UP researchers close in on the secret to aging

The quest for immortality has long fascinated humans, and inspired countless tales – now, in two new studies published in the journals Nature and Science, University of Pretoria (UP) researchers, along with a team of global experts known as the Mammalian Methylation Consortium, are a step closer to unmasking the secret of aging in mammals, thus raising important questions – and answers.

“Uncovering DNA methylation landscapes that are associated with maximum lifespan and birth length in mammals, including humans, has implications for developing interventions to promote healthy aging and prevent age-related diseases,” says Professor Nigel Bennett of UP.

Together with a team of international scientists, Prof Bennett, Dr Daniel Hart and Dr Darren Pietersen of the University’s Department of Zoology and Entomology in the Faculty of Natural and Agricultural Sciences studied more than 15 000 samples across 348 species in 25 out of 26 taxonomic orders, and found that both the genome and epigenome influence the biological characteristics and traits of different species. These traits include physical features, susceptibility to diseases, and behaviour, and are influenced by genetic and environmental factors. The study offers insight into aging and the lifespans across different mammal species. Analysing these cells and the effects of epigenetic factors such as lifestyle could help to predict the onset of age-related diseases and how to treat them.

“The study could contribute to a better understanding of the genetic and epigenetic basis of aging and lifespan in mammals, including humans, by providing insights into the evolution of lifespan and aging across different species of mammals,” Prof Bennett says. “We have helped to develop a universal pan-mammalian clock. This is a mathematical formula that we believe can accurately estimate age in all mammal species.”

Being able to determine the age of mammals in the wild will help to understand their stage of development, and possible diseases or treatments. This has implications for conservation and the preservation of endangered species; this includes the identification of population dynamics, such as whether a particular animal is still able to reproduce. In addition, the clock can be used in forensic science to estimate the correct age of a victim at the time of death or the age of a suspect based on forensic evidence.

Aging has long been thought to be the result of random cellular damage or degradation over time, but this latest research shows that the epigenetic aspects of aging in fact follow a predetermined “programme”. “By understanding the evolutionary conservation of aging and its relationship with developmental processes across all mammals, we can try to identify biomarkers of aging that can be used to diagnose and treat various ailments,” Dr Hart explains.

“The study made use of DNA methylation to compare the changes to epigenetic factors that affect mammals, like environment and lifestyle, which can affect one’s health or genetic makeup,” Dr Pietersen says. “Epigenetic refers to changes in gene codes that occur without any alteration in the DNA sequence. These changes can be influenced by various factors such as environmental conditions, lifestyle and aging. The findings of our study suggest that aging has remained relatively unchanged over long periods of evolutionary time, and there are similarities in developmental processes across all mammals.”

DNA methylation involves the natural addition of a methyl (one carbon atom bonded to three hydrogen atoms) group to one of the four (cytosine) nucleotide bases of the DNA molecule, which can affect the control of gene expression – turning genes on or off. Gene expression cells are all cells in the body. Any defect in gene expression will result in problems, including cancer, obesity and autoimmune conditions. DNA methylation patterns can vary between cell types and tissues, and can be influenced by environmental factors. In mammals, these specific methylation levels change with age.

This study has important implications for a range of fields, from forensics to conservation and biomedical research; this is because the universal pan-mammalian clock can be used to study the effects of environmental factors, such as diet and lifestyle, on the aging process and the development of age-related diseases.

Click on the infographic in the sidebar to learn how the pan-mammalian clock was developed or click on the photo to see the clock.

Researchers

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  Professor Nigel Bennett

  Professor Nigel Bennett has been at the University of Pretoria (UP) for 26 years. He holds a BSc (Hons) in Zoology, which he obtained at Bristol University in the UK, and undertook his PhD studies at the University of Cape Town.
  
  His research focus is animal physiology and behaviour using the African mole rat as his model animal. His work is directed primarily at studying the social regulation of reproduction in mole rats.
  
  Prof Bennett’s research record ranks him among the best researchers studying social regulation of reproduction in any group of mammals in the world. He has investigated cooperative breeding in mammals from a variety of perspectives. This multi-faceted approach has led to an integrated understanding of reproductive suppression in mole rats of a type that has not been achieved for any other taxa. His research has set the benchmark for our understanding of phylogenetic and ecological constraints that regulate reproductive success and social evolution in mammalian species.
  Prof Bennett has always been interested in why some organisms adopt a social lifestyle and others do not. As a young boy, he was fascinated by how wood ants worked for the common good of a queen. His interest in mole rats came about while he was an undergraduate at Bristol University, after he had read a seminal paper by scientist Jennifer Jarvis on cooperative breeding in the naked mole rat. Upon obtaining a position as a doctoral candidate, Prof Bennett wanted to see if this was a feature common to other African mole rats. He went on to study the Damaraland mole rat, and found it to have incredible social organisation similar to that of social insects and termites.
  
