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Though they were once considered an inevitable consequence of the passing of time, these and other “hallmarks of ageing” may be amenable to modulation. It is even possible that they may be caused by a single underlying biological process that could provide a powerful intervention target. This raises the possibility of not only preventing diseases individually but reversing the entire process that underpins their development.\n\nA growing set of useful, well-characterised biomarkers is making it increasingly possible to predict what the unfolding of biological processes over time will do to a specific individual’s health. Among the most widely used is a statistical tool known as an epigenetic clock, which can benchmark the comparative rate of deterioration of an individual or their organs against population data. This measure of biological (rather than chronological) age offers not only diagnosis but new therapeutic targets. Abnormally fast deterioration, identified via these biomarkers,[1](/citation/2025-02-2-3-1/) may be corrected by epigenome editing to restore the system to a youthful state, for instance.\n\nThe ability to tinker with ageing via epigenetic modification is only one part of an ongoing reassessment of the wider human genome and how we can interact with it to extend healthy life. The non-coding elements that make up 98 per cent of the genome — until recently dismissed as “junk DNA” — have been revealed as an important but poorly understood source of age-related physiological deterioration. Now recast as the “dark genome”, this vast trove of elements may also prove a new source of biomarkers to diagnose and promote longevity and health.\n\nUnderstanding how these elements change under the influence of lifestyle factors — exercise, diet, habits and so on — to accelerate or decelerate biological ageing is also a fast-moving area of research. A deeper understanding of the dark genome and epigenetic rejuvenation will reveal why certain lifestyle factors affect populations differently, Meanwhile, we are already entering an era of “lifestyle mimetics”: clinical trials are under way on small-molecule drugs that chemically imitate the consequences of lifestyle choices that contribute to resilience (fasting, for instance), or suppress processes that harm the system.\n\nThe most important focus in the near term is validation of biomarkers and targets. However, this will require better data, which can be obtained only through finding new ways to raise funds for research without compromising sensitive medical data. Investigations of the dark genome will create vast volumes of new data that could be usefully mined by AI for new insights, but this can only happen with innovative new trial designs built on a model that assures patient data integrity and trust.\n\n\n**KEY TAKEAWAYS**\n\nMany decades after scientific insights significantly extended human lifespan, research is making inroads into improving our healthspan — the amount of time for which we have a healthy, productive existence. Research has begun to identify important **Biomarkers of ageing** that help to identify potential problems and enable researchers to understand why some people age more robustly than others. The epigenome, a suite of mechanisms that regulate gene expression, are strongly associated with ageing. **Rejuvenating the epigenome** through various means is becoming a viable path towards increasing healthspan. A significant proportion of the genome that was previously ignored as “junk” is also now a target for healthspan extension. Certain parts of the **dark genome** seem to be involved in a number of ageing-associated processes, and finding ways to intervene here could prove impactful. Investigations of the role of **Lifestyle modification** in ageing are also proving fruitful. Patterns of sleep, exercise, nutrition and circadian rhythms are all associated with ageing, and improving the effectiveness of lifestyle interventions and understanding the biological transducers that mediate such effects could assist with the development of drugs that engender them."},"intro":{"text":"Ageing was once thought to be an inescapable fact of human life. "},"anticipatoryImpact":{"text":"Three fundamental questions guide GESDA’s mission and drive its work: Who are we, as humans? How can we all live together? How can we ensure the well-being of humankind and the sustainable future of our planet? We asked researchers from the field to anticipate what impact future breakthroughs could have on each of these dimensions. This wheel summarises their opinions when considering each of these questions, with a higher score indicating high anticipated impact, and vice versa.