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Refeeding-associated AMPK_γ1 complex activity is a hallmark of health and longevity.

ABSTRACT: 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 AMPK_γ1 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 AMPK_γ1 prevents metabolic quiescence and preserves healthy aging in vertebrates, offering potential avenues for intervention.

SUBMITTER: Ripa R

PROVIDER: S-EPMC10724066 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Refeeding-associated AMPK<sub>γ1</sub> complex activity is a hallmark of health and longevity.

Ripa Roberto R Ballhysa Eugen E Steiner Joachim D JD Laboy Raymond R Annibal Andrea A Hochhard Nadine N Latza Christian C Dolfi Luca L Calabrese Chiara C Meyer Anna M AM Polidori Maria Cristina MC Müller Roman-Ulrich RU Antebi Adam A

Nature aging 20231113 12

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 tr ...[more]

PMID: 37957359

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Project description:The basic reproduction ratio, R0, is a fundamental concept in epidemiology. It is defined as the total number of secondary infections brought on by a single primary infection, in a totally susceptible population. The value of R0 indicates whether a starting epidemic reaches a considerable part of the population and causes a lot of damage, or whether it remains restricted to a relatively small number of individuals. To calculate R0 one has to evaluate an integral that ranges over the duration of the infection of the host. This duration is, of course, limited by remaining host longevity. So, R0 depends on remaining host longevity and in this paper we show that for long-lived hosts this aspect may not be ignored for long-lasting infections. We investigate in particular how this epidemiological measure of pathogen fitness depends on host longevity. For our analyses we adopt and combine a generic within- and between-host model from the literature. To find the optimal strategy for a pathogen from an evolutionary point of view, we focus on the indicator [Formula: see text], i.e., the optimum of R0 as a function of its replication and mutation rates. These are the within-host parameters that the pathogen has at its disposal to optimize its strategy. We show that [Formula: see text] is highly influenced by remaining host longevity in combination with the contact rate between hosts in a susceptible population. In addition, these two parameters determine whether a killer-like or a milker-like strategy is optimal for a given pathogen. In the killer-like strategy the pathogen has a high rate of reproduction within the host in a short time span causing a relatively short disease, whereas in the milker-like strategy the pathogen multiplies relatively slowly, producing a continuous small amount of offspring over time with a small effect on host health. The present research allows for the determination of a bifurcation line in the plane of host longevity versus contact rate that forms the boundary between the milker-like and killer-like regions. This plot shows that for short remaining host longevities the killer-like strategy is optimal, whereas for very long remaining host longevities the milker-like strategy is advantageous. For in-between values of host longevity, the contact rate determines which of both strategies is optimal.

Project description:The AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by sensing the metabolic status of the cell. AMPK is regulated by phosphorylation and dephosphorylation as a result of changing AMP/ATP levels and by removal of inhibitory ubiquitin residues by USP10. In this context, we identified the GID-complex, an evolutionarily conserved ubiquitin-ligase-complex (E3), as a negative regulator of AMPK activity. Our data show that the GID-complex targets AMPK for ubiquitination thereby altering its activity. Cells depleted of GID-subunits mimic a state of starvation as shown by increased AMPK activity and macroautophagic/autophagic flux as well as reduced MTOR activation. Consistently, gid-genes knockdown in C. elegans results in increased organismal lifespan. This study may contribute to understand metabolic disorders such as type 2 diabetes mellitus and morbid obesity and implements alternative therapeutic approaches to alter AMPK activity.AbbreviationsACTB: actin, beta; ADP: adenosine diphosphate; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ARMC8: armadillo repeat containing 8; ATP: adenosine triphosphate; BafA1: bafilomycin A1; BCAA: branched chain amino acid; BICC1: BicC family RNA binding protein 1; BSA: bovine serum albumin; CAMKK2 kinase: calcium/calmodulin dependent protein kinase kinase 2, beta; CHX: cycloheximide; DMEM: Dulbecco's modified Eagle's medium; E1: ubiquitin-activating enzyme; E2: ubiquitin-conjugating enzyme; E3: ubiquitin ligase; ECAR: extracellular acidification rate; FACS: fluorescent associated cell sorter; FBP1: fructose-bisphosphatase 1; FCCP: carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone; G6P: glucose-6-phosphate; GDP: guanosine diphosphate; GFP: green fluorescent protein; GID: glucose induced degradation deficient; GMP: guanosine monophosphate; GTP: guanosine triphosphate; HBP1: high mobility group box transcription factor 1; HPRT: hypoxanthine guanine phosphoribosyl transferase; KO: knock out; LE: long exposure; MAEA: macrophage erythroblast attacher; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MKLN1: muskelin 1; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin; NES: normalized enrichment score; OCR: oxygen consumption rate; PBS: phosphate buffered saline; PCK1: phosphoenolpyruvate carboxykinase 1, cytosolic; PCR: polymerase chain reaction; PFA: paraformaldehyde; RANBP9: RAN binding protein 9; RING: really interesting new gene; RMND5: required for meiotic nuclear division5 homolog; RPS6: ribosomal protein S6; RPTOR: regulatory associated protein of MTOR, complex 1; SE: short exposure; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TSC2: tuberous sclerosis complex 2; TUBA4A: tubulin; TUBE: tandem ubiquitin binding entities; Ub: ubiquitin; UPS: ubiquitin proteasome system; WDR26: WD repeat domain 26; WT: wild type.

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Refeeding-associated AMPK_γ1 complex activity is a hallmark of health and longevity.

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Refeeding-associated AMPK<sub>γ1</sub> complex activity is a hallmark of health and longevity.

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

Publications

Refeeding-associated AMPK<sub>γ1</sub> complex activity is a hallmark of health and longevity.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Refeeding-associated AMPK_γ1 complex activity is a hallmark of health and longevity.