A new method to identify genes that affect life-span

Despite much research in the last decades, the genetic causes why animals have such different longevities remain largely unknown mostly because ageing results of such a myriad of factors that to identify single gene’s effects is almost impossible. But now a study just published in the journal AGE might help to change that as researchers Pedro Magalhães and Yang Li from the Institute of Integrative Biology, University of Liverpool in the UK unveil a new approach, the molecules linked to longevity already identified by this approach and which include proteins involved in DNA repair and also in the clearing of abnormal proteins. The work – that uses an algorithm to identify proteins mutating in parallel with the increase of lifespan – shows how longevity has been affected by natural selection, provides clues on key processes behind ageing, as well as introducing a method that can now become an important tool to understand the genetics of old age.

In the last decades much work has been done on ageing not only because people are living longer, but also because we, as a society, have become obsessed with youth. Despite this, we remain very far from understand its genetic basis as shown by the fact that even the sirtuin gene – one of the most promising discoveries in ageing research in recent years that led to the launch of several anti-ageing products – is now being questioned. The problem is that ageing not only affects multiple body functions, but is also influenced by both a variety of genes and environmental factors.

Interestingly, biological and fossil data suggest that longevity has increased continuously during mammalian evolution, and particularly in the lineages leading to humans. This and the fact that evolutionary theory predicts that genes that confer higher longevity would be selected during evolution as long no other major selective pressures occur, led to the idea behind the new study by Magalhães and Li. Their hypothesis was that in that case the proteins/genes that determine longevity should be under accelerated evolution in the mammals’ lineages where longevity increased and could be identified through that.

To try to prove this and find genes and biological processes linked to longevity, the researchers started with the identification of mammals that had evolved during the path towards humans – so from the initial mammal radiation and over a long period of time –, that had distinct longevities and a fully sequenced genome (to allow their comparison). 36 species were found and these shared more than 15 thousand proteins that could be tested. After predicting how these proteins would look in ancestral species, Magalhães and Li used an algorithm developed by themselves to look for patterns in cross-species genome comparisons and identify those proteins that suffered accelerated evolution as longevity increased. They were able to find several “signatures”, and identifying several genes potentially linked to longevity, including DNA repair genes and the ubiquitin pathway, which recycles abnormal proteins. In fact, one of the hallmarks of ageing is the accumulation of damaged molecules such as DNA, proteins and lipids with this leading to cellular dysfunction and death, which underlie much of the ageing process. Magalhães and Li’s results show that at least some repair systems were selected for, and, arguably, optimized in long-lived species.

As Magalhães explains: “The genetic basis for longevity differences between species remains a major puzzle of biology. A mouse lives less than five years and yet humans can live to over 100 for example. If we can identify the proteins that allow some species to live longer than others we could use this knowledge to improve human health and slow the ageing process. Here we developed a method to detect proteins whose molecular evolution correlates with longevity of a species. The proteins we detected changed in a particular pattern, suggesting that evolution of these proteins was not by accident, but rather by design to cope with the biological processes impacted by ageing, such as DNA damage. The results suggest that long-lived animals were able to optimise bodily repair which will help them fend off the ageing process.”