Genetic perturbation of AMP biosynthesis extends lifespan and restores metabolic health in a naturally short-lived vertebrate

Astre, Gwendoline; Atlan, Tehila; Goshtchevsky, Uri; Oron-Gottesman, Adi; Smirnov, Margarita; Shapira, Kobi; Velan, Ariel; Deelen, Joris; Levy, Tomer; Levanon, Erez Y.; Harel, Itamar

doi:10.1016/j.devcel.2023.05.015

Cited by 11 publications

(2 citation statements)

References 191 publications

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“…The specific sample sizes can be found in the figure legends. We did not use a statistical method to predetermine the sample size; however, they are consistent with those reported in previous studies on the same topic 47 , 51 , 56 , 57 , 62 . Fish were indiscriminately allocated to groups for all experiments and no data were excluded from our study.…”

Section: Methodssupporting

confidence: 83%

“…This could indicate that AMPK γ2 function is physiologically required exclusively upon fasting and explains why, unlike AMPK γ1 , chronic activation of AMPK γ2 leads to metabolic dysfunction in normally fed mice or humans. Astre et al showed that mutation in the APRT gene, a key enzyme in AMP biosynthesis, mimics a caloric-restriction effect, inducing lifespan extension in killifish males 57 . This effect was associated with higher expression of the γ2 subunit.…”

Section: Discussionmentioning

confidence: 99%

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Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity

Ripa,

Ballhysa,

Steiner

et al. 2023

Nat Aging

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Late-life-initiated dietary interventions show limited efficacy in extending longevity or mitigating frailty, yet the underlying causes remain unclear. Here we studied the age-related fasting response of the short-lived killifish Nothobranchius furzeri. Transcriptomic analysis uncovered the existence of a fasting-like transcriptional program in the adipose tissue of old fish that overrides the feeding response, setting the tissue in persistent metabolic quiescence. The fasting–refeeding cycle triggers an inverse oscillatory expression of genes encoding the AMP-activated protein kinase (AMPK) regulatory subunits Prkag1 (γ1) and Prkag2 (γ2) in young individuals. Aging blunts such regulation, resulting in reduced Prkag1 expression. Transgenic fish with sustained AMPKγ1 countered the fasting-like transcriptional program, exhibiting a more youthful feeding and fasting response in older age, improved metabolic health and longevity. Accordingly, Prkag1 expression declines with age in human tissues and is associated with multimorbidity and multidimensional frailty risk. Thus, selective activation of AMPKγ1 prevents metabolic quiescence and preserves healthy aging in vertebrates, offering potential avenues for intervention.

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