AGE/DOSE
Metabolism

A New Pharmaceutical Targeting Both NAD⁺ and mTOR Pathways Shows Efficacy Against NASH and ALS

Recently developed BIOIO-1001 modulates two aging pathways to alter fat metabolism and improves the age-related conditions non-alcoholic steatohepatitis (NASH) and amyotrophic lateral sclerosis (ALS) in mice.

By Bennett M. Sherman

Key Points

  • Researchers genetically analyzed human cells to find two aging pathways related to lipid (fat) metabolism – nicotinamide adenine dinucleotide (NAD+) metabolism and mammalian target of rapamycin (mTOR) – targeted by BIOIO-1001.
  • BIOIO-1001 reduces liver enzymes associated with scarring and disease in NASH mice.
  • The pharmaceutical extends life without paralysis and overall lifespan in ALS mice.

The geroscience hypothesis proposes that a therapeutic treating an underlying aging process should prevent multiple age-related diseases. Two examples of pathways that researchers have targeted to treat multiple aging-associated conditions are NAD+ metabolism and the mTOR pathway. Yet how these two pathways relate to one another and whether drugs can target both simultaneously has been unexplored, until now.

In a non-peer reviewed publication, Peterson and colleagues from the Washington University School of Medicine in St. Louis showed that a novel molecule called BIOIO-1001 targets both NAD+ metabolism and the mTOR pathway. By improving fat metabolism, BIOIO-1001 alleviated fibrosis in a mouse model of non-alcoholic steatohepatitis and extended life without paralysis and overall lifespan in a mouse model of ALS. Peterson and colleagues’ publication presents an intriguing idea that pharmaceuticals may converge on more than one aging pathway to treat multiple conditions.

BIOIO-1001 Treats NASH and ALS by Targeting mTOR and NAD+

Peterson and colleagues utilized CRISPRa (CRISPR activation) technology, a means to increase protein production from specific genes, in human cells to find which proteins were sensitized to high BIOIO-1001 concentrations. Interestingly, they found two proteins involved in lipid metabolism – lipin1 (LPIN1) and sirtuin3 (SIRT3) – from the mTOR and NAD+ metabolism pathways, respectively, that were sensitized to the drug. These findings indicate that by targeting these two proteins involved in fat metabolism, BIOIO-1001 converges on molecules from two aging pathways.

Because fat metabolism plays a significant role in NASH (liver inflammation) pathology, the Washington University-based team assessed whether BIOIO-1001 can treat NASH in mice. The researchers fed mice a NASH-inducing high-fat diet for three months and then treated with BIOIO-1001 for three weeks. The researchers measured liver alanine transaminase (ALT) levels – an indicator of liver inflammation and disease – to find whether BIOIO-1001 mitigates NASH. They found that while NASH significantly increased liver ALT concentrations, BIOIO-1001 lowered them. These results show that BIOIO-1001 can be used to effectively ameliorate NASH in a mouse model.

(Li et al., 2023 | bioRxiv) BIOIO-1001 reduces levels of the inflammation and disease-associated enzyme alanine transaminase (ALT) in mice with NASH. Mice fed a NASH-inducing diet (HTF-C) showed significantly elevated ALT levels, yet BIOIO-1001 (1001) diminished them. Treatment with the anti-diabetes drug pioglitazone (PIO) had a similar effect.

Because fat metabolism plays a role in other age-related diseases like ALS, Peterson and colleagues measured how BIOIO-1001 affects an ALS mouse model. The researchers utilized mice with an ALS-inducing mutation and treated them with BIOIO-1001. Compared to untreated ALS mice, those treated with BIOIO-1001 showed a 29% increase in the days it took for paralysis to set in. Interestingly, BIOIO-1001 also increased the lifespan of ALS mice by 26%. These findings show that BIOIO-1001 not only can also be used to treat mouse models of ALS.

(Li et al., 2023 | bioRxiv) BIOIO-1001 extends life without paralysis and overall lifespan in mice with ALS. F) Mice with ALS that were given BIOIO-1001 had a 29% increase in their life spent without paralysis. G) ALS mice given BIOIO-1001 had a 26% extension to their remaining lifespan.

Rapamycin, a molecule that targets the mTOR pathway, has been shown to increase mouse lifespan. Moreover, increasing NAD+ with its precursor NMN has been shown to mitigate cardiovascular, metabolic, and neurological diseases. BIOIO-1001 converges on these two aging-related pathways, and Peterson and colleagues showed that by doing so, it can be used to treat two aging-related diseases – NASH and ALS.

Finding New Ways to Treat Diseases with Fat Metabolism Pathology

Other research has shown synergistic effects of using multiple molecules like nicotinamide mononucleotide (NMN) and Chinese herbal supplements to target more than one aging pathway to protect organs like the heart during chemotherapy. This is the first study that shows a single compound targets multiple age-associated pathways to treat more than one disease. Future studies should examine other compounds that target mTOR and NAD+ metabolism at the same time by converging on fat metabolism proteins LPIN1 and SIRT3. Researchers could then make better drugs to combat NASH and ALS. Moreover, researchers should find whether BIOIO-1001 can treat other age-related conditions with fat metabolism pathology like diabetes and kidney disease.

Model and Dosage

Model: C57BL/6J mice and SOD1 G93A mutant mice

Dosage: 30 mg/kg/day of BIOIO-1001 and 30 mg/kg/day of pioglitazone

Source

Li J, Kumar S, Miachin K, Bean NL, Halawi O, Lee S, Park J, Pierre TH, Hor JH, Ng SY, Wallace KJ, Rindtorff N, Miller TM, Niehoff ML, Farr SA, Kletzien RF, Colca J, Tanis SP, Chen Y, Griffett K, McCommis KS, Finck BN, Peterson TR. A dual MTOR/NAD+ acting gerotherapy. bioRxiv [Preprint]. 2023 Jan 19:2023.01.16.523975. doi: 10.1101/2023.01.16.523975. PMID: 36711589; PMCID: PMC9882180.

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