tag:theconversation.com,2011:/global/topics/senescent-cells-24501/articlesSenescent cells – The Conversation2023-07-06T12:27:34Ztag:theconversation.com,2011:article/2020962023-07-06T12:27:34Z2023-07-06T12:27:34ZAging is complicated – a biologist explains why no two people or cells age the same way, and what this means for anti-aging interventions<figure><img src="https://images.theconversation.com/files/535886/original/file-20230705-16248-djnyz1.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">While some people may be older in chronological age, their biological age might be much younger.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/close-up-of-older-chinese-womans-eye-royalty-free-image/1082691656">FangXiaNuo/E+ via Getty Images</a></span></figcaption></figure><p>You likely know someone who seems to <a href="https://theconversation.com/are-you-a-rapid-ager-biological-age-is-a-better-health-indicator-than-the-number-of-years-youve-lived-but-its-tricky-to-measure-198849">age slowly</a>, appearing years younger than their birth date suggests. And you likely have seen the opposite – someone whose body and mind seem much more ravaged by time than others. Why do some people seem to glide though their golden years and others physiologically struggle in midlife? </p>
<p>I have <a href="https://scholar.google.com/citations?user=DDc-okgAAAAJ&hl=en">worked in the field of aging</a> for all of my scientific career, and I teach the cellular and molecular biology of aging at the University of Michigan. Aging research doesn’t tend to be about finding the one cure that fixes all that may ail you in old age. Instead, the last decade or two of work points to aging as a multi-factoral process – and no single intervention can stop it all.</p>
<h2>What is aging?</h2>
<p>There are many different definitions of aging, but scientists generally agree upon <a href="https://doi.org/10.1007/978-3-319-69892-2_29-1">some common features</a>: Aging is a time-dependent process that results in increased vulnerability to disease, injury and death. This process is both intrinsic, when your own body causes new problems, and extrinsic, when environmental insults damage your tissues.</p>
<p>Your body is comprised of <a href="https://medlineplus.gov/genetics/understanding/basics/cell/">trillions of cells</a>, and each one is not only responsible for one or more functions specific to the tissue it resides in, but must also do all the work of keeping itself alive. This includes metabolizing nutrients, getting rid of waste, exchanging signals with other cells and adapting to stress.</p>
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<figcaption><span class="caption">Aging results from a number of physiological factors.</span></figcaption>
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<p>The trouble is that every single process and component in each of your cells <a href="https://doi.org/10.1016/j.cell.2022.11.001">can be interrupted or damaged</a>. So your cells spend a lot of energy each day preventing, recognizing and fixing those problems. </p>
<p>Aging can be thought of as a gradual loss of the ability to <a href="https://doi.org/10.1113/JP275072">maintain homeostasis</a> – a state of balance among body systems – either by not being able to prevent or recognize damage and poor function, or by not adequately or rapidly fixing problems as they occur. Aging results from a combination of these issues. Decades of research has shown that nearly every cellular process becomes more impaired with age.</p>
<h2>Repairing DNA and recycling proteins</h2>
<p>Most research on cellular aging focuses on studying how DNA and proteins change with age. Scientists are also beginning to address the potential roles many other important biomolecules in the cell play in aging as well.</p>
<p>One of the cell’s chief jobs is to maintain its DNA – the instruction manual a cell’s machinery reads to produce specific proteins. DNA maintenance involves protecting against, and accurately repairing, damage to genetic material and the molecules binding to it. </p>
<p>Proteins are the workers of the cell. They perform chemical reactions, provide structural support, send and receive messages, hold and release energy, and much more. If the protein is damaged, the cell uses <a href="https://doi.org/10.1093/jnci/92.19.1564">mechanisms involving</a> <a href="https://theconversation.com/research-that-shines-light-on-how-cells-recover-from-threats-may-lead-to-new-insights-into-alzheimers-and-als-163210">special proteins</a> that either attempt to fix the broken protein or send it off for recycling. Similar mechanisms tuck proteins out of the way or destroy them when they are no longer needed. That way, its components can be used later to build a new protein.</p>
<h2>Aging disrupts a delicate biological network</h2>
<p>The cross-talk between the components inside cells, cells as a whole, organs and the environment is a complex and ever-changing network of information. </p>
<p>When all processes involved in creating and maintaining DNA and protein function are working normally, the different compartments within a cell serving specialized roles – <a href="https://www.genome.gov/genetics-glossary/Organelle">called organelles</a> – can maintain the cell’s health and function. For an organ to work well, the majority of the cells that make it up need to function well. And for a whole organism to survive and thrive, all of the organs in its body need to work well. </p>
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<a href="https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of cross-section of an animal cell and its organelles" src="https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=375&fit=crop&dpr=1 600w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=375&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=375&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=471&fit=crop&dpr=1 754w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=471&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/535889/original/file-20230705-19007-k74rlb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=471&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Each organelle within a cell carries out specific functions.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/internal-structure-of-an-animal-cell-3d-rendering-royalty-free-image/1306045773">Jian Fan/iStock via Getty Images Plus</a></span>
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<p>Aging can lead to dysfunction at any of these levels, from the sub-cellular to the organismal. Maybe a <a href="https://doi.org/10.1016/j.arr.2020.101154">gene encoding an important protein for DNA repair</a> has become damaged, and now all of the other genes in the cell are more likely to be repaired incorrectly. Or perhaps the cell’s <a href="https://theconversation.com/cells-routinely-self-cannibalize-to-take-out-their-trash-aiding-in-survival-and-disease-prevention-199148">recycling systems</a> are unable to degrade dysfunctional components anymore. Even the <a href="https://doi.org/10.1016%2FS2213-8587(18)30026-3">communication systems</a> between cells, tissues and organs can become compromised, leaving the organism less able to respond to changes within the body. </p>
<p>Random chance can lead to a growing burden of molecular and cellular damage that is progressively less well-repaired over time. As this damage accumulates, the systems that are meant to fix it are accruing damage as well. This leads to a <a href="https://doi.org/10.1038%2Fs43587-021-00150-3">cycle of increasing wear and tear</a> as cells age.</p>
<h2>Anti-aging interventions</h2>
<p>The interdependence of life’s cellular processes is a double-edged sword: Sufficiently damage one process, and all the other processes that interact with or depend on it become impaired. However, this interconnection also means that bolstering one highly interconnected process could improve related functions as well. In fact, this is how the most successful anti-aging interventions work. </p>
<p>There is no silver bullet to stop aging, but certain interventions do seem to slow aging in the laboratory. While there are ongoing clinical trials investigating different approaches in people, most existing data comes from animals like nematodes, flies, mice and nonhuman primates. </p>
<p>One of the best studied interventions is <a href="https://doi.org/10.1126/science.abe7365">caloric restriction</a>, which involves reducing the amount of calories an animal would normally eat without depriving them of necessary nutrients. An FDA-approved drug used in organ transplantation and some cancer treatments <a href="https://doi.org/10.1007/s11357-020-00274-1">called rapamycin</a> seems to work by using at least a <a href="https://doi.org/10.1016/j.arr.2020.101240">subset of the same pathways</a> that calorie restriction activates in the cell. Both affect signaling hubs that direct the cell to preserve the biomolecules it has rather than growing and building new biomolecules. Over time, this cellular version of “reduce, reuse, recycle” removes damaged components and leaves behind a higher proportion of functional components.</p>
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<figcaption><span class="caption">The effects of calorie restriction on aging are still under study.</span></figcaption>
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<p>Other interventions include changing the <a href="https://theconversation.com/can-this-new-anti-ageing-supplement-turn-back-the-clock-126795">levels of certain metabolites</a>, selectively <a href="https://doi.org/10.1111%2Fjoim.13141">destroying senescent cells</a> that have stopped dividing, changing the <a href="https://theconversation.com/hangry-bacteria-in-your-gut-microbiome-are-linked-to-chronic-disease-feeding-them-what-they-need-could-lead-to-happier-cells-and-a-healthier-body-199486">gut microbiome</a> and <a href="https://doi.org/10.1111%2Facel.12338">behavioral modifications</a>.</p>
<p>What all of these interventions have in common is that they affect core processes that are critical for cellular homeostasis, often become dysregulated or dysfunctional with age and are connected to other cellular maintenance systems. Often, these processes are the central drivers for mechanisms that protect DNA and proteins in the body. </p>
<p>There is no single cause of aging. No two people age the same way, and indeed, neither do any two cells. There are countless ways for your basic biology to go wrong over time, and these add up to create a unique network of aging-related factors for each person that make finding a <a href="https://theconversation.com/despite-research-breakthroughs-an-anti-aging-pill-is-still-a-long-way-off-44949">one-size-fits-all anti-aging treatment</a> extremely challenging.</p>
<p>However, researching interventions that target multiple important cellular processes simultaneously could help improve and maintain health for a greater portion of life. These advances could help people live longer lives in the process.</p><img src="https://counter.theconversation.com/content/202096/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ellen Quarles does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Aging is a culmination of factors spanning from your cells to your environment. A number of interconnected processes determine how quickly your body is able to repair and recover from damage.Ellen Quarles, Assistant Professor in Molecular, Cellular, and Developmental Biology, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1988492023-03-15T12:21:15Z2023-03-15T12:21:15ZAre you a rapid ager? Biological age is a better health indicator than the number of years you’ve lived, but it’s tricky to measure<figure><img src="https://images.theconversation.com/files/514749/original/file-20230310-2079-5uhxpf.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2122%2C1410&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Healthspan measures incorporate quality of life in ways that lifespan does not.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/female-babyboomer-jumping-into-lake-royalty-free-image/92930493">Ira T. Nicolai/The Image Bank via Getty Images</a></span></figcaption></figure><p>Do you ever wake up some days and think, “When I was younger, I could survive on just four hours of sleep, but now it seems like I need 10”? Or have you ever walked out of the gym and “felt” your knees?</p>
<p>Almost everyone experiences these kinds of signs of aging. But there are some people who seem to defy their age. The late U.S. Supreme Court Justice <a href="https://www.cbsnews.com/news/remembering-rbg-justice-ruth-bader-ginsburg-a-woman-who-lived-a-life-defying-expectations/">Ruth Bader Ginsberg</a> stayed on the bench until her death at age 87. The “Great British Bake Off” judge <a href="https://www.bbc.com/news/entertainment-arts-58982697">Mary Berry</a>, now in her 80s, continues to inspire people all over the world to bake and enjoy life. And actor <a href="https://www.washingtonpost.com/arts-entertainment/2021/11/10/paul-rudd-sexiest-man-alive-people/">Paul Rudd</a> was named People magazine’s “Sexiest Man Alive” in 2021 at age 52 while still looking like he’s in his 30s. Is age just a number then? </p>
<p>Researchers have focused a lot of attention on understanding the causes and risk factors of age-related diseases like Alzheimer’s, dementia, osteoporosis and cancer. But many ignore the major risk factor for all of these diseases: aging itself. More than any individual risk factor such as smoking or lack of exercise, the number of years you’ve lived predicts onset of disease. Indeed, aging increases the risk of multiple chronic diseases <a href="https://doi.org/10.1016/j.cub.2012.07.024">by up to a thousandfold</a>. </p>
