reduced clearance of the energy substrates glucose and FFA, which leads to abnormalities in thermogenesis, thermoregulation and energy metabolism [39–41]. Animal studies have confirmed that the age-related decline in thermogenic adipose function may involve multiple underlying mechanisms [42]. In aged mice, elevated H₂O₂ levels in BAT markedly activate the integrated stress response (ISR), leading to phosphorylation of eukaryotic initiation factor 2α (eIF2α), increased expression of activating transcription factor 4 (ATF4), and suppression of UCP1 expression, ultimately resulting in lipid accumulation, impaired thermogenic function of BAT, and reduced cold tolerance, indicating that ISR activation by oxidative stress may be a pivotal mechanism underlying thermogenic dysfunction during adipose tissue aging [43]. In aged mice, elevated expression of Parkin and fibroblast growth factor 21 (FGF21), together with reduced levels of UCP1 and peroxisome proliferators-activated receptors gamma co-activator 1α (PGC-1α) and increased expression of C-C motif chemokine ligand 2 (CCL2) and nitric oxide synthase 2 (NOS2) in SAT, indicates that aging diminishes energy expenditure, promotes inflammatory responses, and compromises the browning capacity of WAT [44]. In prematurely aging mice, BAT shows decreased expression of UCP1, PGC-1α, silent information regulator 1 (SIRT1), superoxide dismutase 1 (SOD1), optic atrophy 1 (OPA1), and mitochondrial transcription factor A (TFAM), accompanied by elevated levels of IL-1β, IL-6, matrix metalloproteinase 3 (MMP-3), and reactive oxygen species (ROS), indicating that impaired mitochondrial biogenesis, oxidative stress, and chronic inflammation collectively contribute to reduced thermogenic capacity in BAT [45]. Moreover, aging induces the accumulation of mitochondrial DNA mutations in thermogenic adipose tissue, which impairs mitochondrial function, promotes the excessive release of pro-inflammatory cytokines, compromises oxidative clearance, and diminishes sympathetic nerve activity, thereby disrupting thermogenic adipose function [42, 46]. Therefore, the age-related decline in thermogenic adipose function may contribute to elevated metabolic health risks.

Decreased proliferation and differentiation of APSCs

APSCs, a pivotal component of the stromal vascular fraction (SVF) in adipose tissue, possess robust differentiation and proliferation capacities, contribute to tissue renewal and functional regulation, and are closely associated with adipose tissue plasticity [5, 47]. Adipose plasticity denotes the capacity of adipose tissue to remodel structurally and modulate functionally in response to various physiological or pathological stimuli, such as aging, overnutrition, or cold exposure [48]. APSCs are pivotal regulators of adipose plasticity, mediating structural and functional adaptations of adipose tissue through sensing external cues and activating specific transcriptional programs [48]. However, aging leads to a decline in APSC number and progressive exhaustion, which is manifested by a gradual reduction in their proliferative and differentiation capacities [49]. Studies have shown that aging-related declines in APSC proliferation and differentiation are closely associated with macrophage-secreted transforming growth factor beta 1 (TGF-β1), which significantly upregulates P16 and P21 expression while downregulating PPARγ, CCAAT/enhancer binding proteins α (C/EBPα), and fatty acid binding protein 4 (FABP4) in APSCs from aged mice, leading to DNA damage and mitochondrial ROS accumulation and thereby inhibiting APSC proliferation and differentiation [50]. Concomitantly, telomere shortening and DNA damage may act as critical triggers impairing the differentiation capacity of aged ASPCs [51], as telomere attrition has been demonstrated to induce adipocyte hypertrophy and insulin resistance in the SAT of telomerase reverse transcriptase (TERT)-knockout mice, and is closely associated with aging, obesity, and diabetes [52]. In addition, PPARγ and C/EBPα, essential transcription factors governing lipidogenic differentiation of APSCs, exhibit an age-dependent decline in both activity and expression [53]. In senescent 3T3-L1 adipocytes, PPARγ and C/EBPα expression was significantly downregulated, accompanied by decreased expression of glucose transporter 4 (GLUT4), insulin receptor substrate-1 (IRS-1), and APN, whereas IL-6 and MCP-1 expression was markedly upregulated, collectively inhibiting adipocyte differentiation; furthermore, lipopolysaccharide (LPS) stimulation exacerbated the downregulation of PPARγ and C/EBPα, indicating that inflammatory signaling may accelerate senescence-associated adipocyte dysfunction [54]. Meanwhile, TNF-α expression was significantly increased in preadipocytes of aged rats, inducing elevated C/EBP homologous protein (CHOP) expression and promoting the formation of a CHOP-C/EBPα heterodimer, which subsequently inhibited preadipocyte differentiation [55]. Other studies have confirmed that aging-related dysfunction of APSCs limits adipose tissue plasticity [56, 57]. Decreased expression of C/EBPα and PPARγ alongside increased activities of cysteine-aspartic acid protease 3 (Caspase-3) and Bcl-2-associated X (BAX) in FA-treated APSCs from aged rats resulted in reduced APSC differentiation capacity and facilitated the release of excess FFA to nonadipose tissues for ectopic accumulation, thereby exacerbating lipotoxicity [58]. Expression of IL-1β, microRNA-203b-5p (miR-203b-5p), Caspase-3 and inositol-requiring enzyme 1 (IRE-1) was upregulated in APSCs isolated subcutaneously from aged horses, while mitofusion 1 (MFN1), C-X-C chemokine receptor type 4 (CXCR4) and octamer transcription factor 3/4 (Oct 3/4) expression was downregulated and senescence-associated β-galactosidase (SA β-gal) activity was increased, leading to a senescent phenotype characterized by chronic inflammation, apoptosis, mitochondrial dysfunction, DNA structural changes, endoplasmic reticulum stress and insulin resistance, which collectively impair APSC proliferation and differentiation [59]. Therefore, aging progressively diminishes the proliferation and differentiation capacities of APSCs, resulting in impaired metabolic regulation and reduced plasticity of adipose tissue.