  Prof Bennett is now the world leader in African mole rat biology, particularly in reproductive physiology. A research milestone for him was discovering that breeding female naked mole rats orchestrate non-breeding males and females in the colony to exhibit high prolactin levels. This inhibits the release of hormones that stimulate the development of reproductive activities in the gonads, as evidenced by a lack of follicular development in ovaries and a reduction in numbers and motile sperm in testes. Prolactin also results in individuals exhibiting helping behaviour and cooperative care of the young.
  
  After nearly three decades of research on the reproduction of social African mole rats, Prof Bennett has not been able to determine how the breeding female actually inhibits reproduction in physiologically suppressed animals. This would be the magic bullet for potential contraception in humans.
  He leads a research group that strives to unravel how social evolution arose in African mole rats – solving this puzzle has important implications as to how social evolution arose among hominids. Essentially, it comes down to food acquisition and protection from predators, which is a central theme in social evolution in most mammalian groups.
  
  Two people influenced his career: Prof Brian Follett – who supervised Prof Bennett’s honours project and whose infectious enthusiasm for science and incredible lectures fired up Prof Bennett’s imagination – and Prof Jennifer Jarvis, who drove his passion to work on mole rats.
  
  In 2021, Prof Bennett was made an honorary member of the American Society of Mammalogists, a title bestowed on fewer than 100 luminaries in a century. He has been a visiting professor at the School of Chemical and Biological Sciences at the University of London’s Queen Mary College since 2005. More recently, he was a visiting professor at the Department of Zoology at King Saud University in Saudi Arabia.
  
  He is a member of the Academy of Science of South Africa, and a fellow of the Zoological Society of London, the Royal Society of South Africa and the African Academy of Sciences.
  
  Prof Bennett was awarded the UP Chancellor’s Medal for his research on three occasions and has received the Exceptional Academic Achiever Award for the past 14 years. He was also the recipient of the Zoological Society of Southern Africa’s gold medal and received the Havenga Prize for outstanding contributions to Life Sciences, awarded by the Academy of Science and Arts of South Africa. UP awarded him the University of Pretoria Commemorative Research Medal for being one of the top 100 scientists in 100 years of its existence.
  
  Prof Bennett has served as president of the Zoological Community of Southern Africa for two years. He is also editor-in-chief of the Journal of Zoology and a past editor of Proceedings of the Royal Society B: Biological Sciences. In 2013, he was the handling editor of Biology Letters, another Royal Society of London journal. He has published 433 papers in international peer-reviewed scientific journals, co-authored a specialist book published by Cambridge University Press and has penned 15 chapters in books.
  
  In his spare time, Prof Bennett travels to different countries in Africa to explore the wildlife. He particularly enjoys visiting the mountain gorillas in Rwanda and Uganda, and the eastern lowland gorillas of the Democratic Republic of the Congo. He is also an avid collector of African art and frequently visits markets to add to his collection.
  
  If he were not a researcher, Prof Bennett would have liked to have been a game warden in one of East Africa’s national parks to contribute to the protection of the incredible African fauna from poaching.
  
  ORCID ID: 0000-0001-9748-2947
  

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  Dr Daniel Hart

  Dr Daniel Hart is a postdoctoral fellow at the University of Pretoria. His research focuses on the evolutionary physiological and biomedical studies of African vertebrates.
  
  Dr Daniel Hart was part of an international team with Prof Nigel Bennett whose research into African mole-rats was not only published in the distinguished journal Science but made the cover.
  
  Prof Nigel Bennett, a professor in UP’s Department of Zoology and Entomology, and post-doctoral fellow Dr Daniel Hart worked closely with the Max Delbrück Center for Molecular Medicine in Berlin, Germany on their recent research, the findings of which show that mole-rats communicate in their own dialect.
  
  He tells us more about their groundbreaking research.
  
  What makes African mole-rats so interesting?
  DH: They are great models to show how animals adapt to their environment. For example, their broad spectrum of sociality has been brought about by the different species inhabiting different climatic regions. Simultaneously, their incredible ability to withstand hypoxic (low oxygen) conditions has come about because of their exclusive subterranean lifestyle.
  
  What made you focus your research on them?
  DH: When I began my research career, a wise mentor gave me a piece of advice: study animals that you can ask interesting questions about. So far, I have not found an animal that you can ask more interesting questions about than African mole-rats ­­– the number of exciting questions and answers that mole-rats have to offer drew me to studying them.
  
  How does their social and communication habits have an impact on how we understand them?
  
  DH: Naked mole-rats live in large families (50 to 60 individuals), with some colonies reaching 300, controlled by one female, the queen. Each colony member has its own “job”, and everyone recognises their own colony and family members, even in the dark. Even after the vast number of studies on these amazing animals, how the colony structure is maintained has somewhat eluded us. But, like humans, it may come down to dialects to some extent. From this study, we have learnt that each mole-rat colony has its own dialect, dictated by the queen, allowing colony cohesion and detection of intruders. Interestingly, this dialect can be learnt, which is an uncommon ability in most animals. This new understanding brings us closer to figuring out how these large families work together and stay together. This understanding can possibly help us in furthering our knowledge about human dialects.
  
  Are there any other animals that provide as interesting an array of applications as the mole-rat?
  
