It has been suggested that a-synuclein (aSyn), a major player in Parkinson's disease (PD), plays a role in Alzheimer's disease (AD). Several reports have also concluded that aSyn and amyloid-beta (Ab) are mechanistically linked, although how is unclear. Synapse loss is an early feature in both PD and AD and held to be the driver of both diseases. We have previously uncovered a signalling pathway required for Ab-driven dendritic spine loss - a non-canonical branch of Wnt signalling known as the Wnt/Planar Cell Polarity (Wnt/PCP) pathway. We asked if a synaptotoxic form of aSyn known to impact dendritic spines, the A53T autosomal dominant PD mutant form of aSyn (A53T-aSyn), might act on synapses through the same pathway. Here, by blocking all Wnt activity with the porcupine inhibitor IWP2, we show that A53T-aSyn driven spine loss is Wnt-dependent. By silencing Daam1, which is unique to Wnt/PCP, we show that A53T-aSyn spine loss is Daam1-dependent. Finally, using the pan-ROCK inhibitor fasudil indicates the mechanism also involves ROCK1/2, which Daam1 signals to via RhoA to modulate actin cytoskeletal dynamics within dendritic spines. Together, these observations indicate that A53T-aSyn-driven spine loss involves the Wnt/PCP pathway, the same pathway that mediates Ab synaptotoxicity. This indicates that Ab and aSyn are mechanistically connected and that a common pathway is responsible for synapse loss in AD and PD. It also begins to explain why this group of neurodegenerative diseases have many features in common and suggests that drugs which target Wnt/PCP could be of benefit for both AD and PD. ### Competing Interest Statement The authors have declared no competing interest.

Neutrophil extracellular traps (NETs) are large structures composed of chromatin, histones and granule-derived proteins released extracellularly by neutrophils. They are generally considered to be a part of the antimicrobial defense strategy, preventing the dissemination of pathogens. However, overproduction of NETs or their ineffective clearance can drive various pathologies, many of which are associated with advanced age and involve uncontrolled inflammation, oxidative, cardiovascular and neurodegenerative stress as underlying mechanisms. Targeting NETs in the elderly as an anti-aging therapy seems to be a very attractive therapeutic approach. Therapeutic apheresis with a specific filter to remove NETs could be a promising strategy worth considering.

BACKGROUND:Dementia poses a significant global health challenge. Anthocyanins neutralize free radicals, modulate signaling pathways, inhibit pro-inflammatory genes, and suppress cytokine production and may thus have positive cognitive effects in people at increased risk of dementia. We aim to investigate the effects of purified anthocyanins on cognitive function in people at increased risk of dementia according to their inflammation status based on blood-based inflammatory biomarkers. METHODS:This is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial. Cluster analysis was performed to categorize two groups based on their individual inflammatory biomarker profile using multiplex sandwich ELISA for the quantitative measurement of cytokines. Descriptive statistics and longitudinal models assessed cognitive outcomes. The primary comparison was the group difference at week 24 based on a modified intention-to-treat analysis. RESULTS:Cluster analysis revealed two distinct inflammatory biomarker profiles. In Cluster 1 (high levels of inflammation biomarkers), anthocyanin treatment showed a statistically significant improvement on cognitive function compared to placebo at 24 weeks. No significant differences were observed in Cluster 2 (low levels of inflammation biomarkers). The demographic characteristics, cognitive scores, and biomarker distributions were similar between treatment groups at baseline. However, cluster 1 exhibited higher BMI, diabetes prevalence, medication usage, and lower HDL cholesterol levels. CONCLUSION:Individuals with elevated levels of inflammation markers benefited from anthocyanin treatment to enhance cognitive performance, whereas those with lower levels did not. The anti-inflammatory and antioxidant properties of anthocyanins make them a promising intervention, and future prospective trials in people with increased inflammation are warranted.

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.

