A dual MTOR/NAD+ acting gerotherapy

Abstract

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 biomarkers 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.

Recent Insights into the Biomarkers, Molecular Targets and Mechanisms of Non-Alcoholic Steatohepatitis-Driven Hepatocarcinogenesis

“…It has been recently reported that natural products, including phenols, flavonoids, glycosides, quinones, terpenoids, pyrazines, alkaloids, and phenylpropanoids, have antioxidant, energy-producing, anti-inflammatory, anti-apoptotic, and anti-aging effects, which mainly influence the AMPK/Nrf2/mTOR, Nrf2/HO-1, NAMPT/NAD(+)/SIRT, AMPK/SIRT1/PGC-1alpha and PKCs/PARPs/NF-kB signaling pathways, thereby regulating NAD(+) metabolism to prevent and treat NAFLD [ 117 ]. Hepatoprotective effects, caused by the inhibition of PI3K/Akt/mTOR signaling and effective alleviation of oxidative stress damage and ER stress induced by excessive lipid accumulation in hepatocytes, and activation of autophagy were observed for agonists of AMPK thymoquinone [ 118 ] and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) [ 119 ], agonist of GLP-1/glucagon cotadutide [ 120 ], an antagonist of sphingosine 1-phosphate receptor 2 (S1PR2) JTE-013 [ 26 ], activator of PI3K, autophagy-related genes (ATG) and agonist of Nrf2, PPARα and hemeoxygenase-1 (HO-1) pterostilbene [ 121 ], flavonoid with antioxidant properties involving CYP7A1, quercetin [ 122 ], Pueraria flavonoids [ 92 ], a novel gerotherapy compound, BIOIO-1001 [ 123 ], a natural nonenzymatic antioxidant with low toxicity schisandrin B (Sch B) [ 124 ], H1-antihistamines (AHs) [ 125 ], fat soluble polyphenol Tanshinone IIA (TsIIA) [ 126 ], purendan (PRD) [ 127 ], down-regulating the expression of p-mTOR, p-S6K1 and SREBP-1c, chrysin [ 128 ], red pepper seed extract (RPS) [ 129 ], Gardenia Fructus (GF) extracts [ 130 ], curcumin [ 131 ], and magnesium [ 132 ].…”