transforming-growth-factor-beta and Aging--Premature

The Klotho protein deficiency is known to participate in premature aging. As an aging suppressor, Klotho is an important molecule in aging processes and its overexpression results in longevity. Due to many reasons, the insulin/insulin-like growth factor-1 (IGF-1) has been considered as a key pathway in aging research. The Klotho gene is closely related to this pathway. The Klotho gene encodes a transmembrane protein that after cleavage is also found as a secreted protein. Importantly, its overexpression suppresses insulin/IGF-1 signaling and thus extends the lifespan. In addition, Klotho participates in the regulation of several other intracellular signaling pathways, including regulation of FGF23 signaling, cAMP, PKC, transforming growth factor-β (TGF-β), p53/p21, and Wnt signaling. The aim of this review is to summarize current literature that shows the involvement of Klotho in the regulation of several intracellular pathways. The results of our review clearly indicate that Klotho participates in several intracellular signaling pathways, and by regulating them, Klotho is involved in aging and longevity.

Topics: Aging, Premature; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Insulin; Insulin-Like Growth Factor I; Klotho Proteins; Longevity; Transforming Growth Factor beta; Wnt Signaling Pathway

Skin homeostasis relies on fine-tuning of epidermis-dermis interactions and is affected by aging. While extracellular matrix (ECM) proteins, such as integrins, are involved in aging, the molecular basis of the skin changes needs to be investigated further. Here, we showed that integrin co-receptor, SLC3A2, required for cell proliferation, is expressed at the surface of resting dermal fibroblasts in young patients and is reduced drastically with aging. In vivo SLC3A2 dermal fibroblast deletion induced major skin phenotypes resembling premature aging. Knockout mice (3 months old) presented strong defects in skin elasticity due to altered ECM assembly, which impairs epidermal homeostasis. SLC3A2 dermal fibroblast loss led to an age-associated secretome profile, with 77% of identified proteins belonging to ECM and ECM-associated proteins. ECM not only contributes to skin mechanical properties, but it is also a reservoir of growth factors and bioactive molecules. We demonstrate that dermal fibroblast SLC3A2 is required for ECM to fully exert its structural and reservoir role allowing proper and efficient TGF-β localization and activation. We identified SLC3A2 as a protective controller of dermal ECM stiffness and quality required to maintain the epidermis to dermis interface as functional and dynamic.

Topics: Aging, Premature; Animals; Cell Proliferation; Cells, Cultured; Dermis; Epithelium; Extracellular Matrix Proteins; Fibroblasts; Fusion Regulatory Protein 1, Heavy Chain; Homeostasis; Humans; Mice; Mice, Knockout; Protein Transport; Transforming Growth Factor beta

Diastolic heart failure is a major cause of mortality in the elderly population. It is often preceded by diastolic dysfunction, which is characterized by impaired active relaxation and increased stiffness. We tested the hypothesis that senescence-prone (SAMP8) mice would develop diastolic dysfunction compared with senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging of the ratio of blood flow velocity through the mitral valve during early (E) vs. late (A) diastole was reduced from 1.3 ± 0.03 in SAMR1 mice to 1.2 ± 0.03 in SAMP8 mice (P < 0.05). Tissue Doppler imaging of the early (E') and late (A') diastolic mitral annulus velocities found E' reduced from 25.7 ± 0.9 mm/s in SAMR1 to 21.1 ± 0.8 mm/s in SAMP8 mice and E'/A' similarly reduced from 1.1 ± 0.02 to 0.8 ± 0.03 in SAMR1 vs. SAMP8 mice, respectively (P < 0.05). Invasive hemodynamics revealed an increased slope of the end-diastolic pressure-volume relationship (0.5 ± 0.05 vs. 0.8 ± 0.14; P < 0.05), indicating increased left ventricular chamber stiffness. There were no differences in systolic function or mean arterial pressure; however, diastolic dysfunction was accompanied by increased fibrosis in the hearts of SAMP8 mice. In SAMR1 vs. SAMP8 mice, interstitial collagen area increased from 0.3 ± 0.04 to 0.8 ± 0.09% and perivascular collagen area increased from 1.0 ± 0.11 to 1.6 ± 0.14%. Transforming growth factor-β and connective tissue growth factor gene expression were increased in the hearts of SAMP8 mice (P < 0.05 for all data). In summary, SAMP8 mice show increased fibrosis and diastolic dysfunction similar to those seen in humans with aging and may represent a suitable model for future mechanistic studies.

Topics: Age Factors; Aging; Aging, Premature; Analysis of Variance; Animals; Cardiac Catheterization; Collagen; Connective Tissue Growth Factor; Diastole; Disease Models, Animal; Echocardiography, Doppler, Pulsed; Elasticity; Fibrosis; Gene Expression Regulation; Heart Failure; Hemodynamics; Mice; Mice, Transgenic; Myocardium; RNA, Messenger; Transforming Growth Factor beta; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

The temporal and spatial immunolocalization of TGF-betas and their receptors in the intervertebral disk of senescence-accelerated mouse (SAM) was examined to determine the biological roles played by TGF-betas and their receptors in the process of intervertebral disk degeneration. Ten male SAM and ICR mice aged 8, 24 or 50 weeks after birth were used for this experiment. Histological and immunohistochemical studies using specific antibodies for TGF-beta1, -beta2, -beta3, TbetaR-I, and TbetaR-II were performed. Intervertebral disks of SAM exhibited more degenerative changes than those of ICR mice. Expression of TGF-betas and TbetaRs in disk of SAM and ICR mice was observed at 8 weeks of age, and became weaker with aging. Our results suggest TGF-betas may play a role in the growth and maintenance of intervertebal disks.

Topics: Aging, Premature; Animals; Immunoenzyme Techniques; Intervertebral Disc; Male; Mice; Mice, Inbred AKR; Mice, Inbred ICR; Mice, Mutant Strains; Protein Isoforms; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta