Effects of C02 driven ocean acidification on ontogenetic stages of the cutllefisii SEPIA OFFICINALIS

Occan acidification due to anthropogenic emissions of CO, is the rew kid on the block of climate change research and has received considerable attention as changes in seawater acidity and carbonate chemistry caa severely affect marine organisms from the species to the ecosystem level. The degree of sensitivity within a species can vary greatly aloeg ontogeny. olVr leading to highest sensitivities .n early life stages Recent ssadies using the cuttlefish Septa officinalis, demonstrated that it's oviparous developmental mode can constitute an additional dulSenge for early life stages as increases in environmental pCO, add on top lo the already high COj concentration irtiide the egg The nucnxnvironment inside the egg is characterized by low pH. hypoxia, hypercapnia and high ammonia concentrations as a result of the animal's metabolism and the limited diffusion permeability of the egg capsule. This oviparous developmental mode ia combination with tower pH regulatory capacities are probably the major reasons why S officinalis embryo∗ respond more sensitively towards seanater acidification compared to adalts Although stronger hypercapnia levels (>0.3 kPa; < pH 75) could demonstrate potentially negative effects on the development, metabolism and calcification, acidification levels as predicted for the coming century will probably not severely affect S. officinalis. This relative tolerance may be a consequence of a lifestyle in benthac coastal habitats, pre- Adapiiag S. officinalis to natural fluctuations in environmental. Effects of C02 driven ocean acidification on ontogenetic stages of the cutllefisii SEPIA OFFICINALIS (PDF Download Available). Available from: https://www.researchgate.net/publication/304749386_Effects_of_C02_driven_ocean_acidification_on_ontogenetic_stages_of_the_cutllefisii_SEPIA_OFFICINALIS [accessed Jan 10 2018]

Mechanistic studies on the physiology of CO2 tolerance in cephalopods

Beschreibung (original): Elevated environmental CO2 concentrations (hypercapnia) are a stressor that has lately received considerable attention: anthropogenic CO2 emissions are predicted to lead to a rise in surface ocean pCO2 from 0.04 kPa up to 0.08 - 0.14 kPa within this century. The increased hydration of CO2 changes seawater chemistry, causing a drop in ocean pH. This phenomenon has been termed “ocean acidification” (OA). Changes in aquatic CO2 partial pressure affect the physiology of all water breathing animals as the CO2 concentration in body fluids will increase as well in order to maintain a substantial outward directed diffusion gradient for CO2. Among the aquatic taxa some have been identified as rather sensitive species (e.g. less active calcifying species such as corals or echinoderms) whereas others (many active species such as adult fish and cephalopods) can tolerate high CO2 concentrations over long exposure times. It was shown that more tolerant organisms share the ability to compensate for a hypercapnia induced acidosis by actively accumulating bicarbonate and eliminating protons from their body fluids. This process requires the presence of an acid-base regulating machinery consisting of a variety of ion transporters and channels. Using in situ hybridization and immuno histochemical methods, the present work demonstrates that Na+/K+-ATPase (NKA), a V-type-H+-ATPase (V-HA), and Na+/HCO3- cotransporter (NBC) are co-localized in NKA-rich cells in the gills of cephalopods. Furthermore, mRNA expression patterns of these transporters and selected metabolic genes were examined in response to moderately elevated seawater pCO2 (0.16 and 0.35 kPa) over a time-course of six weeks in different ontogenetic stages. Our findings support the hypothesis that the energy budget of adult cephalopods is not significantly compromised during long-term exposure to moderate environmental hypercapnia. However, the down regulation of ion-regulatory and metabolic genes in late stage embryos, taken together with a significant reduction in somatic growth, indicates that in contrast to adult cephalopods early life stages are challenged more severely by elevated seawater pCO2. This increased sensitivity of cephalopod early life stages could be due to two primary reasons. The first is related to gill development: similar to the situation in fish and decapod crustaceans, the cephalopod gill is the most important site for ion-regulatory processes. During larval development, rudimentary gill structures occur at stage 20, and differentiate over the course of embryonic development as well as after hatching. This differentiation indicates that gas exchange and ion regulatory capacity might be fully activated only after leaving the protective egg capsule. This could partially explain the higher susceptibility of embryonic stages to environmental hypercapnia. The second reason for a higher sensitivity is due to the oviparous type of development in cephalopods. Cephalopod embryos are exposed to very low egg fluid pO2 values (0.3 kPa) under control conditions during the final phase of embryonic development. This is due to increasing metabolic rates and the egg casing acting as a diffusion barrier for dissolved gases. The present work demonstrates that environmental pCO2 is additive to the natural accumulation of CO2 in the perivitelline fluid (PVF). This almost linear increase of PVF pCO2 is necessary in order to conserve the CO2 diffusion gradient across the egg capsule that drives excretion of metabolic CO2 to the seawater. Thus, alterations in environmental pCO2 create a greater challenge to the developing embryo in comparison to juveniles or adults. Despite the lack of adult-like high capacity ion regulatory epithelia (e.g. gills or kidneys) the present work demonstrates for the first time that cephalopod embryonic stages exhibit convergent acid-base regulatory features compared to teleosts. Epidermal ionocytes scattered on skin and yolk sac appear to be responsible for ionic and acid-base regulation before gill epithelia become functionable. Acid-base regulatory capacities are important for fish and cephalopod embryos, due to the beforehand mentioned, challenging abiotic conditions inside the protecting egg capsule. These epidermal ionocytes were characterized via immunohistochemistry, in situ hybridization and vital dye staining techniques. Similar to findings obtained in teleosts NHE3-rich cells take up sodium in exchange for protons, illustrating the energetic advantage of NHE based proton excretion in marine organisms. Using in vivo electrophysiological techniques, it was proven that acid equivalents are secreted by the yolk and skin integument. The findings of the present work add significant knowledge to our mechanistic understanding of hypercapnia tolerance in marine organisms, as it demonstrates that cephalopods which were identified as powerful acid-base regulators in the context of ocean acidification already need to exhibit strong acid-base regulatory abilities during all phases of their life cycle. The convergence of key acid-base regulatory proteins in cephalopods and fish suggest that in a variety of marine ectothermic animals extracellular pH regulation mechanisms may follow common evolutionary principles