Recent evidence highlights the importance of trace metal micronutrients such as zinc (Zn) in coronary and vascular diseases. Zn2+ plays a signalling role in modulating endothelial nitric oxide synthase and protects the endothelium against oxidative stress by up-regulation of glutathione synthesis. Excessive accumulation of Zn2+ in endothelial cells leads to apoptotic cell death resulting from dysregulation of glutathione and mitochondrial ATP synthesis, whereas zinc deficiency induces an inflammatory phenotype, associated with increased monocyte adhesion. Nuclear factor-E2-related factor 2 (NRF2) is a transcription factor known to target hundreds of different genes. Activation of NRF2 affects redox metabolism, autophagy, cell proliferation, remodelling of the extracellular matrix and wound healing. As a redox-inert metal ion, Zn has emerged as a biomarker in diagnosis and as a therapeutic approach for oxidative-related diseases due to its close link to NRF2 signalling. In non-vascular cell types, Zn has been shown to modify conformations of the NRF2 negative regulators Kelch-like ECH-associated Protein 1 (KEAP1) and glycogen synthase kinase 3β (GSK3β) and to promote degradation of BACH1, a transcriptional suppressor of select NRF2 genes. Zn can affect phosphorylation signalling, including mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinases and protein kinase C, which facilitate NRF2 phosphorylation and nuclear translocation. Notably, several NRF2-targeted proteins have been suggested to modify cellular Zn concentration via Zn exporters (ZnTs) and importers (ZIPs) and the Zn buffering protein metallothionein. This review summarises the cross-talk between reactive oxygen species, Zn and NRF2 in antioxidant responses of vascular cells against oxidative stress and hypoxia/reoxygenation.

Citation: Woods T, Palmarini N, Corner L and Siow R (2024) Quantum healthy longevity from cells to cities. Front. Aging 5:1416447. doi: 10.3389/fragi.2024.1416447

DailyColors™ is a supplement made up of several phytonutrients that aims to replicate elements from the Mediterranean diet. These include fruit, berry and vegetable extracts that are rich in key phytochemicals such as Quercetin, Catechins, Phloretin, Ellagic Acid, and Anthocyanins. Here, we determined the effects of DailyColors™ on the blood biomarkers associated with the diverse mechanisms implicated in ageing and age-related diseases, including mitochondrial function, inflammation, and oxidative stress, as well as on saliva’s DNA methylation pattern. Thirty adult participants (mean (SD) age = 67.0 (7.5) years) with a body mass index over 25 were recruited into this randomised, double-blind, placebo-controlled, cross-over trial (two one-week treatment periods, separated by a one-week washout period). During the placebo period, we observed a significant increase in blood CD38 concentrations from the baseline to 24 h (p-value = 0.019). This was not observed in the active period. Increased CD38 is reportedly associated with subsequent mitochondrial dysfunction and inflammation. Next, there was a decreasing trend of plasma 4-HNE levels, an oxidative stress biomarker, after a one-week intake of DailyColors™. Furthermore, following a one-month open-label follow-up in 26 participants, we observed hypermethylation of the candidate CpG site cg13108341 (q-value = 0.021), which was against the observed trend for this site during ageing. Taken together, while minimal effects were observed in this study, DailyColors™ supplementation may be beneficial by altering and alleviating age-related changes. Longer and larger scale trials of DailyColors™ supplementation are warranted.

In recent years, there has been a paradigm shift with regards to ageing, challenging its traditional perception as an inevitable and natural process. Researchers have collectively identified hallmarks of ageing, nine of which were initially proposed in 2013 and expanded in 2023 to include disabled macroautophagy, chronic inflammation, and dysbiosis, enhancing our understanding of the ageing process at microscopic, cellular, and system-wide levels. Strategies to manipulate these hallmarks present opportunities for slowing, preventing, or reversing age-related diseases, thereby promoting longevity. The interdependence of these hallmarks underscores the necessity of a comprehensive, systems-based approach to address the complex processes contributing to ageing. As a primary risk factor for various diseases, ageing diminishes healthspan, leading to extended periods of compromised health and multiple age-related conditions towards the end of life. The significant gap between healthspan and lifespan holds substantial economic and societal implications. The inaugural Longevity Med Summit (4–5 May 2023, Cascais, Portugal) provided an international forum to discuss the academic and industry landscape of healthy longevity research, preventive medicine and clinical practice to enhance healthspan.

