IR represents a fundamental and shared metabolic defect that fuels a self-perpetuating, bidirectional pathological cycle between skeletal muscle and the vasculature, thereby accelerating the progression of both sarcopenia and atherosclerosis (56, 57). Skeletal muscle, being the primary site for postprandial glucose disposal, sees its metabolic function critically impaired in sarcopenia. The reduction in muscle mass and quality directly diminishes the body’s capacity for insulin-mediated glucose clearance, leading to compensatory hyperinsulinemia (21, 58). This hyperinsulinemia is not merely a marker of compensation but an active contributor to pathology, as it exerts direct catabolic effects on muscle tissue and promotes endothelial dysfunction (58). At the molecular level within myocytes, IR disrupts the anabolic PI3K/Akt signaling pathway. This impairment not only blunts protein synthesis but also leads to the activation of FoxO transcription factors. Activated FoxO upregulates the expression of the muscle-specific E3 ubiquitin ligases Atrogin-1 and MuRF-1, orchestrating the proteasomal degradation of key contractile proteins and driving muscle atrophy (59). Concurrently, IR induces a state of anabolic resistance, whereby the skeletal muscle becomes less responsive to the protein-synthetic stimulus of both insulin and essential amino acids, further crippling its maintenance and repair capabilities (60, 61). The metabolic consequences extend beyond glucose, as IR in adipose tissue triggers enhanced lipolysis, elevating circulating FFAs. These FFAs are taken up by muscle and esterified into toxic lipid intermediates like DAGs and ceramides. DAGs activate protein kinase C (PKC) isoforms that serine-phosphorylate and inhibit the insulin receptor substrate 1 (IRS-1), while ceramides activate Protein Phosphatase 2A (PP2A), which dephosphorylates and deactivates Akt, thereby locally exacerbating IR and promoting further atrophy (56, 62).

Conversely, the impact of IR on the vascular endothelium is a primary driver of atherogenesis and directly compromises muscle health. In a state of IR, insulin signaling in endothelial cells becomes selectively impaired in the PI3K/Akt/eNOS axis. This results in reduced production of the vasoprotective molecule NO (63, 64). Critically, the MAPK pathway remains sensitized to insulin, leading to a pathological imbalance. This unchecked MAPK signaling promotes the overexpression of the potent vasoconstrictor ET-1, upregulates the expression of adhesion molecules such as VCAM-1 and ICAM-1, and increases the secretion of PAI-1. This shift creates a pro-inflammatory, pro-thrombotic, and pro-atherogenic endothelial phenotype that initiates and accelerates plaque formation (48, 65). The resulting endothelial dysfunction and the associated microvascular rarefaction significantly impair blood flow and nutrient delivery to skeletal muscle. This creates a state of relative muscle ischemia, which exacerbates metabolic stress, limits exercise capacity, and contributes to further muscle wasting, thereby directly feeding into the sarcopenic process (5, 57, 63) (As shown in Figure 2).

This intricate crosstalk establishes a feed-forward vicious cycle: sarcopenia-induced systemic IR worsens endothelial health, while vascular IR and microcirculatory impairment hinder muscle perfusion and metabolism, deepening sarcopenia.

Chronic, low-grade inflammation, termed “inflammaging,” is a cornerstone of the aging process and a critical bidirectional link between sarcopenia and atherosclerosis. This persistent inflammatory state is not merely a passive association but an active driver of pathology in both muscle and vasculature, creating a self-reinforcing cycle of tissue degeneration (66, 67). The expansion and dysfunction of VAT serve as a primary hub for systemic inflammaging (68). In obesity and aging, hypertrophied adipocytes and infiltrating immune cells, particularly pro-inflammatory M1 macrophages, secrete a plethora of inflammatory mediators, including TNF-α, IL-6, and IL-1β (69, 70). This VAT-derived cytokine flood, drained into the portal circulation, perpetuates a state of chronic systemic inflammation that simultaneously attacks skeletal muscle and the arterial wall (71–74).

