One of the Ways Researchers Narrow the Search for Drugs to Slow Aging
Small molecule and drug candidate libraries are huge. Much of modern medical research is a process of screening subsets of those libraries in search of molecules that can produce benefits with minimal side-effects. Usually the output of a successful screen is taken as a starting point for further exploration and molecular tinkering, to improve the effect or minimize undesirable side-effects. The great hope for gene therapy is that it will render all of this largely obsolete by offering ways to directly influence a molecular mechanism to a configurable degree without meaningful side-effects. That remains a way off in the future, however, and meanwhile a very sizable slice of medical research is still all about finding which cataloged molecules might be interesting to work with.
Thus when it comes to aging, a majority of efforts are focused on adjusting the operation of metabolism via small molecules from the catalogs, interacting with one of the known aging-related mechanisms discovered via examination of the biology of calorie restriction, or autophagy, or other stress response mechanisms. This is somewhat depressing: none of this work offers either hope or possibility of doing more than slightly increasing human life span, yet it is where most the funding and effort is focused. An increasing fraction of those initiatives are concerned with ways to speed up this process, to make it more rational, to cut down the number of molecules to be assessed. These advances are interesting to the degree that they can be applied more generally, to any area of development. There are parts of the SENS rejuvenation research portfolio in which small molecule drug discovery might lead to useful therapies, for example.
Several bioinformatic methods have been developed to identify potential geroprotective drugs. For instance, caloric restriction (CR) mimetics have been identified, by comparing genes differentially expressed in rat cells exposed to serum from CR rats and rhesus monkeys with gene expression changes caused by drugs in cancer cell lines. Structural and sequence information on ageing-related proteins have been combined with experimental binding affinity and bioavailability data to rank chemicals by their likelihood of modulating ageing in the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Drug-protein interaction information has also been used to predict novel pro-longevity drugs for C. elegans, using a set of effective and ineffective lifespan-extending compounds and a list of ageing-related genes. A similar approach used chemical descriptors of ageing-related compounds from the DrugAge database together with gene ontology terms related to the drug targets. Enrichment of drug targets has been assessed for a set of human orthologs of genes modulating longevity in animal models to identify new anti-ageing candidates.
Despite the increasing interest in drug-repurposing for human ageing, research has tended to focus on predicting life-extending drugs for animal models. However, the translation from non-mammalian species to humans is still a challenge, and certain aspects of ageing may be human-specific. Only a few studies have focused on data from humans. For instance, researchers applied the GeroScope algorithm to identify drugs mimicking the signalome of young human subjects based on differential expression of genes in signalling pathways involved in the ageing process. Another study correlated a set of genes up- and down-regulated with age in the human brain with drug-mediated gene expression changes in cell lines from the Connectivity Map.
In the present study, we rank-ordered drugs according to their probability of affecting ageing, by measuring whether they targeted more genes related to human ageing than expected by chance, by calculating the statistical significance of the overlap between the targets of each drug and a list of human ageing-related genes. Additionally, to enhance the power of the approach, we mapped the drugs' gene targets and ageing-related genes to pathways, gene ontology terms, and protein-protein interactions, and repeated the analysis. We found that, independently of the data source used, the analysis resulted in a list of drugs significantly enriched for compounds previously shown to extend lifespan in laboratory animals. We integrated the results of seven ranked lists of drugs, calculated using the different data sources, into a single list, and we experimentally validated the top compound, tanespimycin, an HSP-90 inhibitor, as a novel pro-longevity drug.