tag:theconversation.com,2011:/us/topics/biogerontology-24500/articlesBiogerontology – The Conversation2021-11-25T13:05:09Ztag:theconversation.com,2011:article/1720202021-11-25T13:05:09Z2021-11-25T13:05:09ZWhy it’s still a scientific mystery how some can live past 100 – and how to crack it<figure><img src="https://images.theconversation.com/files/433737/original/file-20211124-23-1a3gecl.jpg?ixlib=rb-1.1.0&rect=113%2C1%2C685%2C660&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Centenarian buddies in Sardinia.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/villagrande-stresaili-sardinia-october-2019-two-1543833944">Sabino Parente/Shutterstock</a></span></figcaption></figure><p>A 35-year-old man <a href="https://pubmed.ncbi.nlm.nih.gov/18544745/">only has a 1.5% chance of dying in the next ten years</a>. But the same man at 75 has a 45% chance of dying before he reaches 85. Clearly, ageing is bad for our health. On the bright side, we have made unprecedented progress in understanding the fundamental mechanisms that control ageing and late-life disease. </p>
<p>A few tightly linked biological processes, sometimes called the <a href="https://pubmed.ncbi.nlm.nih.gov/23746838/">“hallmarks of ageing”</a>, including our supply of stem cells and communication between cells, act to keep us healthy in the early part of our lives – with <a href="https://theconversation.com/the-secret-to-staying-young-scientists-boost-lifespan-of-mice-by-deleting-defective-cells-54068">problems arising as these start to fail</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/34699859/">Clinical trials are ongoing</a> to see if targeting some of these hallmarks can improve <a href="https://pubmed.ncbi.nlm.nih.gov/31542391/">diabetic kidney disease</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/29997249/">aspects of</a> <a href="https://pubmed.ncbi.nlm.nih.gov/33977284/">immune function</a> and age-related <a href="https://pubmed.ncbi.nlm.nih.gov/30616998/">scarring of the lungs</a> among others. So far, so good.</p>
<p>Unfortunately, big, unanswered questions remain in the biology of ageing. To evaluate what these are and how to address them, the <a href="https://www.afar.org/">American Federation For Aging Research</a>, a charity, recently convened a series of <a href="https://www.afar.org/imported/AFAR_GeroFuturesThinkTankReport_November2021.pdf">meetings for leading scientists and doctors</a>. The experts agreed that understanding what is special about the biology of humans who survive more than a century is now a key challenge. </p>
<p>These centenarians <a href="https://www.statista.com/chart/18826/number-of-hundred-year-olds-centenarians-worldwide/">comprise less than 0.02% of the UK population</a> but have exceeded the life expectancy of their peers by almost 50 years (babies born in the 1920s typically had a life expectancy of less than 55). How are they doing it?</p>
<p>We know that centenarians live so long because they are unusually healthy. They remain in good health for about 30 years longer than most normal people and when they finally fall ill, they are only sick for a very short time. This <a href="https://pubmed.ncbi.nlm.nih.gov/27377170/">“compression of morbidity”</a> is clearly good for them, but also benefits society as a whole. In the US, the medical care costs for a centenarian in their last two years of life <a href="https://www.cdc.gov/nchs/data/series/sr_10/sr10_198.pdf">are about a third of those of someone who dies in their seventies</a> (a time when most centenarians don’t even need to see a doctor).</p>
<p>The children of centenarians are also much healthier than average, indicating they are inheriting something beneficial from their parents. But is this genetic or environmental?</p>
<h2>Centenarians aren’t always health conscious</h2>
<p>Are centenarians the poster children for a healthy lifestyle? For the general population, watching your weight, not smoking, drinking moderately and eating at least five servings of fruit and vegetables a day can <a href="https://pubmed.ncbi.nlm.nih.gov/27296932/">increase life expectancy by up to 14 years</a> compared with someone who does none of these things. This difference <a href="https://publications.parliament.uk/pa/ld5801/ldselect/ldsctech/183/18305.htm#_idTextAnchor012">exceeds that seen</a> between the least and most deprived areas in the UK, so intuitively it would be expected to play a role in surviving for a century. </p>
<p>But astonishingly, this needn’t be the case. <a href="https://pubmed.ncbi.nlm.nih.gov/21812767/">One study</a> found that up to 60% of Ashkenazi Jewish centenarians have smoked heavily most of their lives, half have been obese for the same period of time, less than half do even moderate exercise and under 3% are vegetarians. The children of centenarians appear no more health conscious than the general population either. </p>
