Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2067/48981
Titolo: Young transgenic hMTH1 mice are protected against dietary fat-induced metabolic stress—implications for enhanced longevity
Autori: Marcon, Francesca
Meschini, Roberta 
Iorio, Egidio
Palleschi, Simonetta
De Luca, Gabriele
Siniscalchi, Ester
Conti, Luigi
Chirico, Mattea
Pisanu, Maria Elena
De Battistis, Francesca
Rossi, Barbara
Minoprio, Anna
Giuliani, Alessandro
Karran, Peter
Bignami, Margherita
Rivista: AGING CELL 
Data pubblicazione: 2022
hMTH1 protects against mutation during oxidative stress. It degrades 8-oxodGTP to exclude potentially mutagenic oxidized guanine from DNA. hMTH1 expression is linked to ageing. Its downregulation in cultured cells accelerates RAS-induced senescence, and its overexpression in hMTH1-Tg mice extends lifespan. In this study, we analysed the effects of a brief (5 weeks) high-fat diet challenge (HFD) in young (2 months old) and adult (7 months old) wild-type (WT) and hMTH1-Tg mice. We report that at 2 months, hMTH1 overexpression ameliorated HFD-induced weight gain, changes in liver metabolism related to mitochondrial dysfunction and oxidative stress. It prevented DNA damage as quantified by a comet assay. At 7 months old, these HFD-induced effects were less severe and hMTH1-Tg and WT mice responded similarly. hMTH1 overexpression conferred lifelong protection against micronucleus induction, however. Since the canonical activity of hMTH1 is mutation prevention, we conclude that hMTH1 protects young mice against HFD by reducing genome instability during the early period of rapid growth and maximal gene expression. hMTH1 protection is redundant in the largely non-growing, differentiated tissues of adult mice. In hMTH1-Tg mice, expression of a less heavily mutated genome throughout life provides a plausible explanation for their extended longevity.
URI: http://hdl.handle.net/2067/48981
ISSN: 1474-9726
DOI: 10.1111/acel.13605
Diritti: Attribution 4.0 International
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