Researchers have shown that many interventions known to increase lifespan also share similar gene expression profiles, and this knowledge may help pave the way for identifying new interventions to increase healthy lifespan and delay the diseases of aging.
Identifying longevity signatures
A team of researchers, including Professor Vadim Gladyshev from Harvard Medical School, has just published a new study that takes a systems approach to understanding the principles underlying lifespan and longevity in different species in the hope of identifying new interventions against aging.
Using RNA sequencing, the researchers examined the changes to the gene expression of mice following eight types of interventions known to extend lifespan. RNA sequencing uses high-throughput sequencing methods to provide insight into the transcriptome of a cell, which is is the sum total of all the messenger RNA molecules expressed by its genes. This technique uses next-generation sequencing to show the presence and quantity of RNA in a biological sample at any given moment in time, making it ideal to analyze the continuously changing cellular transcriptome.
The researchers discovered that there were certain gene expression patterns, so-called “longevity signatures”, that were associated with extended lifespan regardless of which of the eight interventions were used. They then expanded the study to include 17 interventions using public data and noted once again that there were similar changes to gene expression. They found that many of these interventions, with the exception of rapamycin, produced similar gene expression changes.
Using this information, the research team was able to identify a number of additional potential interventions that might extend lifespan. The researchers hope that the discovery of these longevity signatures will allow them to predict other potential lifespan-increasing interventions that may be effective but have, until now, been overlooked.
The GENtervention app
With all of this in hand, the team developed the GENtervention app, which visualizes the associations between gene expression changes and longevity. In the interest of making their data and tools available for other researchers in the community to use, the GENtervention app has been made freely available; you can visit the GENtervention website here if you would like to make use of this tool.
GENtervention allows the user to examine gene expression data, and for each gene, it offers the following options:
- Gene expression changes aggregated across datasets for every individual intervention
- Gene expression changes in all available datasets across lifespan-extending interventions
- The association of expression change with the size of the longevity effect (signatures associated with the degree of the lifespan extension effect)
The study is quite in depth, and we highly recommend taking the time to read it; if you are a researcher, perhaps consider using the GENtervention toolkit.
Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but the general principles of lifespan extension remain unclear. Here, we performed RNA sequencing (RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences.
Expanding this analysis to 17 interventions with public data, we observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues.
We further applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794, and ascorbyl-palmitate.
Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.
There are thousands of drugs and naturally occurring molecules with a variety of properties and targets, so this increased understanding of the epigenetic results of lifespan-increasing interventions could help drive further progress and their potential translation to humans.