<p>However, <a href="https://doi.org/10.1038/s41586-018-0457-8">no two people age the same</a>. Although age is the principal risk factor for several chronic diseases, it is an unreliable indicator of how quickly your body will decline or how susceptible you are to age-related disease. This is because there is a difference between your chronological age, or the number of years you’ve been alive, and your biological age – your physical and functional ability.</p>
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<figcaption><span class="caption">As the author notes in her TED Talk, aging is not just a number.</span></figcaption>
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<p>I am a <a href="https://scholar.google.com/citations?user=tqI8C_UAAAAJ&hl=en">scientist interested in redefining “age.”</a> Instead of benchmarking chronological age, my lab is invested in <a href="http://agresearchlab.com">measuring biological age</a>. Biological age is a <a href="https://doi.org/10.1016/j.jacc.2019.11.062">more accurate measure of healthspan</a>, or years lived in good health, than chronological age, and doesn’t directly correlate with wrinkles and gray hairs. Rapid agers experience a faster rate of functional deterioration relative to their chronological age. </p>
<p>My grandmother, who lived to be 83 but was bedridden and could not remember who I was for the last few years of her life, was a rapid ager. My grandfather, on the other hand, also lived until he was 83, but he was active, functional and even did my homework with me until he passed away – he was a healthy ager.</p>
<p>With the unprecedented <a href="https://www.who.int/news-room/fact-sheets/detail/ageing-and-health">growth of the world’s aging population</a>, I believe that figuring out ways to measure biological age and how to maintain or delay its advance is critical not only for individual health, but also for the social, political and economic health of our society. Detecting rapid agers early on presents an opportunity to delay, change or even reverse the trajectory of biological aging. </p>
<h2>Genetics and biological age</h2>
<p>Biological aging is multifaceted. It arises from a complex mix of genetic traits and is <a href="https://doi.org/10.1016/j.jacc.2019.11.062">influenced by factors</a> like microbiome composition, environment, lifestyle, stress, diet and exercise.</p>
<p>Genetics were once thought to have no influence on aging or longevity. However, in the early 1990s, researchers reported the first studies identifying <a href="https://doi.org/10.1098/rstb.2010.0276">genes that were able to extend the lifespan</a> of a small roundworm. Since then, multiple observations support the influence of genetics on aging.</p>
<p>For example, children of long-lived parents and even those with long-lived siblings <a href="https://doi.org/10.1038/ejhg.2011.40">tend to live longer</a>. Researchers have also <a href="https://doi.org/10.1038/s41576-019-0183-6">identified multiple genes</a> that influence longevity and play a role in resilience and protection from stress. These include genes that repair DNA, protect cells from free radicals and regulate fat levels.</p>
<p>However, it is clear from studies in identical twins – who share the same genes but not the same exact lifespans – that genes are not the only factor that influences aging. In fact, genes probably account for only <a href="https://www.scientificamerican.com/article/genetic-factors-associated-with-increased-longevity-identified/">20% to 30% of biological age</a>. This suggests that other parameters can strongly influence biological aging.</p>
<h2>Environmental and lifestyle effects</h2>
<p>Researchers have found that environmental and lifestyle factors heavily influence biological age, including social connectedness, <a href="https://doi.org/10.1001/jamanetworkopen.2021.24387">sleeping habits</a>, <a href="https://www.cnn.com/2023/01/02/health/hydration-disease-aging-death-risk-study-wellness/index.html">water consumption</a>, exercise and diet. </p>
<p><a href="https://doi.org/10.1016/j.alcr.2019.02.002">Social connectedness</a> is essential for well-being throughout life. But social connections can be challenging to maintain over time due to loss of family and friends, depression, chronic illness or other factors. Several studies have reported a <a href="https://doi.org/10.1073/pnas.1219686110">strong link</a> between social isolation and increased stress, morbidity and mortality.</p>
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<a href="https://images.theconversation.com/files/514754/original/file-20230310-449-nugrkx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Three women dancing together in a park" src="https://images.theconversation.com/files/514754/original/file-20230310-449-nugrkx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/514754/original/file-20230310-449-nugrkx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/514754/original/file-20230310-449-nugrkx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/514754/original/file-20230310-449-nugrkx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/514754/original/file-20230310-449-nugrkx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/514754/original/file-20230310-449-nugrkx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/514754/original/file-20230310-449-nugrkx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Social connectedness and physical activity are linked to well-being throughout life.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/three-ladies-listening-to-music-and-dancing-royalty-free-image/1152656857">Filippo Bacci/E+ via Getty Images</a></span>
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<p>Similarly, diet and exercise are strong influencers of biological age. <a href="https://doi.org/10.1177/1559827616637066">Blue zones</a>, which are areas around the world where people live long lives, attribute their successful aging to diet, exercise and social connectedness. Mostly plant-based meals and spurts of activity throughout the day are well-known “secrets” of healthspan and longevity. Although newer studies on the effects of diet interventions such as intermittent fasting and time-restricted feeding on longevity have not been rigorously tested, they do show multiple health benefits, including <a href="https://doi.org/10.1007/s00125-022-05752-z">better glucose</a> and <a href="https://doi.org/10.1186/s12986-021-00613-9">insulin regulation</a> </p>
<p>While genetics is difficult to control, diet and exercise can be modified to delay biological aging.</p>
<h2>How to measure biological age</h2>
<p>Currently, there is no effective test to predict an individual’s health trajectory early enough in life in order to intervene and improve quality of life with age. Scientists are interested in identifying a molecule that is sensitive and specific enough to serve as a <a href="https://doi.org/10.1038/s41576-022-00511-7">unique fingerprint for biological age</a>. </p>
<p>Considering the health and resilience of the individual instead of focusing solely on disease state is important in discussions on biological age. Resilience is the state of <a href="https://doi.org/10.1093%2Fgeroni%2Figab046.621">adapting and bouncing back</a> from a health challenge and is often more predictive of functional health. A molecular aging fingerprint may provide a tool to help identify people who are less resilient and require more aggressive monitoring and early intervention to preserve their health and help <a href="https://doi.org/10.1038%2Fs43587-021-00044-4">reduce gender, racial and ethnic health disparities</a>.</p>
<p>There are several promising molecular markers that may serve as biological age fingerprints.</p>
<p>One of these markers are epigenetic clocks. <a href="https://www.cdc.gov/genomics/disease/epigenetics.htm">Epigenetics</a> are chemical modifications of DNA that control gene function. Several scientists have found that DNA can get “marked” by methyl groups in a pattern that changes with age and could potentially act as a <a href="https://theconversation.com/epigenetic-and-social-factors-both-predict-aging-and-health-but-new-research-suggests-one-might-be-stronger-200153">readout for aging</a>.</p>
<p>It is important to note, however, that while epigenetic clocks have been valuable in predicting chronological age, they do not equate to biological age. In addition, it is unclear how these epigenetic marks work or how they contribute to aging.</p>
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<a href="https://images.theconversation.com/files/514752/original/file-20230310-140-5j83gz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Older adult holding gold balloons of the number 70 in a backyard" src="https://images.theconversation.com/files/514752/original/file-20230310-140-5j83gz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/514752/original/file-20230310-140-5j83gz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/514752/original/file-20230310-140-5j83gz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/514752/original/file-20230310-140-5j83gz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/514752/original/file-20230310-140-5j83gz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/514752/original/file-20230310-140-5j83gz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/514752/original/file-20230310-140-5j83gz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Age is so much more than a number.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/happy-man-with-number-70-helium-balloons-in-royalty-free-image/1187298370">Klaus Vedfelt/DigitalVision via Getty Images</a></span>
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<p>Another well-regarded marker of biological age is the build-up of dysfunctional cells called senescent or <a href="https://theconversation.com/cells-become-zombies-when-the-ends-of-their-chromosomes-are-damaged-a-tactic-both-helpful-and-harmful-for-health-186445">zombie cells</a>. Cells become senescent when they experience multiple types of stress and become so damaged that they cannot divide anymore, releasing molecules that cause chronic low-grade inflammation and disease.</p>
<p><a href="https://doi.org/10.1111/acel.12344">Animal studies</a> have shown that getting rid of these cells can improve healthspan. However, what clearly defines senescent cells in humans is still unknown, making them challenging to track as a measure of biological age.</p>
<p>Lastly, the body <a href="https://doi.org/10.1126/sciadv.add6155">releases unique metabolites</a>, or chemical fingerprints, as byproducts of normal metabolism. These metabolites play a dynamic and direct role in physiological regulation and can inform functional health. My lab and others are figuring out the exact makeup of these chemicals in order to figure out which can best measure biological age. A lot of work still remains on not only identifying these metabolites, but also understanding how they affect biological age.</p>
<p>People have long sought a fountain of youth. Whether such an elixir exists is still unknown. <a href="https://doi.org/10.1038/s43587-022-00278-w">But research</a> <a href="https://doi.org/10.1038/ncomms3192">is starting</a> <a href="https://doi.org/10.1073/pnas.2107621118">to show</a> that delaying biological age may be one way to live healthier, fuller lives.</p><img src="https://counter.theconversation.com/content/198849/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Aditi Gurkar receives funding from National Institute on Health, Richard King Mellon Foundation, AFAR/Hevolution. </span></em></p>Aging is a major risk factor for many chronic diseases. Figuring out what influences longevity and how to identify rapid agers could lead to healthier and longer lives for more people.Aditi Gurkar, Assistant Professor of Geriatric Medicine, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1864452022-07-19T12:25:44Z2022-07-19T12:25:44ZCells become zombies when the ends of their chromosomes are damaged – a tactic both helpful and harmful for health<figure><img src="https://images.theconversation.com/files/473984/original/file-20220713-9184-rhhs18.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3000%2C2213&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Telomeres (red) at the ends of chromosomes protect your DNA from damage.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/JUr1Ay">Thomas Ried/NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>Damage to the ends of your chromosomes can create “zombie cells” that are still alive but can’t function, according to our recently published study in <a href="https://doi.org/10.1038/s41594-022-00790-y">Nature Structural and Molecular Biology</a>.</p>
