The gut microbiota (GM), the set of microorganisms that colonizes our intestinal tract, can undergo many changes, some of which are age related. Several studies have shown the importance of maintaining a healthy GM for a good quality of life. In the elderly, maintaining a good GM may become a real defense against infection by pathogens, such as C. difficile. In addition to the GM, bile acids (BAs) have been shown to provide an additional defense mechanism against the proliferation of pathogenic bacteria and to regulate bacterial colonization of the gut. BAs are molecules produced in the host liver and secreted with the bile into the digestive tract, and they are necessary for the digestion of dietary lipids. In the gut, host-produced BAs are metabolized by commensal bacteria to secondary BAs. In general GM and host organisms interact in many ways. This review examines the relationship between GM, BAs, aging, and possible new approaches such as dietary interventions, administration of ursodesoxycholic acid/tauroursodesoxycholic acid (UDCA/TUDCA), and probiotics to enrich the microbial consortia of the GM in the elderly and achieve a eubiotic state necessary for maintaining good health. The presence of Firmicutes and Actinobacteria together with adequate levels of secondary BAs would provide protection and improve the frailty state in the elderly. In fact, an increase in secondary BAs has been observed in centenarians who have reached old age without serious health issues, which may justify their active role in achieving longevity.

Blood bacterial DNA (BB-DNA) has been identified as a novel biomarker for metabolic dysfunction, yet its relationship with epigenetic features in type 2 diabetes mellitus (DM2) patients remains largely unexplored. This study investigated the relationship between BB-DNA and epigenetic, inflammatory, and aging-related markers in 285 elderly both with and without DM2. BB-DNA levels were higher in DM2 patients than in non-diabetic subjects, with the highest levels in those with severe renal impairment. BB-DNA showed a positive association with plasma IL-1β, linking bacterial DNA to systemic inflammation. Epigenetic analysis revealed a negative correlation between BB-DNA and DNA methylation-based leukocyte telomere length, suggesting accelerated aging in DM2. Additionally, BB-DNA was positively associated with DNAm-based biological age estimators, particularly DNAmPhenoAge and DNAmAge Skin Blood Clock. BB-DNA also correlated with DNAmVEGFA and DNAmCystatin C, key markers of diabetic nephropathy and vascular dysfunction. Furthermore, BB-DNA levels were associated with hypomethylation of genes involved in inflammation (e.g., IL1β, TNFα, IFNγ), cellular senescence (p16, p21, TP53), and metabolic regulation (e.g., IGF1, SREBF1, ABCG1, PDK4). These associations suggest that increased BB-DNA may reflect and potentially promote a pro-inflammatory and pro-senescent epigenetic profile in DM2. Importantly, many of these associations remained significant after adjusting for diabetes status, supporting BB-DNA as a robust biomarker across clinical subgroups. These findings provide new insights into the relationship between BB-DNA, inflammation, and epigenetic aging in DM2, highlighting BB-DNA as a potential biomarker for disease progression and complications, particularly in relation to renal dysfunction and systemic inflammation.

Ageing is characterized by progressive metabolic and inflammatory dysregulation, in which methylglyoxal (MGO), a highly reactive dicarbonyl by-product of glycolysis, is involved in the formation of advanced glycation end products (AGEs). This review provides an integrated overview of the bidirectional relationship between MGO-derived carbonyl stress and the gut microbiota, focusing on its implications for ageing and age-related diseases. We summarize current evidence on MGO production, clearance, tissue distribution, and reactivity, with particular attention to the intestinal lumen as a site where dietary compounds, host metabolism, and microbial activity converge. Age-related dysbiosis may impair intestinal barrier integrity, alter microbial metabolite production, and promote chronic low-grade inflammation, thereby reinforcing metabolic dysfunction and favoring free MGO accumulation. Conversely, MGO and AGEs can reshape microbial communities, compromise epithelial tight junctions, and amplify inflammatory signalling through receptor-dependent and independent mechanisms. Evidence from in vitro, animal, and clinical studies supports a role for the MGO–microbiota axis in metabolic, cardiovascular, gastrointestinal, neurodegenerative, and frailty-related conditions. Targeting microbiota composition, intestinal barrier function, and MGO scavenging pathways may therefore represent a promising strategy to mitigate carbonyl stress and preserve health during ageing.

