AAV-mediated expression of secreted and transmembrane αKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice
Roig-Soriano, Joan (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Griñán-Ferré, Christian (Universitat de Barcelona. Institut de Neurociències)
Espinosa-Parrilla, J. F. (Universitat Autònoma de Barcelona)
Abraham, Carmela R (Boston University School of Medicine)
Bosch i Merino, Assumpció (Instituto de Salud Carlos III)
Pallàs, Mercè (Universitat de Barcelona. Institut de Neurociències)
Chillón Rodríguez, Miguel (Institució Catalana de Recerca i Estudis Avançats)

Date:	2022
Abstract:	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. Intraventricular administration of AAV vectors expressing secreted and transmembrane Klotho isoforms, rescued accelerated aging phenotype of SAMP8 mice. An improvement in cognitive and physical performance, recovery of epigenetic, inflammatory and senescence markers, as well as structural changes in long bones of these mice was detected.
Grants:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-106 Agencia Estatal de Investigación PID2019-104034RB-I00 Agencia Estatal de Investigación PID2020-116735RB-I00 Ministerio de Economía y Competitividad PCIN-2015-229 Ministerio de Economía, Industria y Competitividad SAF2016-33307
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	AAV9 ; Anti-aging ; Epigenetics ; Klotho ; Neurodegeneration ; Osteoporosis ; SAMP8 ; Senescence
Published in:	Aging Cell, Vol. 21 (march 2022) , ISSN 1474-9726

DOI: 10.1111/acel.13581
PMID: 35274439

15 p, 2.1 MB

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