100 Problems For The Science Of Ageing

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Scientifically informed attempts to delay the ageing process are still relatively new in comparison to efforts to cure individual age related diseases. The biology of ageing is made up of many different probable mechanisms, and most of them are under-explored. This means that there are many different directions in which this research could be taken, and scientists don’t always agree on which direction will be the most fruitful. In this article, researchers put together a curated list of 100 open problems in longevity research, in the hope that it will help others to plot a clearer path towards meaningful progress.

Collecting the data

Researchers started by collecting data via a website where scientists and other users could submit problems they wanted to see solved. Some problems were also sourced from an in-person workshop where 24 scientists working in the field could discuss and submit what they thought were the most pressing problems. The authors then curated this list, removing less relevant problems and duplicate submissions until they were left with a list of 100. Machine learning tools were then used to search the scientific literature and determine which problems appeared most frequently in scientific papers.

The Top 10 Unsolved Problems

Three of the 10 most commonly discussed unsolved problems were very broad in nature, with the most common question of all being simply ‘Why do we age?’. Less general problems involved the contribution of specific mechanisms to ageing, such as whether somatic mutations (mutations in the genetic code of non-reproductive cells) cause ageing, and what mechanisms allow long-lived species to age more slowly than other species.

The least commonly discussed problems, on the other hand, mostly involved either highly specific mechanistic questions, or questions relating to newer and under-explored interventions targeted at ageing, such as whether removing certain compounds from the blood can slow the ageing process.

Most Unsolved Problems Are About Interventions And Mechanisms

The researchers assigned each problem to an overarching theme, so that they could see what types of unsolved problem were most common among the top 100. They found that over half of the unsolved problems came from one of three categories: interventions (questions about how specific interventions affect ageing), ageing mechanisms (broad questions about how we age, for example ‘how much do hormonal changes contribute to ageing?’) and molecular mechanisms (more specific questions about molecular drivers of ageing, for example ‘how much does telomere shortening contribute to ageing?’).

Problems related to animal models and translating findings in animals to humans, environmental factors contributing to ageing, and understanding how ageing differs between individuals were the least common types of problem among the top 100.

Implications

Most of the top 100 unsolved problems are about the fundamental mechanisms of ageing and whether or not interventions targeting those mechanisms actually have a measurable effect. Though fundamental problems such as why we age are popular points of discussion, we don’t necessarily need to solve them in order to begin treating ageing in humans – we just need to find a treatment that works, and improving our understanding of the mechanisms of ageing can help point us in the right direction.

Some scientists argue that research is too focussed on fundamental questions and not focussed enough on practical results. We already have many ideas about what the fundamental drivers of ageing are and how they could be targeted, but very few of the most promising ideas have been thoroughly tested in animal models, let alone humans. Unfortunately, the currently available tools for testing these ideas leave much to be desired, as exemplified by two of the top 10 most referenced problems: how can we measure biological age and how does ageing in animal models relate to ageing in humans?

We can measure biomarkers of ageing in humans – certain variables that correlate closely with chronological age. It is commonly (and inaccurately) stated that having a biological age of (for example) 39 when you are 40 years old indicates that you are biologically 1 year younger than expected. Yet we don’t know for sure that these biomarkers of ageing actually correspond to intrinsic biological age – they are simply one of the best practical solutions we have. This means that there’s no proven way to measure whether a treatment slows ageing in humans in the short term, and long-term studies are prohibitively expensive.

Measurements in animal models are easier, because scientists can pick animals that don’t live very long and see if a treatment improves their health in old age or extends lifespan in a relatively short-duration study. However, there are significant unsolved problems here as well, such as which aspects of the ageing process are shared between common animal models and humans, or why mice can have widely varying lifespans even when they are genetically identical and housed in exactly the same environment.

Notably absent from the top 10 most referenced problems is any question about how environmental factors influence human ageing. The environmental and physical factors category was also the smallest category with only two unsolved problems in the entire list. Those problems were about how environmental temperature influences ageing and how ageing influences risk of death from environmental causes. If this is reflective of reduced research interest in environmental drivers of ageing, then this is a shame as this is some of the only research individuals are actually able to take action on at the moment.

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You can explore the full list of unsolved problems here. There are many different paths that the study of ageing could take, meaning the field is still full of potential. However, scientists will always disagree about which is the best path forward until we have better ways of measuring whether a given strategy is actually successful in slowing ageing or not.