In skeletal muscle, these circulating cytokines activate distinct pro-atrophic pathways. TNF-α robustly activates the IκB kinase/NF-κB signaling cascade. NF-κB translocation to the nucleus directly transcribes the genes encoding MuRF-1, thereby accelerating the ubiquitin-proteasome system-mediated breakdown of myofibrillar proteins (75). IL-6, in a dualistic manner, can signal through its membrane-bound receptor or via a soluble receptor (trans-signaling). Chronic IL-6 exposure, particularly via trans-signaling, activates the JAK/STAT pathway. This leads to the upregulation of Suppressor of Cytokine Signaling 3 (SOCS3), which directly inhibits IGF-1 receptor signaling, thereby blunting the critical PI3K/Akt/mTOR anabolic pathway necessary for muscle protein synthesis and repair (76–78). Furthermore, local inflammation within the muscle milieu, characterized by M1 macrophage infiltration, impairs the function of satellite cells severely compromising the regenerative capacity of skeletal muscle in response to damage or stress (79–81).

In parallel, the same inflammatory mediators potently drive atherosclerotic progression. TNF-α and IL-1β activate the vascular endothelium, increasing the expression of adhesion molecules (e.g., VCAM-1, ICAM-1) and promoting the recruitment of monocytes into the subendothelial space (82). Within the nascent plaque, these monocytes differentiate into macrophages, which engulf oxLDL to become lipid-laden foam cells, the hallmark of early atherosclerotic lesions (83). These activated immune cells further produce additional cytokines (IL-6, TNF-α) and MMPs, the latter of which degrade the fibrous cap of advanced plaques, rendering them vulnerable to rupture and causing acute thrombotic events like myocardial infarction (84).

Cellular senescence, a state of irreversible growth arrest, is a key contributor. Senescent cells accumulate with age in both muscle and vasculature and secrete a powerful cocktail of pro-inflammatory factors, proteases, and growth factors known as the senescence-associated secretory phenotype (SASP) (3). The SASP directly promotes muscle fiber atrophy and endothelial dysfunction, creating a locally aggravated inflammatory environment (85, 86). Extracellular vesicles (EVs), including exosomes, have been identified as novel vehicles for inter-tissue communication. For instance, endothelial-derived EVs carrying specific microRNAs (e.g., miR-92a) can be taken up by skeletal muscle cells, where they suppress insulin signaling and promote atrophy. Conversely, EVs from atrophying muscle may carry pro-inflammatory cargo that can activate endothelial cells (87). The gut microbiome also plays a role; dysbiosis can lead to increased intestinal permeability, allowing bacterial lipopolysaccharide to enter the circulation, a condition known as metabolic endotoxemia, which triggers systemic inflammation through Toll-like receptor signaling, impacting both muscle and vasculature (88, 89). In summary, inflammaging is not a background phenomenon but an active pathological force. It is fueled by visceral fat and cellular senescence, transmitted via cytokines and EVs, and amplified by gut dysbiosis, which collectively dismantles muscle integrity and destabilizes the vascular wall, thereby inextricably linking the progression of sarcopenia and atherosclerosis (As shown in Figure 3).

Ectopic lipid deposition represents a critical physical manifestation of systemic metabolic dysregulation, wherein lipid overflow from dysfunctional adipose tissue infiltrates and compromises non-adipose organs, thereby directly linking the pathogenesis of sarcopenia and atherosclerosis (90, 91). This process, far beyond inert storage, involves the accumulation of bioactive lipid species that actively disrupt cellular signaling and fuel a bidirectional vicious cycle. The initiating event is often the failure of subcutaneous adipose tissue to expand healthily in the face of chronic energy surplus, leading to hypertrophic, hypoxic, and inflamed adipocytes. This dysfunctional state, particularly in visceral fat, results in uncontrolled lipolysis, flooding the circulation with excess FFAs (92) and setting the stage for ectopic deposition (37). The liver and skeletal muscle become primary sinks for this lipid overflow (93).