\n\n* Anticipated impact on who we are as humans\n* Anticipated impact on how we will all live together\n* Anticipated impact on the well-being of humankind and sustainable future of our planet"},"indicatorValues":[{"id":"65c55cf49e947c438698aae3","value":"0.573","numericValue":0.573,"year":2024,"indicator":{"id":"65c55cf29e947c438698aa4d","name":"Anticipation Potential","title":null,"slug":"anticipation-potential","dataSetId":"ANTICIPATION_POTENTIAL","color":null}},{"id":"68a6867b0ac1330579fd78a5","value":"0.5694","numericValue":0.5694,"year":2025,"indicator":{"id":"65c55cf29e947c438698aa4d","name":"Anticipation Potential","title":null,"slug":"anticipation-potential","dataSetId":"ANTICIPATION_POTENTIAL","color":null}}],"editions":[{"id":"66ab1bb636a8f2f336a557bf","name":"2024","slug":"2024","numericValue":2024},{"id":"684951c963371e51d83bdf31","name":"2025","slug":"2025","numericValue":2025}],"anticipatoryImpactImage":{"image":{"id":"image_gesda-platform/image-asset/psp-pl-2-25-2-3_image__PSP-PL2_25_2.3_yn6qsu","url":"https://res.cloudinary.com/shapeable/image/upload/v1760070064/gesda-platform/image-asset/psp-pl-2-25-2-3_image__PSP-PL2_25_2.3_yn6qsu.webp"}},"embeds":{"citations":[{"id":"691a78a5c0043bba84a9df2d","slug":"2025-02-2-3-1","url":"https://doi.org/10.1038/s43587-022-00220-0.","name":"The relationship between epigenetic age and the hallmarks of aging in human cells","authors":[{"id":"691a78a4c0043bba84a9df2b","name":"S. Kabacik et al.","slug":"s-kabacik-et-al"}],"authorShowsEtAl":null,"edition":null,"publication":"Nature Aging","accessDate":null,"startPage":484,"volume":2,"footnoteNumber":1,"year":null}],"imageAssets":[]},"surveyObservations":{"text":"The role of biomarkers and lifestyle modification on Healthspan Extension are reasonably well known, and both fields are now seen as mature. There is, however, relatively little awareness outside of the scientific community on **Biomarkers of ageing** — as a consequence, the need for multilateral action is seen as high. Fully understanding the influence that the **Dark genome** and transposable elements have on ageing will remain a challenge for at least 25 years. **Rejuvenating the epigenome** is the area with the highest scope for multilateral action."},"color":{"id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD","darkValue":"#045059","veryDarkValue":"#011b1e"},"banner":{"id":"6a923c56d215991948806010","name":"\"To the bone\" by Tatiana Kochetkova, University of Bern","description":{"text":"\"To the bone\" by Tatiana Kochetkova, University of Bern"},"image":{"id":"image_gesda-platform/banner/to-the-bone-by-tatiana-kochetkova-university-of-bern_image__22To_the_bone_22_by_Tatiana_Kochetkova_University_of_Bern_c3kosv","url":"https://res.cloudinary.com/shapeable/image/upload/v1787968588/gesda-platform/banner/to-the-bone-by-tatiana-kochetkova-university-of-bern_image__22To_the_bone_22_by_Tatiana_Kochetkova_University_of_Bern_c3kosv.jpg","thumbnails":{"mainBanner":{"url":"https://res.cloudinary.com/shapeable/image/upload/c_limit,w_1440/v1787968588/gesda-platform/banner/to-the-bone-by-tatiana-kochetkova-university-of-bern_image__22To_the_bone_22_by_Tatiana_Kochetkova_University_of_Bern_c3kosv.jpg","url2x":"https://res.cloudinary.com/shapeable/image/upload/c_limit,w_2880/v1787968588/gesda-platform/banner/to-the-bone-by-tatiana-kochetkova-university-of-bern_image__22To_the_bone_22_by_Tatiana_Kochetkova_University_of_Bern_c3kosv.jpg"}}}},"chartImage":{"id":"65c55cee9e947c438698a960","slug":"chart-2-3-radical-health-extension","image":{"id":"image_gesda-22/image-asset/chart-2-3-radical-health-extension_image__TRR-2_3-TBC-01","url":"https://res.cloudinary.com/shapeable/image/upload/v1668986378/gesda-22/image-asset/chart-2-3-radical-health-extension_image__TRR-2_3-TBC-01.png","url2x":null}},"citations":[{"__typename":"Platform_Citation","_schema":{"label":"Citation","pluralLabel":"Citations"},"typeLabel":"Journal","slug":"2025-02-2-3-1","url":"https://doi.org/10.1038/s43587-022-00220-0.","name":"The relationship between epigenetic age and the hallmarks of aging in human cells","authors":[{"id":"691a78a4c0043bba84a9df2b","name":"S. Kabacik et al.","slug":"s-kabacik-et-al"}],"authorShowsEtAl":null,"edition":null,"publication":"Nature Aging","accessDate":null,"startPage":484,"volume":2,"footnoteNumber":1,"year":null}],"subTopics":[{"id":"65c55d4f9e947c438698b675","name":"Biomarkers of ageing","path":"/sub-topics/biomarkers-of-ageing","outlineNumber":"2.3.1","slug":"biomarkers-of-ageing","__typename":"Platform_SubTopic","color":{"id":"65c55cbc9e947c438698a325","name":"Teal","value":"#44AFCD"},"topic":{"id":"65c55d599e947c438698b7b6","slug":"healthspan-extension","path":"/topics/healthspan-extension"},"intro":{"text":"Thanks to the interplay of their genes with environmental factors, some people age more robustly than others. Years lived is therefore not a reliable predictor of future health and longevity. Much more useful is “biological age”, derived from analysis of biological factors known as biomarkers. Research has identified a vast range of biomarkers that can help chart the accumulation of molecular and cellular damage that leads to age-dependent deterioration.