Towards natural mimetics of metformin and rapamycin

Abstract

Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals—safer, naturally-occurring compounds—that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.

Using the drug-protein interactome to identify anti-ageing compounds for humans

“…We performed an interaction-based similarity analysis and found that the genotoxic compounds cluster separately from the other drugs, suggesting that they have a similar mechanism of action (S2 text). Similarities were also identified regarding the mechanisms of action of sorafenib and regorafenib, bexarotene and GW-501516, and sirolimus and ECGC, in agreement with previous studies [36].…”

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

“…In the present study, we show that ISLQ treatment increases cellular ROS, and that this is involved in mediating the cytotoxic effects of ISLQ on human NB cells. It is also worth noting that a recent study identified ISLQ as a natural mimetic of rapamycin [68], which is an FDA-approved mTOR inhibitor that has anti-carcinogenic effects in NB cells [69]. Treatment of NB cells with rapamycin for 24 h has been shown to increase cellular levels of ROS [70], which is consistent with the increases in cellular oxidative stress in MYCN-amplified SK-N-BE(2) cells induced by ISLQ treatment for 24 h, found in our study.…”

Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects

“…One of the most impactful applications of DL in biomedicine was in the applications of generative models to de novo molecular design [32][33][34][35][36] . In the context of aging research, these new methods can be combined for geroprotector discovery [37][38][39][40][41] . Indeed, since 2013, many aging clocks have been developed in both humans and other model organisms.…”

Withania somnifera (Indian ginseng) in diabetes mellitus: A systematic review and meta‐analysis of scientific evidence from experimental research to clinical application

“…Similarly, W. somnifera decreased MDA (a secondary product of LPO) levels in patients with type‐2 diabetes (Usharani, Fatima, et al, ; Usharani, Kishan, et al, ). The observed antioxidant activities of W. somnifera might be, majorly, attributed to its active constituent withaferin A—a steroidal lactone (Aliper et al, ; Lee et al, ) as well other bioactive elements—steroidal alkaloids/lactones such as withanine, somniferine, withanone sitoindosides VII–X and withanolide A, D and G (Durg et al, ; Mirjalili, Moyano, Bonfill, Cusido, & Palazón, ).…”

“…W. somnifera also showed glucose lowering activity through insulinotropic effects which improves insulin sensitivity by reducing hyperinsulinemia and insulin resistant besides improving glucose tolerance (Anwer et al, ). The recent in ‐ silico screening revealed that withaferin A mimics the anti‐aging properties of mTOR inhibitors, that is, metformin and rapamycin (Aliper et al, ); the two FDA‐approved drugs which tops the list of drugs mimicking caloric restriction (Ingram et al, ). Further, Lee et al demonstrated withaferin A as a potential leptin sensitizer with great anti‐diabetic effects in mice (Lee et al, ).…”