We are witnessing an unprecedented escalation of the incidence and prevalence of diabetes worldwide. According to the International Diabetes Federation, in 2021, 537 million people were affected by diabetes, and projections estimate that the number will rise to 783 million by 2045, with 3 in 4 adults living in low- and middle-income countries [ [1] Sun H. Saeedi P. Karuranga S. Pinkepank M. Ogurtsova K. Duncan B.B. et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022; 183109119 Abstract Full Text Full Text PDF Scopus (1919) Google Scholar ]. Changing this trajectory represents a priority, considering that diabetes accelerates ageing and is one of the leading causes of cardiovascular (CV) and renal disease, cognitive decline, multimorbidity, frailty, and shortened life expectancy, and it imposes a huge economic burden on health care systems [ [2] Tomic D. Shaw J.E. Magliano D.J. The burden and risks of emerging complications of diabetes mellitus. Nat Rev Endocrinol. 2022; 18: 525-539 Crossref PubMed Scopus (111) Google Scholar ]. Despite advances in therapies, people with diabetes have their life expectancy decreased by up to 10 years [ [3] Wright A.K. Kontopantelis E. Emsley R. Buchan I. Sattar N. Rutter M.K. et al. Life Expectancy and Cause-Specific Mortality in Type 2 Diabetes: A Population-Based Cohort Study Quantifying Relationships in Ethnic Subgroups. Diabetes Care. 2017; 40: 338-345 Crossref PubMed Scopus (103) Google Scholar ].

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Zinc is an important component of cellular antioxidant defenses and dysregulation of zinc homeostasis is a risk factor for coronary heart disease and ischemia/reperfusion injury. Intracellular homeostasis of metals, such as zinc, iron and calcium are interrelated with cellular responses to oxidative stress. Most cells experience significantly lower oxygen levels in vivo (2-10 kPa O-2) compared to standard in vitro cell culture (18kPa O-2). We report the first evidence that total intracellular zinc content decreases significantly in human coronary artery endothelial cells (HCAEC), but not in human coronary artery smooth muscle cells (HCASMC), after lowering of O-2 levels from hyperoxia (18 kPa O-2) to physiological normoxia (5 kPa O-2) and hypoxia (1 kPa O-2). This was paralleled by O-2-dependent differences in redox phenotype based on measurements of glutathione, ATP and NRF2-targeted protein expression in HCAEC and HCASMC. NRF2-induced NQO1 expression was attenuated in both HCAEC and HCASMC under 5 kPa O-2 compared to 18 kPa O-2. Expression of the zinc efflux transporter ZnT1 increased in HCAEC under 5 kPa O-2, whilst expression of the zinc-binding protein metallothionine (MT) decreased as O-2 levels were lowered from 18 to 1 kPa O-2. Negligible changes in ZnT1 and MT expression were observed in HCASMC. Silencing NRF2 transcription reduced total intracellular zinc under 18 kPa O-2 in HCAEC with negligible changes in HCASMC, whilst NRF2 activation or overexpression increased zinc content in HCAEC, but not HCASMC, under 5 kPa O-2. This study has identified cell type specific changes in the redox phenotype and metal profile in human coronary artery cells under physiological O(2 )levels. Our findings provide novel insights into the effect of NRF2 signaling on Zn content and may inform targeted therapies for cardiovascular diseases.