[2](/citation/2025-02-2-3-2/) \n"},"description":{"text":"Epigenetic clocks — a type of biomarker that estimates biological age by analysing DNA methylation patterns — can estimate accelerated biological ageing in cells, tissues or organs.[3](/citation/2025-02-2-3-3/) This is a means of identifying problematic biochemical trends before diseases manifest. More recent advances integrate statistics from multiple epigenetic biomarkers to predict mortality.[4](/citation/2025-02-2-3-4/)\n\nValidating these biomarkers so that they are reliable and consistent is the key to making biological age a useful tool. Because biomarkers are statistical tools whose power lies in the amount of data that they can draw on, the more population data that is available against which to benchmark individuals, the more accurately the tools will be able to identify patterns and make predictions. One promising model, the Global Neurodegeneration Proteomics Consortium,[5](/citation/2025-02-2-3-5/) combines the data of 40,000 individuals and solves data-privacy issues via federation of access and cloud analysis. Mining this and future large datasets, including the UK Biobank, will refine biomarkers of ageing.\n"},"anticipationScores":{"text":"The Anticipation Potential of a research field is determined by the capacity for impactful action in the present, considering possible future transformative breakthroughs in a field over a 25-year outlook. A field with a high Anticipation Potential, therefore, combines the potential range of future transformative possibilities engendered by a research area with a wide field of opportunities for action in the present. We asked researchers in the field to anticipate: \n\n1. The *uncertainty* related to future science breakthroughs in the field\n2. The *transformative* *effect* anticipated breakthroughs may have on research and society\n3. The *scope for action* in the present in relation to anticipated breakthroughs. \n\nThis chart represents a summary of their responses to each of these elements, which when combined, provide the *Anticipation Potential* for the topic. See [methodology](/science-anticipation/methodology) for more information."},"anticipationScoresImage":{"id":"68e8943763d1c853e9788bd0","image":{"id":"image_gesda-platform/image-asset/2-3-1-sub-anti-2026_image__2.3.1_sub_anti_2026_bjgwqr","url":"https://res.cloudinary.com/shapeable/image/upload/v1760072740/gesda-platform/image-asset/2-3-1-sub-anti-2026_image__2.3.1_sub_anti_2026_bjgwqr.webp","url2x":null,"width":1200,"height":1200}},"horizons":[{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a79f","name":"2.3.1 - 25-year horizon","slug":"2-3-1-25-year-horizon","intro":{"text":"Biomarkers directly improve healthspan"},"description":{"text":"AI-led data analysis robustly correlates biomarkers of ageing with the underlying processes of ageing. Researchers gain a mechanistic understanding of how healthy and unhealthy ageing diverge. Age care based on personalised biomarkers becomes part of standard medical care, resulting in population-wide improvements in healthspan. \n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89c","name":"25-year horizon","slug":"25-year-horizon","years":25,"title":"25-year","subtitle":"horizon"},"embeds":{"citations":[]}},{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a79e","name":"2.3.1 - 10-year horizon","slug":"2-3-1-10-year-horizon","intro":{"text":"Biological age is normalised"},"description":{"text":"Validated biomarkers enter the clinic more widely, approved either as companion diagnostics or independent predictors. Moderately invasive, inexpensive biomarkers of ageing, such as age-related molecular changes in blood, become part of standard clinical care and monitoring. Measurements from wearables collect non-invasive data that has been validated against epigenetic clocks, allowing more data to be collected. Large cohorts and established biobanks unlock genetic information that leads to better models of cognitive decline. Research pins down which diseases are primarily caused by biological ageing.\n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89b","name":"10-year horizon","slug":"10-year-horizon","years":10,"title":"10-year","subtitle":"horizon"},"embeds":{"citations":[]}},{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a79d","name":"2.3.1 - 5-year horizon","slug":"2-3-1-5-year-horizon","intro":{"text":"Beta testers and bigger data assist research"},"description":{"text":"Datasets get bigger and more diverse. New sample analysis platforms make it possible to compare across cohorts for many different studies. More biomarkers are validated, and more companies use this information, making it available, initially, to private customers. Researchers begin to analyse molecular underpinnings of previously published clinical trials of successful ageing interventions, generating better models and driving deeper