Bring Out Your Dead… I’m Not Dead Yet (8+ Benefits Of Reducing Indy)

Bring Out Your Dead… I’m Not Dead Yet (8+ Benefits Of Reducing Indy)

Reducing the expression of the gene INDY has shown to improve the health and longevity of humans, flies, mice, and worms. R

In this post, we will discuss the benefits of lower INDY levels and how to prevent higher INDY levels.

Contents:

  1. Basics Of Indy

  2. Benefits Of Reduced Indy

  3. How To Reduce Indy Expression

  4. What Increases INDY Expression?

  5. Caveats

  6. Mechanism Of Action

Basics Of Indy

I’m Not Dead Yet (INDY) is a gene that has shown to play a role in longevity and metabolism.

Its name originates from a well-known comic line in Monty Python and the Holy Grail. R

In a nutshell, reducing INDY promotes longevity by mimicing the benefits of Caloric Restriction (CR):

  • Increase Mitochondrial Growth, Insulin Sensitivity, and Intestinal Stem Cell Integrity R

  • Prevent Fatty Liver Disease, Insulin Resistance and Weight Gain R

In humans, Indy mRNA is mainly expressed in the liver, less in the brain and testis, while small levels of Indy mRNA expression were found in the kidneys, thymus, ovaries, adipose tissue, stomach, and colon. R R

Benefits Of Reduced Indy

1. Increases Longevity

Reduced expression of the Indy gene in flies and worms has showed to extend longevity in all, but one study. R R R R R R R R

One way it does this is by increasing AMPK (more discussed below). R

2. Mimics Caloric Restriction

Reducing INDY expression can mimic the important aspects of caloric restriction (in flies, worms, and mice so far) without reducing any caloric intake. R R

For example, compared to normal mice during the aging process on a high fat diet, knockdown of INDY in mice gain less weight, have reduced liver fat, less insulin resistance and increased insulin sensitivity. R R

Flies with lower Indy expression have decreased whole body fat stores, lower expression of insulin-like proteins, and increased mitochondrial numbers. R R

Reduces INDY expression in elderly flies have also shown to increase spontaneous physical activity. R

See post on other caloric restriction mimetics for more info.

3. Increases Mitochondrial Biogenesis

Lower INDY levels can increase the growth of new mitochondria (mitochondrial biogensis).

For example, reduced INDY levels are associated with reduced Adenosine Triphosphate (ATP) levels, which in turn activates AMP-activated Protein Kinase (AMPK), an energy sensor in the cells, which increases mitochondrial biogenesis by activating mitochondrial transcriptional co-activator peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α). R R R R R

4. Preserves Intestinal Stem Cell Homeostasis

Preservation of Intestinal Stem Cell (ISC) homeostasis has a key role in maintaining normal midgut function and contributes to extended health and longevity. R

Reducing Indy expression increases PGC-1 in the gut and redox status the gut leading to longevity extension and ISC homeostasis. R

5. Increases Weight Loss

When INDY levels are low, citrate levels are lower, thus activity of beta-oxidation is increased and Fatty Acid Synthesis (FAS) is upregulated. R

Reduced Indy also helps against weight gain. R

6. Insulin Resistance

mIndy is increased in liver of obese humans and non-human primates with Non-Alcoholic Fatty Liver Disease (NAFLD). R

For example, in insulin resistant patients with NAFLD , hepatic mINDY expression is increased. R

Reduction of INDY reduces liver accumulation of diacylglycerols (DAG) and ceramides, thus helping prevent the development of insulin resistance and Type 2 Diabetes (T2D). R

INDY reduction may also counteract Non-Alcoholic Steatohepatitis (NASH) development from a diet low in Methionine and Choline. R

AMPK also increases insulin sensitivity, contributing to the beneficial effects of Indy reduction on glucose metabolism. R

7. May Reduce Cancer

Indy is a member of SLC13A5 transporter and reducing expression of SLC13A5 has shown to protect against liver cancer. R

8. May Reduce Inflammation

Interleukin-6 (IL-6), an inflammatory mediator, was identified as a regulator of mIndy by binding to its cognate receptor. R

IL-6 markedly induced mIndy transcription via the IL-6-receptor (IL-6R) and activation Signal Transducer and Activator of Transcription 3 (STAT3). R

In vivo, activation of the IL-6-Stat3 pathway stimulates mIndy expression, enhances cytoplasmic citrate influx and augments fat accumulation in the liver. R

In contrast, deletion of mIndy expression completely prevents the stimulating effect of IL-6 on citrate uptake and reduces liver inflammation. R

How To Reduce Indy Expression

How to reduce Indy expression:

  • Caloric restriction (flies ages on a CR diet have INDY mRNA reduces to 50% of controls) R R

  • Compound 2 R

  • Compound 4a R

  • Small dicarboxylate molecules - selectively inhibit mIndy citrate uptake in vitro in human hepatocytes and hepatic citrate uptake in vivo in mice. R

  • Starvation (INDY is regulated by glucagon released during early starvation; glucagon binds to the CREB (cAMP-dependent and cAMP-responsive element protein)-dependent binding site in the promoter region of mIndy and transiently increases mIndy expression) R R

  • Tocilizumab R

  • 2′-O-methoxyethyl chimeric antisense oligonucleotides R

What Increases Indy Expression?

  • Aging R

  • Aryl hydrocarbon receptor (AhR, such as energy-rich diet or benzo[a]pyrene) R

  • High Caloric Diet R

  • High Fat + High Sugar Diet (primates) R

  • IL-6 R

  • Lipopolysaccharide (LPS increases INDY 5-fold) R

  • Lithium R

  • Oxidative Stress R

  • Paraquat R

  • Pregnane X Receptor (PXR) R

  • Rifampicin R

  • STAT3 R

Caveats

INDY heterozygous flies lay more eggs during their life compared to controls, however, under CR condition, Indy heterozygous flies have reduced fecundity due to lower energy resource caused by the effect of reduced Indy on metabolism. R

CR does not further extend longevity of long-lived Indy heterozygous flies and shortens longevity of Indy homozygous flies. R

mIndy mutations are also associated with neonatal epilepsy, developmental delays, and variable cognitive impairment. R

Epilepsy may be due to disrupted energy production and altered metabolism in brain cells, an imbalance in GABA and glutamate production, or a reduced inhibition of excitatory N-Methyl-D-Aspartate (NMDA) receptors. R

It is important to note that mIndy-/- mice or mice treated with small mIndy competitive inhibitors did not develop seizures. R

Mechanism Of Action

Simple (reducing INDY):

  • Increases AMPK R

  • Increases PGC-1α R R

  • Reduces ATP R

  • Reduces Citrate R

  • Reduces ROS R

Advanced:

  • The Indy gene product is a cation-independent, electroneutral tricarboxylate carrier, able to transport citrate across the plasma membrane as its preferred substrate. R