Accumulation of senescent cells

In mammals, adipose tissue represents a major reservoir of senescent cells during aging, containing diverse cell types such as mature adipocytes, progenitor cells, immune cells, and endothelial cells [60]. The accumulation of senescent cells is driven by factors such as replicative stress, chronic stimulation by pro-inflammatory cytokines, and metabolic dysregulation, all of which are marked by elevated expression of senescence-associated markers including SA β-gal, P53, P21, and P16 [61, 62]. Studies have demonstrated that the expression of SA β-gal, P16, and P21 is markedly upregulated in WAT and BAT of aged rats and mice, indicating widespread activation of cellular senescence in adipose tissue with advancing age [63, 64]. Meanwhile, senescent cells actively secrete various bioactive cytokines, a phenomenon known as senescence-associated secretory phenotype (SASP) [65]. SASP is considered one of the most critical hallmarks of cellular senescence, mainly consisting of soluble pro-inflammatory cytokines, soluble receptors, nitrogen monoxide (NO), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and extracellular matrix (ECM) macromolecules [65]. SASP secretion can cause excessive ROS production, cell death, loss of protein homeostasis, nutrient sensing dysregulation, mitochondrial dysfunction, insulin resistance, tissue remodeling, and infiltration of pro-inflammatory cytokines, thereby promoting a favorable environment for the onset and progression of age-related diseases [66]. Notably, SASP is not only expressed by senescent adipocytes but may also be present in other tissue cells affected by adipose tissue aging, such as hepatocytes and myocytes, facilitating inter-tissue crosstalk that exacerbates systemic metabolic dysregulation [67]. Although senescent cells serve as a tumor-suppressive defense mechanism, their accumulation in adipose tissue can trigger various pathological changes, including impaired adipogenesis, excessive inflammation, dysregulated adipokine secretion, adipocyte hypertrophy, and reduced differentiation capacity of APSCs [68]. Studies have confirmed that aged mice display increased numbers of SA β-gal-positive cells, T cells, and macrophages in gonadal WAT, accompanied by elevated expression of p16, p21, and forkhead box protein P3 (FOXP3), along with upregulation of MCP-1, TNF-α, and C-X-C motif chemokine ligand 2 (CXCL2), leading to increased VAT mass and decreased SAT mass [69]. This is likely attributed to senescent adipocytes persistently secreting SASP cytokines, which promote immune cell recruitment and sustain a pro-inflammatory microenvironment, thereby disrupting adipose tissue homeostasis [70]. Another study found that aged obese mice exhibit significantly increased SA β-gal activity, upregulated P53 and P16 expression, markedly shortened telomere length, and elevated expression of SASP and inflammatory markers in gonadal WAT, suggesting that the interaction between obesity and aging accelerates senescent cell accumulation in adipose tissue, enhances SASP secretion and inflammation activation, thereby inducing functional decline and metabolic dysregulation [71, 72]. Therefore, aging facilitates the persistent accumulation of senescent cells in adipose tissue, thereby disrupting systemic metabolic homeostasis.

Immunosenescence

Immunosenescence denotes the age-associated remodeling of the immune system, leading to immune dysfunction and chronic inflammation [73]. Studies showed that adipose tissue aging exacerbated immune dysfunction by reshaping the immune microenvironment, increasing the secretion of pro-inflammatory cytokines, and promoting aberrant immune cell infiltration, indicating that adipose tissue aging is a key contributor to immunosenescence [5]. Aged adipose tissue demonstrates extensive infiltration of various immune cells, including macrophages, B cells, T cells, dendritic cells, and eosinophils, which secrete diverse cytokines closely linked to adipose tissue dysfunction and heightened risk of metabolic dysregulation [74]. Studies have confirmed that aged mice exhibit accumulation of T cells, neutrophils, and macrophages in BAT, accompanied by significantly increased S100A8 expression, which suppresses RNA-binding motif protein 3 (RBM3) expression, upregulates P16 and P21, and downregulates UCP1 and PGC-1α expression, thereby impairing sympathetic innervation and thermogenic function, suggesting that adipose tissue aging disrupts immune homeostasis by inducing aberrant immune cell infiltration and chronic inflammation, thereby contributing to impaired thermogenesis and metabolic dysfunction [75]. In aged mice, the expression of the macrophage marker V-set and immunoglobulin domain containing 4 (VSIG4) is elevated in gonadal WAT and upregulated in an age-dependent manner, showing a strong correlation with the physiological frailty index (PFI) and cancer incidence, indicating that changes in the immune microenvironment caused by adipose tissue aging may contribute to macrophage phenotypic shifts, and that VSIG4 could serve as an immune marker of adipose tissue aging [76]. In aged female mice, the number of proinflammatory macrophages, B cells, and T cells increases in VAT, along with elevated leukotriene B4 receptor 1 (BLT1) expression in VAT macrophages [77]. In vitro experiments show that leukotriene B4 (LTB4) stimulation significantly upregulates BLT1 and IL-6 expression in LPS-induced bone marrow-derived macrophages from aged mice, while IL-4 treatment markedly reduces expression of the M2 macrophage marker CD206, suggesting that activation of the LTB4/BLT1 signaling pathway in aging adipose tissue may promote macrophage polarization toward a pro-inflammatory phenotype and aggravate disruptions in immune homeostasis [77]. Another study demonstrated that aged mice exhibit significantly impaired differentiation capacity of ASPCs, increased numbers of B and T cells, and a reduced proportion of eosinophils in VAT, which collectively lead to elevated serum glucose and insulin levels, enlarged adipocyte size, and increased fat accumulation, suggesting that changes in immune cell composition triggered by adipose tissue aging may exacerbate metabolic disturbances and promote adipocyte hypertrophy and fat accumulation [78]. Therefore, adipose tissue aging impairs systemic immune function by remodeling the immune microenvironment and promoting aberrant immune cell activation.

Effects of adipose tissue aging on metabolic organ abnormalities

Adipose tissue, as a vital endocrine, immune, and regenerative organ, plays a central role in maintaining energy homeostasis and regulating glucose and lipid metabolism, while interacting with other organs to orchestrate systemic metabolic regulation [79]. Notably, adipose tissue communicates with various tissues and organs through the secretion of a wide array of cytokines via autocrine, paracrine, and endocrine pathways, and can undergo functional alterations in response to external signals [80–87]. However, adipose tissue aging can induce a range of pathological alterations, including dysregulated lipid metabolism, lipotoxicity, chronic inflammation, fibrosis, insulin resistance, and immune dysfunction, thereby playing a role in abnormalities in metabolic organs [88, 89]. Numerous studies have confirmed that adipose tissue aging may be an important risk factor for metabolic organ abnormalities (Table 1), and delaying adipose tissue aging may represent a crucial strategy for alleviating metabolic organ abnormalities.

Table 1.

