The longevity gene mIndy (I’m Not Dead, Yet) affects blood pressure through sympathoadrenal mechanisms

Abstract

Reduced expression of the plasma membrane citrate transporter INDY (acronym I’m Not Dead, Yet ) extends life span in lower organisms. Deletion of the mammalian Indy ( mIndy ) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.

Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder

“…In addition to a neurologic phenotype, loss of SLC13A5 in mice reduces growth parameters such as weight and length [15,16]. Loss of SLC13A5 in mice also reduces blood pressure and heart rate [16]. These data suggest that reduced citrate transport may have widespread consequences beyond the previously described neurologic phenotype in the patients.…”

“…In addition to growth inhibition, rodents with loss of SLC13A5 had decreased blood pressure and heart rates [16]. It will be important for future studies to investigate whether SLC13A5 Citrate Transporter Disorder patients show differences in cardiovascular function.…”

“…Mice lacking SLC13A5 show increased propensity for seizures as part of the neurologic phenotype [14]. In addition to a neurologic phenotype, loss of SLC13A5 in mice reduces growth parameters such as weight and length [15,16]. Loss of SLC13A5 in mice also reduces blood pressure and heart rate [16].…”

INDY as a Therapeutic Target for Cardio-Metabolic Disease

“…In a recent study, blood pressure was measured through implanted telemetry probes in freely moving mIndy knockout mice and in wildtype controls [ 43 ]. Animals were on standard chow, and body composition did not differ between groups.…”

“…Concomitant reductions in blood pressure and in heart rate could point towards centrally mediated sympathetic inhibition in mIndy knockout animals. Indeed, urinary norepinephrine and epinephrine excretion was substantially reduced in mIndy knockout mice [ 43 ].…”