Small molecules for cell reprogramming: a systems biology analysis.

If somatic stem cells would be able to maintain their regenerative capacity over time, this might, to a great extent, resolve rejuvenation issues. Unfortunately, the pool of somatic stem cells is limited, and they undergo cell aging with a consequent loss of functionality. During the last decade, low molecular weight compounds that are able to induce or enhance cell reprogramming have been reported. They were named "Small Molecules" (SMs) and might present definite advantages compared to the exogenous introduction of stemness-related transcription factors (e.g. Yamanaka's factors). Here, we undertook a systemic analysis of SMs and their potential gene targets. Data mining and curation lead to the identification of 92 SMs. The SM targets fall into three major functional categories: epigenetics, cell signaling, and metabolic "switchers". All these categories appear to be required in each SM cocktail to induce cell reprogramming. Remarkably, many enriched pathways of SM targets are related to aging, longevity, and age-related diseases, thus connecting them with cell reprogramming. The network analysis indicates that SM targets are highly interconnected and form protein-protein networks of a scale-free topology. The extremely high contribution of hubs to network connectivity suggests that (i) cell reprogramming may require SM targets to act cooperatively, and (ii) their network organization might ensure robustness by resistance to random failures. All in all, further investigation of SMs and their relationship with longevity regulators will be helpful for developing optimal SM cocktails for cell reprogramming with a perspective for rejuvenation and life span extension.

Metabolic remodelling of mice by hypoxic-hypercapnic environment: imitating the naked mole-rat.

We hypothesised that hypoxic-hypercapnic environment (HHE) could induce metabolic suppression and associated benefits for health and longevity, as observed in the naked-mole rat (NMR). We developed a model of self-produced HHE (similar to a natural habitat of NMRs), which is simple, reliable and natural, and does not require external sources of gases or complex technical equipment. Here, we showed for the first time that a chronic exposure of mice to HHE could be a unique tool for NMR-like metabolic remodeling, resulting in a long-term and substantial decrease in metabolic rate, body temperature, and food consumption, without significant changes in expression of stress-related genes. Unexpectedly, the HHE accelerated skin wound healing, despite the lower energy expenditure. The self-produced HHE could be considered a model of voluntary calorie restriction. All in all, a chronic exposure to HHE offers a potential of being a lifespan-extending intervention as well as an efficient tool for treating the overweight and associated metabolic disorders.