Regulation of multiple ageing-like phenotypes by inducible klotho gene expression in klotho mutant mice

Masuda, Hiroaki; Chikuda, Hirotaka; Suga, Tatsuo; Kawaguchi, Hiroshi; Kuro‐o, Makoto

doi:10.1016/j.mad.2005.07.007

Cited by 107 publications

(89 citation statements)

References 14 publications

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“…We have previously shown that PPAR gamma agonist ameliorated aging-related renal injury, in part by increasing Klotho expression. 25,26 In the current study, transplantation of young bone marrow significantly preserved Klotho expression and inhibited its downstream IGF-1 receptor ␤ phosphorylation in aging kidneys. Klotho may also regulate age-dependent stem cell regenerative capacity through the Wnt pathway.…”

Section: Discussionmentioning

confidence: 51%

Cells Derived from Young Bone Marrow Alleviate Renal Aging

Yang

Rossini²,

Ma³

et al. 2011

Journal of the American Society of Nephrology

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Bone marrow-derived stem cells may modulate renal injury, but the effects may depend on the age of the stem cells. Here we investigated whether bone marrow from young mice attenuates renal aging in old mice. We radiated female 12-mo-old 129SvJ mice and reconstituted them with bone marrow cells (BMC) from either 8-wk-old (young-to-old) or 12-mo-old (old-to-old) male mice. Transfer of young BMC resulted in markedly decreased deposition of collagen IV in the mesangium and less ␤-galactosidase staining, an indicator of cell senescence. These changes paralleled reduced expression of plasminogen activator inhibitor-1 (PAI-1), PDGF-B (PDGF-B), the transdifferentiation marker fibroblast-specific protein-1 (FSP-1), and senescence-associated p16 and p21. Tubulointerstitial and glomerular cells derived from the transplanted BMC did not show ␤-galactosidase activity, but after 6 mo, there were more FSP-1-expressing bone marrow-derived cells in old-to-old mice compared with young-to-old mice. Young-to-old mice also exhibited higher expression of the anti-aging gene Klotho and less phosphorylation of IGF-1 receptor ␤. Taken together, these data suggest that young bone marrow-derived cells can alleviate renal aging in old mice. Direct parenchymal reconstitution by stem cells, paracrine effects from adjacent cells, and circulating anti-aging molecules may mediate the aging of the kidney.

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Section: Discussionmentioning

confidence: 51%

Cells Derived from Young Bone Marrow Alleviate Renal Aging

Yang

Rossini²,

Ma³

et al. 2011

Journal of the American Society of Nephrology

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“…15,22,23 Our approach, however, is to not alter natural Klotho levels from the birth of the animal, until key stages in the aging process are reached. Then levels are specifically modified in the brain through administration of AAVrh10 vectors with neuronal tropism.…”

Section: Discussionmentioning

confidence: 99%

Secreted αKlotho isoform protects against age-dependent memory deficits

et al. 2017

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αKlotho is a gene regulator of aging, increasing life expectancy when overexpressed and accelerating the development of aging phenotypes when inhibited. In mice, expression levels of the secreted isoform Klotho (s-KL) are very high in the brain, suggesting that s-KL activity may have an important role in the nervous system. Here we study the functional relevance at behavioural level of modifying s-KL levels in the aging brain. We used AAVrh10 vectors to deliver and sustained expression of s-KL in 6-and 12-monthold wild-type C57BL/6J males. This study demonstrates for we believe the first time in vivo that 6 months after a single injection of s-KL into the central nervous system, long-lasting and quantifiable enhancement of learning and memory capabilities are found. More importantly, cognitive improvement is also observable in 18-month-old mice treated once, at 12 months of age. These findings demonstrate the therapeutic potential of s-KL as a treatment for cognitive decline associated with aging.

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“…In contrast, overexpression of the gene encoding klotho extends lifespan in the mouse. 15 Sirtuin 1 is a class III histone deacetylase that deacetylates not only histone substrates but also many key transcription factors and co-factors, such as p53, FoxOs, peroxisome proliferator-activated receptor ␥ (PPAR-␥) co-activator-1␣, and NF-B, [16][17][18][19] thereby affecting crucial cellular pathways involved in response to stress, metabolism, and possibly elongation of lifespan. NF-B activity may be a key link to age-related nephropathy and atherosclerosis.…”

Section: What Is Known About Cell Senescence?mentioning

confidence: 99%