<p>When cells prepare to divide, their DNA is tightly wound around proteins to form chromosomes that provide structure and support for genetic material. At the ends of these chromosomes are repetitive stretches of DNA called <a href="https://www.genome.gov/genetics-glossary/Telomere">telomeres</a> that form a protective cap to prevent damage to the genetic material. However, telomeres shorten each time a cell divides. This means that as cells divide more and more as you age, your telomeres become increasingly shorter and more likely to lose their ability to protect your DNA.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram depicting chromosomes in the nucleus, highlighting the telomeres at the ends of each DNA-containing arm." src="https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=381&fit=crop&dpr=1 600w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=381&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=381&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=479&fit=crop&dpr=1 754w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=479&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=479&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Telomeres serve as protective caps at the ends of each chromosome.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/telomere-chromosome-and-dna-royalty-free-illustration/961320764">FancyTapis/iStock via Getty Images</a></span>
</figcaption>
</figure>
<p>Damage to genetic material can lead to mutations that cause cells to divide uncontrollably, resulting in cancer. Cells avoid becoming cancerous when their telomeres become too short after dividing too many times and potentially accruing damage along the way, however, by entering a zombielike state that stops cells from from dividing through a process called <a href="https://doi.org/10.7554/eLife.72449">cellular senescence</a>.</p>
<p>Because they are resistant to death, senescent – or “zombie” – cells accumulate with age. They can be beneficial to health by promoting senescence in nearby cells at risk of becoming cancerous and attracting immune cells to clear out cancer cells. But they can also contribute to disease by impairing tissue healing and immune function, and by secreting chemicals that promote inflammation and tumor growth.</p>
<p>We wanted to know if direct damage to telomeres can be sufficient to trigger senescence and make zombie cells. In order to figure this out, we needed to confine damage just to the telomeres. So we attached a protein to the telomeres of human cells grown in the lab. Then we added a dye to the protein that makes it sensitive to light. Shining a far-red light (or light with a wavelength slightly shorter than infrared light) on the cells induces the protein to produce oxygen <a href="https://www.verywellhealth.com/information-about-free-radicals-2249103">free radicals</a> – highly reactive molecules that can damage DNA – right at the telomeres, sparing the rest of the chromosome and the cell.</p>
<p>We found that direct damage to the telomeres was sufficient to turn cells into zombies, even when these protective caps weren’t shortened. The reason for this, we discovered, was likely a result of <a href="https://doi.org/10.1038%2Fncb2897">disrupted DNA replication</a> at the telomeres that leaves chromosomes even more susceptible to damage or mutations. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of chromosomes with telomeres damaged by oxidation" src="https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=348&fit=crop&dpr=1 600w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=348&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=348&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=437&fit=crop&dpr=1 754w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=437&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=437&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The telomeres (green) at the tips of chromosomes (blue) damaged by free radicals become fragile (green arrows) and trigger senescence.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/s41594-022-00790-y">Ryan Barnes/Opresko Lab</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
</figcaption>
</figure>
<h2>Why it matters</h2>
<p>Telomeres naturally shorten with age. They limit how many times a cell can divide by signaling cells to become zombies when they reach a certain length. But an excess of free radicals produced from both normal bodily processes as well as exposure to harmful chemicals like air pollution and tobacco smoke can lead to a condition called <a href="https://doi.org/10.1016/j.mad.2018.03.013">oxidative stress</a> that can accelerate telomere shortening. This can prematurely trigger senescence and contribute to age-related diseases, including <a href="https://doi.org/10.1172/jci120216">immunodeficiency</a>, <a href="https://doi.org/10.1038%2Fs41556-022-00842-x">cardiovascular disease</a>, <a href="https://doi.org/10.1038/nrg3246">metabolic disease</a> and <a href="https://doi.org/10.1016%2Fj.cell.2020.12.028">cancer</a>.</p>
<p>Our study reveals that telomeres not only serve as alarm clocks that indicate a cell divided too many times, but also as warning bells for harmful levels of oxidative stress. Age-related shortening of telomeres isn’t the only thing that triggers senescence; telomere damage is also sufficient to turn a cell into a zombie.</p>
<h2>What other research is being done</h2>
<p>Researchers are studying treatments and interventions that can protect telomeres from damage and prevent zombie cell accumulation. A number of studies in mice have found that removing zombie cells can promote healthy aging by improving <a href="https://doi.org/10.1111/acel.13296">cognitive function</a>, <a href="https://doi.org/10.1038/nature10600">muscle mass and function</a> and recovery from <a href="https://doi.org/10.1126/science.abe4832">viral infections</a>. </p>
<p>Researchers are also developing drugs called <a href="https://doi.org/10.1146/annurev-pharmtox-050120-105018">senolytics</a> that can either kill zombie cells or prevent them from developing in the first place.</p>
<h2>What’s next</h2>
<p>This study focuses on the consequences of telomere damage in actively dividing cells, like kidney and skin cells. We’re now looking at how this damage will play out in cells that don’t divide, like neurons or heart muscle cells. While researchers have shown that the telomeres of nondividing cells and tissues <a href="https://doi.org/10.1038/s41556-022-00842-x">become more dysfunctional with age</a>, it’s unclear why this happens when these telomeres should not be shortening in the first place.</p><img src="https://counter.theconversation.com/content/186445/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Patricia Opresko receives funding from the National Institutes of Health and has received funding from the Glenn Foundation for Medical Research. </span></em></p><p class="fine-print"><em><span>Ryan Barnes receives funding from:
NIA F32AG067710-01
NIEHS K99ES033771</span></em></p>The protective caps at the ends of chromosomes naturally shorten over time. Researchers found that direct damage can prematurely trigger senescence and contribute to age-related diseases like cancer.Patricia Opresko, Professor of Environmental and Occupational Health, University of PittsburghRyan Barnes, Postdoctoral Researcher in Environmental and Occupational Health, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1534092021-01-27T19:23:39Z2021-01-27T19:23:39ZAnti-ageing treatments: these two drug types are being investigated<figure><img src="https://images.theconversation.com/files/380853/original/file-20210127-21-17zfkks.jpg?ixlib=rb-1.1.0&rect=6%2C27%2C4601%2C3039&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Repurposed drugs and senolytics could bring us five more years of disease-free life.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/aged-couple-jogging-public-park-smile-1798837510">Zoran Pucarevic/ Shutterstock</a></span></figcaption></figure><p>While more people may be living longer than ever before, this increase in life expectancy is accompanied by the development of age-related diseases – such as cancer or type 2 diabetes. This is why the a <a href="https://publications.parliament.uk/pa/ld5801/ldselect/ldsctech/183/18302.htm">major new parliamentary report</a> has been published in the UK, advocating greater investment in novel treatments that slow ageing, in a bid to bring people five more years of healthy, disease-free life. </p>
<p>The hope is that such treatments would either shorten the period of disease we experience at the end of our life, or extend our total lifespan while keeping the disease period the same.</p>
<p>Ageing is so far known to be caused by nine biological mechanisms, sometimes called the “<a href="https://pubmed.ncbi.nlm.nih.gov/23746838/">hallmarks of ageing</a>”. In order to prevent ageing in our tissues, cells, and molecules, we need to be able to slow or prevent these hallmarks of ageing from taking place. While there are numerous treatments currently being investigated, two approaches currently show the most promise in slowing the development of age-related disease.</p>
<h2>Repurposed drugs</h2>
<p>One area researchers are investigating is looking at whether any medicines already exist which could tackle ageing. This method is advantageous in that billions of pounds have already been spent on testing the safety and efficacy of these drugs and they are already in routine clinical use in humans. Two in particular are promising candidates. </p>
<p>The first is rapamycin, which was originally developed as <a href="https://pubmed.ncbi.nlm.nih.gov/1102508/">an immunosupressive</a>. But when taken at low doses, it’s been found to <a href="https://pubmed.ncbi.nlm.nih.gov/19587680/">extend the lifespans of mice</a> by around 15%. This is accompanied by the slowing <a href="https://pubmed.ncbi.nlm.nih.gov/22587563/">multiple age-related changes</a>, such as tendon stiffening and liver and heart degeneration. In other animal models, it’s been shown to slow the development of <a href="https://pubmed.ncbi.nlm.nih.gov/20376313/">Alzheimer’s</a> and <a href="https://pubmed.ncbi.nlm.nih.gov/15146184/">Huntington’s disease</a>. In older humans it dramatically <a href="https://theconversation.com/existing-medicines-could-help-improve-immune-function-in-vulnerable-older-adults-147516">improves immune function and vaccination responses</a>. </p>
<p>Rapamycin slows ageing by inhibiting the protein <a href="https://pubmed.ncbi.nlm.nih.gov/32899412/">mTOR</a>, which regulates the process of protein production in cells. Inhibiting it allows cells to recycle damaged proteins instead of allowing these to build up. Normally, mTOR allows these damaged protein cells to build up because it requires less energy for cells to continue building more new protein over recycling the old ones. But this buildup of proteins in cells can mean cells don’t function as well as they should. Inhibiting mTOR can enable cells to continue functioning properly.</p>
<p>The second promising medicine is metformin. Originally licensed to <a href="https://www.nhs.uk/medicines/metformin/">treat type 2 diabetes</a>, researchers noticed after decades of use that patients taking it had <a href="https://pubmed.ncbi.nlm.nih.gov/28802803/">lower rates of death and illness</a> than those who didn’t – independent of their diabetes. </p>
<p>Data from a range of studies conducted in cells, animals, and humans show that metformin works by <a href="https://pubmed.ncbi.nlm.nih.gov/23521863/">suppressing the inflammation</a> caused by <a href="https://theconversation.com/the-secret-to-staying-young-scientists-boost-lifespan-of-mice-by-deleting-defective-cells-54068">senescent cells</a>. A cell enters senescence as a result of stress – such as damage to its DNA. These cells then cease to divide as a defence against becoming cancerous – but the continual inflammation they cause triggers chronic and destructive remodelling of tissue, akin to scarring. As these cells build up in the body’s tissues, they cause or exacerbate diseases and problems of ageing such as cardiovascular disease, cancer, cognitive impairment – even wrinkles.</p>
<figure class="align-center ">
<img alt="A box of metformin tablets." src="https://images.theconversation.com/files/380854/original/file-20210127-19-142f7rz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/380854/original/file-20210127-19-142f7rz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/380854/original/file-20210127-19-142f7rz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/380854/original/file-20210127-19-142f7rz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/380854/original/file-20210127-19-142f7rz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/380854/original/file-20210127-19-142f7rz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/380854/original/file-20210127-19-142f7rz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The diabetes drug can stop inflammation from senescent cells.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/southminster-essex-06122020-box-28-metformin-1754907857">Robbie M/ Shutterstock</a></span>
</figcaption>
</figure>
<p>Metformin also <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771567/">enhances protein recycling</a>, and improves mitochrondrial function. This is central to a cell’s capacity to generate energy and undergo normal metabolism. This is why the drug is slated as a key candidate <a href="https://www.afar.org/tame-trial">in clinical trials</a>.</p>
<h2>Senolytics and senomodifiers</h2>
<p>Another category of drugs currently being developed are senolytics and senomodifiers. These aim to kill or modify the behaviour of senescent cells. This would prevent these cells from accumulating in the body and may slow age-related physical decline. </p>
<p>These drugs, including compounds such as <a href="https://pubmed.ncbi.nlm.nih.gov/28416161/">dasatinib</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/26711051/">navitoclax</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/33242601/">quercetin</a> (found in many fruits and vegetables) and <a href="https://pubmed.ncbi.nlm.nih.gov/30279143/">fisetin</a> (found in strawberries), have been found to kill senescent cells.</p>