understanding. \n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89a","name":"5-year horizon","slug":"5-year-horizon","years":5,"title":"5-year","subtitle":"horizon"},"embeds":{"citations":[]}}],"indicatorValues":[{"id":"65c55cf49e947c438698aa58","value":"0.548","numericValue":0.548,"year":2024,"indicator":{"id":"65c55cf29e947c438698aa4d","name":"Anticipation Potential","title":null,"slug":"anticipation-potential","dataSetId":"ANTICIPATION_POTENTIAL","color":null}},{"id":"68eddb16af9e6d6d63270dff","value":"0.560","numericValue":0.56,"year":2025,"indicator":{"id":"65c55cf29e947c438698aa4d","name":"Anticipation Potential","title":null,"slug":"anticipation-potential","dataSetId":"ANTICIPATION_POTENTIAL","color":null}}],"embeds":{"citations":[{"slug":"2025-02-2-3-2","url":"https://doi.org/10.1038/s41591-019-0673-2.","name":"Undulating changes in human plasma proteome profiles across the lifespan","authors":[{"name":"B. Lehallier et al."}],"authorShowsEtAl":null,"edition":null,"publication":"Nature Medicine","accessDate":null,"startPage":1843,"volume":25,"footnoteNumber":2,"year":null},{"slug":"2025-02-2-3-3","url":"https://doi.org/10.1186/gb-2013-14-10-r115.","name":"DNA methylation age of human tissues and cell types","authors":[{"name":"S. Horvath"}],"authorShowsEtAl":null,"edition":null,"publication":"Genome Biology","accessDate":null,"startPage":3156,"volume":14,"footnoteNumber":3,"year":null},{"slug":"2025-02-2-3-4","url":"https://doi.org/10.1111/acel.13608.","name":"Integrative analysis of clinical and epigenetic biomarkers of mortality","authors":[{"name":"T. Huan et al."}],"authorShowsEtAl":null,"edition":null,"publication":"Aging Cell","accessDate":null,"startPage":13608,"volume":21,"footnoteNumber":4,"year":null},{"slug":"2025-02-2-3-5","url":"https://doi.org/10.1002/alz.095579.","name":"The Global Neurodegeneration Proteomics Consortium — biomarker and drug target discovery across >40,000 biosamples for AD, PD, ALS, FTD, and aging","authors":[{"name":"M. Bringmann et al."}],"authorShowsEtAl":null,"edition":null,"publication":"Alzheimers & Dementia","accessDate":null,"startPage":95579,"volume":20,"footnoteNumber":5,"year":null}],"imageAssets":[]}},{"id":"65c55d4f9e947c438698b668","name":"Rejuvenating the epigenome","path":"/sub-topics/rejuvenating-the-epigenome","outlineNumber":"2.3.2","slug":"rejuvenating-the-epigenome","__typename":"Platform_SubTopic","color":{"id":"65c55cbc9e947c438698a325","name":"Teal","value":"#44AFCD"},"topic":{"id":"65c55d599e947c438698b7b6","slug":"healthspan-extension","path":"/topics/healthspan-extension"},"intro":{"text":"The ageing process is associated with changes in the mechanisms that regulate gene expression, including DNA methylation, histone modification and chromatin remodelling. Though the underlying DNA sequence remains unchanged, these disruptions to the epigenome impact cell and tissue resilience against disease. Resetting an aged epigenome to a youthful state therefore offers the prospect of rejuvenation rather than merely slowing the pace of ageing: it makes cells, tissues and organisms actually younger rather than simply slowing their decline."},"description":{"text":"Epigenetic reprogramming to turn the body’s somatic cells into pluripotent cells has been investigated for decades. This is mediated by proteins called transcription factors and has been shown to have rejuvenating effects in preclinical trials.[6](/citation/2025-02-2-3-6/) However, the mechanism (which uses four transcription factors — known collectively as OSKM — that are delivered by viral payload) carries an inherent risk of cancer.[7](/citation/2025-02-2-3-7/) Safety will be key to human translation, meaning that potentially cancer-causing transcription factors will need to be replaced by small molecule drugs or other alternatives. Early work identifying safer transcription factors, including HNF4 alpha, which can rejuvenate the liver, is under way. The epigenome may also be targeted more indirectly, including by the SIRT6 activator fucoidan or forskolin.[8](/citation/2025-02-2-3-8/) \n\nInstead of in vivo modification, ex vivo interventions could be undertaken to reprogram aged stem cells before reintroducing them to the body. This would allow more control of the process. This approach is a focus of current research for reprogramming transplant organs, such as kidneys and hearts, which are epigenetically rejuvenated before being introduced into a recipient.[9](/citation/2025-02-2-3-9/)\n"},"anticipationScores":{"text":"The Anticipation Potential of a research field is determined by the capacity for impactful action in the present, considering possible future transformative breakthroughs in a field over a 25-year outlook. A field with a high Anticipation Potential, therefore, combines the potential range of future transformative possibilities engendered by a research area with a wide field of opportunities for action in the present. We asked researchers in the field to anticipate: \n\n1. The *uncertainty* related to future science breakthroughs in the field\n2. The *transformative* *effect* anticipated breakthroughs may have on research and society\n3. The *scope for action* in the present in relation to anticipated breakthroughs. \n\nThis chart represents a summary of their responses to each of these elements, which when combined, provide the *Anticipation Potential* for the topic. See [methodology](/science-anticipation/methodology) for more information."