Study of the role of BCL-XL in healthy aging and frailty prevention

• Autores: Aurora Román Domínguez
• Directores de la Tesis: Consuelo Borrás Blasco (dir. tes.), José Viña Ribes (codir. tes.), Cristina Mas Bargues (codir. tes.)
• Lectura: En la Universitat de València ( España ) en 2023
• Idioma: inglés
• Tribunal Calificador de la Tesis: Angelo Parini (presid.), Marta Inglés de la Torre (secret.), Lucía Gimeno-Mallench (voc.)
• Programa de doctorado: Programa de Doctorado en Fisiología por la Universitat de València (Estudi General)
• Materias:
  • Ciencias de la vida
    • Antropología (física)
      • Envejecimiento somático
    • Biología celular
    • Biología humana
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: TESEO
• Resumen

  • Aging is defined as an intrinsic, progressive, deleterious and inevitable multifactorial phenomenon that occurs as a result of the gradual accumulation of damage at cellular and molecular levels. Due to the recent discovery of BCL-XL being overexpressed in peripheral blood mononuclear cells from centenarians, a new approach has emerged to investigate the BCL-XL function in healthy aging. The major goal of this thesis is to study the role of BCL-XL in frailty and healthy aging in transgenic mice overexpressing a human form of BCL-XL in T cells. For this, we used the heterozygous transgenic mice from Cg-Tg(LCKprBCL2L1)12Sjk/J strain, which express the human BCL-XL cDNA sequence in all thymocyte subsets.

    We measured physical performance parameters such as spontaneous activity, body weight, grip strength, motor coordination, physical endurance, and frailty. We also measured metabolic parameters such as respiratory metabolism, intake, body composition and glucose tolerance. We also measured T cell purity, cellular senescence, apoptosis, autophagy, cell death and mitochondrial function.

    Our results showed that transgenic mice exhibit better physical performance reduced frailty at advanced ages. Mice total body mass and body fat percentage were positively correlated with age in wild type mice but not in transgenic mice although no differences of intake were observed between strains. Additionally, a reduction of glucose intolerance in 15-23-month-old transgenic mice was observed. In T cells, increased autophagic response to starvation was observed in old transgenic mice-derived T cells compared to wild type-derived T cells. Additionally, apoptosis was increased in transgenic mice-derived T cells at 17-20 months of age under physiological conditions (freshly isolated cells). On the contrary, apoptosis was reduced in transgenic mice-derived T cells at 2-5 and 8-11 months of age under more hostile conditions (cultured cells), both in absence and in presence of the apoptotic inducer dexamethasone. When studying mitochondrial function of T cells, we also observed a significantly reduction of oxygen consumption rate and proton leak under basal conditions in 2-5 and 8-11-month-old transgenic mice-derived T cells compared to wild type mice-derived T cells.

    In conclusion, BCL-XL overexpression in T cells attenuates physical performance and prevents frailty during aging, helps to maintain a youthful body composition and enhanced glucose tolerance in transgenic mice. In addition, T cells overexpressing BCL-XL exhibit an enhanced cellular function by being more resistant to apoptosis under stressful conditions, showing an improved autophagic response to starvation and having a lower oxygen consumption and proton leak.