Effects of adipose tissue aging on metabolic organ abnormalities

Metabolic organ abnormalities	Adipose tissue aging–associated changes	Key marker protein expression	Pathological effects	Therapeutic strategies	Refs
Cardiovascular	Accumulation of senescent cells in VAT	P53, P21, P16, COX-2, NADPH, IL-6, TNF-α ↑ eNOS ↓	Promotes arterial dysfunction and endothelial injury, inducing hypertension	Surgical removal of VAT	[93]
	Fibrosis of VAT	OPN, TGF-β1, TGF-β2↑	Promotes myocardial fibrosis, reduces myocardial contraction and cardiac pumping capacity, impairing cardiac function	Surgical removal of VAT or knockdown of OPN expression	[94]
	Macrophage infiltration in VAT	Caspase-3/7, TNF-α, IL-1β, NLRP3, MCP-1, MIP1α, NOX2, Eotaxin, p16INK4a ↑ eNOS↓	Promotes endothelial dysfunction, increasing the risk of cardiovascular injury	—	[95]
	Macrophage infiltration in VAT	F4/80, TNF-α, IL-6, IL-1β, CCL2, CCL3, CXCL2 ↑	Promotes macrophage accumulation, leading to atherosclerotic lesions	Surgical removal of VAT	[96]
Liver	Increased VAT mass	ACC1, ChREBP, ACC2, PPARγ, FOXO1 ↑ LPL, p-Akt, p-mTOR, p-PRAS40 ↓	Promotes hepatic lipid accumulation and insulin resistance, exacerbating hepatic steatosis	Curcumin supplementation	[100]
	Increased VAT mass	AST, ALT ↑, UCP1 ↓	Promotes hepatic lipid accumulation and thermogenic dysfunction, exacerbating hepatic steatosis	BTS supplementation	[101]
	Increased VAT mass	FFA, Insulin, PEPCK, CRTC2, G-6-pase ↑ CAT, GSH-Px, PRKAA2 ↓	Promotes hepatic fat deposition and insulin resistance, aggravating liver injury	APH supplementation	[102]
	Inflammatory response and apoptosis in VAT	Caspase-3/7, TNF-α, F4/80, NOS2, ALT ↑	Promotes inflammatory response and apoptosis, induces hepatic fatty acid and TAG accumulation, exacerbating fatty liver injury	—	[103]
Skeletal Muscle	Intramuscular fat accumulation	PPARγ ↑ WISP1, BMP3B, Follistatin ↓	Promotes intramuscular fat accumulation, reducing muscle mass	Knockdown of GIPR expression	[106]
	Intramuscular fat accumulation	P16, Atrogin1, MuRF1, PAI-1, IL-1β ↑ Myh1/4, Myogenin ↓	Promotes intramuscular fat accumulation, exacerbating muscle atrophy	Surgical removal of intramuscular fat or knockdown of PAI-1 expression	[107]
	Inhibits myocyte proliferation and differentiation	miR-let-7d-3p ↑ HMGA2, CCNA1, CCNB1, CDK6, PAX3, NOTCH1 ↓	Inhibits proliferation and differentiation of muscle progenitor cells	Inhibits miR-let-7d-3p expression	[108]
	Inhibits myocyte proliferation and differentiation	MuRF1, MSTN ↑ MyHC-IIb ↓	Inhibits myocyte proliferation and differentiation, inducing muscle atrophy–like phenotype	—	[109]
Brain	Brain iron accumulation	IL-6, IL-27, MMP-3, Hepcidin, Ferritin ↑ FPN, NG2, MAG, CNPase ↓	Promotes chronic inflammation, iron accumulation, reduced oligodendrocyte precursor cell differentiation, and demyelination in the brain	Surgical removal of VAT	[112]
	Synaptic dysfunction in the brain	miR-87-3p↑ Circ_SXC, 5-HT1B, GABA-B-R1, NaCP60E ↓	Leads to abnormal synaptic signaling in neurons, promoting brain injury	—	[113]
	Increased VAT mass	IL-1β, IL-6, TNF-α, IBA-1, CD68 ↑ Claudin-5, Occludin ↓	Enhances neuroinflammation, promoting blood-brain barrier disruption	Surgical removal of VAT	[114]
	Reduced proliferation and differentiation capacity of APSCs	P53 ↑ p-Akt, p-AMPKα, SIRT1, PGC-1α, CTH, HO-1, Nrf-2, BDNF, TRKB ↓	Promotes neuronal death and oxidative stress, damaging prefrontal cortex integrity	Injection of young APSCs	[115]

Abbreviations: COX-2 cyclooxygenase-2, NADPH nicotinamide adenine dinucleotide phosphate, IL-6 interleukin 6, TNF-α tumor necrosis factor-α, eNOS endothelial nitric oxide synthase, VAT visceral adipose tissue, OPN osteopontin, TGF-β1 transforming growth factor beta 1, Caspase-3/7 cysteine-aspartic acid protease 3/7, NLRP3 Nod-like receptor protein 3, MCP-1 monocyte chemoattractant protein-1, MIP1α macrophage inflammatory protein-1α, NOX2 nicotinamide adenine dinucleotide phosphate oxidase 2, CCL2 C-C motif chemokine ligand 2, CXCL2 C-X-C motif chemokine ligand 2, ACC1 acetyl coenzyme A carboxylase 1, ChREBP carbohydrate response element binding protein, PPARγ peroxisome proliferator activated receptor γ, FOXO1 forkhead box protein O1, LPL lipoprotein lipase, Akt protein kinase B, p-mTOR phosphorylated-mammalian target of rapamycin, AST aspartate transaminase, ALT alanine transaminase, UCP1 uncoupling protein 1, BTS bofutsushosan, FFA free fatty acid, PEPCK phosphoenolpyruvate carboxykinase, CRTC2 CREB-regulated transcription coactivator 2, G-6-pase glucose-6-phosphatase, CAT catalase, GSH-Px glutathione S-transferase peroxidase, PRKAA2 protein kinase AMP-activated catalytic subunit alpha 2, NOS2 nitric oxide synthase 2, WISP1 WNT1-inducible signalling pathway protein 1, BMP3B bone morphogenetic protein 3B, GIPR gastric inhibitory polypeptide receptor, MuRF1 muscle ring finger protein 1, PAI-1 plasminogen activator inhibitor-1, Myh1/4 myosin heavy chain 1/4, miR microRNA, HMGA2 high mobility group A2, CCNA1 cyclin A1, CDK6 cyclin-dependent kinase 6, PAX3 paired box 3, NOTCH1 neurogenic locus notch homolog protein 1, MSTN Myostatin, MMP-3 matrix metalloproteinase 3, FPN ferroportin, NG2 neuron glial antigen 2, MAG myelin-associated glycoprotein, CNPase 2',3'-cyclic nucleotide 3'- phosphodiesterase, Circ circular RNA, 5-HT1B 5-Hydroxytryptamine (serotonin) receptor 1B, GABA-B-R1 metabotropic GABA-B receptor subtype 1, NaCP60E Na channel protein 60E, IBA-1 ionized calcium-binding adapter molecule 1, AMPKα AMP-activated protein kinase alpha subunit, SIRT1 silent information regulator 1, PGC-1α peroxisome proliferators-activated receptors gamma co-activator 1α, CTH cystathionine gamma-lyase, HO-1 heme oxygenase 1, Nrf-2 nuclear factor erythroid 2-related factor 2, BDNF brain-derived neurotrophic factor, TRKB tyrosine kinase B

