Ultra-Processed Foods and Chronic Kidney Disease: Could Age-Related Inflammation Be the Connection?

CKD unfolds within a chronic state of low-grade inflammation that progressively impairs renal architecture and function. Within the kidney, tissue-resident and infiltrating macrophages act as central regulators of innate immune activity, coordinating inflammatory responses in the local microenvironment. Macrophages express a diverse array of pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs). These receptors detect and respond to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), such as lipopolysaccharide (LPS). Engagement of these receptors, together with signaling initiated by cytokine receptors such as those for tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), activates intracellular kinase cascades that converge on nuclear factor κB (NF-κB) signaling. Phosphorylation and subsequent degradation of the inhibitor of κB (IκB) releases NF-κB from cytoplasmic sequestration, enabling its translocation to the nucleus and transcriptional activation of pro-inflammatory cytokines, chemokines and adhesion molecules. Through autocrine amplification of macrophage activation and paracrine recruitment of additional immune cells, these mediators establish a persistent inflammatory niche within renal tissue [16,17].

Inflammatory signaling in CKD is closely intertwined with oxidative stress pathways. Sustained NF-κB activation can attenuate the activity of nuclear factor erythroid 2–related factor 2 (Nrf2), the principal regulator of cellular antioxidant defense systems. Crosstalk between these pathways occurs through modulation of the Kelch-like ECH-associated protein 1 (Keap1)–Nrf2 regulatory axis and competition for transcriptional co-activators, ultimately reducing the expression of cytoprotective and detoxifying enzymes. As antioxidant capacity declines, reactive oxygen species (ROS) and reactive nitrogen species (RNS) accumulate, promoting lipid peroxidation, protein carbonylation and the formation of advanced glycation end products (AGEs). Many of these oxidative modifications function as DAMPs, reinforcing PRR-mediated signaling and thereby facilitating inflammatory circuits that contribute to progressive renal injury [17,18].

A further escalation of inflammatory activity occurs with activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Assembly of this multiprotein complex requires two sequential signals. The initial priming step is driven by PRR-dependent NF-κB activation, which upregulates transcription of NLRP3 together with the inactive cytokine precursors pro-IL-1β and pro-IL-18. A second signal arises from cellular stress and metabolic perturbations, most commonly triggered by adenosine triphosphate (ATP)-mediated potassium efflux, mitochondrial dysfunction and lysosomal destabilization. Damaged mitochondria generate excessive mitochondrial ROS and release oxidized mitochondrial DNA (mtDNA) into the cytosol, where it acts as a potent DAMP. At the same time, redistribution of cardiolipin from the inner to the outer mitochondrial membrane promotes direct interaction with NLRP3, facilitating inflammasome assembly, whereas lysosomal rupture provides an additional activating signal through the cytosolic release of cathepsins [19,20,21].

Integration of these signals promotes oligomerization of NLRP3 and recruitment of the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) together with pro-caspase-1. Within this complex, caspase-1 undergoes autocatalytic activation and cleaves pro-IL-1β and pro-IL-18 into their mature inflammatory forms. Activated caspase-1 also processes gasdermin D (GSDMD), generating an N-terminal fragment that inserts into the plasma membrane to form pores. This process initiates pyroptosis, a lytic form of programmed cell death characterized by the release of intracellular alarmins and additional DAMPs. The resulting enhancement of innate immune signaling perpetuates the inflammatory milieu that typifies CKD and contributes to progressive renal tissue injury [19,20,21]. Figure 2 depicts the main inflammatory pathways implicated in the pathogenesis and progression of CKD.

Aging is a complex biological process marked by a gradual loss of physiological resilience across organs and tissues, resulting from the cumulative accumulation of cellular and molecular damage over lifetime. This deterioration reflects the progressive dysregulation of multiple pathways, including genomic instability, telomere shortening, epigenetic modifications, mitochondrial dysfunction, impaired proteostasis, and defective autophagy. Together, these alterations compromise cellular homeostasis and progressively weaken tissue maintenance. Aging is also associated with stem cell depletion and disrupted intercellular communication, which further diminish tissue integrity and regenerative potential [22,23].

A central hallmark of aging is cellular senescence, a state of essentially irreversible cell-cycle arrest accompanied by extensive metabolic, transcriptional, and phenotypic reprogramming [24]. Senescent cells, although no longer capable of proliferation, remain metabolically active and adopt a distinct secretory profile, known as the senescence-associated secretory phenotype (SASP). This program includes a broad array of pro-inflammatory cytokines, chemokines, growth factors, and matrix-remodeling enzymes that reshape the local tissue microenvironment. Through sustained SASP secretion, senescent cells induce paracrine senescence in neighboring cells, modify extracellular matrix architecture, and reinforce a persistent pro-inflammatory milieu. The progressive accumulation of senescent cells, together with their altered secretory activity and reduced regenerative potential, is increasingly recognized as a major driver of tissue dysfunction and the onset of age-related diseases [25,26].

