Scientists discover fundamental causes of ageing

Ageing is mainly the result of concerted action by our own genes and not, as long believed, by random wear and tear and loss of function, according to a new study by a team of scientists at Queen Mary University of London, University College London and Cambridge University.

The report, published in the journal Current Biology, shows how the ageing process results from normal biological processes that are useful in early life which continue pointlessly in later life, and cause diseases of ageing.

Fat worms Benedetto
Like us humans, C. elegans develop age-related pathologies, including age-related obesity (fat labelled in green). Credit: A. Benedetto

The deteriorative part of ageing (which biologists call senescence) is now the main cause of disease and death worldwide. This includes dementia, cancer, cardiovascular disease, chronic obstructive pulmonary disease and many other illnesses. Yet scientists have struggled to identify the causes of senescence. Much recent effort has tried to discover the basic principles of aging by studying simple animals such as Caenorhabditis elegans, a nematode worm that lives on fruit, and dies of old age after only 2-3 weeks.

“Discovering the causes of ageing in these little creatures could provide the key to understanding human ageing, and where late-life diseases come from” said Dr Marina Ezcurra (Queen Mary University of London), a lead author of the paper. “That is why we are so excited about our new findings.”

The new study describes how biological processes that make young worms better able to reproduce run-on pointlessly in older worms and cause disease. Specifically, the worms consume their own bodies as raw material to synthesize yolk for eggs, and run-on of this process causes organ atrophy and senescent obesity in elderly worms.

“For decades scientists studying ageing have thought of ageing bodies as wearing out much like cars do, from build up of damage” said Professor David Gems, another lead author of the study. “What’s exciting about this new work is that it shows something completed different. It turns out that what kills us when we’re old is not random damage, but our own genes. We’re not like cars,” he said.

The new discoveries support a theory of ageing proposed recently by a Russian biologist, Mikhail Blagosklonny, based on an older theory by G.C. Williams. The latter proposed that genes evolve to optimise fitness in early life, even though they may sometimes have destructive effects in later life. “It seems that natural selection is short-sighted and ageing is the price we pay,” said Professor Gems. According to Blagosklonny, useful biological programs run-on to become pathogenic “quasi-programmes”. Blagosklonny draws an analogy between development and running a bath. If you leave the water running, the program for filling your bath becomes a quasi-program to flood your bathroom. The new study shows that quasi-programmes are indeed a major underlying cause of ageing.

The findings in Current Biology are consistent with another recent study from some of the same authors. This showed how the futile activation in unfertilized eggs of programs meant to generate embryos causes tumour formation in ageing worms [Wang et al., npj Aging and Mechanisms of Disease 4: 6, published June 13th 2018].

“I think this work marks a real paradigm shift in our understanding of ageing,” said Dr Marina Ezcurra. “The findings are surely applicable to humans, since genes that control the destructive processes that we’ve been studying are known to control lifespan not only in worms but also in mammals,” she said.

A key finding in the study is that pathological atrophy is promoted by the process of autophagy (or self eating). “This really surprised us since autophagy is usually thought to protect against ageing rather than to cause it,” said Dr Alexandre Benedetto, also author of the study. “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, which causes senescence. So it’s like: ‘Can we ever have too much of a good thing?’ Answer: Yes, we can,” he added.

“I’ve been studying ageing in C. elegans for 25 years, and it’s amazing to see its underlying mechanisms revealed.” said Professor Gems. “This is so important, because if you want to treat a disease you really need to understand what causes it. And senescence has really become the mother of all diseases. So understanding it is good news for all of us.”

References

Ezcurra, M., Benedetto, A., Sornda, T., Gilliat, A.F., Au, C., Zhang, Q., van Schelt, S., Petrache, A.L., Wang, H., de la Guardia, Y., Bar-Nun, S., Tyler, E., Wakelam, M.J., Gems, D, C. elegans Eats its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies’ will be published in Current Biology on 13th August, 17:00 UK time and is under a strict embargo until this time.

Related, recent paper cited here:

Wang, H., Zhao, Y., Ezcurra, M., Benedetto, A., Gilliat, A.F., Hellberg, J., Ren, Z., Galimov, E.R., Athigapanich, T., Girstmair, J., Telford, M.J., Dolphin, C.T., Zhang, Z., Gems, D, ‘A Parthenogenetic Quasi-program Causes Teratoma-like Tumors During Aging in Wild-type C. elegans’ npj Aging and Mechanisms of Disease 4: 6 [published June 13th 2018].

 

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