<p>Senolytic drugs have already shown promise in treating <a href="https://pubmed.ncbi.nlm.nih.gov/31542391/">diabetic kidney disease</a> and <a href="https://pubmed.ncbi.nlm.nih.gov/30616998/">idiopathic pulmonary fibrosis</a>, both age-related diseases partly caused by senescent cells. There’s also evidence that resveratrol (a compound found in grapes) <a href="https://pubmed.ncbi.nlm.nih.gov/29041897/">reverses cell senescence</a>. </p>
<p>Many human cells enter senescence when they lose their telomeres – the protective caps on the ends of chromosomes. Two compounds have so far shown promise in activating the <a href="https://pubmed.ncbi.nlm.nih.gov/31485647/">telomere repair enzyme</a> telomerase, preventing telomeric shortening. This would ultimately prevent senescent cells from forming in the first place. One such compound has also been shown to <a href="https://pubmed.ncbi.nlm.nih.gov/21426483/">extend heathy lifespan in female mice</a> and is entering clinical trials now to see whether it’s effective at <a href="https://pubmed.ncbi.nlm.nih.gov/32965237/">reversing immune system ageing</a> in humans.</p>
<h2>Challenges</h2>
<p>Despite these developments, there are still many questions left for researchers to answer. For example it’s still not entirely clear whether <a href="https://publications.parliament.uk/pa/ld5801/ldselect/ldsctech/183/183.pdf">alterations to the epigenome</a> (which regulate the activity of a gene) cause ageing or are caused by it. If these changes are the cause of ageing, then we currently have little ability to alter them – though ongoing research of this process in animals may give us clues to how the process works in humans.</p>
<p>Evolution itself may also be a barrier to developing therapies. Many therapies have so far only been shown to be effective in animals with very different <a href="https://pubmed.ncbi.nlm.nih.gov/30737473/">evolutionary histories to humans</a>. Worse, most of the compounds identified only <a href="https://pubmed.ncbi.nlm.nih.gov/27312235/">lengthen lifespan in one sex</a> but not the other. This might be because of the <a href="https://pubmed.ncbi.nlm.nih.gov/32205429/">different evolutionary pressures</a> operating on the male and female genomes. If so, then understanding these pressures better may provide us with clues to the development of more effective treatments. But we won’t know for sure until the treatments are in human trials.</p><img src="https://counter.theconversation.com/content/153409/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard Faragher has received funding from the BBSRC for his work on the biology of ageing. He serves on the Board of Directors of the American Federation for Aging Research (AFAR) and on the Scientific Advisory Board of the Longevity Vision Fund. He is a Trustee of the Biogerontology Research Foundation.</span></em></p>Preventing age-related disease could give us five more years of healthy life in older age.Richard Faragher, Professor of Biogerontology, University of BrightonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1266422019-11-27T11:01:09Z2019-11-27T11:01:09ZWhy ageing should be classified as a disease<figure><img src="https://images.theconversation.com/files/302650/original/file-20191120-515-1k6wdii.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/nephew-touching-grandfathers-hand-sunlight-267900116">Brilliant Eye/Shutterstock</a></span></figcaption></figure><p>Since the time of the ancient Greeks, doctors and philosophers have argued whether ageing is a disease or a natural process. Many authors of the <a href="http://exhibits.hsl.virginia.edu/antiqua/humoral/">Hippocratic Corpus</a> argued that growing old invariably leads to frailty, disability and death, hence they saw ageing as a progressive and incurable disease. But the Roman physician Galen argued that while diseases are abnormal, ageing is universal, so ageing is a natural process rather than a disease. This dichotomy persists to this day and frames our conceptions of the problems of ageing and our proposed solutions. </p>
<p>Unlike Galen and Hippocrates, modern scientists understand how <a href="https://www.cell.com/abstract/S0092-8674(13)00645-4">some of the biological mechanisms that cause ageing work</a>. One of these, <a href="https://www.cell.com/cell/pdf/S0092-8674(19)31121-3.pdf">cellular senescence</a>, sheds important light on the ancient dichotomy. </p>
<p>When cells enter senescence (become old), they release a range of <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060301">inflammatory factors and enzymes</a> that break down the tissue in which they reside. This lets immune cells reach the senescent cells and kill them. But if this process fails, senescent cells accumulate, changing the tissues in which they reside, causing many of the degenerative changes we perceive as ageing and age-related disease.</p>
<p>Cellular senescence is common across the tissues of the body and happens throughout life. When <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115505/">senescent cells build up in the skin</a> causing wrinkles it is considered a “natural change”. Yet when <a href="https://www.sciencedirect.com/science/article/pii/S0531556510002238">senescent cells build up in the heart and blood vessels</a>, causing blood vessels to calcify, we call it “cardiovascular disease”. This is an error of logic and categorisation and not due to the intrinsic nature or complexity of pathology or disease.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/302663/original/file-20191120-515-15n7lgy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/302663/original/file-20191120-515-15n7lgy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/302663/original/file-20191120-515-15n7lgy.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/302663/original/file-20191120-515-15n7lgy.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/302663/original/file-20191120-515-15n7lgy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/302663/original/file-20191120-515-15n7lgy.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/302663/original/file-20191120-515-15n7lgy.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Why are wrinkles considered natural?</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/very-nice-emotional-portrait-elderly-man-76859833">Laurin Rinder/Shutterstock</a></span>
</figcaption>
</figure>
<h2>Haphazard coding</h2>
<p>Categories matter. So an international group of researchers we led and whose conclusions we support <a href="https://science.sciencemag.org/content/366/6465/576">suggested changes</a> to the <a href="https://www.who.int/classifications/icd/en/">World Health Organization’s International Classification of Disease (ICD)</a>. The ICD classification system began in the 19th century and is regularly updated. It provides the codes used to classify and report medical diagnoses and procedures. And it is central to understanding the causes of illness and death around the world.</p>
<p>The classification system is rooted in defining and grouping pathologies and diseases that, because of the “natural process” versus “disease” dichotomy, means that ageing changes are coded haphazardly – they are incomplete and inaccurate, and they overlap. </p>
<p>These new proposals intend to ensure the ICD has a complete list of pathologies and disorders related to ageing, and to make sure that the full spectrum and extent of degenerative changes are accounted for. This would mean that all ageing-related pathologies are included in disease or disorder classifications. This doesn’t currently take place. For example, a <a href="https://www.jamda.com/article/S1525-8610(16)30181-5/fulltext">code exists for age-related muscle wasting (sarcopenia)</a>, but there are no comprehensive codes covering the age-related wearing out of other organs.</p>
<p>As a result, an ageing “disease” classified and assessed for the level of severity in one organ can be unclassified in another. With a lack of classifications and staging, pathological ageing changes may not be logged. This means that treatment needs may be overlooked, such as atrophy, calcification and ageing in organs and tissues where these are not classified or assessed for severity. </p>
<p>Current treatments, including diet and exercise, could be effectively applied. And <a href="https://bmcmolcellbiol.biomedcentral.com/articles/10.1186/s12860-017-0147-7">there are</a> <a href="https://www.ncbi.nlm.nih.gov/pubmed/29997249">several</a> <a href="https://science.sciencemag.org/content/364/6441/636">drugs</a>, old and new, that could be used to prevent or reverse ageing. But, under the current ICD, opportunities to treat these problems might be missed. </p>
<p>This is a matter of particular concern at a time when the first drugs designed to target major mechanisms of ageing are entering <a href="https://clinicaltrials.gov/ct2/show/NCT04063124">clinical trials</a>. To deal with this, the group has proposed <a href="https://science.sciencemag.org/content/366/6465/576">classifications for ageing changes to cover all tissues, organs and glands</a> at the relevant level of detail. </p>
<p>A complete staging system similar to those used for tumours has also been proposed. The objective is to ensure that all pathology in ageing patients is recognised, recorded and treated, where possible. </p>
<p>The ICD is regularly updated and expanded to reflect progress in scientific and medical understanding, and the next edition is due to be published on January 1 2022. Given the importance of ageing in good health, we hope that the World Health Organization will accept the proposals and begin to classify the problems of ageing with a completeness that matches the scale of the problem.</p><img src="https://counter.theconversation.com/content/126642/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard Faragher serves on the Board of Directors of the American Federation for Aging Research and the Biogerontology Foundation. He is a member of the Scientific Advisory Board of the World Vision Fund.</span></em></p><p class="fine-print"><em><span>Stuart Calimport owns shares in GlaxoSmithKline plc and Syncona Limited.</span></em></p>Ageing is a disease and one that will increasingly be treatable.Richard Faragher, Professor of Biogerontology, University of BrightonStuart Calimport, Honorary Fellow, University of Liverpool, Imperial College LondonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1251572019-10-28T11:33:41Z2019-10-28T11:33:41ZAdvances in anti-ageing research: how chemistry could hold the key to better health<figure><img src="https://images.theconversation.com/files/298510/original/file-20191024-170475-147qtv5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/reverse-aging-process-make-young-again-440514766">Shutterstock/Lightspring</a></span></figcaption></figure><p>Given the opportunity to live much longer lives, many of us might feel less than thrilled at the prospect. After all, you might think, who would want to live an extra 20 years dealing with arthritis, dementia or heart problems? </p>
<p>But what if those years could be filled with youthful vigour – or at least middle-aged comfort? </p>
<p>The ability to reverse, or slow down, the degenerative processes that come with increased age has been a long held human aspiration. Indeed it has provided a consistent focus for decades of scientific research on ageing. </p>
<p>But it is only in the last ten years that the replacement of palliative treatments (which suppress the symptoms of age-related diseases) with genuine anti-degenerative medicines (which prevent and repair) has become more than a pipe dream. </p>
<p>This paradigm shift stems from <a href="https://www.nature.com/articles/s41586-018-0457-8">recent research</a> that shows that just a few biological root causes underpin almost all the diseases of old age. Such a discovery is an opportunity to address a wide range of illnesses simultaneously with treatments that target single biological mechanisms. For the first time, ageing has become “druggable”.</p>
<p>One leading cause of age-related changes, including illness, is known as “<a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/cellular-senescence">cell senescence</a>”. This is a consequence of evolution that only really comes into play when organisms outlive their normal reproductive age, or are subjected to a very damaging environment. When cells become senescent they can no longer divide, and typically behave in a way that damages the tissue around them. </p>
<p>For many years, much of the gerontological community had considered cell senescence to be a symptom rather than a cause of age-related decline. However, recent <a href="https://theconversation.com/the-secret-to-staying-young-scientists-boost-lifespan-of-mice-by-deleting-defective-cells-54068">groundbreaking research</a> showed that removing senescent cells from mice not only prevents normal ageing, but actually reverses many of the symptoms. This proof that senescent cells cause ageing finally provides us with the potential to develop a “cure”. </p>