},"anticipationScoresImage":{"id":"68e89f6363d1c853e9788c9c","image":{"id":"image_gesda-platform/image-asset/2-3-2-sub-anti-2026_image__2.3.2_sub_anti_2026_wjygjx","url":"https://res.cloudinary.com/shapeable/image/upload/v1760075605/gesda-platform/image-asset/2-3-2-sub-anti-2026_image__2.3.2_sub_anti_2026_wjygjx.webp","url2x":null,"width":1200,"height":1200}},"horizons":[{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a2","name":"2.3.2 - 25-year horizon","slug":"2-3-2-25-year-horizon","intro":{"text":"In vivo rejuvenation becomes widespread"},"description":{"text":"In vivo reprogramming targets normal human ageing. Research identifies a master cell type that systemically rejuvenates tissues, enabling new forms of intervention.\n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89c","name":"25-year horizon","slug":"25-year-horizon","years":25,"title":"25-year","subtitle":"horizon"},"embeds":{"citations":[]}},{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a1","name":"2.3.2 - 10-year horizon","slug":"2-3-2-10-year-horizon","intro":{"text":"Rejuvenation becomes safe"},"description":{"text":"Livers, hearts and kidneys are transplanted after perfusion with epigenome-modifying agents that rejuvenate the organs. In vivo reprogramming of specific pathologies is tested on debilitating single-tissue pathologies for which risk is tolerable, for example COPD, chronic kidney disease and rheumatoid arthritis.\n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89b","name":"10-year horizon","slug":"10-year-horizon","years":10,"title":"10-year","subtitle":"horizon"},"embeds":{"citations":[]}},{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a0","name":"2.3.2 - 5-year horizon","slug":"2-3-2-5-year-horizon","intro":{"text":"Ex vivo rejuvenation begins"},"description":{"text":"Researchers investigate a range of safer transcription factors. Trial results reveal the biomarkers that intervention affects and identify specific mechanisms of action. Advances in biomarker research clarifies the distinction between rejuvenation and regeneration, helping to focus future research on rejuvenation."},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89a","name":"5-year horizon","slug":"5-year-horizon","years":5,"title":"5-year","subtitle":"horizon"},"embeds":{"citations":[]}}],"indicatorValues":[{"id":"65c55cf49e947c438698aa93","value":"0.592","numericValue":0.592,"year":2024,"indicator":{"id":"65c55cf29e947c438698aa4d","name":"Anticipation Potential","title":null,"slug":"anticipation-potential","dataSetId":"ANTICIPATION_POTENTIAL","color":null}},{"id":"68eddb8faf9e6d6d63270e30","value":"0.650","numericValue":0.65,"year":2025,"indicator":{"id":"65c55cf29e947c438698aa4d","name":"Anticipation Potential","title":null,"slug":"anticipation-potential","dataSetId":"ANTICIPATION_POTENTIAL","color":null}}],"embeds":{"citations":[{"slug":"2025-02-2-3-6","url":"https://doi.org/10.1007/s11357-024-01269-y.","name":"Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy","authors":[{"name":"S. Horvath et al."}],"authorShowsEtAl":null,"edition":null,"publication":"GeroScience","accessDate":null,"startPage":809,"volume":47,"footnoteNumber":6,"year":null},{"slug":"2025-02-2-3-7","url":"https://doi.org/10.1038/s41467-024-46020-5.","name":"The long and winding road of reprogramming-induced rejuvenation","authors":[{"name":"A. D. Yücel and V. N. Gladyshev"}],"authorShowsEtAl":null,"edition":null,"publication":"Nature Communications","accessDate":null,"startPage":1941,"volume":15,"footnoteNumber":7,"year":null},{"slug":"2025-02-2-3-8","url":"https://doi.org/10.1101/2025.03.24.645072.","name":"SIRT6 activator fucoidan extends healthspan and lifespan in aged wild-type mice","authors":[{"name":"S. A. Biashad et al."}],"authorShowsEtAl":null,"edition":null,"publication":"bioRxiv","accessDate":null,"startPage":645072,"volume":null,"footnoteNumber":8,"year":null},{"slug":"2025-02-2-3-9","url":"https://doi.org/10.1172/JCI123946.","name":"Mixing old and young: enhancing rejuvenation and accelerating aging","authors":[{"name":"A. Lau et al."