Adipose tissue aging and cardiovascular abnormalities

The cardiovascular system, consisting of the heart and blood vessels, is responsible for transporting oxygen, delivering nutrients, and removing metabolic waste to maintain physiological homeostasis [90]. However, adipose tissue aging can lead to increased VAT mass and adipocyte hypertrophy, impaired thermogenic capacity, infiltration of proinflammatory cytokines, and mitochondrial dysfunction, subsequently aggravating cardiovascular abnormalities [91, 92]. Studies have confirmed that adipose tissue aging induces senescent cell accumulation in VAT and fibrosis, which exacerbate cardiovascular abnormalities [93, 94]. VAT mass was significantly increased in aged mice, with upregulated P53, P21, and P16 expression, elevated cyclooxygenase-2 (COX-2) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase levels, downregulated endothelial nitric oxide synthase (eNOS), and increased IL-6 and TNF-α, indicating that adipose tissue aging promotes VAT senescent cell accumulation, oxidative stress, inflammation, arterial dysfunction, endothelial damage, and hypertension. Removal of VAT significantly improved vascular function by inhibiting oxidative stress and inflammation, restoring vasodilation, and attenuating blood pressure elevation, suggesting that reducing VAT can alleviate aging-related cardiovascular injury [93]. In aged mice, osteopontin (OPN) expression was significantly elevated in plasma and VAT, alongside upregulated pro-fibrotic cytokines TGF-β1 and TGF-β2, promoting myocardial fibrosis, impairing myocardial contraction and cardiac pumping capacity, and ultimately compromising cardiac function. Surgical removal of VAT or knockdown of OPN significantly decreased plasma OPN and TGF-β1 levels, inhibited SMAD family member 3 (SMAD3) phosphorylation, reduced type I and III collagen deposition, and alleviated myocardial fibrosis in aged mice, suggesting that adipose tissue aging impairs cardiac function via activation of the OPN-TGF-β1-SMAD3 pathway [94]. Additional studies have confirmed that macrophage infiltration in VAT driven by adipose tissue aging contributes to cardiovascular injury [95, 96]. In periaortic VAT of aged obese mice, ROS levels surged alongside significant upregulation of Caspase-3/7, Nod-like receptor protein 3 (NLRP3), MCP-1, macrophage inflammatory protein-1α (MIP1α), nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), and Eotaxin expression, accompanied by downregulation of eNOS and increased p16^INK4a activity, collectively contributing to endothelial dysfunction and indicating that aging promotes macrophage infiltration, apoptosis, inflammation, oxidative stress in periaortic VAT, thereby increasing cardiovascular injury risk [95]. Upregulation of F4/80, IL-1β, CCL2, CCL3, and CXCL2 in VAT of aged mice resulted in macrophage infiltration and increased secretion of inflammatory mediators. Transplantation of VAT from aged mice into the right common carotid artery of low-density lipoprotein receptor (LDLR)^−/− young mice enlarged atherosclerotic plaques at the graft site and in the distal vascular bed, with increased macrophage accumulation and inflammatory mediator secretion in the distal vessels. Removal of macrophages from VAT alleviated atherosclerotic lesions, suggesting that immune abnormalities in adipose tissue aging promote atherogenesis [96]. In summary, adipose tissue aging promotes senescent cell accumulation in VAT, upregulates pro-fibrotic cytokines, oxidative stress, inflammatory responses, and macrophage infiltration, thereby exacerbating cardiovascular injury. However, most research has focused on VAT mass increase, with fewer studies investigating the molecular mechanisms by which aging of other adipose depots (SAT or BAT) contributes to cardiovascular abnormalities.

Adipose tissue aging and liver abnormalities

The liver is a multifunctional visceral organ that regulates nutrient metabolism, bile production, blood volume, endocrine activity, and lipid and cholesterol homeostasis [97]. However, aging adipose tissue promotes pro-inflammatory cytokine release, mitochondrial dysfunction, and ectopic lipid accumulation, thereby accelerating hepatic lipid droplet buildup and increasing susceptibility to fatty liver injury [98, 99]. Studies have confirmed that adipose tissue aging-induced increases in VAT mass promote fatty liver injury [100–102]. In aged female mice, increased VAT mass elevated hepatic TAG and cholesterol levels, resulting in hepatic lipid accumulation and aggravated insulin resistance. Curcumin supplementation significantly downregulated the expression of acetyl coenzyme A carboxylase 1 (ACC1), carbohydrate response element binding protein (ChREBP), ACC2, PPARγ, and FOXO1 in VAT, while upregulating lipoprotein lipase (LPL), p-Akt, phosphorylated-mammalian target of rapamycin (p-mTOR), and p-PRAS40, thereby reducing VAT mass and lowering hepatic TAG deposition and insulin resistance, suggesting that suppression of VAT expansion may prevent hepatic steatosis [100]. In aged mice, increased VAT mass and decreased mitochondrial UCP1 expression in BAT led to elevated serum levels of aspartate transaminase (AST) and alanine transaminase (ALT), promoted hepatic lipid droplet accumulation, and indicated that adipose tissue aging contributed to VAT expansion and thermogenic adipose dysfunction, thereby exacerbating hepatic steatosis. Bofutsushosan (BTS) extract significantly reduced VAT mass and enhanced mitochondrial UCP1 expression in BAT, thereby reducing hepatic lipid droplet accumulation in aged mice. Furthermore, BTS extract inhibited TAG accumulation in HepG2 hepatocytes treated with oleic acid–albumin or high glucose in vitro, thereby ameliorating hepatic steatosis [101]. In aged mice, VAT and liver mass were significantly increased, resulting in elevated plasma levels of FFA and insulin, downregulated expression of catalase (CAT), glutathione S-transferase peroxidase (GSH-Px), and protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) in the liver, and upregulated expression of phosphoenolpyruvate carboxykinase (PEPCK), CREB-regulated transcription coactivator 2 (CRTC2), and glucose-6-phosphatase (G6Pase), indicating that increased VAT mass promoted lipid accumulation and insulin resistance by modulating hepatic antioxidant enzymes and glucose metabolism pathways, thereby exacerbating liver injury. Supplementation with animal protein hydrolysate (APH) significantly reduced VAT mass in aged mice, inhibited adipocyte hypertrophy and fibrosis, and ameliorated liver injury [102]. Additional research has demonstrated that inflammation and apoptosis resulting from adipose tissue aging can promote the progression of steatohepatitis [103]. In aged mice, upregulated expression of Caspase-3/7, TNF-α, F4/80, and NOS2 in the liver and VAT, coupled with increased M1 macrophage infiltration and elevated serum ALT levels, suggests that aging enhances inflammation and apoptosis in the liver and adipose tissue, thereby promoting hepatic accumulation of FA and TAG, reducing insulin sensitivity, and aggravating fatty liver injury. In vitro experiments have confirmed that, upon stimulation with the FA agonist Jo2, primary hepatocytes from aged mice exhibit significantly higher numbers of dead cells compared to primary hepatocytes from young mice, suggesting that aging-related chronic inflammation and apoptosis in the liver and adipose tissue may contribute to the progression of fatty liver injury [103]. In summary, adipose tissue aging contributes to increased VAT mass, impaired thermogenic function of BAT, inflammation, immunosenescence, and apoptosis, thereby exacerbating fatty liver injury. However, current studies have primarily focused on the effects of adipose tissue aging on hepatic abnormalities, whereas aging-related changes in the liver and interactions with adipose tissue aging, resulting in synergistic damage, remain largely unexplored.