Aging is also accompanied by a progressive decline in immune competence, a phenomenon collectively termed immunosenescence. This process encompasses both quantitative and functional changes across adaptive and innate immune compartments, resulting in impaired immune surveillance, reduced pathogen clearance, and dysregulated inflammatory responses. In the adaptive immune system, thymic involution leads to a marked reduction in naïve T cell output, alongside expansion of memory and terminally differentiated T cell populations. These shifts are often accompanied by loss of the co-stimulatory molecule CD28 on T lymphocytes, reflecting replicative exhaustion and diminished proliferative capacity [27,28]. Innate immune cells undergo substantial remodeling with age as well. Natural killer (NK) cells exhibit shifts between CD56^bright and CD56^dim subsets, altering CD16 expression and their cytokine production and cytotoxic functions, potentially compromising NK-mediated immune surveillance. Dendritic cells (DCs) similarly experience functional decline, with myeloid DCs displaying impaired antigen presentation and modified responsiveness to PAMPs and DAMPs. Moreover, aged DCs adopt a pro-inflammatory bias, producing elevated levels of cytokines such as IL-6 and TNF-α [29,30].

Within this biological context, the concept of inflammaging, first introduced by Claudio Franceschi in 2000, describes the chronic, low-grade inflammatory state that develops during aging in the absence of overt infection. Inflammaging results from cumulative activation of innate and adaptive immune pathways and is closely linked to both immunosenescence and the progressive accumulation of senescent cells. Multiple mechanisms converge to sustain this pro-inflammatory milieu, including persistent SASP secretion, mitochondrial dysfunction, oxidative stress, and the accumulation of DAMPs. Persistent inflammatory signaling drives tissue injury, metabolic dysregulation, and progressive organ dysfunction, thereby heightening susceptibility to a broad spectrum of age-related diseases [31,32]. Figure 3 presents the principal drivers of inflammaging.

Organs with high metabolic demand and intricate microvascular architecture, such as the kidney, are particularly susceptible to the cumulative effects of inflammaging. Both innate and adaptive immune mechanisms contribute to CKD pathophysiology, linking systemic inflammatory aging with progressive renal injury [33]. Patients with advanced CKD, especially those with ESRD, frequently display features of premature immunological aging. This phenotype is characterized by reductions in naïve T cells alongside expansion of highly differentiated or senescent T cell populations [34]. Persistent inflammatory and oxidative signaling ultimately drives adverse structural remodeling in the kidney, including glomerulosclerosis, tubular atrophy, thickening of the glomerular basement membrane, and expansion of interstitial fibrosis [33,35].

Mounting epidemiological evidence links dietary patterns rich in UPFs with inflammatory dysregulation. In a cross-sectional study of 1986 adults aged 46 to 70 years, Millar et al. reported that higher UPF intake was associated with increased circulating concentrations of IL-6 and TNF-α, elevated total leukocyte counts, and a higher neutrophil-to-lymphocyte ratio. Part of this relationship likely reflects the greater prevalence of adiposity among individuals with high UPF consumption, consistent with the fundamental role of excess adipose tissue as a source of pro-inflammatory cytokines [36]. However, the inflammatory signal cannot be attributed to adiposity alone, since other data support that associations between UPF intake and inflammatory markers persist after adjustment for body mass index (BMI) and other metabolic confounders [37,38]. Age-dependent effects have also been described, particularly in children, where the association between UPF intake and circulating IL-6 appears to become evident from around nine years of age [39].

Numerous studies have linked the macronutrient composition of UPFs to insulin resistance, inflammation, and overall metabolic dysregulation, with the formation of AGEs playing a vital role. Nevertheless, the pro-inflammatory impact of UPFs cannot be explained solely by their macronutrient profile [40]. This limitation has redirected focus toward non-nutritional constituents introduced during industrial processing. Among these, EDCs such as bisphenol A (BPA) and phthalates have emerged as key candidates. Experimental data indicate that these compounds perturb cellular redox homeostasis and immune function through tightly interconnected mechanisms. In particular, they enhance the generation of ROS, interfere with intracellular signaling networks, and modulate immune cell dynamics by influencing both proliferation and apoptotic pathways. Sustained oxidative stress, in turn, impairs Nrf2-mediated antioxidant defenses, creating a permissive environment for persistent inflammatory activation [41].