  DH: We are fortunate, as Africa has a treasure trove of unique animals with remarkable features and abilities. One such animal we are working on is the tenrec, which is a fantastic model of a prehistoric mammal. With these animals, we hope to peer back in time to unravel essential questions about evolution. Like the mole-rats, they also possess remarkable physiological and molecular traits, which could be vital to biomedical studies.
  
  What do you do in your spare time?
  DH: I have quite a big interest in other scientific subjects, namely astrophysics, astronomy and cosmology. I also enjoy listening to books or podcasts on these subjects and reading articles when I get a chance. Also, I am passionate about sport, so I enjoy catching up on the world’s sporting events when I can.

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  Dr Darren Pietersen

  Dr Darren Pietersen completed his studies at the University of Pretoria (UP), beginning with research as an undergraduate student. After obtaining a PhD, he undertook two postdoctoral degrees at UP, one in the Faculty of Veterinary Science and the other in the Department of Zoology and Entomology, cumulatively spanning 15 months. Since then, he has been a research fellow at the Mammal Research Institute in UP’s Department of Zoology and Entomology.

  Dr Pietersen says he is doing research at UP because it is a world-renowned university that is well known for its mammal research.

  He describes his research as “varied”, as it covers mammals, reptiles and birds, all with an underlying theme of conservation. “I like studying the under-studied species, and particularly enjoy any research that will help us better conserve threatened species and, in that way, contribute to the betterment of the world.”

  His current research is focused on pangolins, especially the threatened Temminck’s pangolin. He has been studying pangolins for the past 14 years, and is the lead author or co-author of several scientific articles, book chapters as well as national and global conservation assessments, such as the International Union for Conservation of Nature (IUCN) Red List assessments.

  The IUCN Red List of Threatened Species, also known as the Red Data Book, is an inventory of the global conservation status and extinction risk of biological species. Dr Pietersen has been invited to attend several national and global workshops on pangolins and is a member of the IUCN Species Survival Commission Pangolin Specialist Group.

  He was also part of the core team that reassessed the conservation status of all the reptile species occurring in South Africa, Lesotho and eSwatini, to be published by the South African National Biodiversity Institute later this year. Additionally, he is a member of the core group that will be reassessing all the southern African amphibian species’ conservation statuses early next year, and a member of the IUCN Species Survival Commission Skink Specialist Group and the IUCN Species Survival Commission Snake Specialist Group.

  A recent highlight was being part of the Mammalian Methylation Consortium which, in August 2023, published a paper each in Science and Nature investigating the factors underlying mammalian ageing and developing a universal pan-mammalian clock.

  “Also in August 2023, I published an article with Prof Mark Robertson of UP’s Department of Zoology and Entomology,” Dr Pietersen says. “The paper compares the diets of four ant- and termite-specialist mammals. I found the publishing of this article particularly rewarding because the idea first came to me more than 10 years ago when I started studying pangolins. It took several years before I started working on the article, and even longer to get it through the peer-review process. It was great to finally get it published.”

  Dr Pietersen says his parents have always been extremely supportive, no matter how crazy his ideas were. “The amazing childhood that I experienced undoubtedly pushed me into a research career.”

  He says he has met and collaborated with many amazing academics in his career, but the person that stands out is Prof Armanda Bastos of the Department of Zoology and Entomology at UP. He first met Prof Bastos as a third-year student when she presented some of their Zoology modules.

  “Later that year, I knocked on her office door and presented her with an outlandish honours project that I wanted to undertake the following year with her as main supervisor,” Dr Pietersen recalls. “To my surprise and utter joy, she agreed. I was not the easiest student to supervise, but Prof Bastos always supported and guided me. She was co-supervisor of my PhD, and made a tremendous difference to my study. I always appreciate her honesty and advice, and she is always genuinely interested in what I’m doing. I have had the privilege of co-supervising several students with her, and we still collaborate on various projects.”

  Dr Pietersen hopes to conserve threatened species and, through rigorous scientific research (rather than emotions), to help identify which species really require conservation effort.

  “Part of the dream is to research species that are listed as ‘Data Deficient’ on the IUCN Red List,” he says. “Gathering more information on these species will allow us to move them into an appropriate threat category and allocate appropriate resources for their conservation.”

  As for why his research matters, he says: “Certain chunks of it probably doesn’t serve much purpose other than personal curiosity, but at least some of it does influence species conservation assessments [the IUCN Red List of Threatened Species] and national policies, and in so doing, helps to conserve species.”

  His advice to school learners or undergraduates who are interested in his field is to follow their dreams and never give up. “One’s life rarely follows the path that you envision, but everything happens for a reason, and eventually you will get where you are meant to be. Above all else, follow your passion, not money – life’s too short to be doing something that you don’t enjoy.”

  In terms of hobbies and interests, Dr Pietersen says he is an all-round naturalist. “I spend most of my free time looking for reptiles, amphibians or birds, or learning the names of new plants if I’m in a new area. I also do a lot of reviewing for various scientific journals; I am an associate editor for Herpetology Notes and the editor of African Herp News.”

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Related Infographic

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  Developing the pan-mammalian clock

Related Photo

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  The pan-mammalian clock