<p>Follow up work has revealed that the positive effects of senescent cell removal in mice extend to <a href="https://www.sciencedirect.com/science/article/pii/S0914508719301285">myocardial infarction</a> (which causes heart attacks), <a href="https://www.sciencedirect.com/science/article/pii/S2468501118300117">Alzheimer’s disease</a> and <a href="https://journals.lww.com/co-lipidology/Fulltext/2019/06000/Senescent_cells_in_the_development_of.5.aspx">metabolic dysfunction</a>. The challenge now is to translate these findings to treatments in ageing humans. </p>
<p>To that end, <a href="https://investingnews.com/daily/life-science-investing/longevity-investing/top-longevity-stocks-alkahest-calico-elysium-health-navitor/">major investors</a> have now joined researchers in the search for ways to kill, remove or rejuvenate senescent cells. And they have made exciting progress. </p>
<p>For example, when combined, dasatanib (a leukaemia drug) and quercetin (a natural product found in vegetables), show improved health and lifespan in mice. And <a href="https://www.sciencedirect.com/science/article/pii/S2352396418306297?via%3Dihub">early results</a> from clinical trials of this combination have demonstrated the first ever alleviation of physical dysfunction in patients with <a href="https://www.nhs.uk/conditions/idiopathic-pulmonary-fibrosis/">idiopathic pulmonary fibrosis</a>, a progressive degenerative lung disease with no current effective treatment. </p>
<p>The list of common side effects associated with dasatanib means it would likely be restricted to only the most seriously ill patients. But the trials give hope for medicinal chemists to develop a more palatable second generation of similar drugs. </p>
<h2>Miracle molecules</h2>
<p>An alternative strategy is the rejuvenation of senescent cells. Resveratrol, found in red wine and chocolate, <a href="https://bmcmolcellbiol.biomedcentral.com/articles/10.1186/s12860-017-0147-7">was shown</a> to be able to rejuvenate senescent cells in the lab, restoring their molecular “fingerprint” and growth to that of normal youthful cells. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/298512/original/file-20191024-170489-853ty5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/298512/original/file-20191024-170489-853ty5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=330&fit=crop&dpr=1 600w, https://images.theconversation.com/files/298512/original/file-20191024-170489-853ty5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=330&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/298512/original/file-20191024-170489-853ty5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=330&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/298512/original/file-20191024-170489-853ty5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=415&fit=crop&dpr=1 754w, https://images.theconversation.com/files/298512/original/file-20191024-170489-853ty5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=415&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/298512/original/file-20191024-170489-853ty5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=415&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Resveratrol rich.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/food-rich-resveratrol-grapes-plums-goji-1178996866?src=SEYesX41_xSZMA3BZ21HYw-1-13">Shutterstock/Artemidovna</a></span>
</figcaption>
</figure>
<p>Importantly, this work also demonstrated that small synthetic modifications were able to tune the effects achieved –- again demonstrating that a medicinal chemistry approach to the problem is highly likely to be successful. </p>
<p>Elsewhere, Fisetin, a natural product found in strawberries, apples and onions, was <a href="https://www.ncbi.nlm.nih.gov/pubmed/30279143">recently shown</a> to confer both improvements in health and a reduction in the senescent cell load in old mice. It is now also the subject of clinical trials. </p>
<p>Interestingly, Fisetin also interacts with other key ageing mechanisms, such as <a href="https://pubs.acs.org/doi/abs/10.1021/acs.jafc.5b00821">nutrient sensing</a> – the biological mechanism that underlies the well known health and lifespan increasing effects of calorie restriction.</p>
<p>It is not yet clear whether this is a new kind of “super-therapeutic” that simultaneously targets more than one cause of ageing, or whether it will reveal a new piece of the jigsaw that allows us to integrate the known paths to morbidity into a coherent whole. </p>
<p>The research conducted so far, just using natural products and existing drugs, has shown unequivocally that small molecules can produce a broad spectrum of anti-degenerative effects. </p>
<p>Drug discovery for ageing is moving beyond its infancy, and preventative medicine that will revolutionise 21st-century healthcare is now genuinely possible. Now we need to add synthetic medicinal chemistry to the mix – to develop safe and effective drugs that will help us all into a healthier and more active future.</p><img src="https://counter.theconversation.com/content/125157/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lizzy Ostler is a trustee of the British Society for Research on Ageing and receives funding from the Horserace Betting Levy Board. </span></em></p>Has the chemistry of ageing come of age?Lizzy Ostler, Head of Chemistry, University of BrightonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1180192019-07-12T12:05:55Z2019-07-12T12:05:55ZDNA testing companies offer telomere testing – but what does it tell you about aging and disease risk?<figure><img src="https://images.theconversation.com/files/279839/original/file-20190617-118526-1vzymuy.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A telomere age test kit from Telomere Diagnostics Inc. and saliva
collection kit from 23andMe.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/seattle-usa-july-6-2017-new-672722578?src=n_CtwFbEEZev1k4RH8-TdA-1-59&studio=1">Anna Hoychuk/Shutterstock.com</a></span></figcaption></figure><p>Over the past few years direct-to-consumer genetic tests that extract information from DNA in your chromosomes <a href="https://www.technologyreview.com/s/610233/2017-was-the-year-consumer-dna-testing-blew-up/">have become popular</a>. Through a simple cheek swab, saliva collection or finger prick, companies offer the possibility of learning more about your family tree, ancestry, or risk of developing diseases such as Alzheimer’s or even certain cancers. More recently, <a href="https://doi.org/10.1038/embor.2011.166">some companies</a> offer tests to measure the tips of chromosomes, called telomeres, to learn more about aging.</p>
<p>But what exactly are telomeres, what are telomere tests, and what are companies claiming they can tell you? Age based on your birthday versus your “telomere age”?</p>
<p>Telomeres play a big role in keeping our chromosomes and bodies healthy even though they make up only a tiny fraction of our total DNA. The Greek origins of the word telomere describes where to find them. “Telo” means “end” while “mere” means “part.” Telomeres cap both ends of all 46 chromosomes in each cell, and protect chromosomes from losing genetic material. They are often compared to the plastic tips at the ends of shoelaces that prevent fraying.</p>
<p><a href="http://www.opreskolab.com">We are</a> <a href="https://www.publichealth.pitt.edu/home/directory/patricia-opresko">molecular</a> <a href="https://www.jefferson.edu/university/jmc/departments/biochemistry/faculty-staff/faculty/elise.html">biologists</a> studying how chemicals, agents from the environment and metabolism damage telomeres and affect their lengths and function, and how damaged telomeres affect the health of our cells and genome. The idea of offering telomere length as part of a genetic test is intriguing since telomeres protect our genetic material. But equating telomere length with something as complex as aging struck us as tricky and overly simplistic. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/279837/original/file-20190617-118539-130f0e2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/279837/original/file-20190617-118539-130f0e2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/279837/original/file-20190617-118539-130f0e2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=300&fit=crop&dpr=1 600w, https://images.theconversation.com/files/279837/original/file-20190617-118539-130f0e2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=300&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/279837/original/file-20190617-118539-130f0e2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=300&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/279837/original/file-20190617-118539-130f0e2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=377&fit=crop&dpr=1 754w, https://images.theconversation.com/files/279837/original/file-20190617-118539-130f0e2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=377&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/279837/original/file-20190617-118539-130f0e2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=377&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Telomeres get shorter with each round of cell division.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/telomere-shortening-each-round-cell-division-708788029?studio=1">Kateryna Kon/Shutterstock.com</a></span>
</figcaption>
</figure>
<h2>Link between telomere length and human diseases</h2>
<p>Telomeres are important for human health and despite their protective function, they are not indestructible. Telomeres shorten every time a cell divides and shorten progressively as we age.</p>
<p>When telomeres become too short or lost, the chromosome tips are left unprotected and become sticky. This can cause chromosomes to fuse. To prevent further chromosome shortening and fusions, the cells enter senescence, a state in which they can no longer divide. Although they lose the ability to rejuvenate tissues, senescent cells can still promote inflammation and secrete factors that favor growth of nearby pre-cancerous or cancerous cells.</p>
<p>Unfortunately, our lifestyle can actually accelerate the shortening. Environmental exposures such as sunlight, air pollution, cigarette smoke and even inflammation or poor diet can damage cell components, including DNA. They do this by generating unstable oxygen molecules, or free radicals. Telomeres are particularly susceptible to damage by free radicals. </p>
<p>In collaboration with chemist <a href="https://www.cmu.edu/bio/people/faculty/bruchez.html">Marcel Bruchez</a>, we developed a new tool that damages only the telomeres. Using this tool we discovered that oxidative damage to telomeres is sufficient to not only accelerate their shortening but also to cause <a href="https://doi.org/10.1016/j.molcel.2019.04.024">telomere loss</a>. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/9gxogiUvVkk?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Our study shows oxidative damage to telomeres directly causes shortening.</span></figcaption>
</figure>
<p>In previous laboratory experiments, scientists found that eliminating senescent cells from mice led to the <a href="https://doi.org/10.1038/nature10600">delay or prevention of diseases and conditions</a> associated with aging including heart disease, diabetes, osteoporosis and lung fibrosis. This has led to the <a href="https://doi.org/10.1111/jgs.14969">pursuit of new drugs called senolytics</a> that could eliminate senescent cells in humans.</p>
<h2>Is longer better?</h2>
<p>Since short telomeres cause cells to senesce, this makes them interesting targets for healthy, disease-free aging. Also, since telomeres shorten with age, regardless of exposure to toxins this led to the notion that telomere length may provide information about a person’s “true” biological age. </p>
<p>Commercial tests typically measure telomere lengths or amounts of telomeric DNA in a blood sample. Companies compare your telomeres to telomeres from people of similar age to try to determine the biological age of your blood cells. </p>
<p>However, just as individuals of the same age vary in height and weight, so do telomeres. If a child falls in the 40th percentile for height, this means compared to 100 girls her age she is taller than 40. For this reason, charts similar to growth charts for children have been generated for telomeres. </p>
<p>Individuals with telomere lengths below the first percentile are at risk for developing specific diseases including anemia, immunodeficiency and pulmonary fibrosis, <a href="https://doi.org/10.1016/j.gde.2015.06.004">likely due to a gene mutation that impairs telomere maintenance</a> </p>
<p>At the other extreme, individuals with <a href="https://doi.org/10.1016/j.gde.2015.06.004">gene mutations that lead to very long telomeres</a> above the 99th percentile are at greater risk for developing inherited forms of melanoma and brain cancers. Longer telomeres allow a cell to divide more times, and with every division there is a chance that an error during genome duplication produces a mutation that promotes cancer. In a way, telomeres follow the Goldilock’ principle. Telomeres that are too short or too long are not optimal.</p>
