A dual MTOR/NAD+ Acting Gerotherapy

This is a new pre-print paper from Tim Peterson’s company Bio IO that is focusing on longevity drugs. This seems potentially of interest for people here because of our interest both in mTOR and the NAD+ pathways and because many people here seem to use NAD boosters. Tim is leader of a Lab at the Washington University in St. Louis, and worked for a time in the Sabatini lab. He’s also doing interesting work on senolytics. See the last post here: Senolytics Topically Administered to Skin for Antiaging Effects - #31 by DrM

The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it’s largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with a novel class of N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, we identified lipid metabolism centering on SIRT3 as a point of intersection of the mTOR/insulin and NAD+ pathways. In vivo testing indicated that BIOIO-1001 reduced high fat, high sugar diet-induced metabolic derangements, inflammation, and fibrosis, each being characteristic of non-alcoholic steatohepatitis (NASH). An unbiased screen of patient datasets suggested a potential link between the anti-inflammatory and anti-fibrotic effects of BIOIO-1001 in NASH models to those in amyotrophic lateral sclerosis (ALS). Directed experiments subsequently determined that BIOIO-1001 was protective in both sporadic and familial ALS models. Both NASH and ALS have no treatments and suffer from a lack of convenient biomarkers to monitor therapeutic efficacy. A potential strength in considering BIOIO-1001 as a therapy is that the blood biomarker that it modulates, namely plasma triglycerides, can be conveniently used to screen patients for responders. More conceptually, to our knowledge BIOIO-1001 is a first therapy that fits the geroscience hypothesis by acting on multiple core aging pathways and that can alleviate multiple conditions after they have set in.

2023.01.16.523975v1.fullSmall.pdf (1.7 MB)

It’s very interesting that rapamycin and NAD have Sirt3 as a common pathway.
Also interesting, at least in regards to prevention of ALS, elevation of triglycerides is a positive biomarker.
The other way to upregulate Sirt3 is with honokiol, one of the main components of magnolia bark.

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Yep. Honokiol.

The below article points to other Sirt3 activators; it claims that

“A recent study by Karnewar et al. showed that metformin increases SIRT3 activity and delays endothelial senescence and vascular aging.”

It also mentions rhodiola rosea and Dihydromyricetin

This second article points to plain myricetin, not dihydromyricetin.

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