Longevity Briefs: How Did We Evolve Our Exceptional Lifespans?

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:

Generally speaking, larger animal species are also longer-lived. Whales and elephants feature among both the largest and the longest-living mammals, while rodents live a brief existence. Yet this relationship between size and lifespan has glaring outliers that still perplex scientists to this day. Humans are of course one of those outliers – we are capable of living longer than elephants and many whale species despite being many times smaller. In the rodent department, there are the naked mole rats – rodents that can live upwards of 30 years, while their similarly-sized evolutionary neighbours are lucky to see three years.

To what do these outliers owe their exceptional lifespans? The answer to that question could hold important clues as to how we could one day greatly extend the lifespan potential of our own species. In this study, researchers use genetic sequencing data from many mammalian species in an attempt to uncover the broader picture. What are the overarching genetic characteristics that are associated with the evolution of a longer maximum lifespan potential?

The discovery:

Researchers investigated the relationship between maximum lifespan potential (MLSP) and gene family size in 46 mammalian species with fully sequenced genomes. Gene families are groups of genes with similar functions that have arisen through duplication events. This is when a gene or a group of genes is duplicated as part of a random mutation. If these extra genes confer an evolutionary advantage, they may spread within the species and eventually mutate further, giving rise to a group of similar genes – a gene family. The researchers hypothesized that expansions in certain gene families might be associated with longer lifespans, since previous research had already suggested this to be the case in select species like bowhead whales.

They discovered that 236 gene families showed significant expansion in species with higher MLSP. Since larger gene families are also associated with other factors that are known to influence lifespan, like body mass and brain size relative to body mass, these confounders had to be taken into account. After some statistical analysis, relative brain size appeared to explain some of the relationship between larger gene families and MLSP, but researchers also observed that many gene families associated with MLSP had functions relevant to the immune system.

Researchers then investigated gene expression and alternative splicing (a process that allows the same gene to produce multiple different protein variants). This is possible because proteins are built using RNA templates copied from the DNA code, but these RNA copies can be spliced together in different ways to create different templates and therefore different proteins. They found that, when looking at human data specifically, MLSP-associated genes produced more unique RNA than other genes, suggesting that the diversity of the RNA templates from the same genes might have some role to play in maximum lifespan.

Finally, they compared their findings with existing databases of genes associated with human longevity and ageing. They found that there was not much overlap between the genes they had identified in this study and those identified in previous studies, but there was significant overlap in what those genes did. This included roles in immune function once again, but also in DNA repair, apoptosis (when damaged cells self destruct), autophagy (when cells recycle damaged parts of themselves), senescence (when damaged cells stop dividing) and genes that are targets for drugs known to extend animal lifespan.

The implications:

This research suggests a potential important link between immune system function and the evolution of longer lifespans in some mammals (including us), despite not following trends in body mass. The immune system does indeed play an important role in ageing and in the prevention of age-related diseases. Immune cells constantly surveil the body and eliminate senescent cells. These are cells that have reached their replication limit and are no longer able to divide, and are thought to contribute to ageing through the harmful signalling molecules they release. The immune system also hunts cancer cells and destroys them before they are able to multiply. In the brain, meanwhile, resident immune cells are important for cleaning up cellular debris and misfolded proteins that are believed to drive cognitive ageing and neurodegenerative disease.

Likewise, human genes associated with maximum lifespan in both this and previous studies were also linked to other factors believed to be important in ageing, such as DNA damage and repair. Such findings do not necessarily tell us that these factors are the cause of lifespan variation, but they do give us some confidence that we are looking in the right general directions.