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Monday, 24 March 2014

The Secrets of Ageing

Ageing by r000pert (Creative Commons)
Stormy weather ahead? Image credit: r000pert
At the moment at least, ageing is an inevitable part of life. And yet scientists don’t really understand how, or why, we age. It is thought that a combination of pre-programmed bodily changes and environmental issues are responsible[1], but how these interact isn’t clear. Some researchers in this area aim to help us make better lifestyle choices[2], such as eating more healthily or exercising more, in order to live a long and healthy life. Others meanwhile are looking for a way to stop the ageing process in its tracks[3].

Perhaps the first question that needs answering before we can fully understand the ageing process is whether it’s something coded into our genes, or simply a case of our bodies ‘wearing out’. From an evolutionary point of view, once an animal has passed reproductive age it’s of little use, and may not be worth the food needed to keep it alive. This means it makes sense for animals to die as soon as they are no longer fertile. There have been some suggestions that human women live so long post-menopause because they were useful in helping to look after their grandchildren[4], so their offspring were more successful. However it isn’t clear that this benefit would run to humans living as long as we do now. Another possibility is that rather than being an evolutionary advantage, ageing is purely a result of damage accumulating in our bodies - meaning that if we could prevent that damage, we may be able to extend our lifespans indefinitely.

Lefty clock by Ross Berteig
Is ageing built in to our biological design? Or caused by our bodies wearing out?
Image credit: Ross Berteig

One of the ways in which our bodies are damaged as we get older is down to the build-up of free radicals. Free radicals are produced as a normal part of metabolism, and are important for cells to signal and communicate with each other. But they are highly reactive, as they have an unpaired electron in their outer shell. This means they tend to interact with molecules in the body, and in doing so can cause a cell to die or become cancerous. If too many are produced, the body’s natural protective mechanisms can’t handle the onslaught, and damage can occur. This is known as oxidative stress, which builds up as you get older. Taking in extra antioxidants, from foods such as blueberries, is thought to help neutralise free radicals by providing them with the electron they need[5]. However more research is needed before we can say for sure that consuming antioxidants can prevent disease or extend life[6].

Throughout our lives our bodies have to grow, change and heal. The chromosomes that make up our DNA replicate themselves, allowing cells to divide. This is a difficult process, and each time it occurs the very ends of each chromosome are missed. This would be really bad news if it meant that information was lost during each cell division, but luckily nature has a solution. The end section of each chromosome is called a telomere. This is a section of repeating nucleotides which protect the rest of the chromosome, preventing important information from being lost. But as the telomere gets shorter with each cell division, the number of times the cell can divide is limited. It isn't known whether it’s the act of the telomeres shortening that causes the symptoms of ageing, but researchers are nevertheless keen to determine whether it is possible to replenish these sequences[7]. In some types of cell such as stem cells, an enzyme replenishes the telomeres after each division, meaning the cells can, in theory, live forever. Harnessing this ability may bring us one step closer to eternal youth.

Diagram infographic explaining DNA, genes, nucleotides and chromosones
DNA is made from long chains of nucleotides tightly packed into structures called chromosomes, together with some associated proteins. A gene is a sequence of nucleotides along a DNA strand. Image credit: University of Leicester

While some scientists are trying to discover the common factors that cause all of us to age, others are investigating why some people survive an unusually long time, despite not living particularly healthy lifestyles. It’s likely that the difference is down to their DNA[8]. We know that people react differently to different drugs and lifestyles, but isolating the genes responsible is a mammoth task. In many cases, it’s a combination of genetics and environmental influences that leads to a particular disease developing[9]. One day, genetic testing may lead to medicine for all diseases being personalised for each individual, and help us to live longer and healthier lives. Already, testing for genes linked with breast cancer allow at-risk individuals to take preventative measures[10], and the dosage of some drugs can be altered depending on a person’s genetic make up[11]. For the moment, however, for most diseases the days of personalised medicine is a long way off.

Even if it was possible to find a gene “responsible for” every disease, it’s still not that simple. Although all cells in our body (other than red blood cells) contain a full copy of our DNA, not all of it is used in each cell. The genes which make up our DNA tells cells how to make various proteins, so only the genes that carry instructions for making proteins the cell needs will be activated. How genes are regulated is complex, and isn’t well understood. As well as internal factors, like what kind of cell the DNA is in, environmental factors such as diet have an influence. This area of research, known as epigenetics, has had a huge impact on our understanding of genetics. It shows that what’s coded in our DNA is not the full story. Our lifestyle, and even that of our parents and grandparents[12], can influence which genes are turned on and so affect our health and how we age.

Artist's impression of DNA with the word SECRET written in light beneath it
Unlocking the secrets contained without our DNA has only just begun. Only time will tell what our DNA can really tell us about ourselves. Image credit: Jurvetson

As the search for the secret to eternal life continues, scientists have begun to turn to other animals for clues. Various different animals have been hailed as holding the secret to eternal youth. One of these is the naked mole rat, which lives in East Africa. Most other rodents of its size have short life-spans (a maximum of 4-5 years for mice and rats) but the naked mole rat can live for over 20[13]. Scientists are trying to explain why they can live such a long time, but it may be due to their very low metabolism, and their ability to reduce it further during times of hardship. These periods could give them a chance to deal with oxidative stress more effectively, so their body would accumulate less damage than it otherwise would. They also seem to be hugely resistant to cancer - in fact, a naked mole rat with cancer has never been discovered[14]. Mining the secrets of the animal kingdom may be our best bet in our fight to extend our healthy life-span.

