Abstract
We have recently discovered six plant extracts that delay yeast chronological aging. Most of them affect different nodes, edges and modules of an evolutionarily conserved network of longevity regulation that integrates certain signaling pathways and protein kinases; this network is also under control of such aging-delaying chemical compounds as spermidine and resveratrol. We have previously shown that, if a strain carrying an aging-delaying single-gene mutation affecting a certain node, edge or module of the network is exposed to some of the six plant extracts, the mutation and the plant extract enhance aging-delaying efficiencies of each other so that their combination has a synergistic effect on the extent of aging delay. We therefore hypothesized that a pairwise combination of two aging-delaying plant extracts or a combination of one of these plant extracts and spermidine or resveratrol may have a synergistic effect on the extent of aging delay only if each component of this combination targets a different element of the network. To test our hypothesis, we assessed longevity-extending efficiencies of all possible pairwise combinations of the six plant extracts or of one of them and spermidine or resveratrol in chronologically aging yeast. In support of our hypothesis, we show that only pairwise combinations of naturally-occurring chemical compounds that slow aging through different nodes, edges and modules of the network delay aging in a synergistic manner.
Highlights
Different patient-customized combinations of Chinese plants have been for centuries used in traditional Chinese herbal medicine to prevent and treat a wide range of human diseases [1,2,3,4]
The major aspects and basic mechanisms of aging and aging-associated pathology have been conserved over the course of evolution; they include the following: 1) the hallmark events of aging, such as the age-related accumulation of genomic damage, deterioration of telomeres, epigenetic perturbations, impairment of cellular proteostasis, deregulation of nutrient-sensing systems, decline in mitochondrial functionality, accumulation of senescent cells, decrease of the abundance and functionality of stem cells, anddeterioration of intercellular communications [68]; 2) the nutrient- and energy-sensing signaling network of longevity regulation, which integrates the insulin/insulin-like growth factor 1 (IGF-1) pathway, AMP-activated protein kinase/target of rapamycin (AMPK/TOR) pathway, cAMP/protein kinase
This network integrates the following signaling pathways and protein kinases: 1) the pro-aging target of rapamycin complex 1 (TORC1) pathway; 2) the pro-aging protein kinase A (PKA) pathway; 3) the pro-aging Pkb-activating kinase homologs 1 and 2 (PKH1/2) (Pkb-activating kinase homolog) pathway; 4) the anti-aging sucrose non-fermenting protein 1 (SNF1) pathway; 5) the anti-aging ATG pathway; 6) the pro-aging protein kinase a pro-aging protein kinase (Sch9), which is activated by the TORC1 and PKH1/2 pathways; and 7) the anti-aging protein kinase an anti-aging protein kinase (Rim15), which is suppressed by the TORC1, PKA and PKH1/2 pathways (Supplementary Figure 1) [67, 87, 96, 97, 103,104,105,106,107]
Summary
Different patient-customized combinations of Chinese plants have been for centuries used in traditional Chinese herbal medicine to prevent and treat a wide range of human diseases [1,2,3,4]. A development of such multicomponent therapies with the help of high-throughput screening methods for identifying effective combinations of therapeutic compounds represents an essential strategy of modern medicine [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. The significant progress in developing multicomponent and multitargeted therapeutics has been facilitated by the advances in mathematical, computational and pharmacological approaches to study compound combination effects [37, 49,50,51,52,53,54,55,56,57,58]
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