Adipose tissue aging and skeletal muscle abnormalities

Skeletal muscle, the largest endocrine organ in the body, comprises approximately 40% of total body mass and plays a crucial role in maintaining systemic metabolic homeostasis [104]. However, adipose tissue aging can induce intramuscular lipid accumulation, myocyte death, macrophage-mediated inflammation, muscle fiber type switching, alterations in muscle composition, and metabolic dysregulation in skeletal muscle, thereby promoting skeletal muscle abnormalities [105]. Research has confirmed that aging-induced ectopic fat accumulation contributes to skeletal muscle degeneration [106, 107]. In aged mice, intramuscular adipose tissue was markedly increased, accompanied by reduced tibialis anterior muscle fiber diameter, grip strength, and physical activity, indicating that intramuscular fat accumulation due to aging impairs muscle mass and function. By contrast, aged gastric inhibitory polypeptide receptor (GIPR)^−/− mice exhibited significantly reduced WAT and intramuscular fat, along with improved muscle mass and performance. In vitro experiments confirmed that GIP treatment upregulated PPARγ expression in tibialis anterior fibro-adipogenic progenitor cells, promoted intramuscular adipogenesis, and significantly suppressed the expression of WNT1-inducible signalling pathway protein 1 (WISP1), bone morphogenetic protein 3B (BMP3B), and Follistatin. However, GIP failed to induce adipogenesis in GIPR^−/− fibro-adipogenic progenitor cells, highlighting the essential role of GIPR in intramuscular fat accumulation and suggesting that GIPR inhibition may promote muscle regeneration [106]. Aged mice exhibit significantly increased intramuscular adipose tissue, accompanied by reduced expression of myosin heavy chain 1/4 (Myh1/4) and Myogenin, together with elevated levels of P16, atrophy-related gene 1 (Atrogin1), muscle ring finger protein 1 (MuRF1), PAI-1, and IL-1β in skeletal muscle, indicating that intramuscular fat accumulation promotes muscle atrophy possibly by impairing muscle differentiation, enhancing cellular senescence, and exacerbating local inflammation, whereas removal of intramuscular fat alleviates muscle atrophy in aged mice. Cellular experiments demonstrated that PAI-1 upregulated the expression of Atrogin1, MuRF1, P21, and FOXO1 in dexamethasone (Dex)-treated C2C12 myoblasts, thereby promoting muscle cell atrophy, suggesting that PAI-1 is a key inducer of muscle atrophy and that inhibition of PAI-1 may improve aging-related muscle atrophy [107]. Other studies have confirmed that aging of adipose tissue inhibits myocyte proliferation and differentiation [108, 109]. Exosomal miR-let-7d-3p derived from intramuscular adipose tissue of aged mice targeted and downregulated high mobility group A2 (HMGA2) expression in muscle progenitor cells of young mice, thereby reducing the expression of cyclin A1 (CCNA1), CCNB1, cyclin-dependent kinase 6 (CDK6), paired box 3 (PAX3), and neurogenic locus notch homolog protein 1 (NOTCH1), significantly inhibiting muscle progenitor cell proliferation, suggesting that miR-let-7d-3p enriched in aging adipose tissue disrupts muscle progenitor cell proliferation via suppression of the HMGA2 pathway, representing a key mechanism underlying aging-related impairment of muscle regeneration [108]. In vitro experiments revealed that 3T3-L1 adipocytes exhibited a pronounced senescent phenotype after 18 days of induced differentiation. The conditioned medium from these senescent adipocytes, when co-cultured with C2C12 myoblasts, significantly upregulated MuRF1 expression, suppressed MyHC-IIb expression, and elevated myostatin (MSTN) levels, indicating that senescent adipocytes inhibit myogenic cell proliferation and differentiation while promoting a phenotype resembling muscle atrophy [109]. In summary, adipose tissue aging induces intramuscular lipid accumulation, impairs the proliferation and differentiation of myogenic cells, and promotes muscle atrophy, thereby contributing to skeletal muscle deterioration. However, most studies to date have focused on the unidirectional regulation from adipose tissue to skeletal muscle, and whether a feedback loop exists between adipose tissue and skeletal muscle remains unclear.