}],"authorShowsEtAl":null,"edition":null,"publication":"The Journal of Clinical Investigation","accessDate":null,"startPage":4,"volume":129,"footnoteNumber":9,"year":null}],"imageAssets":[]}},{"id":"65c55d4f9e947c438698b679","name":"Dark genome","path":"/sub-topics/dark-genome","outlineNumber":"2.3.3","slug":"dark-genome","__typename":"Platform_SubTopic","color":{"id":"65c55cbc9e947c438698a325","name":"Teal","value":"#44AFCD"},"topic":{"id":"65c55d599e947c438698b7b6","slug":"healthspan-extension","path":"/topics/healthspan-extension"},"intro":{"text":"For decades, biomedical research has largely focused on the 1.5 per cent of the human genome that codes for proteins, dismissing the rest as “junk DNA”. However, in light of recent insights into the millions of repetitive DNA sequences it comprises, this “junk” has now been recast as the “dark genome”. "},"description":{"text":"Of particular interest for geroscience are transposons: repeating, self-replicating DNA sequences that can alter their location in the genome.[10](/citation/2025-02-2-3-10/) Also known as “jumping genes”, they make up about half of the genome. Their activity — which increases with an organism’s age — can alter chromosome structure, destabilise the genome, trigger immune response and inflammation,[11](/citation/2025-02-2-3-11/) and create other conditions that have been tied to poor health outcomes in old age.[12](/citation/2025-02-2-3-12/) Turning them off seems to have broad health benefits, as revealed in HIV antiretroviral therapies that turn off the “LINE” transposons (among the most prevalent repeating sequences, and major contributors to human genetic variation).[13](/citation/2025-02-2-3-13/)  This reverses the age-accelerating effects of HIV with no health trade-offs.[14](/citation/2025-02-2-3-14/) Doing so holds promise for other diseases associated with LINE-1, such as rheumatoid arthritis[15](/citation/2025-02-2-3-15/) and lupus.[16](/citation/2025-02-2-3-16/)\n\nHowever, manipulating the dark genome will be more complex than simply finding a general-purpose “off” switch. Preclinical trials are beginning to show that, under certain conditions, some parts of the dark genome might have beneficial effects. Also, a better understanding of how non-coding elements interact with coding elements may yield a rich new source of new biomarkers and potentially even therapies. Our understanding of the dark genome has been hampered by technological limitations of DNA and RNA sequencing requiring fragmentation followed by aligning to reference sequences to forecast the underlying sequence. New technologies, including nanopore, which allows direct reading of long sequences of DNA and RNA, are advancing our understanding of the dark genome,[17](/citation/2025-02-2-3-17/) but more research into these intricate relationships and how to balance the trade-offs is needed. Excitingly, the dark genome appears to be responsive to rejuvenation, so a better understanding of rejuvenation may also shed light on it. \n"},"anticipationScores":{"text":"The Anticipation Potential of a research field is determined by the capacity for impactful action in the present, considering possible future transformative breakthroughs in a field over a 25-year outlook. A field with a high Anticipation Potential, therefore, combines the potential range of future transformative possibilities engendered by a research area with a wide field of opportunities for action in the present. We asked researchers in the field to anticipate: \n\n1. The *uncertainty* related to future science breakthroughs in the field\n2. The *transformative* *effect* anticipated breakthroughs may have on research and society\n3. The *scope for action* in the present in relation to anticipated breakthroughs. \n\nThis chart represents a summary of their responses to each of these elements, which when combined, provide the *Anticipation Potential* for the topic. See [methodology](/science-anticipation/methodology) for more information."},"anticipationScoresImage":{"id":"68e8981d63d1c853e9788c18","image":{"id":"image_gesda-platform/image-asset/2-3-3-sub-anti-2026_image__2.3.3_sub_anti_2026_culwbn","url":"https://res.cloudinary.com/shapeable/image/upload/v1760073741/gesda-platform/image-asset/2-3-3-sub-anti-2026_image__2.3.3_sub_anti_2026_culwbn.webp","url2x":null,"width":1200,"height":1200}},"horizons":[{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a5","name":"2.3.3 - 25-year horizon","slug":"2-3-3-25-year-horizon","intro":{"text":"Research identifies harmful elements of dark genome"},"description":{"text":"Identification of** specific, harmful elements that carry no hidden benefits to an organism leads to improved therapies with reduced side effects. We untangle the other ways activation of the dark genome affects multiple, often unrelated, traits that affect apparently unrelated tissues and cell types.\n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89c","name":"25-year horizon","slug":"25-year-horizon","years":25,"title":"25-year","subtitle":"horizon"},"embeds":{"citations":[]}},{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a4","name":"2.3.3 - 10-year horizon","slug":"2-3-3-10-year-horizon","intro":{"text":"AI assists dark-genome research"},"description":{"text":"AI identifies many of the functions of non-coding elements and their effects on healthspan. It becomes possible to biochemically separate adaptive from maladaptive changes induced by jumping genes. First drugs developed to target specific transposable elements. Dark genome yields anti-cancer drugs.