Posted on Jun 08, 2019, 6 p.m.
A biomarker of aging has emerged: transcriptomic signature, which consists of expression data from relatively few genes. This was discovered in a long term study of the long lived nonparasitic roundworm Caenorhabditis elegans, and consequently helped to narrow the search for possible life extension drugs from the database of FDA approved drugs; top candidates achieved up to 30% extension of mean lifespan.
Findings published in Scientific Reports describe how RNA sequencing datasets of age dependent transcriptomes produced from C.elegans isogenic strains and populations with different lifespans were compiled by an international team of researchers led by Peter Fedichev of the Moscow Institute of Physics and Technology. Researcher suggests the rate of aging can be impacted without overhauling underlying molecular mechanisms, and their findings may be relevant beyond models, pointing to interventions that may alter human trajectories.
Normal wild type worms as well as mutant worms were used to assess expression profiles at a range of adult ages leveraging machine learning techniques to analyze results and compare to earlier data available from public resources to produce the MetaWorm dataset; analysis of the dataset confirmed and extended the pattern of transcriptomic shifts that accompany nematode aging.
“Our main concern was that aging in an extremely long-living worm might be totally different from that of normal, wild-type nematodes. In that case, the radical extension of lifespan would require complex interventions, and studies of animals with drastically slowed aging would not help us in our search for a truly effective anti-aging therapy.” said Fedichev.
On the molecular level the process of aging in nematodes always unfolds in the same way, observed differences in lifespan appear to reflect changes in the rate of aging; similar effects are proposed to be achievable without genetic interventions.
The Connectivity Map created at the Broad Institute of MIT and Harvard was used to look for FDA approved drugs that alter human gene expression in a way opposing the age related changes observed for corresponding genes in nematodes.
Of the 1,309 drugs in the database 10 candidates were chosen that appear to act on genes in the desired direction: anisomycin, camptothecin, GW-8510, H-7, lanatoside C, alsterpaullone, doxorubicin, azacitidine, tonzonium bromide, metamizole sodium. 6 of the drugs had documented anti-aging potential and 4 had never been studied in this context before. All 10 drugs were demonstrated to slow down again in nematodes to different degrees, the most efficient extending lifespan by 30%.
According to the researchers, “The observed temporal scaling of survival curves and aging trajectories, together with the robust pattern of gene-expression changes associated with aging, appeared to be universal across extremely diverse biological conditions tested in our experiments. From this, we deduce that life-extending effects are achieved by stabilizing the gene regulatory network and by slowing the rate of aging, rather than by qualitatively changing the molecular machinery of the whole organism. This means that the course of aging of the super-long-lived strains can be potentially mimicked therapeutically, and hence eventually would lead to dramatically increased lifespan without detrimental effects.”
“The usual procedure involves laborious screening of large libraries of potential drugs. Unfortunately, even successful hits sometimes get missed by chance or due to non-optimal dosage. Our method allows for a targeted search of the compounds with the required activity, including FDA-approved drugs. The latter compounds have the advantage that they have already passed all the necessary clinical trials and can be used off-label as anti-aging drugs.” notes Andrei Tarkhov of the Skolkovo Institute of Science and Technology.
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