<p>Compared to peers with the same food consumption, wealth and body weight, however, <a href="https://pubmed.ncbi.nlm.nih.gov/29050682/">they have half the prevalence of cardiovascular disease</a>. There is something innately exceptional about these people.</p>
<h2>The big secret</h2>
<p>Could it be down to rare genetics? If so, then there are two ways in which this could work. Centenarians might carry unusual genetic variants that extend lifespan, or instead they might lack common ones that cause late-life disease and impairment. Several studies, including our own work, <a href="https://pubmed.ncbi.nlm.nih.gov/32860726/">have shown</a> that centenarians have just as many bad genetic variants as the general population. </p>
<p>Some even carry two copies of the largest known common risk gene for Alzheimer’s disease (APOE4), but still don’t get the illness. So a plausible working hypothesis is that centenarians carry rare, beneficial genetic variations rather than a lack of disadvantageous ones. And the best available data is consistent with this.</p>
<p>Over 60% of centenarians have genetic changes that alter the genes which regulate growth in early life. This implies that these remarkable people are human examples of a type of lifespan extension observed in other species. Most people know that <a href="https://pubmed.ncbi.nlm.nih.gov/28803893/">small dogs tend to live longer than big ones</a> but fewer are aware that this is a general phenomenon across the animal kingdom. <a href="https://pubmed.ncbi.nlm.nih.gov/26857482/">Ponies can live longer than horses</a> and many strains of laboratory mice with dwarfing mutations <a href="https://pubmed.ncbi.nlm.nih.gov/29653683/">live longer than their full-sized counterparts</a>. One potential cause of this is reduced levels of a growth hormone called IGF-1 – although human centenarians <a href="https://pubmed.ncbi.nlm.nih.gov/28630896/">are not necessarily shorter than the rest of us</a>.</p>
<figure class="align-center ">
<img alt="Image of a chihuahua standing on a caucasian shepherd." src="https://images.theconversation.com/files/433917/original/file-20211125-17-1sxsrw8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/433917/original/file-20211125-17-1sxsrw8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/433917/original/file-20211125-17-1sxsrw8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/433917/original/file-20211125-17-1sxsrw8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/433917/original/file-20211125-17-1sxsrw8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/433917/original/file-20211125-17-1sxsrw8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/433917/original/file-20211125-17-1sxsrw8.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">
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<span class="caption">Small dogs live longer than large ones.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/young-chihuahua-dog-caucasian-shepherd-173551097">anetapics/Shutterstock</a></span>
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<p>Obviously, growth hormone is necessary early on in life, but there is increasing evidence that high levels of IGF-1 in mid to late life <a href="https://pubmed.ncbi.nlm.nih.gov/18316725/">are associated with increased late-life illness</a>. The detailed mechanisms underlying this remain an open question, but even among centenarians, women with the lowest levels of growth hormone <a href="https://pubmed.ncbi.nlm.nih.gov/24618355/">live longer than those with the highest</a>. They also have better cognitive and muscle function. </p>
<p>That doesn’t solve the problem, though. Centenarians are also different from the rest of us in other ways. For example, they tend to have good cholesterol levels – hinting there may several reasons for their longevity.</p>
<p>Ultimately, centenarians are “natural experiments” who show us that it is possible to live in excellent health even if you have been dealt a risky genetic hand and chose to pay no attention to health messages – but only if you carry rare, poorly understood mutations.</p>
<p>Understanding exactly how these work should allow scientists to develop new drugs or other interventions that target biological processes in the right tissues at the right time. If these become a reality perhaps more of us than we think will see the next century in. But, until then, don’t take healthy lifestyle tips from centenarians.</p><img src="https://counter.theconversation.com/content/172020/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><p class="fine-print"><em><span>Nir Barzilai receives funding from the National Institutes of Health (P01AG021654) (N. B.), The Nathan Shock Center of Excellence for the basic Biology of Aging (P30AG038072) (N. B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N. B.) He is a board member (non profit) for the American Federation for Aging Research (AFAR).
