Why Human Life Expectancy Could Get Stuck At 170

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The Problem

The ageing process is made up of multiple different processes that, while interlinked, will most likely need to be addressed individually in order to substantially slow ageing in humans. Some of these problems are going to be easier to solve than others. Gut dysbiosis, for example (the disruption of the gut microbiome with age) appears to be quite easy to fix with faecal microbiota transplants (transplanting a new microbiome from a young, healthy donor). Others may be harder to solve, but scientists already know of molecular mechanisms that could be leveraged to one day reverse these aspects of ageing as well. For example, the shortening of the telomeres (the protective caps on the ends of the chromosomes) is thought to contribute to ageing, but we know that there are mechanisms for regenerating shortened telomeres, such as via the telomere-elongating enzyme telomerase.

Yet there is one hallmark of ageing for which it’s very difficult to envision a solution within the foreseeable future: genomic instability. Genomic instability refers to the occurrence of random mutations within our cells over time. While most people associate the accumulation of genetic mutations with cancer, genomic instability also impairs overall cell and tissue function as important genes mutate and stop functioning correctly. Why is genomic instability so hard to fix? Genetic mutations are random, which means that each individual cell will have its own unique set of mutations. We might be able to prevent some of these mutations from occurring in the first place, for example by enhancing a cell’s ability to repair damaged DNA accurately. However, it seems like we would need some very futuristic gene editing technology, capable of correcting mutations on a cell-by-cell basis, in order to actually reverse age-related genetic mutations.

We could imagine a future world in which some mutated cells, or entire tissues and organs, could simply be replaced entirely using new, mutation-free cells generated in a lab. But that still leaves the brain and its cells, which cannot be replaced for obvious reasons. We have to assume that even if all other components of the ageing process were solved and humans lived for hundreds of years, the cells of the brain would accumulate more and more mutations until they eventually became completely dysfunctional.

That leads to an interesting question and the subject of this study, which is published in preprint: how long would humans live if genomic instability was the only aspect of ageing that could not be solved? The authors attempt to answer this question with mathematical models.

Building the Model

To achieve their goal, the researchers opted for an incremental approach: instead of trying to build one large, complicated model at once, they started with a simple model and gradually add complexity. Thus, they began with a baseline model in which humans didn’t age at all, but where the mortality rates present in early adulthood remain constant as time progresses.

They then added in mortality from genetic mutations in cells that don’t divide much, such as brain cells. Based on data from sequencing studies, they were able to estimate how often cells would mutate and how often these mutations would cause a cell to die or fail. This allowed them to model how long it would take for whole organs to fail as a result of genetic mutations.

They then had to do the same thing for organs in which cells do divide regularly. This was more complicated as such organs are usually composed of both functional dividing cells that divide a limited number of times, and a pool of self-renewing stem cells that replace functional cells as they die and have their own mutation rates.

Finally, the researchers adjusted their model to account for the fact that some organs are more important than others – some organs inevitably lead to death if they fail (such as the brain) while others (such as the kidneys) have some redundancy or are replaceable.

The Prediction

So, what was the final prediction? The researchers estimated that while organs with high regenerative capacity such as the liver might remain functional for thousands of years through cellular replacement, human survival would be drastically cut short by ‘bottleknecks’ caused by other organs. A human who maintained the mortality risk of a 30 year-old indefinitely (the ‘no ageing’ model) would have a 50% chance of living to 430 years of age. However, when taking into account mutation rates in multiple organs, the model predicted values between 134 and 170 years – roughly double current human life expectancy.

Since this is median life expectancy (the age by which 50% of the population have died), a sizeable proportion of the population would still live significantly longer than this, with the oldest living person predicted to be over 600 years old.

A doubling of life expectancy seems like a big deal, and indeed it would be, but keep in mind that this model is assuming that all other drivers of ageing are completely prevented, meaning that genomic instability would be the only way in which we age. Also, consider that global human life expectancy has already doubled over the last 100 years or so, mostly as a result of a relatively small number of innovations such as improved sanitation, vaccines and other improvements in our ability to treat and prevent infectious diseases.

It should be noted that this model doesn’t take into account possible future innovations, such as the ability to partially or fully replace currently irreplaceable vital organs. The outcomes of the model are also heavily dependant on assumptions about mutation rates and the interdependence of different organs. Attempts to emulate the vast complexity of an entire biological system with comparatively simple mathematical models have to be taken with a pinch of salt. Nevertheless, this study does illustrate an interesting point – when it comes to ageing and age-related diseases, the impact of eliminating one or several different causes of death often has less of an impact on life expectancy than one might intuitively think. For example, it has previously been estimated that a permanent cure for all cancers would only extend human life expectancy by a few years, since many who die from cancer would still have died from something else shortly afterwards.