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Resum
Senescence represents a stage in life associated with elevated incidence of morbidity and increased risk of mortality due to the accumulation of molecular alterations and tissue dysfunction, promoting a decrease in the organism's protective systems. Thus, aging presents molecular and biological hallmarks, which include chronic inflammation, epigenetic alterations, neuronal dysfunction, and worsening of physical status. In this context, we explored the AAV9-mediated expression of the two main isoforms of the aging-protective factor Klotho (KL) as a strategy to prevent these general age-related features using the senescence-accelerated mouse prone 8 (SAMP8) model. Both secreted and transmembrane KL isoforms improved cognitive performance, physical state parameters, and different molecular variables associated with aging. Epigenetic landscape was recovered for the analyzed global markers DNA methylation (5-mC), hydroxymethylation (5-hmC), and restoration occurred in the acetylation levels of H3 and H4. Gene expression of pro- and anti-inflammatory mediators in central nervous system such as TNF-α and IL-10, respectively, had improved levels, which were comparable to the senescence-accelerated-mouse resistant 1 (SAMR1) healthy control. Additionally, this improvement in neuroinflammation was supported by changes in the histological markers Iba1, GFAP, and SA β-gal. Furthermore, bone tissue structural variables, especially altered during senescence, recovered in SAMP8 mice to SAMR1 control values after treatment with both KL isoforms. This work presents evidence of the beneficial pleiotropic role of Klotho as an anti-aging therapy as well as new specific functions of the KL isoforms for the epigenetic regulation and aged bone structure alteration in an aging mouse model.
Idioma original | Anglès |
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Número d’article | e13581 |
Nombre de pàgines | 15 |
Revista | Aging Cell |
Volum | 21 |
Número | 4 |
DOIs | |
Estat de la publicació | Publicada - d’abr. 2022 |
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Navegar pels temes de recerca de 'AAV-mediated expression of secreted and transmembrane αKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice'. Junts formen un fingerprint únic.Projectes
- 2 Acabat
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TERAPIA GENICA PARA ESCLEROSIS LATERAL AMIOTROFICA DIRIGIDA A ESTIMULAR LA NEUROPROTECCION Y LA MODULACION DE LA NEUROINFLAMACION
Edo Salvador, A. (Investigador/a), Bosch, A. (PI), Rey Azpiri, J. D. (Col.laborador/a), Tarrés Mercader, M. (Col.laborador/a), Sanchez Osuna, A. (Investigador/a), Verdes Franquesa, S. (Col.laborador/a) & Onieva Salgado, A. (Col.laborador/a)
1/09/21 → 31/08/24
Projecte: Projectes i Ajuts a la Recerca
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MOLECULAR AND FUNCTIONAL CHARACTERIZATION OF NEW RECOMBINANT CHIMERIC CHRONOKINES. IMPLICATIONS FOR COGNITIVE DECLINE ASSOCIATED WITH AGING
Chillón Rodriguez, M. (PI), ABRAHAM, C. (Col.laborador/a), Blanch Garcia, R. (Col.laborador/a), Cabrera Hurtado, M. (Col.laborador/a), EDO SALVADOR, A. (Col.laborador/a), Esandi Jaúregui, J. (Col.laborador/a), Miravet Delgado, S. (Col.laborador/a), Ontiveros Gonzalez, M. (Col.laborador/a), Puig Ferrer, M.-T. (Col.laborador/a), Roig Soriano, J. (Col.laborador/a), Rubio i Ortega, L. (Col.laborador/a) & ESPINOSA PARRILLA, J. F. (Investigador/a)
1/06/20 → 31/05/23
Projecte: Projectes i Ajuts a la Recerca