Diets dominated by UPFs may also influence biological aging trajectories. Analysis of more than 16,000 adults from the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2010 demonstrated that each 10% increase in energy intake from UPFs corresponded to an estimated 0.21-year increase in biological age. Individuals in the highest consumption category, with UPFs contributing 68 to 100% of total energy intake, exhibited biological ages approximately 0.9 years greater than those with minimal intake, even after accounting for overall diet quality and other confounders [42].

Among the mechanisms proposed, alterations in telomere dynamics have received particular attention. Data from the Seguimiento Universidad de Navarra (SUN) Project, involving nearly 900 older adults, revealed significantly shorter leukocyte telomeres among individuals consuming more than three daily servings of UPFs [43]. Comparable findings have been reported in middle-aged and older Korean populations, where higher intake of sugar-sweetened beverages was associated with reduced telomere length [44]. More recently, Rodrigues et al. highlighted epigenetic remodeling as a potential mechanism through which highly processed dietary exposures may influence aging, primarily via alterations in DNA methylation patterns [45]. Consistent with their role in inflammatory processes, EDCs appear to be key mediators in the association between UPF exposure and biological aging [46]. At the cellular level, BPA, even at low concentrations, has been shown to compromise genomic integrity, disrupt mitochondrial function, and induce structural alterations in cellular architecture [47]. Phthalates have been linked to telomere attrition early in life, whereas acrylamide generated during high-temperature processing promotes cellular senescence and endothelial dysfunction in experimental models [48,49].

Taken together, these observations support a multifactorial model in which the biological impact of UPFs reflects the combined influence of their nutritional profile and chronic exposure to processing-derived chemical agents. Through the convergence of these pathways, UPFs may potentiate inflammatory aging processes and increase susceptibility to chronic diseases, including CKD. Table 2 summarizes key epidemiological studies highlighting the contribution of UPF consumption to inflammatory processes and the acceleration of biological aging.

The human microbiome, comprising the collective genomes of bacteria, viruses, fungi, and archaea, resides predominantly within the gastrointestinal tract, functioning as a metabolic, immunological, and structural extension of the host. Under normal conditions, host tissues and resident microbial communities exist in a tightly regulated equilibrium that supports nutrient metabolism, immune maturation, and epithelial barrier integrity. Disruption of this balance, driven by genetic susceptibility or environmental exposures, can give rise to gut dysbiosis. This state is characterized by alterations in microbial composition, reduced taxonomic diversity, and shifts in microbial metabolic output [50].

Among environmental determinants, early-life antibiotic exposure and sedentary lifestyle are well-recognized contributors to microbial disruption. UPFs may further aggravate these disturbances, particularly by compromising the structural and functional integrity of the intestinal epithelial barrier [51]. This barrier relies on specialized intercellular complexes known as tight junctions (TJs), composed primarily of claudins, occludins, and junctional adhesion molecules (JAMs), which seal the paracellular space between epithelial cells. These multiprotein assemblies regulate selective diffusion of ions and small solutes while preventing the translocation of luminal antigens, microorganisms, and potentially harmful metabolites [50,52].

Evidence indicates that several additives commonly found in UPFs, including emulsifiers, artificial sweeteners, and certain food colorants, can disrupt the molecular organization and stability of TJs. Such perturbations weaken epithelial cohesion, reduce mucus-layer thickness, and compromise barrier defenses. The resulting increase in intestinal permeability, often referred to as “leaky gut,” facilitates systemic translocation of microbial components and metabolites originating from the intestinal lumen. This, in turn, triggers persistent inflammatory signaling, sustained immune cell recruitment, and chronic stress on key regulators of mucosal integrity, including epithelial cells, intestinal stem cells, and Paneth cells. Over time, these pressures can impair epithelial metabolism and regenerative capacity, accelerating functional decline of the intestinal barrier [50,52].

In individuals with CKD, a compromised barrier assumes particular pathological relevance. Increased intestinal permeability enhances systemic exposure to microbiota-derived uremic solutes, including indoxyl sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine N-oxide (TMAO) [53]. TMAO is generated in the liver via oxidation of trimethylamine (TMA), a microbial metabolite produced during the intestinal metabolism of dietary substrates such as L-carnitine, choline, and phosphatidylcholine. Elevated circulating concentrations of these compounds reflect substantial microbial metabolic alterations and have been implicated in multiple pathogenic processes, including systemic inflammation, oxidative stress, endothelial dysfunction, and progressive renal injury [54].

