A dual MTOR/NAD+ acting gerotherapy

Abstract

ABSTRACTThe 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.Brief SummaryThese studies characterize a novel gerotherapy, BIOIO-1001, that identifies lipid metabolism as an intersection of the mTOR and NAD+ pathways.