Evidence for Human Species Longevity to be a Matter of Many Small Adaptations
Why do humans live so much longer than other, short lived species? The researchers here provide evidence to suggest that it is a matter of many small changes, with the specific area of investigation being the the cellular repair mechanisms of autophagy. A world in which differences in longevity between species are the summed contributions from countless small effects is one in which we should discount the possibility that comparative genetic studies - between long-lived and short-lived humans, or between humans and other species - can yield silver bullets, findings that can on their own offer the potential to dramatically improve health and longevity. That expectation, and the sizable mountain of other evidence for the "many tiny contributions" model can be weighed against the recent reports of human PAI-1 mutants with a seven year greater life expectancy than their peers. I wouldn't have wagered on the discovery of such a thing, given what is otherwise known of the genetics of longevity.
Research into the importance of protein called p62 shows that a collection of small adaptations in stress activated proteins, accumulated over millennia of human history, could help to explain our increased natural defences and longer lifespan. Many cells in our body, such as those which make up our brain need to last us a lifetime. To do this our cells have developed ways of protecting themselves. One way is through a process called autophagy, which literally means self-eating, where damaged components are collected together and removed from the cell. "As we age, we accumulate damage in our cells and so it is thought that activating autophagy could help us treat older people suffering from dementia. In order to be able to do this we need to understand how we can induce this cell cleaning."
In the study the authors were able to identify how a protein called p62 is activated to induce autophagy. They found that p62 can be activated by reactive oxygen species (ROS). ROS are by-products of our metabolism that can cause damage in the cell. This ability of p62 to sense ROS allows the cell to remove the damage and to survive this stress. In lower organisms, such as fruit flies, p62 is not able to do this. The team identified the part of the human p62 protein which allows it to sense ROS and created genetically modified fruit flies with 'humanised' p62. These 'humanised' flies survived longer in conditions of stress. "This tells us that abilities like sensing stress and activating protective processes like autophagy may have evolved to allow better stress resistance and a longer lifespan."
Indeed, in the study, the authors found that specific mutations in human p62, which cause a neurodegenerative disease called amyotrophic lateral sclerosis (ALS), can prevent activation of p62 by ROS. These cells are then unable to induce protective autophagy, and this could underlie the premature death of neurons in patients with this devastating age-related disease. The research demonstrates that a collection of small adaptations like that of human p62 could have accumulated over time and these adaptations could underlie our increased natural defences and longer lifespans.
Link: http://www.ncl.ac.uk/press/articles/latest/2018/01/howdidweevolvetolivelonger/
Sometimes mutations can have a fairly large effect on lifespan as indicated above by Reason of 7% for a PAI blood clotting mutation found in one study. I found another such null mutation in my own genome for a SNP in the same gene SERPINE1 rs1799968 SNP that limits expression of the PAI by about 50% when in the heterozygous condition, thus reducing risk of CHD and MI. While the research study on the PAI null mutation increased telomere length by 10% and reduced expression of the PAI protein expression by 50% in the heterozygous condition and increasing lifespan by 7-10 percent, we do not know if the same effects occur in the SNP I present here. It would be useful if some researcher would compare the 2 different null mutations to see if they have the same or similar effects on lifespan. The earlier research study did not determine or cite a SNP number for their null mutation.