SynergyAge, a curated database for synergistic and antagonistic interactions of longevity-associated genes

Abstract

Interventional studies on genetic modulators of longevity have significantly changed gerontology. While available lifespan data are continually accumulating, further understanding of the aging process is still limited by the poor understanding of epistasis and of the non-linear interactions between multiple longevity-associated genes. Unfortunately, based on observations so far, there is no simple method to predict the cumulative impact of genes on lifespan. As a step towards applying predictive methods, but also to provide information for a guided design of epistasis lifespan experiments, we developed SynergyAge - a database containing genetic and lifespan data for animal models obtained through multiple longevity-modulating interventions. The studies included in SynergyAge focus on the lifespan of animal strains which are modified by at least two genetic interventions, with single gene mutants included as reference. SynergyAge, which is publicly available at www.synergyage.info, provides an easy to use web-platform for browsing, searching and filtering through the data, as well as a network-based interactive module for visualization and analysis.

Machine Learning Analysis of Longevity-Associated Gene Expression Landscapes in Mammals

“…A gene may impact longevity not only by itself, but also by cooperation with other genes. Based on the cumulative knowledge of interactions between longevity-associated genes (LAGs), it has been previously shown that genes that have a role in determining average or maximum lifespan (as LAGs for example) may have a variety of combined effects—synergistic, additive, dependent, or antagonistic [ 40 ]. Thus, the total lifespan changes as a result of genetic interventions targeting two genes are usually not the simple sum of their impacts.…”

Knock-down of odr-3 and ife-2 additively extends lifespan and healthspan in C. elegans

“…At day 15, the odr-3;ife-2 animals still showed approximately 42 contractions per minute (compared to 15 contractions per minute in the WT), a 187% increase (p <E-04). On day 15, the odr-3(n1605) and ife-2(ok306) mutations showed a synergistic effect on the pharyngeal pumping, the increase observed in the double mutant being higher than the sum of the individual effects (187% increase compared to 66% + 55% increase for single mutants), corresponding to a fully synergic effect [ 18 ].…”

“…However, due to the existence of complex and intricate interactions between hundreds of longevity-associated genes [ 62 – 64 ], the lifespan modulation obtained with these methods was limited by how much a single gene can influence longevity. While combined genetic interventions that modulate longevity via parallel pathways or drugs targeting multiple evolutionary conserved aging pathways have been shown in many instances to extend lifespan [ 65 ], the number of gene combinations tested so far has not been very high [ 18 ]. Here, we assessed the effects on both lifespan and healthspan, given by the simultaneous inactivation of three genes: odr-3 , ife-2 and cku-70 .…”

“…According to the SynergyAge database - http://synergyage.info/ [ 18 ], the above-mentioned genetic interventions were among the most promising in terms of lifespan extension, when combined with IIS-defective daf-2 mutants [ 39 , 42 , 46 ], a highly desirable property. SynergyAge hosts 133 unique synergistic interactions, involving 108 genes and of these, 62 gene combinations include daf-2.…”

“…This aspect, however, has been unfortunately less popular, mainly because the epistasis between longevity-associated genes, and between the pathways they are involved in, is complex and most often non-linear [ 16 , 17 ], thus requiring much time and resources to be studied. In a recent paper, describing the SynergyAge database, we have defined three types of synergism, applied to the general case of N genetic interventions: 1) full synergism , in which lifespan values are known for all intermediary strains that contain any combination of the N interventions and the lifespan change for the n-mutant is greater than the sum of lifespan changes for any two intermediary k-mutant and (N-k)-mutant, 2) simple synergism , in which lifespan values are known for the final strain (N interventions) and for all single gene interventions, but not for all intermediary k-mutants, and in which the lifespan effect of the N-gene combination is greater than the sum of all the individual effects, and 3) partially known synergism , in which values are available only for an incrementally built model and for all genetic interventions in an N-sequence an increase in lifespan is observed [ 18 ].…”