<h2>Can telomere length predict health outcomes?</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/279847/original/file-20190617-118535-1tn0rfh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/279847/original/file-20190617-118535-1tn0rfh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/279847/original/file-20190617-118535-1tn0rfh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/279847/original/file-20190617-118535-1tn0rfh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/279847/original/file-20190617-118535-1tn0rfh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/279847/original/file-20190617-118535-1tn0rfh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/279847/original/file-20190617-118535-1tn0rfh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Exercise and a healthy diet are associated with longer telomeres.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/senior-couple-on-cycle-ride-countryside-180842051?src=yfmTSGPVrotvd6dZz9Vo8Q-1-46&studio=1">Monkey Business Images/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>But what about telomere lengths in between the extremes? Large studies involving hundreds to thousands of participants show general associations of shorter telomeres with <a href="https://doi.org/10.1161/CIRCGENETICS.113.000485">increased risk for some diseases of aging, including heart disease</a>, whereas <a href="https://doi.org/10.1001/jamaoncol.2016.5945">longer telomeres are associated with increased risk for some types of cancers</a>. </p>
<p>But translating these population studies to predictions about individual life spans and health is difficult. For example, as a group, men are taller than women, but that does not mean all men are taller than women. Similarly, some people with shorter telomeres do not develop heart disease in these population studies. More studies are needed to fully understand what an individual’s telomere length means for their health and aging. </p>
<p>While large population studies show a healthy diet is associated with longer telomeres, published reports about specific supplements <a href="https://doi.org/10.1016/j.metabol.2015.11.004">that claim to support telomere health are lacking.</a></p>
<p>If such a product could extend telomeres, would it be safe? Or would it increase one’s risk for developing cancer due to long telomeres? Can protecting telomeres or slowing their shortening promote disease-free aging? We do not have the answers to these questions yet.</p>
<p>Given the uncertainty and risk of wrong interpretation, should you have your telomeres measured? Maybe, if the results motivate healthy lifestyle changes. For now, a surer bet for healthy aging would be to spend the money on exercise programs and nutritious foods instead. </p>
<p>[ <em><a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=expertise">Expertise in your inbox. Sign up for The Conversation’s newsletter and get a digest of academic takes on today’s news, every day.</a></em> ]</p><img src="https://counter.theconversation.com/content/118019/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Patricia Opresko receives funding from the National Institutes of Health. </span></em></p><p class="fine-print"><em><span>Elise Fouquerel receives funding from National Institutes of Health. </span></em></p>Genetic testing companies are offering tests that analyze the ends of your chromosomes – telomeres – to gauge your health and your real age. But is there scientific evidence to support such tests?Patricia Opresko, Professor of Environmental and Occupational Health, University of PittsburghElise Fouquerel, Assistant Professor of Biochemistry and Molecular Biology, Thomas Jefferson UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1027922018-09-12T11:24:10Z2018-09-12T11:24:10ZAnti-ageing drugs are coming – an expert explains<figure><img src="https://images.theconversation.com/files/235756/original/file-20180911-144470-dbip3i.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">They may not be as far off as you think.</span> <span class="attribution"><span class="source">Pixelbliss/Shutterstock</span></span></figcaption></figure><p>There will be almost ten billion people living on Earth by 2050 and <a href="https://www.weforum.org/agenda/2016/01/how-can-we-make-healthcare-fit-for-the-future">two billion of them will be over the age of 60</a>. Growing old is the primary risk factor for multiple chronic and life threatening conditions such as diabetes or cardiovascular disease. This burdensome morbidity is the most distressing aspect of old age – compromising individual independence and <a href="https://theconversation.com/is-austerity-really-to-blame-for-stalling-life-expectancy-in-england-81206">straining collective healthcare systems</a>. </p>
<p>To help older people flourish, we must understand the biology of ageing at the tissue, cellular and molecular levels, and then turn that understanding into <a href="https://www.youtube.com/watch?v=X-qlo9eVd3c&t=72s">new preventative medicines</a>. Indeed, it was recently suggested that an “anti-ageing pill” <a href="http://www.dailymail.co.uk/news/article-6121913/New-technique-humans-live-150-regrow-organs-price-coffee-day.html">is just around the corner</a>, enabling humans to live to 150 and regenerate organs by 2020 very cheaply. But how excited should we be about such claims? Let’s take a look at the evidence. </p>
<p>Since the time of the <a href="https://www.amazon.co.uk/Experiencing-Old-Age-Ancient-Rome/dp/0415619408">ancient Greeks</a> people have argued about the relationship between ageing and disease. Today it seems probable that essentially all age related diseases are linked to the ageing process. Not all ageing changes are harmful though. In essence, we have a set of health maintenance mechanisms which act to keep us in good condition in the early part of our lives – problems arise as these start to fail with age. An anti-ageing pill would enhance one or more of these mechanisms and keep people healthy.</p>
<h2>Main approaches</h2>
<p>We now understand some of these major mechanisms. For example, <a href="https://theconversation.com/the-secret-to-staying-young-scientists-boost-lifespan-of-mice-by-deleting-defective-cells-54068">senescent cells</a>, dysfunctional cells which build up as we age, are routinely formed and removed over time. This is a health maintenance mechanism which has evolved to keep us cancer free. However, when the removal of these cells fails, they cause damage to tissue – resulting in ageing and ill health. Removing them under laboratory conditions brings a <a href="https://preview.ncbi.nlm.nih.gov/pubmed/29988130">raft of benefits</a>.</p>
<p>The breakdown and synthesis of proteins is also essential to ageing. Partially degraded proteins can build up over time, compromising cellular function. Treatment with the drug rapamycin has been shown to boost normal protein turnover mechanisms – extending <a href="https://www.ncbi.nlm.nih.gov/pubmed/27549339">lifespan in mice</a> and <a href="https://www.ncbi.nlm.nih.gov/pubmed/29997249">improving immune function in people</a>.</p>
<p>As we age, our organs and tissues lose mass and gain waste products. When we are young, the periodic replenishment of cells within organs and tissues by the body’s “reserve army” of uncommitted stem cells (cells that can become specialised cells) <a href="https://www.ncbi.nlm.nih.gov/pubmed/24757526">help keep us healthy</a>, somewhat akin to drawing on your savings when your current account runs low. Stem cell therapy may therefore help counter ageing. </p>
<p>While delivery of stem cells grown outside the body remains difficult, there is evidence that activation of a class of proteins known as the sirtuins can <a href="https://www.ncbi.nlm.nih.gov/pubmed/28994177">enhance this stem cell maintenance</a>. For example, treatment with the compound nicotinamide riboside enhances sirtuin activity and restores <a href="https://www.ncbi.nlm.nih.gov/pubmed/27127236">muscle stem cell function in mice</a>, suggesting a route to treatment.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/235583/original/file-20180910-123128-1dsnlrh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/235583/original/file-20180910-123128-1dsnlrh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/235583/original/file-20180910-123128-1dsnlrh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/235583/original/file-20180910-123128-1dsnlrh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/235583/original/file-20180910-123128-1dsnlrh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/235583/original/file-20180910-123128-1dsnlrh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/235583/original/file-20180910-123128-1dsnlrh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">There are mechanisms that could keep us healthy even in old age.</span>
<span class="attribution"><span class="source">Ljupco Smokovski/Shutterstock</span></span>
</figcaption>
</figure>
<p>A variety of <a href="https://theconversation.com/ageing-in-human-cells-successfully-reversed-in-the-lab-101214">different molecules</a>, some of which are found in the diet, are also able to stop mechanisms that compromise the ability of older people to <a href="https://theconversation.com/compound-found-in-berries-and-red-wine-can-rejuvenate-cells-suggests-new-study-86945">resist acute physiological stress</a>.</p>
<p>In addition to these mechanisms, scientists are beginning to shed light on how the mechanisms that coordinate brain and organ functions are disrupted by ageing and how this <a href="https://theconversation.com/scientists-discover-how-the-brains-hypothalamus-controls-ageing-and-manage-to-slow-it-down-81510">may be delayed in the future</a>. But we already know enough today about at least some health maintenance processes to devise means of pepping them up.</p>
<h2>Pills on the horizon?</h2>
<p>Claims made <a href="https://www.dailymail.co.uk/news/article-6121913/New-technique-humans-live-150-regrow-organs-price-coffee-day.html">in an article</a> about recent research raising hopes for an anti-ageing pill by 2020 are not entirely false, but they aren’t entirely accurate either. The hyperbole concerning nicotinamide riboside, which may restore muscle stem cell activity, is a case in point. It certainly is of <a href="https://f1000research.com/articles/7-132/v1">considerable scientific interest</a>, and is performing well in mice. But it lacks much relevant human data beyond the demonstration that levels can be safely increased by <a href="https://www.nature.com/articles/s41514-017-0016-9.pdf#page=1">supplentation</a>. Nobody has actually shown that these supplements make humans live longer or regrow their organs.</p>
<p>The vaunted 150-year lifespan is also slightly slippery. This is a 25% increase on the longest human <a href="https://en.wikipedia.org/wiki/Jeanne_Calment">lifespan ever</a> and while the extent of lifespan extension is plausible for some experimental animals – such as mice with their senescent cells removed – starting with the maximum human lifespan of 120 and adding 25% inflates the figures to produce a “wow!” effect. Even if you accept that the same percentile extension seen in mice by one method would hold in humans using another, which is questionable, most of us woudln’t live to 150 (there are less than a thousand people aged over 105 in the UK).</p>
<p>Ironically, this kind of story misses out on the genuinely exciting news that pharmaceutical companies are taking the idea of developing healthspan-enhancing drugs increasingly <a href="https://www.juvenescence-book.com/">seriously</a>. This is a notable shift in attitude, but the chasm between intention and achievement remains wide. In fact, humanity has only about 1,500 “molecular entities” (drugs) <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Haynesworth+AND+Kinch">in its medicine chest</a>. </p>
<p>This is because drug development is a costly and time consuming process. Ten years of work and US$2.5 billion would be a fair estimate of the price tag <a href="https://www.scientificamerican.com/article/cost-to-develop-new-pharmaceutical-drug-now-exceeds-2-5b/">from start to finish</a>. Worse still, when developing a drug for ageing, researchers face an additional problem: how do you know if it worked? A “typical” clinical trial lasts a year or two. Nobody is in a position to see if a putative wonder drug adds five or ten years to your lifespan, and who would you test it on anyway?</p>
<p>Fortunately, an elegant solution to this problem has been proposed. Targeting Aging with Metformin (or TAME) – developed in consultation with the FDA – is a new clinical trial protocol. TAME is based on the observation that the time at which an individual develops their initial age-related impairment, such as osteoporosis, diabetes or cardiovascular disease, is highly variable between different individuals (<a href="https://www.health.harvard.edu/heart-health/premature-heart-disease">65 on average</a> for heart attack). But the time from first to second impairment – for example, having diabetes and then developing <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303913/">cardiovascular problems</a> – is much tighter, happening within a span of two to four years.</p>
<p>That means that a drug which improves health maintenance mechanisms will lengthen the period between first event and second event – making it possible to say if it has worked in a short time frame. This would allow companies to, in principle, prescribe a drug for ageing.</p>