Introduction: Aortic pulse wave velocity (Ao-PWV) predicts cardiovascular and kidney disease in type 2 diabetes (T2D). Klotho is a circulating antiaging hormone (sKlotho) with putative cardiorenal protective effects. The relationship between sKlotho and Ao-PWV in diabetic kidney disease (DKD) is unknown. Methods: In a cross-sectional cohort study, the correlation of sKlotho measured by a validated immunoassay, and Ao-PWV measured by applanation tonometry, was investigated in 172 participants with T2D and early stage DKD (all had estimated glomerular filtration rate [eGFR] >45 ml/min) on stable renin angiotensin system (RAS) inhibition. In cultured human aortic smooth muscle cells (HASMCs) stimulated with angiotensin II (AngII), the effects of recombinant human sKlotho pretreatment were assessed on intracellular calcium ([Ca2+]i) responses and expression of proteins associated with proosteogenic HASMC phenotypes. Results: Mean (range) age of the cohort was 61.3 years (40-82) and 65% were male. Mean (& PLUSMN;SD) Ao-PWV was 11.4 (& PLUSMN;2.3) m/s, eGFR 78.8 (& PLUSMN;23.5) and median (interquartile range) sKlotho of 358.5 (194.2-706.3) pg/ ml. In multivariable linear regression analyses, we observed a statistically significant inverse relationship between sKlotho and Ao-PWV, which was independent of clinical risk factors for cardiorenal disease. Pretreatment of cultured HASMC with sKlotho significantly attenuated AngII-stimulated [Ca2+]i transients and reduced osteogenic collagen (Col1a2) expression. Conclusions: In individuals with T2D and early DKD, lower levels of sKlotho are associated with increased Ao-PWV. Taken together with the direct effect of sKlotho on mediators of aortic wall stiffness in vitro, these findings may explain the enhanced risk of cardiorenal disease in DKD.

Zinc (Zn) has antioxidant, anti-inflammatory and anti-proliferative actions, with Zn dysregulation associated with coronary ischemia/reperfusion injury and smooth muscle cell dysfunction. As the majority of studies concerning Zn have been conducted under non-physiological hyperoxic conditions, we compare the effects of Zn chelation or supplementation on total intracellular Zn content, antioxidant NRF2 targeted gene transcription and hypoxia/reoxygenation-induced reactive oxygen species generation in human coronary artery smooth muscle cells (HCASMC) pre-adapted to hyperoxia (18 kPa O2) or normoxia (5 kPa O2). Expression of the smooth muscle marker SM22-α was unaffected by lowering pericellular O2, whereas calponin-1 was significantly upregulated in cells under 5 kPa O2, indicating a more physiological contractile phenotype under 5 kPa O2. Inductively coupled plasma mass spectrometry established that Zn supplementation (10 μM ZnCl2 + 0.5 μM pyrithione) significantly increased total Zn content in HCASMC under 18 but not 5 kPa O2. Zn supplementation increased metallothionein mRNA expression and NRF2 nuclear accumulation in cells under 18 or 5 kPa O2. Notably, NRF2 regulated HO-1 and NQO1 mRNA expression in response to Zn supplementation was only upregulated in cells under 18 but not 5 kPa. Furthermore, whilst hypoxia increased intracellular glutathione (GSH) in cells pre-adapted to 18 but not 5 kPa O2, reoxygenation had negligible effects on GSH or total Zn content. Reoxygenation-induced superoxide generation in cells under 18 kPa O2 was abrogated by PEG-superoxide dismutase but not by PEG-catalase, and Zn supplementation, but not Zn chelation, attenuated reoxygenation-induced superoxide generation in cells under 18 but not 5kPaO2, consistent with a lower redox stress under physiological normoxia. Our findings highlight that culture of HCASMC under physiological normoxia recapitulates an in vivo contractile phenotype and that effects of Zn on NRF2 signaling are altered by oxygen tension.

Global healthcare systems need to evolve to ensure optimal, safe, and ethical utilisation of health data and the latest digital technologies, such as Artificial Intelligence (AI), Privacy Enhancing Technologies (PETs), and Distributed Ledger Technologies (DLTs), to meet the challenges of a global ageing population. Simultaneously, the increasing capabilities of remote measurement technologies and the proliferation of 5G networks demonstrates that digital technologies are now more accessible to a much larger population, offering an opportunity for decentralised democratised health data use that supports individual agency. Given the significant international human and economic cost of cognitive decline and dementia, we propose that a person-centred decentralised health data ecosystem, underpinned by these emerging technologies and opportunities, would reduce burden on cognitive healthcare systems by intervening earlier, accelerate clinical research innovation in dementia, and extend cognitive healthspan. Crucially, we argue for the importance of including the individual, as well as other key stakeholders, in the development, continuing operation, and as a shared beneficiary of any potential accrued value emerging from this ecosystem.

