Effect of Obesity on Senescence

The pathophysiological impact of obesity extends to the acceleration of biological aging, primarily through the induction of cellular senescence. This is orchestrated by metaflammation, a state of chronic, adipose tissue-driven inflammation that systemically disrupts tissue function. A central mechanism is the cellular stress response to persistent nutrient excess, which activates pathways leading to premature senescence [60]. Expanding adipose tissue, particularly visceral fat, becomes dysfunctional, failing to sequester lipids safely and instead releasing a flood of pro-inflammatory adipokines (like leptin and resistin) and cytokines (such as TNF-α and IL-6) into the circulation [61–64]. This chronic systemic inflammation constitutes a potential component of SASPs, essentially broadcasting an aging signal throughout the body. The nutrient surplus characteristic of obesity may induce mitochondrial dysfunction, especially in highly metabolic tissues such as skeletal muscle, liver, and pancreatic β-cells [65–67]. This dysfunction elevates reactive oxygen species (ROS) generation, which surpasses antioxidant capacity and creates a state of oxidative stress. The resulting oxidative damage to macromolecules particularly DNA serves as a primary trigger for cellular senescence by activating the canonical p53/p21 and p16/Rb tumor suppressor pathways, which initiate a stable cell cycle arrest [68].

This ROS-to-senescence mechanistic chain is well established in cell culture models and murine dietary obesity paradigms; however, it is important to note that most direct evidence derives from preclinical systems. Cross-sectional human studies have documented positive associations between BMI and markers of oxidative stress and senescence burden in adipose tissue, but these are correlational and do not establish that ROS accumulation in obesity is the primary driver of senescence onset in vivo. The degree of ROS generation required to trigger p53/p21 pathway activation in human adipocytes under physiological obesity conditions rather than in lipid-overloaded cell lines, remains to be directly quantified.

In addition to fostering inflammation and oxidative stress, obesity disrupts core nutrient-sensing pathways that maintain cellular homeostasis. Chronic hyperglycemia and hyperinsulinemia, hallmarks of obesity-related insulin resistance [69], lead to dysregulation of the IGF-1/AKT/mTOR axis, a central regulator of growth and aging [70, 71]. The consequent hyperactivation of mTOR, a characteristic response to nutrient surplus, suppresses autophagy, a critical quality control mechanism for clearing damaged cellular components [72]. Impaired autophagy accelerates senescence by allowing damage to accumulate [73], while concurrent metabolic stresses disrupt telomere integrity, as evidenced by shorter telomeres in individuals with high body mass index (BMI) [74]. The resulting accumulation of senescent cells acts as a persistent source of inflammatory and pro-senescent signals, fostering a vicious cycle that amplifies aging systemically [40]. The pathological consequences of obesity-driven senescence are multisystemic, underpinning common age-related diseases such as atherosclerosis, osteoarthritis and metabolic dysfunction-associated steatohepatitis (MASH). By synergistically disrupting cellular integrity, obesity functions as a potent accelerator of the aging process [75]. The demonstration that senescent features are mitigable by reducing adiposity underscores the profound therapeutic potential of lifestyle interventions for promoting health span [76].

Beyond cellular senescence, the chronic inflammatory milieu of patients with obesity adipose tissue activates multiple additional programmed inflammatory cell death pathways in adipocytes. Pyroptosis, a caspase-1-dependent, proinflammatory form of cell death mediated by gasdermin D pore formation is now recognized as a predominant mode of adipocyte death in obesity, as adipocytes under metabolic stress display ultrastructural features consistent with this pathway and release the inflammasome-processed cytokines IL-1β and IL-18 directly into the tissue environment [36].

A third pathway, necroptosis executed via the RIPK1/RIPK3/MLKL axis, drives programmed cellular necrosis that releases DAMPs including HMGB1 and mitochondrial DNA, which in turn activate TLR4 and the NLRP3 inflammasome on macrophages, fueling CLS formation and macrophage recruitment [77]. These three pathways, pyroptosis, apoptosis, and necroptosis, are not mutually exclusive; they can be activated simultaneously within the same inflammatory context, a convergent phenomenon collectively termed PANoptosis or inflammatory cell death [78]. Critically, PANoptosis and cellular senescence share upstream triggers, including ROS accumulation, mitochondrial dysfunction, and the nutrient excess characteristic of obesity [79–84], yet produce distinct but complementary proinflammatory outputs: senescent adipocytes survive and secrete SASP mediators [85], while PANoptotic cells die acutely and release a burst of IL-1β, IL-18, and DAMPs [86], as compared with other models, that further prime macrophages and amplify the pro-tumorigenic inflammatory niche [87, 88]. Together, these parallel cell fate mechanisms render patients with obesity adipose tissue a self-sustaining source of inflammatory signals that collectively could drive SASP amplification, immune dysregulation, and ultimately oncogenesis.