Mechanistische Untersuchungen zur Physiologie der CO2 Toleranz bei Cephalopoden

Elevated environmental CO2 concentrations (hypercapnia) are a stressor that has lately received considerable attention: anthropogenic CO2 emissions are predicted to lead to a rise in surface ocean pCO2 from 0.04 kPa up to 0.08 - 0.14 kPa within this century. The increased hydration of CO2 changes seawater chemistry, causing a drop in ocean pH. This phenomenon has been termed “ocean acidification” (OA). Changes in aquatic CO2 partial pressure affect the physiology of all water breathing animals as the CO2 concentration in body fluids will increase as well in order to maintain a substantial outward directed diffusion gradient for CO2. Among the aquatic taxa some have been identified as rather sensitive species (e.g. less active calcifying species such as corals or echinoderms) whereas others (many active species such as adult fish and cephalopods) can tolerate high CO2 concentrations over long exposure times. It was shown that more tolerant organisms share the ability to compensate for a hypercapnia induced acidosis by actively accumulating bicarbonate and eliminating protons from their body fluids. This process requires the presence of an acid-base regulating machinery consisting of a variety of ion transporters and channels. Using in situ hybridization and immuno histochemical methods, the present work demonstrates that Na+/K+-ATPase (NKA), a V-type-H+-ATPase (V-HA), and Na+/HCO3- cotransporter (NBC) are co-localized in NKA-rich cells in the gills of cephalopods. Furthermore, mRNA expression patterns of these transporters and selected metabolic genes were examined in response to moderately elevated seawater pCO2 (0.16 and 0.35 kPa) over a time-course of six weeks in different ontogenetic stages. Our findings support the hypothesis that the energy budget of adult cephalopods is not significantly compromised during long-term exposure to moderate environmental hypercapnia. However, the down regulation of ion-regulatory and metabolic genes in late stage embryos, taken together with a significant reduction in somatic growth, indicates that in contrast to adult cephalopods early life stages are challenged more severely by elevated seawater pCO2. This increased sensitivity of cephalopod early life stages could be due to two primary reasons. The first is related to gill development: similar to the situation in fish and decapod crustaceans, the cephalopod gill is the most important site for ion-regulatory processes. During larval development, rudimentary gill structures occur at stage 20, and differentiate over the course of embryonic development as well as after hatching. This differentiation indicates that gas exchange and ion regulatory capacity might be fully activated only after leaving the protective egg capsule. This could partially explain the higher susceptibility of embryonic stages to environmental hypercapnia. The second reason for a higher sensitivity is due to the oviparous type of development in cephalopods. Cephalopod embryos are exposed to very low egg fluid pO2 values (0.3 kPa) under control conditions during the final phase of embryonic development. This is due to increasing metabolic rates and the egg casing acting as a diffusion barrier for dissolved gases. The present work demonstrates that environmental pCO2 is additive to the natural accumulation of CO2 in the perivitelline fluid (PVF). This almost linear increase of PVF pCO2 is necessary in order to conserve the CO2 diffusion gradient across the egg capsule that drives excretion of metabolic CO2 to the seawater. Thus, alterations in environmental pCO2 create a greater challenge to the developing embryo in comparison to juveniles or adults. Despite the lack of adult-like high