<p>So do be sceptical about claims that you could live to 150 by taking a certain supplement right now – you won’t be able to take an anti-aging pill tomorrow. But, excitingly, the fundamental scientific knowledge, translational strategies and many of the technologies to deliver one are available today.</p><img src="https://counter.theconversation.com/content/102792/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard Faragher is a member of the Board of Directors of the American Federation for Aging Research and a Trustee of the Biogerontology Research Foundation</span></em></p>It has recently been suggested that humans could live to 150 by 2020 simply by taking a certain supplement.Richard Faragher, Professor of Biogerontology, University of BrightonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/869452017-11-14T17:15:28Z2017-11-14T17:15:28ZCompound found in berries and red wine can rejuvenate cells, suggests new study<figure><img src="https://images.theconversation.com/files/194339/original/file-20171113-27632-yuowc9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Resveratrol is a powerful antioxidant found in blueberries.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/success?src=u_wNvOALKPdVF2N00aYUpw-1-3">Resveratrol </a></span></figcaption></figure><p>By the middle of this century the over 60s will outnumber the under 18s <a href="https://link.springer.com/article/10.1007/s12062-009-9012-6">for the first time in human history</a>. This should be good news, but growing old today also means becoming <a href="http://www.bmj.com/content/339/bmj.b4904">frail, sick and dependent</a>. A healthy old age is good for you and a remarkably good deal for society. Improving the overall health of older Americans could save the US alone enough money to pay for clean drinking water for everyone on Earth for the <a href="https://www.youtube.com/watch?v=X-qlo9eVd3c">next 30 years</a>.</p>
<p>But if we want people to be healthy in old age we have to understand the mechanisms underlying the deterioration of our bodies over time. Doing so – and learning how we can prevent it – has been the goal of ageing research for <a href="https://en.wikipedia.org/wiki/British_Society_for_Research_on_Ageing#Rationale">more than 60 years</a>. </p>
<p>There has been astonishing progress made over the last decade. In 2009, it was shown that the drug rapamcyin <a href="https://www.ncbi.nlm.nih.gov/pubmed/19587680">extended the lifespans of mice</a> by 10-15%. Two years later a landmark study showed that experimental clearance of “senescent” cells – dysfunctional cells which build up as we age and cause damage to tissue – <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=BubR1+AND+kirkland">improved healthy lifespan</a> in laboratory mice. These results delighted those of us who had argued for decades that senescent cells were a major cause of late life problems and should therefore be <a href="http://www.sciencedirect.com/science/article/pii/S135964469783293X">therapeutic targets</a>. </p>
<p>Research on both living human cohorts and isolated cells have looked at the types of genes which change in expression levels (the process by which information from a gene is used to make the tens of thousands of proteins needed by a cell during ageing. This <a href="https://www.ncbi.nlm.nih.gov/pubmed/21668623">has revealed</a> that the largest changes occur in genes which regulate how “messenger RNAs” are made. These transfer the information stored in DNA to the cellular machinery which turns it into proteins.</p>
<p>In the human cell, proteins known as “RNA splicing factors” determine which messenger RNA can be made from RNA building blocks in a process known as RNA splicing. The ability of our cells to do this is restricted with ageing. But it was unclear whether this loss is a result of senescent cells accumulating in ageing tissue or something new, occurring in parallel with senescence until now.</p>
<h2>New evidence</h2>
<p>Now our latest study, <a href="https://bmccellbiol.biomedcentral.com/articles/10.1186/s12860-017-0147-7">published in BMC Cell Biology</a> shows that a natural substance can actually rejuvenate senescent cells by targeting RNA splicing. </p>
<p>In our experiments, <a href="https://www.ncbi.nlm.nih.gov/pubmed/29041897">we treated such cells with compounds</a> we synthesised based on resveratrol, <a href="https://theconversation.com/the-french-paradox-turned-out-to-be-an-illusion-but-it-led-to-some-interesting-research-78196">a natural product found in red wine</a>, berries and other foods, reported to alter RNA splicing in cancer cells. Resveratrol – which can be found in many natural foods – is a blunt tool that affects multiple cellular pathways. But our synthetic variants are actually much more precise and we picked ones that preferentially affected RNA splicing. </p>
<p>Senescent human cells treated with our products showed remarkable effects, which we called “rejuvenation”. RNA splicing patterns were rapidly reset to that seen in young cells and then the senescent cultures began to grow again. Variations of this basic experiment showed that splicing factor restriction is separate from senescence but interacts with it.</p>
<p>Restoring RNA splicing rejuvenates senescent cells in part because our cells are normally rendered senescent through <a href="https://theconversation.com/ageing-isnt-fixed-we-can-manipulate-it-to-live-longer-31808">telomere shortening</a>, the gradual loss of the DNA at the ends of chromosomes that occurs with repeated cell division. Some RNA splicing factors that decline with age are capable of helping to repair telomeres and so, if you restore them, they lengthen telomeres back up and stop the cell being senescent. </p>
<p>Restricted splicing has serious implications beyond the capacity of cells to divide and how tissues deal with stress. It limits cell responses, potentially contributing to the increased frailty that is a hallmark of ageing in many organisms including humans. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/194541/original/file-20171114-27632-1u4ewhh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/194541/original/file-20171114-27632-1u4ewhh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/194541/original/file-20171114-27632-1u4ewhh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/194541/original/file-20171114-27632-1u4ewhh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/194541/original/file-20171114-27632-1u4ewhh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/194541/original/file-20171114-27632-1u4ewhh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/194541/original/file-20171114-27632-1u4ewhh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">New research raises hopes that more people can have a healthy old age.</span>
<span class="attribution"><span class="source">Tom Wang</span></span>
</figcaption>
</figure>
<p>Following our discoveries the area of RNA splicing is now ripe for detailed study, not least because cells from old individuals that have not become senescent probably still have compromised splicing. Restricted splicing may prove to be a critical mechanism in the development of a wide range of age-associated diseases.</p>
<h2>Drugs and diet</h2>
<p>Our compounds have allowed us to begin to identify the key molecular pathways that mediate splicing factor restriction and may have a future as a platform for anti-degenerative drugs. But when only one or two in tens of thousands of compounds become medicines none of us are quitting work just yet.</p>
<p>As resveratrol and similar molecules are found in food, our work may have revealed an unsuspected link between diet and RNA splicing. Many groups have shown the <a href="https://www.ncbi.nlm.nih.gov/pubmed/28391393">beneficial effects</a> of diets containing these foods – altered splicing may be one, but not the only, way in which they mediate their effects. However you’d need to drink some 30 litres of red wine a day to achieve the doses of analogues of resveratrol we used in tissue culture. </p>
<p>Pure resveratrol already exists as a dietary supplement. However, we do not recommend taking it just yet. One of the reasons we made the novel compounds was that resveratrol, like many natural products, <a href="https://www.ncbi.nlm.nih.gov/pubmed/23448440">has a whole range of activities</a>, some that appear beneficial and some less so. </p>
<p>Our emphasis on <a href="https://www.afar.org/">achieving health in later life</a> without undue concern for its extension chimes closely with the popular view. Something in excess of 60% of the population <a href="https://www.frontiersin.org/articles/10.3389/fgene.2015.00353/full">do not want thousand-year lifespans</a>, even when given a guarantee of perfect health. </p>
<p>The challenge now is to convert this basic scientific discovery into the benefits people want, and as quickly as possible. Until then, there’s always blueberries …</p><img src="https://counter.theconversation.com/content/86945/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard Faragher receives funding from the Glenn Foundation, is a member of the Board of Directors of the American Aging Association and is a Trustee of the Biogerontology Research Foundation.</span></em></p><p class="fine-print"><em><span>Lizzy Ostler is a trustee and Honorary Treasurer of the British Society for Research on Ageing (Registered Charity 279932). </span></em></p><p class="fine-print"><em><span>Lorna Harries receives funding from the Dunhill Medical Trust and the MRC. She is a trustee and Hon. General Secretary of the British Society for Research on Ageing (BSRA).</span></em></p>Scientists are hoping to one day be able to turn the natural dietary compound resveratrol into medicines to slow down ageing.Richard Faragher, Professor of Biogerontology, University of BrightonLizzy Ostler, Head of Chemistry, University of BrightonLorna Harries, Associate Professor in Molecular Genetics, University of ExeterLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/745572017-03-17T14:29:41Z2017-03-17T14:29:41ZKilling ‘zombie’ cells to improve health in old age<figure><img src="https://images.theconversation.com/files/161150/original/image-20170316-10913-xvyi5c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/458775040?src=P_kJYIxM2FN5ijcqHYWpNw-1-24&size=medium_jpg"> Sergey Shubin/Shutterstock.com</a></span></figcaption></figure><p>Imagine a world where you could take just a single pill for the treatment or prevention of several age-related diseases. Although still in the realms of science fiction, accumulating scientific data now suggests that despite their biological differences a variety of these diseases share a common cause: senescent cells. This has led scientists to find drugs that can destroy these cells.</p>
<p>When cells become damaged, they either self-destruct (apoptosis) or they lose their ability to grow and remain stuck within the body. These are the non-growing senescent cells that no longer carry out their tasks properly. They spew out chemicals that cause damage to cells nearby, sometimes turning them into “zombies” – hence why they are sometimes referred to as “zombie cells”. Eventually, the damage builds up so much that the function of bodily organs and tissues, such as skin and muscle, becomes impaired. At this point, we identify the changes as disease. </p>
<p>Depending on where these senescent cells gather within the body will determine which disease will develop. Senescent cells have now been shown to be linked to <a href="http://www.nature.com/nrm/journal/v15/n7/full/nrm3823.html">several diseases</a>, including <a href="http://science.sciencemag.org/content/354/6311/472.long">cardiovascular disease</a>, <a href="http://diabetes.diabetesjournals.org/content/64/7/2289">type 2 diabetes</a>, <a href="https://academic.oup.com/biomedgerontology/article/doi/10.1093/gerona/glw154/2630057/Transplanted-Senescent-Cells-Induce-an">osteoarthritis</a> and <a href="http://www.sciencedirect.com/science/article/pii/S0092867407008902">cancer</a>. </p>
<p>In <a href="http://www.nature.com/nature/journal/v479/n7372/full/nature10600.html">2011</a> and in <a href="http://www.nature.com/nature/journal/v530/n7589/full/nature16932.html">2016</a>, researchers at the Mayo Clinic in the US showed, through the use of genetically engineered (transgenic) mice, that the removal of senescent cells reduced cancer formation, delayed ageing and protected the mice against age-related diseases. The mice also lived 25% longer, on average. A similar result in humans would mean an increase in life expectancy from 80 years to 100 years. It was proof-of-principle studies like these that laid the groundwork and inspired other researchers to build on these findings. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/161154/original/image-20170316-10911-16e230q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/161154/original/image-20170316-10911-16e230q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=377&fit=crop&dpr=1 600w, https://images.theconversation.com/files/161154/original/image-20170316-10911-16e230q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=377&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/161154/original/image-20170316-10911-16e230q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=377&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/161154/original/image-20170316-10911-16e230q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=474&fit=crop&dpr=1 754w, https://images.theconversation.com/files/161154/original/image-20170316-10911-16e230q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=474&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/161154/original/image-20170316-10911-16e230q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=474&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">I’ll live how much longer?</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/521838493?src=tIuAXDhnqJIM4IqQWoWpYQ-1-4&size=medium_jpg">Kirill Kurashov/Shutterstock.com</a></span>
</figcaption>
</figure>
<h2>Killing a few to save the many</h2>