</span></em></p>Many centenarians haven’t lived healthy lives, so are they genetically different?Richard Faragher, Professor of Biogerontology, University of BrightonNir Barzilai, Professor of Medicine and Genetics, Albert Einstein College of MedicineLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1536122021-01-21T15:22:36Z2021-01-21T15:22:36ZCognitive decline due to ageing can be reversed in mice – here’s what the new study means for humans<figure><img src="https://images.theconversation.com/files/379962/original/file-20210121-15-4reh7k.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C5615%2C3741&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Memory declines with age.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/hands-seniors-playing-puzzle-on-table-1072128554">Robert Kneschke/Shutterstock</a></span></figcaption></figure><p>The ageing global population is the greatest challenge faced by 21st-century healthcare systems. Even COVID-19 is, in a sense, a disease of ageing. The risk of death from the virus roughly <a href="https://pubmed.ncbi.nlm.nih.gov/32300796/">doubles for every nine years</a> of life, a pattern that is almost identical to a host of other illnesses. But why are old people vulnerable to so many different things?</p>
<p>It turns out that a major hallmark of the ageing process in many mammals <a href="https://pubmed.ncbi.nlm.nih.gov/23746838/">is inflammation</a>. By that, I don’t mean intense local response we typically associate with an infected wound, but a low grade, grinding, inflammatory background noise that grows louder the longer we live. This “inflammaging” has been shown to contribute to the development of <a href="https://pubmed.ncbi.nlm.nih.gov/31894547/">atherosclerosis</a> (the buildup of fat in arteries), <a href="https://pubmed.ncbi.nlm.nih.gov/23843680/">diabetes, high blood pressure</a> , <a href="https://pubmed.ncbi.nlm.nih.gov/32007546/">frailty</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/23688930/">cancer</a> and <a href="https://pubmed.ncbi.nlm.nih.gov/30930767/">cognitive decline</a>.</p>
<p>Now a new study <a href="https://www.nature.com/articles/s41586-020-03160-0">published in Nature</a> reveals that <a href="https://theconversation.com/microglia-the-brains-immune-cells-protect-against-diseases-but-they-can-also-cause-them-139232">microglia</a> – a type of white blood cells found in the brain – are extremely vulnerable to changes in the levels of a major inflammatory molecule called <a href="https://www.medicinenet.com/prostaglandin_e2/definition.htm">prostaglandin E2</a>(PGE2). The team found that exposure to this molecule badly affected the ability of microglia and related cells to generate energy and carry out normal cellular processes. </p>
<p>Fortunately, the researchers found that these effects occurred only because of PGE2’s interaction with one specific receptor on the microglia. By disrupting it they were able normalise cellular energy production and reduce brain inflammation. The result was improved cognition in aged mice. This offers hope that the cognitive impairment associated with growing older is a transient state we can potentially fix, rather than the inevitable consequence of ageing of the brain.</p>
<h2>Reversing cognitive decline</h2>
<p>Levels of PGE2 increase as mammals age for a variety of reasons – one of which is probably the increasing number of cells in different tissues <a href="https://pubmed.ncbi.nlm.nih.gov/17560572/">entering a state termed cellular senescence</a>. This means they become dysfunctional and can cause damage to tissue by releasing PGE2 and other inflammatory molecules. </p>
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<img alt="Image of a macrophage cell." src="https://images.theconversation.com/files/379967/original/file-20210121-15-wvjf6n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/379967/original/file-20210121-15-wvjf6n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/379967/original/file-20210121-15-wvjf6n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/379967/original/file-20210121-15-wvjf6n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/379967/original/file-20210121-15-wvjf6n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/379967/original/file-20210121-15-wvjf6n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/379967/original/file-20210121-15-wvjf6n.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">
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<span class="caption">Macrophage cell.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/macrophage-cell-isolated-on-black-background-659776354">Kateryna Kon/Shutterstock</a></span>
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<p>But the researchers also found that <a href="https://www.news-medical.net/life-sciences/What-is-a-Macrophage.aspx">macrophages</a> – another type of white blood cells related to microglia – from people over the age of 65 made significantly more PGE2 than those from young people. Intriguingly, exposing these white blood cells to PGE2 suppressed the ability of their <a href="http://www.mrc-mbu.cam.ac.uk/what-are-mitochondria">mitochondria</a> – the nearest thing a cell has to batteries – to function. This meant that the entire pattern of energy generation and cellular behaviour was disrupted. </p>