Overall, these mechanisms establish a bidirectional pathogenic loop. CKD-associated metabolic disturbances promote microbial imbalance and enhance the generation of gut-derived uremic toxins, which in turn further compromise intestinal barrier integrity and amplify systemic inflammatory signaling. The combined influence of CKD-related metabolic alterations and diets rich in UPFs thus favors sustained microbial dysregulation, reinforcing a cycle that may accelerate renal functional decline. Figure 4 illustrates central pathways through which UPF consumption and CKD converge to promote gut dysbiosis.

Accumulating evidence supports the occurrence of age-related shifts in gut microbiota composition and diversity, although findings across studies remain partly conflicting [55]. For instance, while it is commonly assumed that Akkermansia muciniphila declines with advancing age, some studies report its enrichment in the gut microbiota of healthy, long-lived individuals [56]. Moreover, both the timing and extent of microbiome alterations appear to vary across studies. Claesson et al. demonstrated that older individuals harbor a distinct core microbiota compared with younger adults, characterized by increased abundance of Bacteroides species, altered distributions of Clostridium groups, shifts in phylum-level composition, and considerable inter-individual variability despite relative short-term stability [57]. In contrast, other data suggest that overall microbial composition remains relatively stable until later stages of life, with more pronounced alterations observed in centenarians. In these individuals, the microbiota is marked by restructuring within the phylum Firmicutes, enrichment of facultative anaerobes including pathobionts, and reduced abundance of Faecalibacterium prausnitzii and other taxa with established anti-inflammatory properties. Such changes have been proposed to contribute to the development of inflammaging [58]. It is noteworthy that Santos-Pujol et al. have very recently conducted a multi-omics study of a woman with the most extreme lifespan, i.e., 117 years. In their study, they compared the fecal microbiota composition of this woman using 16S rDNA with 445 samples from 250 women and 195 men aged 61 to 91 years old. They managed to reveal that this supercentenarian woman had a favorable microbiome profile when compared to the control group. More specifically, she had reduced levels of the pro-inflammatory Clostridium genus and more abundance of Bifidobacterium regarding the fecal microbiota composition [59]. With their outstanding study, Santos-Pugol et al. documented that this woman with the most extreme lifespan had a beneficial microbiome composition as well as a younger epigenetic age. Their study provides further insight into the centenarians and most probably supercentenarians gut microbiome, thus advocating that longevity may be associated with a beneficial gut microbiome [59]. In sharp contrast, inflammaging seems to be characterized by a distorted gut microbiome as preliminary results have shown. Advancing age has been further associated with substantial remodeling of gut microbiota function and its immunometabolic interactions. Notably, reductions in key butyrate-producing bacteria, including Eubacterium rectale, may lead to decreased butyrate availability and subsequent impairment of regulatory B cell responses. Aging also alters mucosal immune dynamics within the gut-associated lymphoid tissue, as reflected by reduced proliferative capacity of CD4⁺ T cells in Peyer’s patches and diminished abundance and functionality of lamina propria Th17 cells. Declines in secondary bile acids may further disrupt intestinal immune homeostasis by promoting Th17 polarization while weakening regulatory T cell-mediated immunosuppression [60]. Importantly, the relationship between biological aging and gut dysbiosis appears to be bidirectional, as the gut microbiome continuously interacts with both the intestinal mucosa and the systemic immune system—networks that are closely linked to the development of frailty [61].

Adiposity represents an additional biological context in which metabolic and immune alterations converge with processes resembling accelerated aging [62]. Within adipose tissue, the accumulation of senescent cells contributes to a pro-inflammatory milieu through the secretion of senescence-associated mediators that enhance systemic immune activation. Notably, the clearance of these cells using senolytic agents has been shown to attenuate inflammatory signaling [63]. These mechanisms are particularly relevant to kidney disease. Obesity is strongly linked to major drivers of CKD, including type 2 diabetes (T2D) and hypertension, and may also exert direct renal effects, contributing to obesity-related glomerulopathy [64]. Such interactions may be amplified in dietary contexts characterized by high UPF intake, which is commonly associated with increased adiposity and metabolic disruption [65]. In obesity-associated nephropathy, microbiota-derived signals may additionally intersect with vascular endothelial growth factor A (VEGFA)-related pathways, potentially sustaining inflammatory responses across both renal and systemic compartments [66].

Collectively, although the evidence remains at an early stage and definitive conclusions cannot yet be drawn, these findings suggest that gut dysbiosis-associated inflammaging may represent a critical mechanistic link between high UPF consumption and adverse renal outcomes.

No new data were created or analyzed in this study. Data sharing is not applicable to this article.