Use of autologous cells isolated from elderly patients with multiple comorbidities may account for the modest efficacy of cell therapy in patients with chronic limb threatening ischemia (CLTI). We aimed to determine whether proarteriogenic monocyte/macrophages (Mo/MΦs) from patients with CLTI were functionally impaired and to demonstrate the mechanisms related to any impairment. Proarteriogenic Mo/MΦs isolated from patients with CLTI were found to have an impaired capacity to promote neovascularization in vitro and in vivo compared with those isolated from healthy controls. This was associated with increased expression of human HIV-1 TAT interactive protein-2 (HTATIP2), a transcription factor known to suppress angiogenesis/arteriogenesis. Silencing HTATIP2 restored the functional capacity of CLTI Mo/MΦs, which was associated with increased expression of arteriogenic regulators Neuropilin-1 and Angiopoietin-1, and their ability to enhance angiogenic (endothelial tubule formation) and arteriogenic (smooth muscle proliferation) processes in vitro. In support of the translational relevance of our findings, silencing HTATIP2 in proarteriogenic Mo/MΦs isolated from patients with CLTI rescued their capacity to enhance limb perfusion in the ischemic hindlimb by effecting greater angiogenesis and arteriogenesis. Ex vivo modulation of HTATIP2 may offer a strategy for rescuing the functional impairment of pro–angio/arteriogenic Mo/MΦs prior to autologous delivery and increase the likelihood of clinical efficacy.

High population density and tourism in Southeast Asia increase the risk of mpox due to frequent interpersonal contacts. Our wastewater surveillance in six Southeast Asian countries revealed positive signals for Monkeypox virus (MPXV) DNA, indicating local transmission. This alerts clinicians and helps allocate resources like testing, vaccines and therapeutics in resource-limited countries.