<p>Although PGE2 exerts its effects on cells through a range of receptors, the team were able to narrow down the effect to interaction with just one type (the “EP2 receptor” on the macrophages). They showed this by treating white blood cells, grown in the lab, with drugs that either turned this receptor on or off. When the receptor was turned on, cells acted as if they had been exposed to PGE2. But when they were treated with the drugs that turned it off, they recovered. That’s all fine, but it was done in a petri dish. What would happen in an intact body?</p>
<p>The researchers then carried out one of the cleanest experiments it is possible to perform in biology and one of the best reasons for working on mice. They took genetically modified animals in which the EP2 receptor had been removed and allowed them to grow old. They then tested their learning and memory by looking at their ability to navigate mazes (something of a cliche for researchers) and their behaviour in an “object location test”. This test is a bit like someone secretly entering your house, swapping your ornaments around on the mantelpiece and then sneaking out again. The better the memory, the longer the subject will spend looking suspiciously at the new arrangement, wondering why it has changed. </p>
<p>It turned out that the old genetically modified mice learned and remembered just as well as their young counterparts. These effects could be duplicated in normal old mice by giving them one of the drugs that could turn the EP2 receptor off for one month. So it seems possible that inhibiting the interaction of PGE2 with this particular receptor may represent a new approach to treating late-life cognitive disorders. </p>
<p>There is a long way to go before we are in a position to start using these compounds in humans – even though the prostaglandin systems are very similar. But this study has shed light on a fascinating set of observations linking diet and cognition. </p>
<p>It has been known for some years that eating <a href="https://pubmed.ncbi.nlm.nih.gov/20047325/">blueberries</a> and other fruit and vegetables, such as strawberries and spinach, <a href="https://pubmed.ncbi.nlm.nih.gov/10479711/">improves cognition in rodents and older people</a>. These foods are rich in molecules such as <a href="https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/resveratrol">resveratrol</a>, <a href="https://www.thelancet.com/article/S2352-3964(18)30373-6/fulltext">fisetin</a> and in <a href="https://www.medicalnewstoday.com/articles/324170#overview">quercetin</a>, which have been shown either <a href="https://pubmed.ncbi.nlm.nih.gov/32854855/">to kill</a> or <a href="https://pubmed.ncbi.nlm.nih.gov/29041897/">rescue senescent cells</a>. </p>
<p>There is also evidence that they <a href="https://pubmed.ncbi.nlm.nih.gov/19751497/">block PGE2 at the cellular level</a>, providing another route by which these compounds may exert their beneficial effects. Until something better comes along, this is one more piece of evidence that a bowl of fruit won’t do you any harm. Though it’s probably wise to go easy on the cream.</p><img src="https://counter.theconversation.com/content/153612/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 has received funding from the BBSRC. He is a member of the Scientific Advisory Board of the Longevity Vision Fund and a Trustee of the Biogerontology Research Foundation. </span></em></p>Anti-inflammatory drugs may be able to reverse cognitive decline in the future.Richard Faragher, Professor of Biogerontology, University of BrightonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1267952019-11-19T13:14:58Z2019-11-19T13:14:58ZCan this new anti-ageing supplement turn back the clock?<figure><img src="https://images.theconversation.com/files/301997/original/file-20191115-66921-12amr1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Not a real anti-ageing pill.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/116601979?src=964bebc2-d09f-476b-8e49-464d3622f82e-1-0&size=medium_jpg">Pixelbliss/Shutterstock</a></span></figcaption></figure><p><a href="https://link.springer.com/article/10.1007/s12062-009-9012-6">Increases in lifespan</a> are one of the greatest success stories of modern society. Yet while most of us can expect to live longer, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861644/">we are spending more years in ill health</a>. Reducing this period of ill health at the end of life is the main aim of a group of scientists known as biogerontologists. </p>
<p>By studying ageing in animals, including fruit flies, worms and rodents, biogerontologists have identified biological phenomena involved with ageing that all these organisms share. And some of these biological processes may also <a href="https://www.ncbi.nlm.nih.gov/pubmed/25689319">regulate ageing in humans</a>.</p>
