In August 2018, an article published in the journal of Current Biology states that our genes are the main culprits for our aging-associated breakdown. The publication describes the work of a team of researchers from the UCL, Lancaster University and Queen Mary University of London. They posit that aging in worms is mainly caused by gene malfunction, and not by random wear and tear, a scenario that may also be true for us, humans. Their study suggests that certain processes useful early on in life, become damaging in later life causing age-related diseases.
Aging is the leading cause of human morbidity and death worldwide through its associated pathologies, such as dementia, cancer, and cardiovascular disease, and a pervasive phenomenon across animal species. Despite major advances in aging research, the underlying causes remain unclear. To better understand the mechanism, researchers focused on the basic principles using simpler animals, such as the nematode worm Caenorhabditis elegans, which lives on fruits and dies of old age after only 2-3 weeks.
Using this model organism, the team showed that processes that help young worms better reproduce, become damaging by running on pointlessly later in life. Specifically, they focused on autophagy, the process through which cells recycle their own biomass to generate energy, remove damaged organelles, and produce building blocks for new cellular structures. The described autophagic process, by which the worm’s intestine consumes itself, is advantageous for young animals as it generates yolk needed for eggs, but damaging for older animals where it leads to severe deterioration of the intestine and obesity from a build-up of pooled fats. In turn, this has a negative impact on health as it promotes tumor growth in the uterus and shortens lifespan.
Despite advances in the genetics of longevity, like the discovery of long-lived insulin mutant C.elegans worms, our understanding of the proximate causes of aging remains incomplete. In my opinion, the work published in this article brings us a step closer to a unified and comprehensive understanding of the topic. It highlights that multiple aging pathologies can arise from common underlying mechanisms, and promotes complementing our standard lifespan genetic approaches with the study of senescent pathologies. Hence, lifespan can also be viewed as a function of one or more life-limiting aging pathologies.
It comes as a surprise that the process of autophagy can have such negative health consequences. The dogma dictates that autophagy generally acts to protect us from aging, as it allows cells to dismantle old or malfunctioning organelles and thereby generate new raw material for building new ones. Additionally, autophagy permits cells survive starvation and even protects us against invading pathogens. It can, apparently, also have negative health repercussions in certain developmental contexts.
I think these findings also agree with the proposed hyper-function theory of aging, which postulates that aging is the result of the non-adaptive continuation of developmental and reproductive programs in late life. Thus, mechanisms that support growth and reproductive fitness become quasi-programs in late life that result in age-related pathologies. The findings also agree with another recent study from the same team, showing that inappropriate activation of genes in unfertilized eggs, which are programmed to generate embryos, causes tumors in aging worms.
What does this mean? It means humans are not like cars. We thought for decades that as we age, our bodies are wearing out from a build-up of random damage, much like cars do. It is exciting to see that this work is showing us a different perspective—what brings about our demise with old age is not accumulated damage, but rather our own genes. It seems to me that for natural selection, the advantages certain mechanisms offer young animals outweigh the disadvantages of their continued function later in life.
Although we do not devour our own intestines for reproductive purposes, it seems likely that akin processes may indeed occur in us, humans, as well. An often-reminded example is bone erosion in lactating mammals. Women are able to scavenge calcium from bone to create milk for breastfeeding, which may promote, after menopause, osteoporosis, osteoarthritis and calcified blood vessels.
To treat a disease, I think one really needs first to understand it. In the words of the corresponding author, Prof. Gems, “Senescence has really become the mother of all diseases, so understanding it is good news for all of us.” Furthermore, as genes driving the destructive processes of aging in worms are also known to control lifespan in mammals, such findings may likely be applicable to humans.
More information: Ezcurra, M. Benedetto, et al. (2018) C. elegans Eats its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies. Current Biology.
Author: Sebastian I. Florescu