In skeletal muscle, elevated FFAs are esterified into IMCLs. While IMCLs themselves can be benign energy stores, the specific accumulation of toxic lipid intermediates like DAGs and ceramides is central to pathology (24, 37, 94). DAGs activate novel PKC isoforms, which phosphorylate IRS-1 on serine residues, blunting insulin signaling and contributing to local IR (11, 62, 95). More potently, ceramides activate PP2A and inhibit Akt, the master regulator of anabolism, directly promoting proteolysis and suppressing protein synthesis, thereby driving muscle atrophy (96, 97). This intramyocellular lipotoxicity is now recognized as a key determinant of “muscle quality,” explaining why individuals with similar muscle mass can exhibit vastly different strength and metabolic profiles. Furthermore, lipid droplets can interact with and disrupt mitochondrial membranes, inducing oxidative stress and impairing the energetic capacity necessary for muscle contraction and repair (24).

Concurrently, the liver avidly takes up the excess systemic FFAs, which serve as a substrate for the hepatic overproduction of triglyceride-rich VLDL (98). This VLDL overproduction initiates a cascade of atherogenic lipoprotein remodeling. CETP-mediated exchange transfers triglycerides from VLDL to LDL and HDL in exchange for cholesteryl esters. The resulting triglyceride-enriched LDL and HDL particles become ideal substrates for hepatic lipase, which hydrolyzes the triglycerides, generating sdLDL and small, dense HDL (98). SdLDL particles are highly atherogenic due to their increased susceptibility to oxidation, prolonged circulation half-life, and enhanced propensity for arterial wall retention (49). Meanwhile, the remodeled, dysfunctional HDL loses its capacity to promote reverse cholesterol transport and acquires pro-inflammatory properties, thus failing to protect against atherosclerosis (50, 99).

Beyond this shared origin in lipid overflow, novel mechanisms underscore the direct crosstalk. The concept of a “muscle-liver-vasculature” axis is gaining traction, where lipotoxins produced in insulin-resistant muscle (e.g., specific ceramide species) can be released into the circulation, potentially influencing hepatic VLDL secretion and directly affecting endothelial function (93, 100). Additionally, EVs derived from steatotic hepatocytes or lipid-laden muscle cells have been shown to carry specific lipid cargo (e.g., ceramides) and microRNAs that can be delivered to recipient cells, such as vascular smooth muscle cells, promoting their phenotypic switch to a pro-calcific, pro-inflammatory state, thereby accelerating atherosclerotic plaque maturation and instability (101, 102). Recent studies also highlight the role of perivascular adipose tissue (PVAT), which, when becoming dysfunctional and lipid-laden, loses its vasoprotective properties and secretes pro-inflammatory adipokines directly onto the adjacent arterial wall, creating a localized inflammatory milieu that accelerates atherosclerosis (38, 103) (As shown in Figure 4).

In summary, ectopic lipid deposition is not a passive endpoint but a dynamic and interactive process. It originates from adipose tissue failure, directly impairing muscle function through lipotoxicity, and simultaneously drives atherogenic dyslipidemia. This shared pathway, amplified by emerging inter-organ communication via lipotoxins and EVs, creates a powerful metabolic link that simultaneously deteriorates muscle integrity and vascular health (104, 105).

Age-related hormonal alterations create a shared endocrine milieu that predisposes to the parallel progression of sarcopenia and atherosclerosis (106, 107). This phenomenon extends beyond the decline of individual hormones, representing a state of systemic anabolic withdrawal coupled with a pro-inflammatory endocrine shift, which concurrently undermines the maintenance of muscle and vascular integrity.

Vitamin D deficiency, prevalent in aging and cardiometabolic diseases, exerts pleiotropic effects far beyond calcium metabolism. In skeletal muscle, the activation of the nuclear Vitamin D receptor (VDR) is crucial for myogenic differentiation and the maintenance of satellite cell function (108, 109). VDR signaling suppression impairs mitochondrial function and increases expression of atrophy-related genes, leading to sarcopenia (110). In the vasculature, vitamin D deficiency promotes endothelial dysfunction by upregulating the expression of pro-oxidant NADPH oxidase and downregulating eNOS, reducing NO bioavailability (111). Furthermore, it potentiates the Renin-Angiotensin-Aldosterone System (RAAS), leading to increased angiotensin II, which drives vascular inflammation, smooth muscle cell proliferation, and fibrosis, thereby accelerating atherosclerosis (112, 113). Emerging evidence also indicates that vitamin D exerts direct immunomodulatory effects, and its deficiency permits unchecked activation of the NF-κB pathway in both myocytes and vascular cells, amplifying the local inflammatory response (112, 114, 115).