<p>Scientists attempting to understand and improve the ageing process have identified <a href="https://link.springer.com/article/10.1007/s13659-017-0135-9">many molecules that appear to improve ageing</a> in these animals (although evidence in humans remains scant). These molecules include compounds found in <a href="https://www.nih.gov/news-events/nih-research-matters/how-resveratrol-may-fight-aging">grapes</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/20619334">apples</a> and even <a href="https://www.nature.com/articles/s41598-019-44106-5">bacteria</a>.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/302200/original/file-20191118-66979-kiyanc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/302200/original/file-20191118-66979-kiyanc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=322&fit=crop&dpr=1 600w, https://images.theconversation.com/files/302200/original/file-20191118-66979-kiyanc.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=322&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/302200/original/file-20191118-66979-kiyanc.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=322&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/302200/original/file-20191118-66979-kiyanc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=405&fit=crop&dpr=1 754w, https://images.theconversation.com/files/302200/original/file-20191118-66979-kiyanc.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=405&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/302200/original/file-20191118-66979-kiyanc.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=405&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Life-extending supplements?</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/wet-grapes-red-apple-isolated-on-283127282">Kovaleva_Ka/Shutterstock</a></span>
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<p>Recently, a new molecule has been added to the list of possible anti-ageing drugs: nicotinamide adenine dinucleotide or NAD+ for short. As we age, <a href="https://www.sciencedirect.com/science/article/pii/S1550413117306708?via%3Dihub">levels of NAD+ decrease</a> in many tissues of the body. As NAD+ is involved in many important biological processes, it is thought that this decline might <a href="https://www.sciencedirect.com/science/article/pii/S0962892414000634?via%3Dihub">contribute to ageing</a>. </p>
<p>Research in mice has shown that replenishing NAD+ can improve many elements of ageing, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668137/">including age-associated weight gain, enhanced physical activity, improved ability of the body to process carbohydrates and fats, and improved eye function</a>. This has led some scientists to believe that increasing NAD+ levels is an exciting potential anti-ageing therapy. Indeed, a new anti-ageing supplement called Nuchido TIME+, which is said to boost NAD+ levels, was recently launched in Las Vegas. Nichola Conlon, the founder of the company that makes the supplements, described the pills as a “<a href="https://neconnected.co.uk/breakthrough-anti-ageing-supplement-enjoying-worldwide-success/">breakthrough product in the world of anti-ageing</a>”.</p>
<p>Their research has suggested that Nuchido Time+ increases NAD+ in middle-aged people to the levels of someone 15 years younger. So should we all start taking NAD+ supplements? </p>
<p>To guide this decision, we need to first understand the underlying research that has led to this product being released. Almost all the research into NAD+ and ageing has taken place <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795269/">using cells or animals</a> – not people. Although there are shared biological pathways that link ageing in animals and humans, human ageing is significantly more complex due to the markedly longer length of our lifespan and the complexity of our lifestyles. </p>
<p>It is very difficult to design a study that truly tests anti-ageing therapies because of ethical implications, the length of time humans live for and our complex lifestyles. Instead, studies on human ageing tend to focus on specific age-related conditions or biological changes that seem to occur naturally with age. </p>
<h2>Evidence for NAD+ supplements</h2>
<p>The results reported by Nuchido just tell us that they have been able to increase NAD+ levels more than anyone else, not that this increase has had any measurable improvement in people’s ageing under strict scientific conditions. This evidence may yet come but, for now, what we can say is that if you take Nuchido Time+ you are likely to replenish your NAD+ levels. There is some evidence that NAD+ levels may be improved without the need for supplements, with <a href="https://www.frontiersin.org/articles/10.3389/fnut.2018.00062/full?report=reader">dietary changes</a> and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6577427/">exercise</a> both being reported to alter NAD+ levels in some tissues.</p>
<p>While there is evidence that taking supplements to increase NAD+ levels <a href="https://www.nature.com/articles/s41467-018-03421-7">is safe</a>, there is very little evidence yet that NAD+ supplementation works as an anti-ageing agent in humans. One study has reported that NAD+ supplementation in older adults <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702140/">affected muscle cells</a>, but beyond this, there is little to demonstrate that replenishing NAD+ has a marked impact on ageing. </p>