\n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89b","name":"10-year horizon","slug":"10-year-horizon","years":10,"title":"10-year","subtitle":"horizon"},"embeds":{"citations":[]}},{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a3","name":"2.3.3 - 5-year horizon","slug":"2-3-3-5-year-horizon","intro":{"text":"Understanding transposable elements"},"description":{"text":"The interplay between coding and non-coding regions of the genome is elucidated. The basic understanding of the dark genome — which elements to repress and with which drugs — is established as a new field.[18](/citation/2025-02-2-3-18/) Using biomarkers to establish causality, researchers figure out if these can be used for therapy. Early start-up trials yield results repurposing old drugs against neurodegeneration in ALS and autoimmune diseases like lupus, and more such trials ensue."},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89a","name":"5-year horizon","slug":"5-year-horizon","years":5,"title":"5-year","subtitle":"horizon"},"embeds":{"citations":[{"slug":"2025-02-2-3-18","url":"https://doi.org/10.1186/s13100-023-00306-5.","name":"Proceedings of the inaugural Dark Genome Symposium: November 2022","authors":[{"id":"691a78aec0043bba84a9df6f","name":"J. D. 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Esteban-Cantos et al."}],"authorShowsEtAl":null,"edition":null,"publication":"The Lancet HIV","accessDate":null,"startPage":197,"volume":8,"footnoteNumber":14,"year":null},{"slug":"2025-02-2-3-15","url":"https://doi.org/10.1136/ard.62.7.663.","name":"Overexpression of transcripts containing LINE-1 in the synovia of patients with rheumatoid arthritis","authors":[{"name":"M. Ali et al."}],"authorShowsEtAl":null,"edition":null,"publication":"Annals of the Rheumatic Diseases","accessDate":null,"startPage":663,"volume":62,"footnoteNumber":15,"year":null},{"slug":"2025-02-2-3-16","url":"https://doi.org/10.3109/08916930903374865.","name":"Long interspersed nuclear elements (LINE-1): potential triggers of systemic autoimmune disease","authors":[{"name":"M. K. Crow"}],"authorShowsEtAl":null,"edition":null,"publication":"Autoimmunity","accessDate":null,"startPage":7,"volume":43,"footnoteNumber":16,"year":null},{"slug":"2025-02-2-3-17","url":"https://doi.org/10.1186/s13100-024-00339-4.","name":"Targeted detection of endogenous LINE-1 proteins and ORF2p interactions","authors":[{"name":"M. I. Nielsen et al."}],"authorShowsEtAl":null,"edition":null,"publication":"Mobile DNA","accessDate":null,"startPage":3,"volume":16,"footnoteNumber":17,"year":null}],"imageAssets":[]}},{"id":"65c55d4f9e947c438698b682","name":"Lifestyle modification","path":"/sub-topics/lifestyle-modification","outlineNumber":"2.3.4","slug":"lifestyle-modification","__typename":"Platform_SubTopic","color":{"id":"65c55cbc9e947c438698a325","name":"Teal","value":"#44AFCD"},"topic":{"id":"65c55d599e947c438698b7b6","slug":"healthspan-extension","path":"/topics/healthspan-extension"},"intro":{"text":"Strong epidemiological evidence has confirmed that environment and behaviour are important components of longevity. Sleep, nutrition, exercise and other healthspan-affecting lifestyle choices can cause healthy and unhealthy ageing to diverge.\n"},"description":{"text":"What’s more, the interplay between two or more behavioural or environmental interventions can amplify the efficacy of each, as suggested by mouse trials in which calorie restriction’s moderate benefits for lifespan and healthspan were multiplied several times over by combination with circadian timing patterns of eating.[19](/citation/2025-02-2-3-19/) However, how single or multiple behaviours are transduced into cellular changes is an area of open research. \n\nWhile that research continues, efforts are under way to find ways to boost circadian rhythms associated with not just sleep/wake cycles but also body temperature, blood pressure and so on. Their fluctuations are controlled by time-keeping proteins encoded in master clock genes, and drugs that enhance the master clocks could make us healthier. This should have beneficial effects, since these clocks regulate the genes in all 12 hallmarks of ageing pathways,[20](/citation/2025-02-2-3-20/) and seem to regulate sleep, metabolism and neurodegeneration. In mice, boosting clock gene expression yielded a 15 per cent increase in lifespan.\n\nFinding and measuring biomarkers that link lifestyle choices with clocks will open the possibility of lifestyle mimetics, small-molecule drugs that could manipulate the same pathways and slow ageing before disease manifests.