It is widely thought that lifespans are increasing globally. However, life expectancy has begun to stagnate in the UK, and is falling in more than 50 countries including the USA. Lifespan stagnation or decrease is a consequence of socioeconomic inequalities, lifestyle factors, and the COVID-19 pandemic. In the UK, the National Health Service spends vast sums treating chronic diseases; by some estimates, 40% of its costs go to treating preventable conditions. UK citizens spend a fifth of their lives in poor health, and there is a 20-year difference in healthy life expectancy between the richest and the poorest, a difference that is widening, not narrowing. Together with unprecedented economic uncertainty, geopolitical strife, and post-pandemic recovery challenges, this burden of ill health is having a substantial impact on economic productivity and resilience. Health-care systems based only on response to illness are no longer affordable, and economies need a more productive workforce. The current model, which focuses on reactive sick-care alone, must be shifted to a new one based on proactive prevention, with the ever-growing recognition that the wealth of nations is not possible without the health of populations. In response to this reality, leaders are coming together for a Quantum Healthy Longevity Innovation Mission that aims to structurally leverage the value of existing assets, reduce duplication and waste in funding allocation, and prioritise effective coordination of key organisations1Cox LS Faragher RGA Linking interdisciplinary and multiscale approaches to improve healthspan—a new UK model for collaborative research networks in ageing biology and clinical translation.Lancet Healthy Longev. 2022; 3: e318-e320Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar and resources worldwide (including longevity education and research). We need to radically reimagine short-term, medium-term, and long-term responses at a global, societal, and individual level and significantly invest in an interdependent ecosystem for science and innovation to accelerate healthy longevity at quantum scale and pace. As we are seeing with research on the biology of ageing (geroscience2Ferrucci L Geroscience brings new focus on the life-course approach to health in humans.Innov Aging. 2020; 4: 803Crossref Google Scholar), age-related chronic diseases are not inevitable or untreatable; there are common pathways, defined by the hallmarks of ageing,3López-Otín C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging.Cell. 2013; 153: 1194-1217Summary Full Text Full Text PDF PubMed Scopus (7480) Google Scholar including cell senescence and systemic chronic inflammation, that lead to multiple morbidities. These pathways can now be manipulated with drugs and other interventions4Le Couteur DG Barzilai N New horizons in life extension, healthspan extension and exceptional longevity.Age Ageing. 2022; 51afac156Crossref Scopus (0) Google Scholar early in the disease process, with promising data emerging from early human clinical trials.5Partridge L Fuentealba M Kennedy BK The quest to slow ageing through drug discovery.Nat Rev Drug Discov. 2020; 19: 513-532Crossref PubMed Scopus (134) Google Scholar We need to take a multipronged whole-of-life approach to tackle all the different, but interacting, drivers of health and disease. These include lifestyle factors, such as diet and physical activity; socioeconomic determinants, such as discrimination, early and lifelong education, training and skills, financial status, and social support; and, increasingly, the characteristics of physical environments, such as green spaces and air quality, which need more attention.6Wang C Sierra Huertas D Rowe JW et al.Rethinking the urban physical environment for century-long lives: from age-friendly to longevity-ready cities.Nat Aging. 2021; 1: 1088-1095Crossref PubMed Scopus (4) Google Scholar Particularly, continuous interactions with and cumulative exposures to the surrounding physical and social environments throughout life have crucial roles in later-life outcomes. The Quantum Healthy Longevity blueprint aims to harness such opportunities, address urgent needs, and fulfil aspirations of the UK Innovation Strategy to tackle big, real-world problems in climate and health, by harnessing developments that we are seeing in longevity science and data innovation to maximise access to healthier, longer lives for everyone. Insights from genetics, biological, behavioural, social, environmental, and financial data are underutilised, and there are substantial opportunities to use artificial intelligence (AI) and multimodal learning to predict disease and incentivise healthier living through harnessing such life data. At the heart of improved health and wellbeing is a deep, integrated understanding of people's needs and wants that contribute to maintaining health across the full life course. This notion embraces the emerging research in computational approaches to the psychology of ageing7Mitina M Young S Zhavoronkov A Psychological aging, depression, and well-being.Aging. 2020; 12: 18765-18777Crossref PubMed Scopus (10) Google Scholar that links with biological and biomedical ageing as well as the behavioural aspects for ageing well, including nurturing brain health and investing in brain capital.8Eyre H Faulkenberg M Das S et al.Brain capital: an emerging investment opportunity.Psychiatric Times. 