<p>Much more robust, controlled studies are needed before the effects of NAD+ supplementation on human ageing are better understood. For now, as Nuchido Time+ costs £55 for a 30-day supply, it may be better to focus on factors that are well established at improving ageing, such as <a href="https://www.health.harvard.edu/aging/nutrition-and-aging">eating a healthy diet</a> and <a href="https://www.bbc.co.uk/news/health-47331544">getting regular exercise</a>.</p><img src="https://counter.theconversation.com/content/126795/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>James Brown is affiliated with the British Society for Research on Ageing (BSRA). He has previously received funding to study the effects of NAD+ on metabolism.</span></em></p>Talk of a ‘breakthrough’ in NAD+ anti-ageing supplements may be premature.James Brown, Senior Lecturer in Biology and Biomedical Science, Aston 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/664602016-10-05T17:01:13Z2016-10-05T17:01:13ZIs there a natural limit to how long humans can live?<figure><img src="https://images.theconversation.com/files/140490/original/image-20161005-14246-1qemm8g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Centenarian in Tiantou Village, Guangxi, China.</span> <span class="attribution"><span class="source">ESB Professional/Shutterstock</span></span></figcaption></figure><p>Humans may live longer and longer, but eventually we all grow old and die. This leads to a simple question: is there an intrinsic maximum limit to human lifespan or not? There are two equally simple answers. Either there is a limit or there isn’t. Without data you may as well guess and your chance of being right is, all things considered, 50:50. </p>
<p>To improve your odds of getting the right answer you can employ three basic lines of attack. You can ask yourself why ageing exists, you can try to discover how it works or you can investigate how long people really live, regardless of how they do it. Each provides insights and has limitations. </p>
<p>Now a new study, <a href="http://nature.com/articles/doi:10.1038/nature19793">published in Nature</a>, suggests that there seems to be a limit to human lifespan. However, the results, based on demographic data, are far from conclusive and must be interpreted carefully. They also raise some thorny ethical questions.</p>
<h2>All about reproduction</h2>
<p>Evolutionary arguments can provide some biological context. Ageing is simply an exponential increase in your chance of death and sickness with the passage of time. In the wild, chronologically old creatures are rare, they typically get eaten or succumb to accidents.</p>
<p>Any mutation which makes the organism carrying it better at producing offspring will be favoured, even if the same mutation causes bad things to happen later on in life. Ageing is therefore nothing more than the <a href="https://theconversation.com/why-do-humans-deteriorate-with-age-its-a-biological-puzzle-21824">price paid for early life fertility</a>. It is also possible to carry genetic variations that bring no benefit but cause bad effects to occur only after an organism has reproduced. These are hard for natural selection to remove and thus can also contribute to ageing. </p>
<p>In contrast, evolutionary biology provides little support for the idea that there are “ageing genes” that simply cause their carrier to grow old and die. Genes can do this, but only as a side effect of doing something else. For example, the difference in life expectancy between men and women almost certainly results from the different selection pressures placed on their genomes by sexual selection (typically in nature, male organisms <a href="https://www.amazon.co.uk/Evolution-Desire-Strategies-Human-Mating/dp/046500802X">must compete for mates</a> while females must carefully select them). This is not a “his and hers” <a href="https://www.theguardian.com/science/2016/sep/28/internal-clock-makes-some-people-age-quicker-and-die-younger-regardless-of-lifestyle">choice of genetic clock</a>.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/140494/original/image-20161005-14227-1e147zx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/140494/original/image-20161005-14227-1e147zx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/140494/original/image-20161005-14227-1e147zx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/140494/original/image-20161005-14227-1e147zx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/140494/original/image-20161005-14227-1e147zx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/140494/original/image-20161005-14227-1e147zx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/140494/original/image-20161005-14227-1e147zx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Don’t we all want to live to 100?</span>
<span class="attribution"><span class="source">Sara Robinson/Shutterstock</span></span>
</figcaption>
</figure>
<p>Hydra – small, fresh-water animals – <a href="http://www.dailymail.co.uk/sciencetech/article-2521210/Freshwater-polyp-described-effectively-immortal-scientists.html">seem to be “non ageing”</a> (with fixed rather than increasing chances of death over time). Extrapolation from laboratory data show that even after 1,400 years five per cent of a hydra population kept in these conditions would still be alive. However, they still seem to have upper limits to survival. Also, the existence of an upper limit to a species’ lifespan does not mean that every member of that species has the same chance of reaching it. Simple questions about maximum longevity tend to gloss over this point.</p>
<p>Arguments based on the mechanics of the human body also strongly favour the idea that there are intrinsic upper limits to lifespan. Key human organ systems (such as the kidneys and thymus) show clear and often sex-dependent <a href="https://global.oup.com/academic/product/the-biology-of-aging-9780195167399?cc=gb&lang=en&">reductions in efficiency</a> with age. So progressive decline predicts eventual failure. Assuming, of course, that you don’t try to prevent it declining.</p>
