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Developmental biology - Aging|
Continued Embryonic Growth Drives Aging
"Discovering the causes of ageing in these little creatures could provide the key to understanding human ageing, and where late-life diseases come from. I've been studying ageing in C. elegans for 25 years, and it's amazing to see its underlying mechanisms revealed. It 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 study describes how biological processes that make young worms better able to reproduce - will run-on pointlessly in older worms, causing disease.
"Since genes we've found driving the destructive processes of ageing in worms are known to control lifespan in mammals, we think the findings are applicable to humans and mark a real paradigm shift in our understanding of ageing," says Marina Ezcurra PhD, (UCL and Queen Mary), and first author of the study.
Specifically, they focused on autophagy, where body cells consume their own biomass to recycle components and extract energy. They found the worms' intestine consumes itself (autophagy) to create yolk needed for its eggs. In elderly worms, this process causes severe deterioration of the intestine and obesity from a build-up of pooled fats. In turn, negatively impacting the health of the worm by promoting the growth of tumours in the uterus, which shortens lifespan.
"This really surprised us since autophagy is usually thought to protect against ageing rather than cause it," explains Dr Alex Benedetto, a lead author on the study, formerly at UCL but now at Lancaster University. "It seems that worms crank-up autophagy, which is considered good, to maximise reproductive success, which is also good, but end up overdoing it, causing senescence."
The finding suggests parallels with bone erosion in lactating mammals. In women, a process originally designed to leach calcium from bone to create milk for breastfeeding may have negative effects after menopause, when it instead contributes to osteoporosis, osteoarthritis and calcified blood vessels. When useful biological programmes run-on in later life, they can become disease-causing 'quasi-programs'. Such programs were recently found to indeed be a major underlying cause of ageing.
This does not mean that aging is programmed but instead, it is a continuation of developmental growth driven by genetic pathways to a point where they become harmful. Other examples include an increase in blood pressure causes hypertension and an increase to the eyes' near their vision point causing long-sightedness and a need for reading glasses.
The results of this study are consistent with the results of another recent study from the same team at UCL showing how the futile activation of genes in unfertilized eggs, which are programmed to generate embryos, cause tumours to form in ageing worms.
"For decades scientists studying ageing have thought of ageing bodies as wearing out much like cars do, from a build-up of damage. What's exciting about this new work is that it shows something completely different. It turns out that we are not like cars - what kills us when we're old is not random damage, but our own genes. It seems that natural selection is short-sighted and ageing is the price we pay."
C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies Abstract/Introduction
• C. elegans consume their own intestine to synthesize yolk and promote reproduction
• This causes diseases of aging, including atrophy of the intestine and yolk steatosis
• Intestinal senescence in C. elegans is promoted by autophagy
• Here destructive run-on of wild-type biological programs causes senescent pathologies.
Aging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause senescent pathology. In C. elegans, a major senescent pathology of unknown etiology is atrophy of its principal metabolic organ, the intestine. Here we identify a cause of not only this pathology but also of yolky lipid accumulation and redistribution (a form of senescent obesity): autophagy-mediated conversion of intestinal biomass into yolk. Inhibiting intestinal autophagy or vitellogenesis rescues both visceral pathologies and can also extend lifespan. This defines a disease syndrome leading to multimorbidity and contributing to late-life mortality. Activation of gut-to-yolk biomass conversion by insulin/IGF-1 signaling (IIS) promotes reproduction and senescence. This illustrates how major, IIS-promoted senescent pathologies in C. elegans can originate not from damage accumulation but from direct effects of futile, continued action of a wild-type biological program (vitellogenesis). Longevity varies greatly in the living world. For instance birds are longer-lived than comparably sized mammals. Even amongst mammals, whales are capable of living two orders of magnitude longer than shrews, with confirmed lifespans of 211 years. A species' lifespan is usually greater in captivity than in nature, because of the removal of extrinsic hazards to survival, but the pattern of species differences remains the same. There is an intrinsic limit to lifespan, and ageing is the process that sets this limit. Older adults become less fecund and more likely to die, and their prospects of making a genetic contribution to the next generation thus decline.
Ageing is the accumulation of damage to macromolecules, organelles, cells and tissues. No genes are known to have evolved specifically to cause damage and ageing. Nonetheless, the characteristically different lifespans seen among species indicate that the rate of ageing does evolve. The evolution of longevity can be understood only as a side-effect of the evolution of something else. Yet numerous genes have been identified that accelerate ageing, for example those involved in insulin/insulin-like growth factor (IGF) signalling in invertebrates. Furthermore, their role in ageing appears to be widespread among animal species.
Authors: Marina Ezcurra, Alexandre Benedetto, Thanet Sornda, Ann F. Gilliat, Catherine Au, Qifeng Zhang, Sophie van Schelt, Alexandra L. Petrache, Hongyuan Wang, Yila de la Guardia, Shoshana Bar-Nun, Eleanor Tyler, Michael J. Wakelam, David Gems.
About UCL (University College London)
UCL was founded in 1826. We were the first English university established after Oxford and Cambridge, the first to open up university education to those previously excluded from it, and the first to provide systematic teaching of law, architecture and medicine. We are among the world's top universities, as reflected by performance in a range of international rankings and tables. UCL currently has over 41,500 students from 150 countries and over 12,800 staff. Our annual income is more than £1 billion. http://www.ucl.ac.uk | Follow us on Twitter @uclnews | Watch our YouTube channel YouTube.com/UCLTV
About Lancaster University
Lancaster is a research intensive university that combines world-class research with excellent teaching and high levels of student satisfaction. Rated top ten in the three major UK league tables, Lancaster was named University of the Year by The Times and The Sunday Times Good University Guide 2018. The University also received the TEF Gold (2017) award for outstanding teaching, an outstanding learning environment and delivering excellent employment outcomes for its students. This is the highest possible rating a university can achieve. For more information please see http://www.lancaster.ac.uk/about-us/rankings-and-reputation/
About Queen Mary University of London
Queen Mary University of London is one of the UK's leading universities with 25,332 students representing more than 160 nationalities. A member of the Russell Group, we work across the humanities and social sciences, medicine and dentistry, and science and engineering, with inspirational teaching directly informed by our research. In the most recent national assessment of the quality of research, we were placed ninth in the UK amongst multi-faculty universities (Research Excellence Framework 2014). As well as our main site at Mile End - which is home to one of the largest self-contained residential campuses in London - we have campuses at Whitechapel, Charterhouse Square, and West Smithfield dedicated to the study of medicine and dentistry, and a base for legal studies at Lincoln's Inn Fields. Queen Mary began life as the People's Palace, a Victorian philanthropic project designed to bring culture, recreation and education to the people of the East End. We also have roots in Westfield College, one of the first colleges to provide higher education to women; St Bartholomew's Hospital, one of the first public hospitals in Europe; and The London, one of England's first medical schools.
The authors would like to thank Dr. Alwyn H.A Derijck for valuable feedback.
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C. elegans Eats Its Own Intestine to Make Yolk for its Eggs. This leads to multiple senescent pathologies, one being a yolky lipid (fat) distributed in what is called 'senescent obesity.'
Image Credit: CELL.