Cellular Biochemistry is Never Simple: an Example Involving Autophagy and Aging

Nothing in cellular biology is any way straightforward. All rules have exceptions, enormous complexity is the norm, and old understandings are consistently overturned with the arrival of new data: what was thought to be simple turns out to be anything but simple. Even something like the cellular maintenance processes of autophagy, universally demonstrated to be a good thing in laboratory species, to slow aging when more active, and to accelerate aging when disabled via genetic engineering, are no exception. As demonstrated here, researchers have found that selectively disabling autophagy can actually extend life in nematode worms, possibly because the operation of age-damaged autophagy in some important tissues is actually worse than the absence of running autophagy.

In the publicity materials, this is all wrapped in considerations of antagonistic pleiotropy in the evolution of aging, but I think the mechanics of the thing are more interesting in this case. In lower species like worms and flies there is a fair amount of evidence for some tissues to be especially influential over aging: the intestines, some groupings of neurons in the brain, for example. It is very unclear as to the degree to which this is still the case in mammals. Certainly most things demonstrated to slow aging in short-lived species have far less of an effect in long-lived species such as our own. Nonetheless, this research can be taken as an example of the importance of neurons in the pace of aging in nematodes.

Why we did not evolve to live forever: Unveiling the mystery of why we age

Natural selection results in the fittest individuals for a given environment surviving to breed and pass on their genes to the next generation. The more fruitful a trait is at promoting reproductive success, the stronger the selection for that trait will be. In theory, this should give rise to individuals with traits which prevent ageing as their genes could be passed on nearly continuously. Thus, despite the obvious facts to the contrary, from the point of evolution ageing should never have happened. This evolutionary contradiction has been debated and theorised on since the 1800s. It was only in 1953 with his hypothesis of antagonistic pleiotropy that George C. Williams gave us a rational explanation for how ageing can arise in a population through evolution.

Williams proposed that natural selection enriches genes promoting reproductive success but consequently ignores their negative effects on longevity. Importantly, this is only true when those negative effects occur after the onset of reproduction. Essentially, if a gene mutation results in more offspring but shortens life that's fine. This is because there can be more descendants carrying on the parent's genes in a shorter time to compensate. Accordingly, over time, these pro-fitness, pro-ageing mutations are actively selected for and the ageing process becomes hard-wired into our DNA. While this theory has been proven mathematically and its implications demonstrated in the real world, actual evidence for genes behaving in such as fashion has been lacking.

Now researchers have identified that genes belonging to a process called autophagy - one of the cells most critical survival processes - promote health and fitness in young worms but drive the process of ageing later in life. "These genes haven't been found before because it's incredibly difficult to work with already old animals, we were the first to figure out how to do this on a large scale. From a relatively small screen, we found a surprisingly large number of genes, 30, that seem to operate in an antagonistic fashion. Previous studies had found genes that encourage ageing while still being essential for development, but these 30 genes represent some of the first found promoting ageing specifically only in old worms. Considering we tested only 0.05% of all the genes in a worm this suggests there could be many more of these genes out there to find."

The researchers also found a series of genes involved in regulating autophagy which accelerate the ageing process. These results are surprising indeed, the process of autophagy is a critical recycling process in the cell, and is usually required to live a normal full lifetime. Autophagy is known to become slower with age and the authors of this paper show that it appears to completely deteriorate in older worms. They demonstrate that shutting down key genes in the initiation of the process allows the worms to live longer compared with leaving it running crippled. "Autophagy is nearly always thought of as beneficial even if it's barely working. We instead show that there are severe negative consequences when it breaks down and then you are better off bypassing it all together. It's classic antagonistic pleiotrophy. In young worms, autophagy is working properly and is essential to reach maturity but after reproduction, it starts to malfunction causing the worms to age."

In a final revelation, the team were able to track the source of the pro-longevity signals to a specific tissue, namely the neurons. By inactivating autophagy in the neurons of old worms they were not only able to prolong the worms life but they increased the total health of the worms dramatically. "We turn autophagy off only in one tissue and the whole animal gets a boost. The neurons are much healthier in the treated worms and we think this is what keeps the muscles and the rest of the body in good shape. The net result is a 50% extension of life."

Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans

Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen.

From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4. Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.

Comments

This happens a lot, for example genetic mutations that are beneficial in the young become destructive in the old. Let us hope the SENS therapies work and stop the damage before we grow old and it becomes a problem. Perhaps we should not ignore genetic modification and nanotechnology in the creation of a more robust immune system and also a less error prone ribosome Evolution seems to be working in our favor by gradually increasing our life span.

Posted by: Tj Green at September 16th, 2017 5:57 AM

The second oldest verified man died in 2011 at the age of 114. He practiced autography when he reached 80, never eating supper/evening meal after that time. I read of the oldest living Jewish man who died a couple years ago at 113. He lived on a starvation diet in a concentration camp during WWII. So, maybe autography works for humans when ever you engage in it.

Posted by: Biotechy at September 16th, 2017 10:18 AM

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