<p>Tremendous progress has been made in uncovering the fundamental cell and molecular mechanisms of ageing; removing senescent cells – dysfunctional cells which build up as we age and cause damage to tissue – <a href="https://theconversation.com/the-secret-to-staying-young-scientists-boost-lifespan-of-mice-by-deleting-defective-cells-54068">improves the health and lengthens the lifespan of mice</a> for example. That means it could be argued that the existence of the ability to intervene removes the upper limit to lifespan. A potentially pleasant answer, just not to the question you started with.</p>
<h2>Trends in lifespan</h2>
<p>But is it possible that attempts at preventing early death have also raised the maximum human lifespan and may continue to do so? Studying trends in maximum human lifespan over time could give an answer. But this kind of actuarial calculation is always complex and often wrong. For example in 1921 it was “demonstrated” that <a href="https://books.google.co.uk/books?id=NDCsAAAAIAAJ&pg=PA25&lpg=PA25&dq=Putter+die+%C3%A4ltesten+menschen&source=bl&ots=8ogl2C4WdT&sig=7-t6dxwsxNxl0uXFrfgjsSKOtMQ&hl=en&sa=X&ved=0ahUKEwiRgPmj6cPPAhUIIcAKHd8bAm0Q6AEIKDAB#v=onepage&q=Putter%20die%20%C3%A4ltesten%20menschen&f=false">ages above 105 were “impossible”</a>. Estimating the limits to longevity has since been criticised because every “maximum limit” to lifespan so far proposed <a href="http://www.econ.ku.dk/okocg/VV/VV-Economic%20Growth/articles/artikler-2006/Broken-limits-to-life-expectancy.pdf">has been surpassed</a>. To some people this may indicate that there really is no upper limit to human lifespan.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/140492/original/image-20161005-14212-hfjxps.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/140492/original/image-20161005-14212-hfjxps.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/140492/original/image-20161005-14212-hfjxps.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/140492/original/image-20161005-14212-hfjxps.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/140492/original/image-20161005-14212-hfjxps.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/140492/original/image-20161005-14212-hfjxps.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/140492/original/image-20161005-14212-hfjxps.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Indian supercentenarian Kallu Yadav,aged 110.</span>
<span class="attribution"><span class="source">Utkarshsingh.1992/wikimedia</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>The authors behind the new study analysed global demographic data and examined the reported age at death of “supercentenarians” (individuals older than 110). They showed that although there is evidence for an increase in maximum age at death of about 45-55 days per year from 1970-1995, there is no evidence of any increase beyond this date. Indeed, the age with the greatest improvement in survival plateaued around 1980. </p>
<p>The dataset contains less than 600 individuals but the trend appears significant. Their model predicts that the likelihood of a person exceeding the age of 125 in any given year is less than one in 10,000. The authors argue that we may essentially have “hit a wall” and that a targeted attempt to extend maximum lifespan would be required to break through it.</p>
<p>In its unvarnished form this seems a difficult ethical position to sustain. The number of centenarians is tiny compared to those over 65. Extending the healthy and productive years of the many, not the duration of life of the few, is a more equitable approach and there is <a href="https://www.ncbi.nlm.nih.gov/pubmed/25481271">every sign that this is achievable</a> in the laboratory. </p>
<p>Perhaps the real lesson here is that simple closed questions, in any scientific discipline, are somewhat like asking “who is the most interesting person?” – intoxicatingly profound and practically useless.</p><img src="https://counter.theconversation.com/content/66460/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 the Biotechnology and Biological Sciences Council.</span></em></p>New data suggests humans may not get older than 125 years. But should we take it seriously? Every time a limit to lifespan has been proposed in the past it has been surpassed.Richard Faragher, Professor of Biogerontology, University of BrightonLicensed 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>
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<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">
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<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>
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<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>
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<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">
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<span class="caption">Senescent cells are responsible for wrinkles and disease.</span>
<span class="attribution"><span class="source">Evgeny Atamanenko</span></span>
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<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.