2022; https://www.psychiatrictimes.com/view/brain-capital-an-emerging-investment-opportunityDate accessed: October 22, 2022Google Scholar The core principles underpinning the Quantum Healthy Longevity Innovation Mission draw from a more comprehensive understanding of the environmental factors and their correlations influencing the ability of humans not only to survive, but to thrive in their real world (panel).PanelThe Quantum Healthy Longevity blueprintTakes an exposome approachThe exposome is a concept explaining the complex exposures humans face that can lead to systemic chronic inflammation9Furman D Campisi J Verdin E et al.Chronic inflammation in the etiology of disease across the life span.Nat Med. 2019; 25: 1822-1832Crossref PubMed Scopus (1072) Google Scholar and cumulatively affect lifelong health.10Wild CP Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology.Cancer Epidemiol Biomarkers Prev. 2005; 14: 1847-1850Crossref PubMed Scopus (1192) Google Scholar It includes the food we ingest, the air we breathe, the objects we touch, the psychological stresses we face, and the activities in which we engage.Leverages technologiesTo release breakthrough innovation using quantum computing, robotics, artificial intelligence, synthetic biology, and blockchain and other key emerging technologies.Mobilises brain capitalAn investment category placing a premium on approaches to protect brain health across the lifecourse, encompassing technology and health-care innovations that nurture brain health and skills such as resilience and self-esteem.Focuses on intergenerational engagementTo mobilise people of all ages across the lifecourse, ensuring that there is effective dialogue and meaningful involvement of citizens of all ages, in all communities.Optimises digital engagementEngagement through skills development, citizen-driven co-design, and equitable access to new tools and enabling technologies such as 5G.Is rooted in democratisation of accessAccess to the benefits of a longevity dividend to all people, taking equality, diversity, and inclusion into daily life as a prerequisite.Ensures that compassion is the running threadMaking looking after one another, especially in times of need, a core societal value. Takes an exposome approach The exposome is a concept explaining the complex exposures humans face that can lead to systemic chronic inflammation9Furman D Campisi J Verdin E et al.Chronic inflammation in the etiology of disease across the life span.Nat Med. 2019; 25: 1822-1832Crossref PubMed Scopus (1072) Google Scholar and cumulatively affect lifelong health.10Wild CP Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology.Cancer Epidemiol Biomarkers Prev. 2005; 14: 1847-1850Crossref PubMed Scopus (1192) Google Scholar It includes the food we ingest, the air we breathe, the objects we touch, the psychological stresses we face, and the activities in which we engage. Leverages technologies To release breakthrough innovation using quantum computing, robotics, artificial intelligence, synthetic biology, and blockchain and other key emerging technologies. Mobilises brain capital An investment category placing a premium on approaches to protect brain health across the lifecourse, encompassing technology and health-care innovations that nurture brain health and skills such as resilience and self-esteem. Focuses on intergenerational engagement To mobilise people of all ages across the lifecourse, ensuring that there is effective dialogue and meaningful involvement of citizens of all ages, in all communities. Optimises digital engagement Engagement through skills development, citizen-driven co-design, and equitable access to new tools and enabling technologies such as 5G. Is rooted in democratisation of access Access to the benefits of a longevity dividend to all people, taking equality, diversity, and inclusion into daily life as a prerequisite. Ensures that compassion is the running thread Making looking after one another, especially in times of need, a core societal value. The Mission will harness unfolding opportunities of agile regulatory reform planned by the UK government. It adopts the concept of Trusted Research Environments (TREs) in a federated network through a concierge model in which accredited organisations and networks check in to an AI-enabled Ageing Intelligence platform (National Innovation Centre for Ageing; Newcastle upon Tyne, UK), adhering to agreed standards in ethics, data operability, and governance. The AI platform will evolve into a world-first testbed taking science and innovation out of the laboratory and directly into peoples' homes, with healthy longevity-as-a-service products and services designed and developed for unmet needs that make a real and measurable difference to people's lives and to planetary health too. The Mission also aims to join often disparate and siloed policies and initiatives at the city level that impact infrastructure, including housing and urban planning that, if sensibly connected and coordinated, could much more effectively transform places and have a greater sustainable and tangible impact for people and the planet. The Mission sets out the concept of Longevity Cities that incorporate initiatives such as the Internet of Caring Things, in which connected objects and cognitive systems are designed or repurposed to actively care for people and enhance their biological, physical, mental, and emotional wellbeing, by understanding and measuring what they really value, what they care about, and what matters to them that can generate positive outcomes on their overall health. This intelligence from connected systems can help deliver sustainable environments that make it easy for people to identify, learn, and repeat healthier behaviours and habits to follow healthier lifestyles well before old age, enabled by connected infrastructure, services, and policies that also influence the social determinants responsible for 80% of our health. The platform will be underpinned by the Open Life Data Framework, which is geared to create the enabling conditions for public and private sectors to share data for the public benefit while ensuring public trust (thereby avoiding the backlash that Google's Sidewalk Labs faced when public outcry over privacy concerns halted the project). The framework's rationale was first set out in The Lancet Healthy Longevity,11Green D O'Shaughnessy J Starks G et al.Open Life Data to support healthy longevity for all.Lancet Healthy Longev. 