Autophagy in Nematodes is an Example of Antagonistic Pleiotropy

Antagonistic pleiotropy is the name given to a particular view on the evolution of aging. Natural selection will favor optimization of capacity in early life, when reproduction is possible, but not the optimization of capacity in late life. Given a system in which the decline of aging is already happening to some degree, there will be further selection of processes that work well at the outset but cause harm later on in life. The adaptive immune system is an example of the type: it is highly effective in youth, due to its capacity for memory, but runs down and malfunctions in the later life context of trying to maintain memory of a lifelong exposure to countless varieties of pathogen.

Researchers here present evidence for the cellular maintenance processes of autophagy to be pleiotropic in this way, at least in nematode worms. In this species autophagy works well in the context of a youthful low level of damage, but then becomes actively harmful in the later life context of high levels of damage and dysfunction. Early life capacity for reproduction has a much greater influence on the traits that are selected than late life capacity, and this sort of thing is the outcome.

Ageing in worms mainly results from the direct action of genes and not from random wear and tear or loss of function, and the same is likely to be true in humans, according to research. The study shows that normal biological processes which are useful early on in life, continue to 'run-on' pointlessly in later life causing age-related diseases. The deteriorative part of ageing, called 'senescence', is the main cause of disease and death worldwide as it leads to dementia, cancer, cardiovascular disease, and chronic obstructive pulmonary disease, but scientists have struggled to identify what causes it.

To address this, researchers have focused on discovering the basic principles of ageing by studying simple animals such as Caenorhabditis elegans, a nematode worm used in this study which lives on fruit, and dies of old age after only 2-3 weeks. Specifically, they focused on autophagy, where body cells consume their own biomass to recycle components and extract energy. They found that the worms' intestine consumes itself (autophagy) to create the yolk needed for eggs, and in elderly worms, this process causes severe deterioration of the intestine and obesity from a build-up of pooled fats. In turn, this further impacts on the health of the worm by promoting growth of tumours in the uterus, and shortens lifespan.

"This really surprised us since autophagy is usually thought to protect against ageing rather than cause it. It seems that worms crank-up autophagy, which is considered good, to maximise reproductive success, which is good too, but they end up overdoing it, causing senescence." When useful biological programmes run-on in later life, they can become disease-causing 'quasi-programmes'. Such programmes were recently proposed and the findings support that they are indeed a major underlying cause of ageing. This does not mean that aging is programmed but instead, that it is a continuation of developmental growth driven by genetic pathways to the point where these becomes harmful. Other examples include an increase in blood pressure causing hypertension and an increase to the eyes' near vision point causing long-sightedness and a need for reading glasses.

Link: http://www.lancaster.ac.uk/news/genes-drive-ageing-making-normal-processes-damaging

Comments

This is really a surprising finding. After all, calorie restriction works very well in C elrgantis. Even late in life. So, it is not only the upregulation of autophagy but rather that is probably unbalanced. And unbalanced and inefficient cleanup and repair mechanisms are a major root cause of aging.

So how do the results of this study translate to humans? Probably there is an "ideal" or optimal autophagy profile for which we could aim.

Posted by: Cuberat at August 13th, 2018 5:42 AM

In another example of the adaptive immune system malfunctioning with aging, Glaucome is now thought to be an auto immune condition caused by T cells attacking the nerve cells of eyes after being primed by bacteria:

https://www.genengnews.com/gen-news-highlights/could-glaucoma-be-an-autoimmune-disease/81256124

"Studies in mice by a team at the Massachusetts Eye and Ear Hospital, and the Massachusetts Institute of Technology (MIT) now suggest that glaucoma could be an autoimmune disease. Their findings indicate that the high IOP triggers an autoimmune response by T cells that are primed to attack nerve cells in the eye because of previous contact with the many different types of bacteria that naturally live in the body.

The researchers hope that the discovery could lead to new glaucoma treatments that target this autoimmune reaction. "Our work shows that there is hope for finding a cure for glaucoma, or even preventing its development entirely, if we can find a way to target this pathway," "

Posted by: Jim at August 13th, 2018 6:42 AM

Hi Jim,
While at first surprising, it is all but logical that that glaucoma sold have a significant immune component. Or is ,probably, far from the whole story, but for sure an important contributor.

Posted by: Cuberat at August 14th, 2018 5:06 AM

Maybe or maybe not. Autophagy might be upregulated but not enough. Similarly autoimmune conditions are thought of as bad, but if the white blood cells are attacking cells that have been infected, is it really right to blame so called hyperfunction of the immune system? You'd probably be better off discovering what is causing the infection.

This article is straight out of Blagosklonny's playbook - no bad thing as he's been ignored for too long. But now perhaps the opposite it true, and everything is being blamed on a quasi program adapted for youth but harmful in old age.

Posted by: Mark at August 14th, 2018 5:24 AM

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