\n\nWe may already be administering such drugs. The immunosuppressant rapamycin, whose signalling is increasingly understood to influence longevity and ageing, and the metabolic drug metformin have been in clinical trials for their suspected ability to mimic lifestyle benefits. More recent investigations have studied drugs that target sirtuins. Stimulation of sirtuin 6 (SIRT6) has extended lifespan in mice, rejuvenated the epigenome and silenced transposable elements. Activating SIRT6 or similar epigenetic regulators with small molecules or natural compounds will provide safe ways to improve healthspan.[21](/citation/2025-02-2-3-21/) Fucoidan, a natural SIRT6-activating compound, is under test in a clinical trial for its ability to slow the biomarkers of ageing in humans."},"anticipationScores":{"text":"The Anticipation Potential of a research field is determined by the capacity for impactful action in the present, considering possible future transformative breakthroughs in a field over a 25-year outlook. A field with a high Anticipation Potential, therefore, combines the potential range of future transformative possibilities engendered by a research area with a wide field of opportunities for action in the present. We asked researchers in the field to anticipate: \n\n1. The *uncertainty* related to future science breakthroughs in the field\n2. The *transformative* *effect* anticipated breakthroughs may have on research and society\n3. The *scope for action* in the present in relation to anticipated breakthroughs. \n\nThis chart represents a summary of their responses to each of these elements, which when combined, provide the *Anticipation Potential* for the topic. See [methodology](/science-anticipation/methodology) for more information."},"anticipationScoresImage":{"id":"68e897f763d1c853e9788c15","image":{"id":"image_gesda-platform/image-asset/2-3-4-sub-anti-2026_image__2.3.4_sub_anti_2026_lkx9mc","url":"https://res.cloudinary.com/shapeable/image/upload/v1760073705/gesda-platform/image-asset/2-3-4-sub-anti-2026_image__2.3.4_sub_anti_2026_lkx9mc.webp","url2x":null,"width":1200,"height":1200}},"horizons":[{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a8","name":"2.3.4 - 25-year horizon","slug":"2-3-4-25-year-horizon","intro":{"text":"Interventions target genetic vulnerabilities"},"description":{"text":"Research insights provide the basis for personalised interventions that target the particular needs of an individual’s genetic vulnerabilities and make the most of their resiliences. This would be a personalised intervention mimicking that person’s optimal lifestyle choices."},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89c","name":"25-year horizon","slug":"25-year-horizon","years":25,"title":"25-year","subtitle":"horizon"},"embeds":{"citations":[]}},{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a7","name":"2.3.4 - 10-year horizon","slug":"2-3-4-10-year-horizon","intro":{"text":"Health-extending plans are personalised"},"description":{"text":"Personalised resilience information helps develop a lifestyle prescription map based on how an individual’s body responds to environmental stressors. Researchers develop small-molecule drug candidates to enhance clock function, with benefits in longevity but also short-term benefits for health.\n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89b","name":"10-year horizon","slug":"10-year-horizon","years":10,"title":"10-year","subtitle":"horizon"},"embeds":{"citations":[]}},{"__typename":"Platform_Horizon","id":"65c55ce69e947c438698a7a6","name":"2.3.4 - 5-year horizon","slug":"2-3-4-5-year-horizon","intro":{"text":"Role of circadian clocks becomes clearer"},"description":{"text":"Circadian clocks are recognised as one of the hallmarks of ageing beyond metabolism and immune functions, and become more widely appreciated in cancer and neurodegeneration. Measurement of the resilience response in humans becomes possible. Research reveals how clocks mechanistically affect healthy ageing.\n"},"color":{"__typename":"Platform_Color","id":"65c55cbc9e947c438698a325","name":"Teal","slug":"teal","value":"#44AFCD"},"type":{"__typename":"Platform_HorizonType","id":"65c55ce79e947c438698a89a","name":"5-year horizon","slug":"5-year-horizon","years":5,"title":"5-year","subtitle":"horizon"},"embeds":{"citations":[]}}],"indicatorValues":[{"id":"65c55cf49e947c438698aae6","value":"0.548","numericValue":0.548,"year":2024,"indicator":{"id":"65c55cf29e947c438698aa4d","name":"Anticipation Potential","title":null,"slug":"anticipation-potential","dataSetId":"ANTICIPATION_POTENTIAL","color":null}},{"id":"68eddbeeaf9e6d6d63270e4e","value":"0.450","numericValue":0.45,"year":2025,"indicator":{"id":"65c55cf29e947c438698aa4d","name":"Anticipation Potential","title":null,"slug":"anticipation-potential","dataSetId":"ANTICIPATION_POTENTIAL","color":null}}],"embeds":{"citations":[{"slug":"2025-02-2-3-19","url":"https://doi.org/10.1126/science.abk0297.","name":"Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice","authors":[{"name":"V. 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