Adipose tissue aging and brain abnormalities

The brain serves as the central organ of the nervous system, orchestrating the regulation and integration of vital functions such as perception, movement, language, memory, learning, and higher-order cognition [110]. However, aging of adipose tissue contributes to lipid accumulation, impaired thermogenic function of BAT, diminished proliferation and differentiation potential of ASPCs, mitochondrial dysfunction, and dysregulated cytokine secretion, ultimately exacerbating brain injury [111]. Studies have confirmed that adipose tissue aging contributes to brain iron accumulation and synaptic dysfunction [112, 113]. Decreased ferroportin (FPN) expression and increased IL-6 and MMP-3 expression in the VAT of aged mice resulted in elevated Hepcidin and Ferritin expression in both the brain and VAT, with decreased expression of FPN, neuron glial antigen 2 (NG2), myelin-associated glycoprotein (MAG), and 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNPase), indicating chronic inflammation, iron accumulation, reduced oligodendrocyte precursor cell differentiation, and myelin loss in the brain of aged mice. In contrast, surgical removal of VAT in aged mice down-regulated Hepcidin levels in the remaining adipose tissue and brain, reduced expression of Ferritin, IL-6, and ionized calcium-binding adapter molecule 1 (IBA-1) in the brain, increased levels of FPN, MAG, and myelin basic protein (MBP), decreased p-SMAD1/5 nuclear translocation, and ameliorated brain injury. These findings suggest that inflammation triggered by VAT accumulation elevates brain Hepcidin and Ferritin expression, contributing to myelin loss [112]. The expression of Circular RNA_SXC (Circ_SXC) in the fat body, fat body-derived exosomes, and brain of aged Drosophila was significantly downregulated, resulting in sleep disturbances and markedly reduced daytime and total activity levels. This may involve fat body-derived exosomal Circ_SXC acting as a molecular sponge for miR-87-3p, promoting accumulation of miR-87-3p in the brain, which suppresses the expression of 5-Hydroxytryptamine (serotonin) receptor 1B (5-HT1B), metabotropic GABA-B receptor subtype 1 (GABA-B-R1), and Na channel protein 60E (NaCP60E), leading to abnormal synaptic signaling in neurons of the aged Drosophila brain and contributing to brain injury [113]. Other studies have confirmed that adipose tissue aging, through promoting VAT accumulation and impairing the proliferation and differentiation capacity of ASPCs, accelerates brain injury [114, 115]. Decreased serum testosterone levels and increased VAT mass in aged mice led to elevated expression of IL-1β, IBA-1, and CD68, and reduced expression of Claudin-5 and Occludin in the serum, VAT, and brain, indicating that adipose tissue aging–associated VAT expansion exacerbates chronic inflammation and impairs the blood-brain barrier in aged mice. In contrast, surgical removal of VAT significantly reduced IL-1β, IL-6, and TNF-α levels in the serum, residual adipose tissue, and brain, and improved blood-brain barrier integrity, suggesting that VAT plays a key pro-inflammatory role in aging-related brain injury and that reducing VAT mass can attenuate neuroinflammation and brain damage [114]. Tail vein injection of APSCs from young rats significantly increased the expression of p-Akt, p-AMPKα, SIRT1, PGC-1α, and the p-Akt/Akt ratio, reduced P53 expression, and significantly increased the expression of cystathionine gamma-lyase (CTH), heme oxygenase 1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf-2), brain-derived neurotrophic factor (BDNF), and tyrosine kinase B (TRKB) in the brains of aged mice, promoting neuronal survival, inhibiting oxidative stress, and improving prefrontal cortex integrity, indicating a neuroprotective effect of young APSCs and suggesting that the decreased proliferative and differentiation capacity of APSCs may contribute to aging-induced brain dysfunction [115]. In summary, adipose tissue aging can lead to brain ferritin accumulation, synaptic dysfunction, VAT expansion, reduced proliferative and differentiation capacity of APSCs, and chronic inflammation, collectively promoting brain injury. However, most current studies employ mice or Drosophila models, and species-specific differences in adipose tissue aging and brain pathology may limit clinical translatability, highlighting the need for further investigation into the mechanistic underpinnings of the adipose-brain axis.

Potential mechanisms by which exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities

Adipose tissue, a pivotal metabolic organ, not only regulates energy storage, mechanical buffering, and thermoregulation, but also orchestrates inter-organ communication, thereby contributing essentially to systemic metabolic homeostasis [116]. With aging, adipose tissue aging disrupts the homeostasis of metabolic organs such as the cardiovascular, liver, skeletal muscle, and brain, thereby exacerbating metabolic disorders [117]. Exercise, a safe and effective non-pharmacological intervention, has been shown to markedly ameliorate the effects of adipose tissue aging on metabolic organ abnormalities (Fig. 2), although the underlying mechanisms remain to be fully elucidated [118].

Fig. 2.

Potential mechanisms by which exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities. FNDC5, fibronectin type iii domain-containing protein 5; APJ, apelin peptide jejunum; APN, adiponectin; Mdm2, murine double minute-2; Akt, protein kinase B; TAG, triacylglycerol; DAG, diacylglycerol; CE, cholesteryl ester; MSTN, Myostatin; IL-6, interleukin 6; UCP1, uncoupling protein 1; FGF21, fibroblast growth factor 21; FATP4, fatty acid transport protein 4; TLR4, Toll-like receptor 4; Nrg4, neuregulin 4; NCR1, natural cytotoxicity triggering receptor 1; PRKCB, protein kinase C beta; AQP4, aquaporin-4; Arg-1, arginase-1

Inhibiting inflammatory response

The inflammatory response, as an innate immune defense against harmful stimuli, may play a pivotal role in exacerbating metabolic organ abnormalities associated with adipose tissue aging [119]. Studies have demonstrated that ten weeks of aerobic exercise significantly upregulated fibronectin type iii domain-containing protein 5 (FNDC5)/Irisin expression in the hippocampus of mice with type 2 diabetes-related cognitive impairment and suppressed activation of the Toll-like receptor 4 (TLR4)/myeloid differential protein-88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. This was accompanied by marked downregulation of TNF-α, IL-1β, and IBA-1 expression, reduced hippocampal neuroinflammation and microglial activation, shortened escape latency in the Morris water maze, increased platform crossings and time spent in the target quadrant, and ultimately improved cognitive deficits, suggesting that Irisin plays a critical role in the exercise-mediated improvement of cognitive impairment in type 2 diabetes [120]. Four weeks of aerobic exercise significantly upregulated apelin peptide jejunum (APJ) expression in the hearts of mice with ischemic stroke and targeted downregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3). This intervention reduced TNF-α, IL-1β, and BAX expression, markedly increased B-cell lymphoma-2 (Bcl-2) expression, thereby inhibiting cardiac inflammation and apoptosis, improving ejection fraction and early-to-late diastolic flow velocity ratio (E/A ratio), and ultimately ameliorating cardiac dysfunction, suggesting that APJ is a critical target in exercise-mediated cardioprotection following ischemic stroke [121]. Eight weeks of aerobic exercise significantly upregulated the expression of APN, UCP-1, and IL-10 in the perivascular adipose tissue of mice with type 2 diabetes, reduced the expression of interferon γ (IFN-γ), TNF-α, and IL-6, promoted macrophage polarization toward the M2 phenotype, and suppressed ROS production in both the perivascular adipose tissue and aorta. These changes increased the number of brown adipocytes, improved glucose tolerance and insulin sensitivity, attenuated inflammation and oxidative stress in the perivascular adipose tissue, and ultimately enhanced endothelial function in diabetic mice [122]. In summary, aerobic exercise effectively suppresses the infiltration of inflammatory cytokines into damaged tissues and mitigates metabolic organ injury.