2021; 2: e238-e239Summary Full Text Full Text PDF PubMed Google Scholar taking learnings from the open banking system, which created an open standard to facilitate data sharing and portability between banks and which fuelled the development of a financial technology ecosystem that benefitted consumers. Taking everything together, the Healthy Longevity Innovation Mission could achieve the ultimate prize in longevity research to create a bank of biomarker data and an atlas of geroprotective interventions based on larger and more diverse datasets than hitherto possible. The Mission would act as a TRE for life data accessible to trusted researchers and innovators in academic, non-profit, and commercial environments. It could link to other global initiatives such as Our Future Health, an ambitious research programme recruiting 5 million healthy volunteers to submit blood samples for physiological biomarker data collection at scale. This federated network of TREs enabled by AI could drive a world test bed for healthy longevity in which the community is motivated to evolve methods for new and improved biomarkers correlated with underlying measures of health span. The desired outcomes of the Healthy Longevity Innovation Mission to increase healthy life expectancy and economic resilience are enshrined in the Business Framework for Health, a methodology and core metrics (leading ultimately to an index) being developed by Business for Health with the Confederation of British Industry to measure the positive and negative health impacts of employers, businesses, and investors in three key areas: workforce health, consumer health, and community health. The index will learn from climate change approaches guiding investment to achieve carbon reduction and net zero targets, by adding Health as a core principle into Environmental, Social, and Governance (ESG) criteria to ensure greater investment in health, turning ESG into ESHG. An ESHG framework focused on equitable health outcomes as part of the Healthy Longevity Innovation Mission will help the business and investor community drive positive change through long-term strategic programmes that reduce the risk factors that can damage healthy longevity, incentivised and measured by their impact on positive health and wellbeing outcomes. It is now time to be bold and accelerate the urgent system changes needed to achieve healthy people, planet, and growth. TW reports grants from the Health Foundation supporting research framework for Business for Health (a community interest company or social venture) and for Open Life Data Framework; reports consulting fees from her work as CEO of Collider Health (projects listed on the website), including projects with National Innovation Centre for Ageing and (unpaid) secretariat services to All-Party Parliamentary Group for Longevity; sits on the British Standards Institute standards group for AI in health and care and Ada Lovelace Advisory Board on Health Inequalities; and is a trustee for the British Society for Research on Ageing. LC and NP report Internet of Caring Things, a 5-year programme jointly funded by North of Tyne Combined Authority and Newcastle University and led by the UK National Innovation Centre for Ageing. NB reports grants from the National Institutes of Health (P01AG021654), Nathan Shock Center of Excellence for the basic Biology of Aging (P30AG038072), and Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging; and executive roles with Longevity Biotech Association and Health Longevity Medical Society. JB reports that he is a member of the House of Lords. LSC reports funding from Biotechnology and Biological Sciences Research Council (BB/W01825X/1) and Medical Research Council; BIRAX and Diabetes UK; Public Health England (now UK Health Security Agency); Mellon Longevity Science Programme; UK SPINE (Research England), University of Oxford Medical Sciences Division and Wellcome Trust COVID Bridge Fund; John Fell Fund, University of Oxford; and Elysium Health. LSC also reports her role as co-director of UK Ageing networks and BLAST ageing network (UKRI funded) and voluntary roles with All Party Parliamentary Group for Longevity (UK); European Geriatric Medicine Society special interest group in Ageing Biology; Clinical and Translational Theme panel, Biochemical Society (UK); and Medical Research Council Ageing Research Steering Group. DF reports grants from the Global Center for Reproductive Longevity and Equality (NIH/NCI UG3CA268105-02, NIH/NIA P01AI153559-02, NIH/NIA P01AG066591-02, NIH/NIA U54AG075932-02, NIH/NIA R01 AG 082474-01, and NASA/UW Pro2379); Department for Defense on Strategies to Augment Ketosis for Enhanced Readiness and Disease Reversal; and consulting fees from Human Operations, Edifice Health, Cosmica, and Longevity Fund. HE reports consulting fees from Meadows Mental Health Policy Institute, The Baker Institute for Public Policy at Rice University, Kooth, The Guide App, and PRODEO; honoraria from Global Brain Health Institute (University of California San Francisco and Trinity College Dublin); and support to attend meetings from the Euro-Mediterranean Economists Association. AR is the CEO of Our Future Health that receives grants from Innovate UK and Alnylam, Amgen, AstraZeneca, Boehringer Ingelheim, Exact Sciences, GSK, Illumina, Janssen Research & Development, MSD, Novo Nordisk, Pfizer, Randox Laboratories, Regeneron Genetics Center, Roche, Thermo Fisher Scientific; is a non-executive board member of SNOMED; and is a shareholder in GSK. AS reports that he is co-organiser of The Longevity Forum and receives funding from the Economic and Social Research Council (grant T002204). RS reports consulting fees from Muhdo Health, Domo Health, and Charoen Pokphand Group. All other authors declare no competing interests. A list of references for further reading is available in the appendix. Download .pdf (.12 MB) Help with pdf files Supplementary appendix

Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic-pituitary-adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.