Longevity Briefs: Are Anti-Ageing Drugs Hiding In Plain Sight?

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Despite decades of research and many promising avenues for the development of drugs that can slow the ageing process and delay age-related diseases, we still lack a single proven anti-ageing treatment. To be considered for use in humans, a drug must be safe and effective – the benefits of taking it must be clearly shown to outweigh the risks. This is quite challenging to prove for new drugs targeting the ageing process in healthy people, as the benefits may take decades to become apparent, while the risks of long-term use are unknown. For this reason, most drugs targeting ageing are tested in people with age-related diseases, where the benefits will hopefully be more immediate. However, a drug that doesn’t treat an age-related disease may still have prevented that disease if administered earlier to a healthy person.

While there are many barriers to the development of new drugs, the thousands of existing clinically approved drugs could be an untapped gold mine for targeting the ageing process. Many of these drugs already have safety data for long-term use, so if any of them turn out to have effects on the ageing process, the argument for letting healthy people take them would be much more convincing. But how do we figure out which drugs should be tested? In this study, researchers evaluate the effects of over 6000 approved or experimental drugs in order to see which ones were most closely related to the hallmarks of ageing. The hallmarks of ageing are a group of 11 (formerly 9) interconnected processes that are collectively believed to be responsible for the ageing process and all the diseases that result from it.

The discovery:

Researchers used a ‘network medicine’ approach that they had been developing for over a decade in which the network of genes and proteins that are associated with a particular disease can be grouped into a ‘disease module’. For example, there will be a certain collection of interconnected genes that are perturbed in heart disease, and by looking at which drugs affect those genes and their associated proteins, researchers could identify drug candidates that might have an impact on heart disease. In this study, researchers applied this approach to the hallmarks of ageing, and found that each hallmark was also associated with a cluster of genes and proteins, forming ‘hallmark modules’. These hallmark modules also shared many genes with each other. This makes sense given that these hallmarks are thought to be interconnected, with a subset ‘primary hallmarks’ that drive other hallmarks, and some hallmarks being part of a response to damage caused by the others.

The researchers then evaluated 6,442 approved or experimental drugs from DrugBank (a large online database of drug targets) to identify drugs whose targets overlapped with these hallmark modules. Of course, the goal isn’t just to find drugs that impact these targets, but that also modify them in the correct direction. To solve this problem, researchers introduced “pAGE” (Pro-Age), which compares how a drug changes gene expression against known age-related expression patterns. If a drug shifts a hallmark module towards a ‘younger’ profile, then it gets a positive pAGE score and vice-versa.

Using the above approach, researchers identified 370 drugs with significant potential to modulate at least one hallmark of ageing. Of these, 83 did not target a specific longevity-associated gene, but rather were able to affect hallmark modules through the network of genes and proteins they interacted with. This kind of effect would be effectively invisible to more conventional gene interaction studies. Some examples of identified drugs included oxymetazoline (a nasal decongestant), which could potentially target altered intercellular communication; guanadrel (an anti-hypertension drug), which could target stem cell exhaustion; and deconexent (an omega-3 supplement), which could target epigenetic alterations.

To verify that this technique could actually have meaningful implications, researchers tested their approach on drugs that were already known to extend lifespan in mice in the Interventions Testing Program (which conducts some of the most rigorous mouse lifespan studies), as well as some drugs that are under investigation in human clinical trials. They found that 100% of successful mouse interventions modulated at least one hallmark module, while less than 50% of the failed interventions affected a module. In other words, not all of the drugs that were highlighted by the network approach extended lifespan, but no lifespan-extending drugs were overlooked – there were some false positives but no false negatives. Of 17 compounds in human clinical trials, 11 had significant hallmark interactions. This is perhaps a little less telling because the effects of these drugs on human ageing is still uncertain. There was also some interesting variation in how many hallmarks were affected by different drugs. Aspirin hit six hallmarks while anti-cancer drug dasatinib hit five. Rapamycin, which has produced some of the largest lifespan effects of any drug in mice, only hit a single hallmark.

The implications:

This research provides a technique for identifying repurposable drugs that might delay ageing, with a method that may detect interactions that more direct methods may miss. This approach also reveals not just which drugs might work, but also how they work, by looking a the the specific molecular mechanisms through which they modulate ageing hallmarks.

Ageing is a combination of multiple interconnected processes and is therefore unlikely to be solved by a single intervention. Tools that will allow us to target the hallmarks of ageing in humans can’t come soon enough, but just because a drug looks like it will affect a hallmark, this doesn’t necessarily mean it will affect human longevity. Ultimately, we still need human clinical trials to investigate whether drugs can delay ageing and age-related diseases. Relative to the potential payoff, such trials are still few and far between.