Reducing ectopic fat accumulation

Adipose tissue aging compromises the lipid-buffering and storage capacity of SAT, promoting abnormal accumulation of FFA in metabolic organs, which leads to ectopic fat accumulation and aggravation of metabolic organ abnormalities [123]. Studies have demonstrated that seven weeks of voluntary aerobic exercise significantly downregulated murine double minute-2 (Mdm2), FOXO1, and VEGF-A expression in the VAT and SAT of obese mice. Exercise also suppressed MCP-1 and TNFα expression, upregulated UCP-1 and PPARα expression in SAT, promoted SAT browning, reduced VAT fat accumulation and lipid content in the soleus, gastrocnemius, and heart, lowered mean arterial pressure, and enhanced adipose angiogenesis. These findings suggest that exercise may improve obesity-related metabolic abnormalities by alleviating adipose tissue dysfunction and reducing ectopic lipid deposition [124]. Eight weeks of resistance training significantly increased p-Akt2 levels in the liver of high-fat diet ovariectomized mice. This intervention also decreased levels of FFA, TAG, and malondialdehyde (MDA), while downregulating the expression of sterol regulatory element-binding protein 1c (SREBP1c), ACC, stearoyl-CoA desaturase-1 (SCD1), and glycerol-3-phosphate acyltransferase 1 (GPAT1). These findings indicate that resistance training suppresses hepatic oxidative stress, lipogenesis, and fat accumulation, thereby improving glucose tolerance, insulin sensitivity, and ameliorating hepatic steatosis [125]. Four weeks of treadmill training significantly decreased levels of TAG, diacylglycerol (DAG), cholesteryl ester (CE), ALT, and AST in the liver of obese mice. The training also downregulated the expression of glucagon receptor (GCGR), glucokinase (GCK), diacylglycerol acyltransferase 1 (DGAT1), and carnitine palmitoyl transferase 1 A (CPT1A), upregulated FABP1 expression, and suppressed TNF-α and IL-1β expression. These results indicate that exercise inhibits hepatic lipogenesis, hepatic fat accumulation, and inflammatory responses, while improving glucose tolerance, insulin resistance, and hepatic steatosis [126]. In summary, exercise reduces ectopic fat accumulation and alleviates metabolic organ abnormalities.

Enhancing WAT browning and BAT thermogenesis

Reduced thermogenesis is considered a primary contributor to metabolic dysfunction in the elderly [127], whereas exercise-induced thermogenesis has emerged as an effective therapeutic strategy to mitigate metabolic organ abnormalities associated with adipose tissue aging. Studies have demonstrated that six weeks of intermittent weighted swimming significantly reduced MSTN expression in BAT, WAT, and soleus muscle of male Wistar rats. It also increased interferon regulatory factor-4 (IRF-4), PGC-1α, and UCP1 expression in BAT and WAT, and markedly elevated serum norepinephrine levels. These changes increased BAT adipocyte number, promoted WAT browning, and enhanced BAT thermogenesis, suggesting that intermittent swimming training promotes WAT browning and BAT thermogenesis by inhibiting MSTN expression and activating the PGC-1α-UCP1 pathway in adipose tissue [128]. Eight weeks of aerobic training significantly upregulated IL-6 expression in the plasma and muscle of obese mice. This was followed by increased adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) expression in VAT and SAT, as well as upregulation of PGC-1α, cytochrome c1 (CYC1), T-box transcription factor 1 (TBX1), PR domain-containing protein 16 (PRDM16), and cell-death-inducing DFFA-like effector A (CIDEA) in VAT and SAT. In parallel, hepatic PPARγ expression was downregulated, hepatic TAG and plasma ALT levels were reduced, WAT browning and BAT thermogenesis were enhanced, and both VAT mass and liver weight were decreased in obese mice. These findings suggest that IL-6 is a critical target for the metabolic protective effects of exercise [129]. Six weeks of high-intensity interval training significantly increased tyrosine hydroxylase (TH) and UCP1 expression in the supraspinatus muscle, BAT, and SAT of mice with unilateral rotator cuff tears. This intervention also upregulated protein kinase A (PKA), p-HSL, p-P38, mitogen-activated protein kinase (MAPK), and PGC-1α expression and activated the β3-AR thermogenic signaling pathway, thereby promoting WAT browning and BAT thermogenesis. As a result, muscle atrophy, fat infiltration, and muscle mass were markedly improved in mice with rotator cuff tears [130]. Notably, while exercise-induced browning of WAT and thermogenesis in BAT have been extensively demonstrated in animal models, robust direct evidence in humans remains scarce, and the underlying mechanisms require further elucidation [131]. In summary, exercise promoted WAT browning and BAT thermogenesis in animal models, thereby improving the function of metabolic organs.

Improving lipid metabolism

Lipid metabolism encompasses the synthesis, breakdown, transport, and utilization of lipids within the body, underpinning essential processes such as energy homeostasis, cellular structural integrity, and signal transduction [132]. Aging adipose tissue disrupts critical metabolic processes including lipid synthesis, lipolysis, and fatty acid β-oxidation, thereby contributing to metabolic organ damage [133]. Studies have shown that six weeks of aerobic exercise significantly reduced serum leptin levels and increased APN expression in obese rats, while decreasing serum IL-1β, TNF-α, cholesterol, TAG, and low-density lipoprotein cholesterol levels, suggesting improved lipid transport and distribution [134]. Aerobic exercise also enhanced the expression of UCP1, APN, and IL-10 in perivascular adipose tissue, reduced FABP4 expression, activated the BMP4 signaling pathway, and upregulated p38/MAPK, ATF2, PGC-1α, and SMAD5 expression, while downregulating MCP-1. These changes collectively promoted fatty acid β-oxidation, inhibited lipid synthesis, improved lipolysis imbalance, alleviated local inflammation and BAT dysfunction, thereby ameliorating lipid metabolism disorders, perivascular adipose tissue function, and vascular function [134]. Six weeks of aerobic treadmill exercise markedly decreased Chemerin expression in the gastrocnemius muscle and liver of high-fat diet-fed mice, downregulated FOXO1 and SCD1 protein levels, and increased PGC-1α expression in the gastrocnemius muscle. Additionally, the exercise elevated serum testosterone and gastrocnemius androgen receptor (AR) levels, reduced serum total cholesterol, TAG, and low-density lipoprotein, significantly suppressed fatty acid synthesis, promoted fatty acid β-oxidation, and improved lipid transport and blood lipid metabolism, thereby alleviating lipid metabolism disorders and hepatic steatosis [135]. Eight weeks of aerobic exercise combined with ketogenic diet intervention significantly increased hepatic expression of FGF21, PPARα, and CPT1A, downregulated ACC1 and fatty acid synthase (FAS), promoted fatty acid β-oxidation, inhibited fatty acid synthesis, lowered serum TAG, cholesterol, low-density lipoprotein, and AST levels, reduced hepatic TAG content, thereby decreasing VAT content and liver weight, and ultimately improving hepatic lipid metabolism and alleviating steatosis in obese mice [136]. In summary, aerobic exercise ameliorates lipid metabolism disorders and mitigates metabolic organ abnormalities.