As well as looking for animals that naturally live a long time, researchers have found artificial methods of increasing some animals’ lifespans. For example, severe calorie restriction allowed mice to live 50% longer than normal[15]. However these gains come at a price. The long-lived mice suffered from reduced fertility and flies bred to live longer don't reproduce as successfully their short-lived counterparts[16]. When it comes to humans, while extending life may seem like a good aim, it wouldn’t be so positive if it came at the cost of health. Trials like this are also very difficult to conduct on humans due to the safety risks involved, and the necessarily time-intensive nature of the trial required!

The social implications of extending human life are also of great concern. As people live longer, and the old outnumber the young, the question of how we pay for the older generations is raised. Retirement ages will need to rise with life expectancy, but that can only be feasible if the mental and physical problems that are associated with old age are defeated, so people can work for longer. Currently, researchers believe that human lifespan does have an upper limit[17], so life expectancy won’t just keep increasing indefinitely. What this age limit might be however, isn’t clear, and probably won’t become so for many years to come.

This article was written by our Natural Sciences Editor, Ginny Smith, and one of our summer interns from 2013, Johanna Blee.

References
why don't all references have links?

[1] Pizza, Vincenzo et al. "Neuroinflammation and ageing: current theories and an overview of the data." Reviews on recent clinical trials 6.3 (2011): 189-203. DOI: 10.2174/157488711796575577

[2] Shammas, Masood A. "Telomeres, lifestyle, cancer, and aging." Current opinion in clinical nutrition and metabolic care 14.1 (2011): 28. PMCID: PMC3370421

[3] Severin, FF, and VP Skulachev. "Programmed cell death as a target to interrupt the aging program." Advances in gerontology (Uspekhi Gerontologii) 22.1 (2009): 37. DOI: 10.1134/S2079057011010139

[4] Hawkes, Kristen et al. "Grandmothering, menopause, and the evolution of human life histories." Proceedings of the National Academy of Sciences 95.3 (1998): 1336-1339.

[5] Aruoma, OI. "Nutrition and health aspects of free radicals and antioxidants." Food and Chemical Toxicology 32.7 (1994): 671-683. DOI: 10.1016/0278-6915(94)90011-6

[6] Kaur, Charanjit, and Harish C Kapoor. "Antioxidants in fruits and vegetables–the millennium’s health." International Journal of Food Science & Technology 36.7 (2001): 703-725. DOI: 10.1111/j.1365-2621.2001.00513.x

[7] Epel, Elissa. "How “Reversible” Is Telomeric Aging?" Cancer Prevention Research 5.10 (2012): 1163-1168. DOI: 10.1158/1940-6207.CAPR-12-0370

[8] Slagboom, PE et al. "Genomics of human longevity." Philosophical Transactions of the Royal Society B: Biological Sciences 366.1561 (2011): 35-42. DOI: 10.1098/rstb.2010.0284

[9] Nunes, Tiago et al. "Familial aggregation in inflammatory bowel disease: Is it genes or environment?" World journal of gastroenterology: WJG 17.22 (2011): 2715.

[10] Yen, Tina WF. "Genetic Testing for BRCA Mutations Can Save Lives." Archives of Surgery 146.4 (2011): 479-480.

[11] Xie, Hong-Guang, and Felix W Frueh. "Pharmacogenomics steps toward personalized medicine." Future Medicine 2.4 (2005): 325-337. DOI: 10.2217/17410541.2.4.325

[12] Lillycrop, Karen A. "Effect of maternal diet on the epigenome: implications for human metabolic disease." Proceedings of the Nutrition Society 70.01 (2011): 64-72. DOI: 10.1017/S0029665110004027

[13] Pérez, Viviana I et al. "Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat." Proceedings of the National Academy of Sciences 106.9 (2009): 3059-3064. DOI: 10.1073/pnas.0809620106

[14] Seluanov, Andrei et al. "Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat." Proceedings of the National Academy of Sciences 106.46 (2009): 19352-19357. DOI: 10.1073/pnas.0905252106

[15] Weindruch, Richard. "The retardation of aging by caloric restriction: studies in rodents and primates." Toxicologic pathology 24.6 (1996): 742-745. DOI: 10.1177/019262339602400618

[16] Partridge, Linda, and Martin D Brand. "Special issue on dietary restriction: dietary restriction, longevity and ageing—the current state of our knowledge and ignorance." Mechanisms of ageing and development 126.9 (2005): 911-912 DOI: 10.1016/j.mad.2005.03.023

[17] Carnes, BA, SJ Olshansky, and L Hayflick. "Can human biology allow most of us to become centenarians?" The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 68.2 (2013): 136-142. DOI: 10.1093/gerona/gls142