Longevity Gene INDY is Involved in Blood Pressure Control

The INDY gene has been known to affect longevity in a range of species for quite some time, as I noted at length back in 2015. It is more than 20 years now since INDY was first discovered to affect fly aging, and work continues to link the outcomes on life span to specific effects on aging and cell function. INDY has effects on metabolism that look a lot like those connected to calorie restriction. A such, it tends to improve every aspect of aging, making it challenging to sort out what is cause, what is consequence, what is important, and what is a side-effect. The research noted here is a representative example of incremental progress in understanding the effects of INDY on aging. I doubt this to be a path that leads to any practical outcome for human health and longevity.

Researchers have presented data showing that the longevity gene mammalian Indy (mINDY) is involved in blood pressure regulation. Reduced expression of mINDY, which is known to extend life span in lower organisms and to prevent from diet induced obesity, fatty liver, and insulin resistance in mice, has now been shown to lower blood pressure and heart rate in rodents.

The authors provided mechanistic insights for the underlying physiological mechanism based on in vivo data in a genetic knock out model as well as microarray and in vitro studies. Furthermore, the hypothesis is supported by confirming critical effects in vitro using a small molecule inhibitor of mINDY. The authors conclude that deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.

mIndy deletion attenuates sympathoadrenal support of blood pressure and reduced arterial blood pressure and heart rate in a murine knockout model. Blood pressure was assessed invasively using intra-arterial pressure probes over several days. Urinary analysis for catecholamines and metanephrines as well as unbiased transcriptomic analysis of adrenal glands identified the affected biosynthetic pathways. Indeed, catecholamine biosynthesis was attenuated in mINDY-knockout adrenals, whereas plasma steroids and steroid hormone synthesis were unaffected.

In vitro studies on an adrenal cell line supported this hypothesis. mIndy codes for a carboxylic acid transporter protein expressed in plasma membrane. Citrate, the main substrate of the mINDY transporter, increased catecholamine content, while pharmacological inhibition of mINDY by a small molecule inhibitor blunted the effect.

Link: https://www.eurekalert.org/pub_releases/2021-01/dzfd-tlg012621.php


Nervous System Deletion of Mammalian INDY in Mice Mimics Dietary Restriction-Induced Memory Enhancement (2021) https://doi.org/10.1093/gerona/glaa203
Tissue-specific deletion of mIndy in the nervous system is sufficient to improve memory performance. Mice with systemic or nervous system deletion of mIndy exhibit increased hippocampal neurogenesis and dendritic spine formation in dentate granule cells; these changes are well-documented contributors to enhanced memory performance.

Posted by: Dmitry Dzhagarov at February 2nd, 2021 3:30 PM

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