The Klotho gene is recognized for its anti-aging properties. Its downregulation leads to aging-like phenotypes, whereas overexpression can extend lifespan. Klotho protein exists in three forms: α-klotho, β-klotho and γ-klotho. The α-klotho has two isoforms: a membrane-bound form, primarily in the kidney and brain, and a secreted klotho protein present in blood, urine, and cerebrospinal fluid. Klotho functions as a co-receptor for fibroblast growth factor-23 (FGF23), regulating phosphate metabolism. The membrane-bound form controls various ion channels and receptors, while the secreted form regulates endocrine FGFs, including FGF19 and FGF21. The interaction between β-klotho and FGF21 in muscle is critical in the development of sarcopenic obesity. This systematic review, registered in PROSPERO and conducted following PRISMA guidelines, evaluates klotho levels in individuals with obesity or sarcopenic obesity. The study includes overweight, obese, and sarcopenic obese adults compared to those with a normal body mass index. After reviewing 713 articles, 20 studies were selected, including observational, cross-sectional, cohort studies, and clinical trials. Significant associations between klotho levels and obesity, metabolic syndrome (MS), and cardiovascular risk were observed. Exercise and dietary interventions positively influenced klotho levels, which were linked to improved muscle strength and slower decline. Klotho is a potential biomarker for obesity, MS, and sarcopenic obesity. Further research is needed to explore its mechanisms and therapeutic potential.

Aging is related to changes in the redox status, low-grade inflammation, and decreased endoplasmic reticulum unfolded protein response (UPR). Exercise has been shown to regulate the inflammatory response, balance redox homeostasis, and ameliorate the UPR. This work aimed to investigate the effects of resistance training on changes in the UPR, oxidative status, and inflammatory responses in peripheral blood mononuclear cells of elderly subjects. Thirty elderly subjects volunteered to participate in an 8-week resistance training program, and 11 youth subjects were included for basal assessments. Klotho, heat shock protein 60 (HSP60), oxidative marker expression (catalase, glutathione, lipid peroxidation, nuclear factor erythroid 2-related factor 2, protein carbonyls, reactive oxygen species, and superoxide dismutase 1 and 2), the IRE1 arm of UPR, and TLR4/TRAF6/pIRAK1 pathway activation were evaluated before and following training. No changes in the HSP60 and Klotho protein content, oxidative status markers, and TLR4/TRAF6/pIRAK1 pathway activation were found with exercise. However, an attenuation of the reduced pIRE1/IRE1 ratio was observed following training. Systems biology analysis showed that a low number of proteins (RPS27A, SYVN1, HSPA5, and XBP1) are associated with IRE1, where XBP1 and RPS27A are essential nodes according to the centrality analysis. Additionally, a gene ontology analysis confirms that endoplasmic reticulum stress is a key mechanism modulated by IRE1. These findings might partially support the modulatory effect of resistance training on the endoplasmic reticulum in the elderly.

This pilot study aimed to investigate the role of the Klotho/FGF (fibroblast growth factor) system in biological features associated with premature aging, particularly inflammation and muscle dysfunction, focusing on its association with inflammatory markers, body composition, and muscle function in middle-aged adults. A total of 45 participants aged 50–60 years were enrolled, including 30 patients with obesity (22F/8M) and 15 healthy controls (11F/4M). Comprehensive assessments were conducted, including body composition analysis and muscle function tests. Evaluations of protein expression of Klotho, β-Klotho, FGF19, FGF21, FGF23, TFN-α and IL-10 were assessed in peripheral blood mononuclear cells (PBMCs). A Principal Component Analysis (PCA) was carried out to explore the relationships among variables. Significant differences were observed between the obese and control groups, with obese individuals exhibiting lower levels of Klotho and higher levels of TFN-α. The PCA revealed that higher Klotho levels were positively associated with better muscle function and lower inflammatory markers. These associations suggest that Klotho-related alterations may reflect biological processes linked to inflammation and muscle dysfunction in obesity. These findings suggest that alterations in the Klotho/FGF system may reflect biological pathways commonly associated with aging-related phenotypes in obesity, rather than direct measures of chronological aging. Given the exploratory design and limited sample size, these findings should be interpreted as hypothesis-generating rather than evidence of causal mechanisms.