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 University College London and the Babraham Institute.
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.
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 Professor David Gems (UCL Institute of Healthy Ageing), who led the team of researchers. “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. As part of this analysis, Babraham Institute researchers within the Institute’s Lipidomics facility analysed amounts and changes in the fat molecules (lipids) that accumulate in worms as they age.
Professor Michael Wakelam, Director of the Babraham Institute, who led the lipidomics work, said: “Our research identified yolk lipid production as one of the essential biological processes required to support reproduction but which overruns and contributes to ageing-related decline. This research gives us a new viewpoint on ageing and that perspective allows us to consider new ways to increase healthspan and lifespan.”
“For decades scientists studying ageing have thought of ageing bodies as wearing out much like cars do, from build-up of damage" said Dr Alex Benedetto, a lead author on 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 Dr Benedetto. According to Blagosklonny, useful biological programmes run-on to become pathogenic "quasi-programmes”; by analogy, an oven programme to generate a tasty leg of lamb if left to run too long becomes a quasi-programme generating over-cooked meat. 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 the same team at UCL (Wang et al., npj Aging and Mechanisms of Disease, reference below). This showed how the futile activation in unfertilised eggs of programmes meant to generate embryos causes tumour formation in ageing worms.
“I think this work marks a real paradigm shift in our understanding of ageing,” said Dr Marina Ezcurra, also a lead author on the study. "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 Benedetto. “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.”
The studies were funded by the Wellcome Trust and the Babraham Institute receives core funding from the BBSRC.
Main publication reference
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.
Referenced paper on related work
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 (2018)
This research was supported by funding from the Wellcome Trust. The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC).
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Related resources:Race Against the Ageing Clock: Following our participation in the 2018 Royal Society Summer Science Exhibition find out more about the biology of ageing, how research at the Institute is working to achieve a healthier longer life and how nematode worms are used in our ageing research.
Video explainer: Race Against the Ageing Clock: a journey towards healthier ageing
ImageC. elegans are used in the Babraham Institute’s ageing research to learn more about the ageing process and explore factors that influence ageing. The image above shows genetically identical worms that have been synchronised at the same age and yet show variability in the level of expression of genes. The green fluorescence show the variable expression of an immunity related gene (in green). The red fluorescence corresponds to a reporter gene expressed in the same tissue (epidermis) which is expressed at a similar level in each worm. Image: Laetitia Chauve, Babraham Institute.
Affiliated authors (in author order):
Qifeng Zhang - Lipidomics facility at the time of this research
Michael Wakelam - Group Leader, Signalling programme and Institute Director
About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute receives core funding from the Biotechnology and Biological Sciences Research Council (BBSRC) through an Institute Core Capability Grant.
25 July 2018