Regulating the secretion of adipokines

Adipokines are bioactive substances secreted by adipose tissue that play essential roles in regulating metabolism, immunity, inflammation, insulin sensitivity, and angiogenes [137]. Studies have shown that twelve weeks of aerobic exercise significantly inhibited Adipsin expression in the bone marrow adipose tissue of high-fat diet-induced obese mice, targeting the downregulation of secreted phosphoprotein 1 (Spp1) levels and reducing Spp1-mediated osteoclast activity, thereby inhibiting bone resorption and promoting bone remodeling, significantly increasing tibial trabecular bone mineral density, and improving insulin sensitivity and bone marrow microenvironment abnormalities [138]. Six weeks of swimming exercise significantly reduced the expression levels of fatty acid transport protein 4 (FATP4) and TLR4 in the adipose tissue and liver of obese rats, suppressed TNF-α and IL-6 expression, elevated serum APN and ghrelin levels, and decreased leptin levels, thereby improving lipid metabolism and energy balance and alleviating adipose tissue hypertrophy and hepatic steatosis [139]. Eight weeks of aerobic exercise significantly upregulated neuregulin 4 (Nrg4) and PPARγ expression in the SAT of mice with metabolic dysfunction-associated steatotic liver disease (MASLD). This intervention activated the Nrg4/epidermal growth factor receptor subfamily B member 4 (ERBB4)/Akt signaling pathway and promoted phosphorylation of cyclic GMP-AMP synthase (cGAS), inhibiting cGAS activity. Consequently, liver inflammation mediated by the cGAS-STING pathway was suppressed, leading to improved glucose tolerance and insulin sensitivity, inhibited hepatic lipogenesis and ectopic lipid accumulation, and ameliorated hepatic steatosis [140]. In summary, exercise regulates adipokine secretion and mitigates the risk of metabolic organ damage.

Mitigating immunosenescence

Immunosenescence is defined by impaired adaptive immune responses, persistent low-grade inflammation, and heightened vulnerability to infectious diseases and malignancies. It is increasingly acknowledged as a central mechanism underpinning the initiation and progression of aging-related pathologies [141]. Studies have confirmed that four weeks of aerobic exercise significantly upregulated the expression of CD48, natural cytotoxicity triggering receptor 1 (NCR1), and protein kinase C beta (PRKCB), and downregulated the expression of CD244, Caspase-3, and P16 in the SVF of SAT in aged mice. This intervention also increased the proportions of natural killer cells, eosinophils, and neutrophils, thereby enhancing immune cell activation and reducing VAT mass and body weight in aged mice [142]. Six months of voluntary exercise significantly upregulated the expression of aquaporin-4 (AQP4), synaptophysin, postsynaptic density protein 95 (PSD-95), and activity-regulated cytoskeleton-associated protein (Arc), and downregulated IBA-1 and complement component 1q subcomponent subunit A (C1qA) in the cerebral cortex and hippocampus of aged mice. This intervention reduced microglia and monocyte numbers, suppressed immune activation and inflammation, improved grip strength and daily behaviors in aged mice, alleviated aging-associated pericyte loss, neurovascular unit dysfunction, and vascular leakage, and stabilized blood-brain barrier integrity [143]. Lifelong spontaneous exercise significantly increased the expression of arginase-1 (Arg-1) and CD206, and downregulated intercellular adhesion molecule 1 (ICAM-1) and TNF-α in the WAT of aged mice. This intervention reduced the number of M1-type macrophages, promoted polarization from M1 to M2 phenotype, suppressed inflammatory responses, and improved grip strength in aged mice [144]. In summary, exercise effectively attenuates immunosenescence and delays aging-related pathological alterations.

Conclusion and perspectives

Adipose tissue, as an essential organ for energy storage and metabolism, may be one of the earliest organs to respond to aging, characterized by changes in fat content and redistribution of adipose tissue, decline in thermogenic adipose function, reduced proliferation and differentiation capacity of APSCs, accumulation of senescent cells, and immunosenescence. The characteristic changes of adipose tissue aging are often interrelated and collectively play a role in metabolic abnormalities in the cardiovascular, liver, skeletal muscle, and brain. Exercise, as an important non-pharmacological intervention, can alleviate the effects of adipose tissue aging on metabolic organ abnormalities by inhibiting inflammation, reducing ectopic lipid accumulation, enhancing WAT browning and BAT thermogenesis, improving lipid metabolism, regulating the secretion of adipokines, and mitigating immunosenescence.

In recent years, although adipose tissue aging has received widespread attention, many unresolved questions remain regarding the effects of adipose tissue aging on metabolic organ abnormalities and the potential mechanisms of exercise intervention that urgently need to be elucidated: (1) Current studies mainly focus on animal models or cellular levels, lacking systematic human population research and clinical evidence, thus facing significant challenges in clinical translation and application. (2) The specific molecular mechanisms and signaling networks underlying the effects of adipose tissue aging on metabolic organ abnormalities have not been systematically elucidated. (3) The mechanisms by which different types, intensities, and frequencies of exercise alleviate the effects of adipose tissue aging on metabolic organ abnormalities remain unclear, and evidence supporting precise intervention strategies is still lacking. Future exploration and clarification of these issues can provide novel insights for basic and clinical research on exercise-based prevention and treatment of aging-related diseases.

Authors’ contributions

Conceptualization and design: S.T. and Y.G. Writing of first draft: S.T. Figures and tables: S.T. Final editing of text: Q.L. All authors reviewed the manuscript.

Funding

This study is supported by the National Natural Science Foundation of China (31300978).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.