Background/Objectives: Impaired immunonutritional status is common among hospitalized older adults and may contribute to adverse outcomes through alterations in gut–brain axis pathways involving immune, microbial, and inflammatory mechanisms. The Prognostic Nutritional Index (PNI), a composite marker based on serum albumin and lymphocyte count, may identify patients with altered immunonutritional status and increased clinical vulnerability. This cross-sectional study investigated whether PNI-defined immunonutritional impairment is associated with bacterial and viral DNAemia, inflammation, and neurocognitive conditions in 1016 geriatric patients from the Report-AGE cohort. Methods: Participants were stratified according to PNI into low- and high-PNI groups. Blood bacterial DNA (BB-DNA), Torque teno virus (TTV), herpes simplex virus (HSV-1), varicella-zoster virus (VZV), leukocyte telomere length (LTL), inflammatory and neurodegeneration-related biomarkers were evaluated. Multivariable logistic regression models were used to assess the associations of BB-DNA and PNI with cognitive impairment and interRAI-derived neurocognitive conditions. Results: Low-PNI patients exhibited a higher burden of comorbidities, frailty, and systemic inflammation, alongside increased concentrations of BB-DNA, IL-6, IL-17A, GDF15, osteopontin, FGF21, follistatin, and neurofilament light chain. Among patients with low-PNI, increasing BB-DNA tertiles were associated with progressively higher TTV, HSV-1, and VZV DNAemia, elevated NLR, IL-6, and IL-17A levels, and shorter LTL. In multivariable analyses, low-PNI was independently associated with cognitive impairment (OR: 1.39, 95% CI: 1.06–1.83), easily distracted behavior (OR: 1.75, 95% CI: 1.29–2.35), and behavioral disturbances (OR: 1.80, 95% CI: 1.05–3.06), whereas BB-DNA showed an association with acute changes in mental status (OR: 1.75, 95% CI: 1.09–2.81) and behavioral disturbances (OR: 3.09, 95% CI: 1.11–8.59). Conclusions: These findings suggest that impaired immunonutritional status, bacterial and viral burden, systemic inflammation, and neurocognitive alterations may represent interconnected features of clinical vulnerability, although the cross-sectional design does not establish temporal or causal relationships among these factors.

The glyoxalase pathway detoxifies reactive dicarbonyls generated during hyperglycemia, but the role of its epigenetic regulation in renal dysfunction and inflammatory dysregulation in older adults remains unclear. We investigated CpG-specific DNA methylation within the glyoxal detoxification pathway, focusing on the GLO1 gene, and examined associations with glycemic status, renal function, and systemic inflammation in hospitalized older adults. We identified a single CpG site within the GLO1 gene (cg26053840) significantly associated with fasting glycemia, suggesting that methylation levels at this locus reflects metabolic stress. Higher methylation at cg26053840 was also associated with impaired renal function, including increased serum creatinine and reduced estimated glomerular filtration rate. Additionally, GLO1 methylation correlated with multiple inflammatory indices, including C-reactive protein, erythrocyte sedimentation rate, neutrophil-to-lymphocyte ratio, and the CRP-to-albumin ratio. Associations with circulating cytokines and immune activation markers such as IL-6, IL-17A, GDF-15, CXCL9, CD163, and soluble RAGE further indicated broader immune–metabolic dysregulation. In silico analyses revealed a significant inverse correlation between cg26053840 methylation and GLO1 mRNA expression in the Broad Institute GDAC Firehose dataset. Genomic annotation further identified putative CEBPD and MYF6 transcription factor binding sites in proximity to the CpG site, suggesting a potential regulatory context. These findings support a model in which glycemic dysregulation increases methylglyoxal production, while reduced renal clearance enhances dicarbonyl stress, potentially driving epigenetic modulation of GLO1. These findings suggest the presence of a metabolic–epigenetic–inflammatory axis, although longitudinal and mechanistic studies are required to determine whether it contributes to organ dysfunction and vulnerability in hospitalized older adults.