The age-related decline in testosterone and estrogen represents a critical withdrawal of anabolic and vasoprotective support. In skeletal muscle, testosterone directly activates the androgen receptor to stimulate muscle protein synthesis via the Akt/mTOR pathway and inhibits key regulators of proteolysis, such as FoxO1 (116–118). Similarly, estradiol enhances muscle regenerative capacity and attenuates inflammation. Their decline thus creates a net catabolic state. In the vasculature, both hormones are pivotal for endothelial homeostasis. Testosterone and estradiol promote eNOS activation and NO production, ensuring vasodilation and inhibiting endothelial apoptosis. Estradiol, in particular, exerts potent antioxidant effects by suppressing NADPH oxidase and exerts anti-inflammatory actions by inhibiting NF-κB translocation in vascular smooth muscle cells and macrophages (119, 120). The loss of these protective effects post-menopause and in late-onset hypogonadism creates a permissive environment for oxidative stress, inflammation, and the progression of atherosclerotic plaques (121).

The senescence of the GH/IGF-1 axis results in a profound systemic anabolic deficit (122). In muscle, liver-derived and locally paracrine/autocrine IGF-1 binds to the IGF-1 receptor (IGF-1R), activating the canonical PI3K/Akt pathway to promote protein synthesis, inhibit apoptosis, and support satellite cell activity (123–125). Its decline is a central driver of anabolic resistance and muscle wasting. The vascular system is equally dependent on IGF-1 signaling. IGF-1 is a potent survival factor for endothelial cells, stimulating NO production and protecting against oxidative stress-induced apoptosis (126, 127). It also maintains vascular smooth muscle cell contractility and inhibits their pathological transition to a calcifying phenotype. The age-related decline in IGF-1 is thus associated with endothelial dysfunction, increased arterial stiffness, and enhanced susceptibility to vascular calcification (128, 129).

Beyond these classical axes, recent research highlights the role of bone-muscle cross-talk. Osteocalcin, particularly in its undercarboxylated, hormonally active form, is now recognized to promote muscle function and insulin sensitivity while also exerting protective effects on the endothelium. Age-related decline in osteocalcin may thus represent another endocrine link connecting musculoskeletal decline with vascular aging (130). Similarly, adipose-derived hormones like adiponectin, which typically exerts anti-inflammatory and insulin-sensitizing effects, decline with age and visceral obesity. Low adiponectin levels are associated with both muscle atrophy and accelerated atherosclerosis Thus, the waning of anabolic hormonal support creates a shared environment of vulnerability, predisposing to the parallel progression of muscle wasting and vascular sclerosis (131, 132), highlighting another dimension of the dysregulated endocrine network in aging (131). Moreover, the gut-muscle axis is being elucidated, with evidence suggesting that gut-derived hormones like Ghrelin may not only stimulate appetite but also have direct anti-inflammatory and anabolic effects on skeletal muscle, with potential secondary benefits for vascular health (133) (As shown in Figure 5).

In conclusion, hormonal dysregulation in aging creates a catabolic, pro-oxidant, and pro-inflammatory internal environment that simultaneously dismantles the structural and functional integrity of both skeletal muscle and the vascular system (134, 135). This shared endocrine failure provides a powerful rationale for exploring targeted hormone replacement strategies within an integrated gerotherapeutic framework.

Given the pivotal role of IR in both muscle and vascular dysfunction, interventions that enhance insulin sensitivity are foundational.

Systemic low-grade inflammation is a critical connector, driven largely by VAT. Strategies to reduce inflammatory burden are therefore essential.

Given the role of hormonal decline in both sarcopenia and atherosclerosis, vitamin D and sex hormone replacement therapies hold promise when carefully indicated. Testosterone and estrogen support anabolic signaling via Akt/mTOR in muscle and enhance endothelial NO synthesis in vasculature (116–119, 122, 126, 127). GH/IGF-1 axis modulation may also benefit muscle protein synthesis and vascular repair, though clinical applications require further validation (123–125, 128, 129).