The Longevity Gene Mindy (I'm Not Dead, Yet) Affects Blood Pressure Through Sympathoadrenal Mechanisms

Willmes, Diana M.; Schumann, Tina; Henke, Christine; Kurzbach, Anica; Luft, Friedrich C.; Morawietz, Henning; Helfand, Stephen L.; El‐Armouche, Ali; Mueller, Dominik N; Bornstein, Stefan R.; Tank, Jens; Eisenhofer, Graeme; Daniels, Martin A.; Jordan, Jens; Birkenfeld, Andreas L.

doi:10.1016/s0735-1097(18)32354-4

Cited by 3 publications

(3 citation statements)

References 55 publications

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“…Particularly promising is use of mINDY inhibitors in hepatocarcinoma cells due to their effects on energy required for proliferation and negative effects on oncogenic mTOR signaling. Recent studies in mINDY-KO mice indicate potential use of mINDY inhibitors for regulating blood pressure, increasing motor coordination, and promoting social and recognition memory in mice [ 12 , 53 , 88 ]. There is also an urgent need to study the mechanisms of negative effects of m Indy mutations in neonatal epilepsy in model organisms expressing m Indy human mutations to provide insights for future therapies.…”

Section: Discussionmentioning

confidence: 99%

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Kannan

Rogina

2021

Metabolites

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I’m Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels.

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Section: Discussionmentioning

confidence: 99%

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Kannan

Rogina

2021

Metabolites

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“…These mice are resistant to diet-induced obesity, insulin resistance, diabetes, and other symptoms of metabolic syndrome. A more recent report highlighted another biological feature that is common to Slc13a5 knockout and caloric restriction in mice [32]. This involves the control of blood pressure where total loss of Slc13a5 reduces arterial blood pressure and heart rate via attenuation of catecholamine synthesis in a sympathetic nervous system and adrenal medulla.…”

Section: Biological Consequences Of Slc13a5 Deficiency In Mammals Including Humansmentioning

confidence: 99%

Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions

et al. 2021

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INDY (I’m Not Dead Yet) is a plasma membrane transporter for citrate, first identified in Drosophila. Partial deficiency of INDY extends lifespan in this organism in a manner similar to that of caloric restriction. The mammalian counterpart (NaCT/SLC13A5) also transports citrate. In mice, it is the total, not partial, absence of the transporter that leads to a metabolic phenotype similar to that caloric restriction; however, there is evidence for subtle neurological dysfunction. Loss-of-function mutations in SLC13A5 (solute carrier gene family 13, member A5) occur in humans, causing a recessive disease, with severe clinical symptoms manifested by neonatal seizures and marked disruption in neurological development. Though both Drosophila INDY and mammalian INDY transport citrate, the translocation mechanism differs, the former being a dicarboxylate exchanger for the influx of citrate2− in exchange for other dicarboxylates, and the latter being a Na+-coupled uniporter for citrate2−. Their structures also differ as evident from only ~35% identity in amino acid sequence and from theoretically modeled 3D structures. The varied biological consequences of INDY deficiency across species, with the beneficial effects predominating in lower organisms and detrimental effects overwhelming in higher organisms, are probably reflective of species-specific differences in tissue expression and also in relative contribution of extracellular citrate to metabolic pathways in different tissues

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“…Citrate is particularly interesting because it has been implicated in ageing (Menni et al, 2013; Rogina, 2017), caloric restiction (Rogina, 2017), type 2 diabetes (Birkenfeld et al, 2011; Brachs et al, 2016), blood pressure (Willmes et al, 2021), heart rate (Willmes et al, 2021), memory (Fan et al, 2021) and cancer (Mycielska et al, 2018). Dietary citrate also induces adipocyte inflammation and pre-insulin resistance in mice (Leandro et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Telomerase deficiency in humans is associated with systemic age-related changes in energy metabolism

James

Sagi‐Kiss

Bennett

et al. 2022

Preprint

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SUMMARYUnderlying mechanisms of plasma metabolite signatures of human ageing and age-related diseases are not clear but telomere attrition and dysfunction are central to both. Dyskeratosis Congenita (DC) is associated with mutations in the telomerase enzyme complex (TERT, TERC, DKC1) and progressive telomere attrition. We show extracellular citrate is repressed by canonical telomerase function in vitro and associated with DC leukocyte telomere attrition in vivo; leading to the hypothesis that altered citrate metabolism detects telomere dysfunction. However, citrate and senescence factors only weakly distinguished DC patients from controls, whereas other tricarboxylic acid cycle metabolites, lactate and especially pyruvate distinguished them with high significance, consistent with further metabolism of citrate and lactate in the liver and kidneys. Citrate uptake in certain organs modulates age-related disease in mice and our data has similarities with age-related disease signatures in humans. Our results have implications for the early diagnosis of telomere dysfunction and anti-senescence therapeutics.HighlightsExtracellular citrate is regulated by telomere function in vitro and in vivo.Dyskeratosis Congenita (DC) is a human disease characterized by systemic telomere attrition, which showed an age-related plasma energetic profile, distinct from age-related disease and that of centenarians.The DC profile strikingly out-performed senescence factors in discriminating DC from controls, and pyruvate associated with a low lactate:pyruvate ratio is potentially a useful and cheap minimally invasive diagnostic aid for DC and telomere dysfunction.Mechanistically DC systemic metabolism is indicative of a shift to reduced pyruvate dehydrogenase activity, glycolysis and/or increased citrate and lactate production followed by further metabolism in the kidneys and liver.

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The Longevity Gene Mindy (I'm Not Dead, Yet) Affects Blood Pressure Through Sympathoadrenal Mechanisms

Cited by 3 publications

References 55 publications

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions

Telomerase deficiency in humans is associated with systemic age-related changes in energy metabolism

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