<p>It is not known how many senescent cells need to be present to cause damage to the body, but the harmful effects of the chemicals they release can spread quickly. A few zombie cells may have a huge impact. Drugs for specifically killing senescent cells in order to extinguish their destructive force have recently been revealed and tested on mice. The collective term for these drugs is “senolytics”. </p>
<p>In 2016, two research groups independently published findings on the discovery of two new senolytic drugs which target proteins responsible for protecting senescent cells from cell death. Research lead by scientists from the University of Arkansas, US, <a href="http://www.nature.com/nm/journal/v22/n1/full/nm.4010.html">showed</a> that the drug ABT-263 (Navitoclax) could selectively kill senescent cells in mice, making aged tissues young again. And scientists from the <a href="http://www.nature.com/articles/ncomms11190">Weizmann Institute of Science</a> in Israel used the drug ABT-737 to kill senescent cells in the lungs and skin of mice. </p>
<p>There has also been a lot of interest in the role of senescent cells in pulmonary diseases caused by damage to the lungs. Among the risk factors, smoking is known to speed up lung ageing and disease, partly by attacking healthy cells with toxic chemicals from <a href="http://www.atsjournals.org/doi/abs/10.1165/rcmb.2006-0169OC">cigarette smoke</a> which can result in cells becoming senescent. </p>
<p>In late 2016, <a href="https://insight.jci.org/articles/view/87732">Japanese scientists</a> showed that the removal of senescent cells using genetically engineered mice greatly restored lung function in old mice. A more recent <a href="http://www.nature.com/articles/ncomms14532?WT.feed_name=subjects_biological-sciences">study</a>, lead by scientists at the Mayo Clinic in the US, showed that <a href="http://www.nhs.uk/Conditions/pulmonary-fibrosis/Pages/introduction.aspx">idiopathic pulmonary fibrosis</a> (scarring of the lungs) was linked to an increase in the number of senescent cells and the damaging effects of the chemicals they release. The killing of senescent cells using genetically engineered mice again greatly improved lung function. In the same study, this group also reported the possible use of a combination of drugs, dasatinib and quercetin, to destroy senescent cells. </p>
<p>A <a href="http://www.sciencedirect.com/science/article/pii/S0360301617306314">study</a> published earlier this month from the University of Arkansas, extended their previous findings on the drug ABT-263 to pulmonary fibrosis. They found that ABT-263 treatment reduced the problems caused by senescent cells and reversed the disease in mice. </p>
<h2>There’s money in senolytics</h2>
<p>In light of these accumulating and highly promising findings, a number of start-up biotechnology companies have been created to exploit the health benefits of targeting senescent cells. Probably the most well funded is Unity Biotechnology in the US which <a href="http://www.prnewswire.com/news-releases/unity-biotechnology-announces-116-million-series-b-financing-300352831.html">raised US$116m</a> for research and development.</p>
<p>It will likely be several years before we see senolytic drugs being tested on humans. If you can’t wait that long, exercise may be the answer. A study published in <a href="http://diabetes.diabetesjournals.org/content/65/6/1606">March 2016</a> by the Mayo Clinic showed that exercise prevented the accumulation of senescent cells caused by a high-fat diet in mice. So if the regular health benefits of exercise were not enough to get you off the sofa, maybe the anti-ageing benefits will be.</p><img src="https://counter.theconversation.com/content/74557/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dominick Burton receives funding from Marie Skłodowska-Curie Actions and is a member of the International Cell Senescence Association (ICSA).</span></em></p>Researchers have discovered a new way to fight ageing and age-related disease – going after senescent cells.Dominick Burton, Research Fellow, Aston UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/540682016-02-03T19:13:43Z2016-02-03T19:13:43ZThe secret to staying young? Scientists boost lifespan of mice by deleting defective cells<figure><img src="https://images.theconversation.com/files/110164/original/image-20160203-5853-b05jng.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">We all do what we can to stay young. But what if we could actually slow ageing by just taking a pill?</span> <span class="attribution"><span class="source">Tom Wang </span></span></figcaption></figure><p>The ageing population is one of the greatest challenges facing society. More people are surviving to old age than ever before, but we currently lack the means to keep them healthy and independent. If a treatment existed to reduce sickness and death from ageing by 20% then between now and 2050, the US alone would <a href="https://www.youtube.com/watch?v=2v34Dt6wBkE">save US$4 trillion on healthcare costs</a> – enough money to give everyone on Earth clean drinking water for the next three decades. </p>
<p>However a landmark new study, <a href="http://nature.com/articles/doi:10.1038/nature16932">published in Nature</a>, raises hopes that such a treatment will be possible. The researchers managed to increase the lifespan of mice by an impressive 25% by deleting “senescent” cells, dysfunctional cells which build up as we age and cause damage to tissue. Crucially, the mice lived longer because they were healthier.</p>
<h2>Ageing versus disease</h2>
<p>Unless you are exceptionally thoughtful, unusually well informed or a bio-gerontologist (a specialist in the biology of ageing), everything you think you know about the relationship between the ageing process and diseases such as cancer or atherosclerosis is probably wrong. </p>
<p>We have always known that those around us will grow old, get sick and die. But few of us have stopped to think about how this actually happens. What is the relationship between “natural changes” like wrinkles and “diseases” that can actually kill us?</p>
<p>Greek doctor and philosopher <a href="http://www.bbc.co.uk/history/historic_figures/galen.shtml">Aelius Galen</a> (c. 121-169 AD) set the conceptual framework for our understanding of ageing. He defined disease as an abnormal function. Since ageing is universal it cannot, he reasoned, be a disease by definition. Although there were later variations on this argument, they lead to the same conclusion. If ageing takes place in everyone and disease occurs in only a part of the population then disease and ageing are not synonymous. The former should be cured and the latter endured, or perhaps celebrated, went the conventional wisdom. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/110168/original/image-20160203-5857-bquiq0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/110168/original/image-20160203-5857-bquiq0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=920&fit=crop&dpr=1 600w, https://images.theconversation.com/files/110168/original/image-20160203-5857-bquiq0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=920&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/110168/original/image-20160203-5857-bquiq0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=920&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/110168/original/image-20160203-5857-bquiq0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1156&fit=crop&dpr=1 754w, https://images.theconversation.com/files/110168/original/image-20160203-5857-bquiq0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1156&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/110168/original/image-20160203-5857-bquiq0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1156&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Upper image shows cells of a mouse before the accumulation of senescent cells. Lower image is after.</span>
<span class="attribution"><span class="source">Y tambe/wikimedia</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>But the people making these arguments had no meaningful idea of the mechanisms that cause either ageing or disease. It wasn’t until the 1980s that researchers <a href="http://www.ncbi.nlm.nih.gov/pubmed/8608934">started to really understand</a> the <a href="http://www.ncbi.nlm.nih.gov/pubmed/8265666">biology of ageing</a>. One hypothesis that emerged is that the accumulation of “senescent” cells may be a driving force of ageing. </p>
<p>Senescent cells are formed within the cell populations that divide during life. However, this division is limited as an anti-cancer mechanism and so after a variable degree of replication, cells stop dividing and enter the senescent state.</p>
<p>Once senescent these cells produce a range of inflammatory molecules and undergo other changes which damage tissue. These changes alert the immune system to their presence allowing it to remove them. Unfortunately as the immune system itself ages this capacity declines and the number of senescent cells in tissue increases, leading to ageing. </p>
<h2>Evidence at last?</h2>
<p>A pretty story, but most of the underpinning research was generated in the abnormal environment of the tissue culture dish. For this reason many researchers were sceptical, asking for the real proof. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/110171/original/image-20160203-5819-2nhr3g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/110171/original/image-20160203-5819-2nhr3g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=468&fit=crop&dpr=1 600w, https://images.theconversation.com/files/110171/original/image-20160203-5819-2nhr3g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=468&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/110171/original/image-20160203-5819-2nhr3g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=468&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/110171/original/image-20160203-5819-2nhr3g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=588&fit=crop&dpr=1 754w, https://images.theconversation.com/files/110171/original/image-20160203-5819-2nhr3g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=588&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/110171/original/image-20160203-5819-2nhr3g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=588&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Senescent cells are responsible for wrinkles and disease.</span>
<span class="attribution"><span class="source">Evgeny Atamanenko</span></span>
</figcaption>
</figure>
<p>And the new study provides just that. The researchers genetically engineered mice so that their senescent cells could undergo <a href="https://theconversation.com/how-self-destructing-cells-may-hold-key-to-cancer-cure-31707">programmed cell death</a> if treated with a small molecule. The results of deleting senescent cells in this manner are impressive. Median lifespan increased by about 25%. This is a similar effect to that of two laboratory interventions already known to extend healthy lifespan in mice – <a href="http://tpx.sagepub.com/content/37/1/47">dietary restriction</a> and <a href="http://www.nature.com/nature/journal/v460/n7253/full/nature08221.html">supplementation</a> with the drug <a href="http://www.britannica.com/science/rapamycin">rapamycin</a>.</p>
<p>The animals showed reduced deterioration of several organ systems and delayed development of cancers – without side-effects. The authors of the paper were rightly both excited and modest in pointing out the prospect that deleting senescent cells could eventually extend healthy human lifespan.</p>
<p>There are two ways to achieve this and groups are already working on both. The first of these is to identify <a href="https://www.nia.nih.gov/research/announcements/2015/03/nih-funded-researchers-identify-drugs-eliminate-senescent-cells-mice">drugs which kill senescent cells</a>, and the second is to develop drugs which <a href="http://www.ncbi.nlm.nih.gov/pubmed/26400758">block their effects</a>. Both have promise but perhaps a combination of the two has the most promise of all. However, the road to the clinic can be long. Although tamoxifen is now almost a household name as a breast cancer treatment, it was <a href="http://www.britannica.com/science/tamoxifen">first synthesised</a> in 1962 but not shown to be beneficial until 1972.</p>
<p>Perhaps most importantly, work on senescent cells illustrates that the distinction between ageing and age-related disease, held for so long, is a false dichotomy. Senescent cells in the skin are responsible for wrinkles, a “natural change”, and for cardiovascular disease, “an age-related disease”. </p>
<p>Instead of “ageing” and “disease” mechanisms, mammals have key health maintenance mechanisms and problems start when these fail. Knowing what they are opens the prospect of broad preventative treatments that will allow us to live well and hopefully to live longer too.</p><img src="https://counter.theconversation.com/content/54068/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard Faragher receives funding from the Glenn Foundation for Medical Research and has previously received funded from the European Union and the UK Research Councils. He is affiliated with the British Society for Research on Ageing, the American Aging Association and the American Federation for Aging Research.</span></em></p>Could it one day be possible to stay young without calorie restriction and tough exercise?Richard Faragher, Professor of Biogerontology, University of BrightonLicensed as Creative Commons – attribution, no derivatives.