capacity ion regulatory epithelia (e.g. gills or kidneys) the present work demonstrates for the first time that cephalopod embryonic stages exhibit convergent acid-base regulatory features compared to teleosts. Epidermal ionocytes scattered on skin and yolk sac appear to be responsible for ionic and acid-base regulation before gill epithelia become functionable. Acid-base regulatory capacities are important for fish and cephalopod embryos, due to the beforehand mentioned, challenging abiotic conditions inside the protecting egg capsule. These epidermal ionocytes were characterized via immunohistochemistry, in situ hybridization and vital dye staining techniques. Similar to findings obtained in teleosts NHE3-rich cells take up sodium in exchange for protons, illustrating the energetic advantage of NHE based proton excretion in marine organisms. Using in vivo electrophysiological techniques, it was proven that acid equivalents are secreted by the yolk and skin integument. The findings of the present work add significant knowledge to our mechanistic understanding of hypercapnia tolerance in marine organisms, as it demonstrates that cephalopods which were identified as powerful acid-base regulators in the context of ocean acidification already need to exhibit strong acid-base regulatory abilities during all phases of their life cycle. The convergence of key acid-base regulatory proteins in cephalopods and fish suggest that in a variety of marine ectothermic animals extracellular pH regulation mechanisms may follow common evolutionary principles.Aufgrung der stetig steigenden CO2 Konzentrationen in der Atmosphäre hat Hyperkapnie als abiotischer Stressor in aquatischen Systemen in den letzten Jahren mehr und mehr an Aufmerksamkeit gewonnen. Modellberechnungen zufolge könnte, verursacht durch durch die anthropogenen CO2 Emmissionen, noch innerhalb dieses Jahrhunderts der pCO2 im Oberflächenwasser der Ozeane von derzeit 0.04 auf etwa 0.08 - 0.14 kPa ansteigen. Dies beeinflusst die Karbonatchemie des Meerwassers und hat zur Folge, dass der pH im Oberflächenwasser der Ozeane sinken wird. Dieses Phänomen wurde als Ozeanversauerung bezeichnet. Der Anstieg im CO2 Partialdruck beinflusst alle aquatischen Organismen, da der Anstieg des pCO2 im Wasser ebenfalls zu einer Erhöhung des Blut pCO2 führt. Die Aufrechterhaltung eines ausreichenden pCO2 Gradienten ist essentiell, um die diffundive Exkretion von CO2 vom Körper an das Wasser zu gewährleisten. Unter den marinen Organismen wurden einige taxonomischen Gruppen als besonders sensibel eingestuft (in der Regel weniger aktive, kalzifizierende Spezies wie z.B. Korallen und Echinodermaten), wohingegen aktive Taxa wie adulte Cephalopoden und Fische relativ tolerant erscheinen. Frühere Studien haben gezeigt, dass adulte Cephalopoden und Fische hohe CO2 Konzentrationen über lange Zeiträume tolerieren können, ohne ihr Wachstum oder Kalzifizierungsraten zu verringern. Es hat sich gezeigt, dass diese Toleranz mit der Fähigkeit zusammen hängt, eine Hyperkapnie-induzierte Azidose durch die aktive Akkumulation von Bikarbonat im und / oder durch die Sekretion von Protonen aus dem Blut zu kompensieren. Diese Fähigkeit ist abhängig von einem ionenregulatorischen Apparat, der aus einer Vielzahl von Säure-Base relevanten Transportproteinen besteht. Mit Hilfe von in situ Hybridisierung und immunohistologischen Methoden konnte diese Arbeit zeigen, dass wichtige Transportproteine wie z.B. Na+/K+-ATPase (NKA), H+-ATPase (V-HA), und Na+/HCO3- Kotransporter (NBC) in spezialisierten Epithelien in der Cephalopodenkieme kolokalisiert sind. Darüber hinaus wurden Expressionsmuster dieser Transporter und weiterer ausgewählter metabolischer Gene in Bezug auf erhöhte Seewasser pCO2 (0,16 und 0,35 kPa) über eine Dauer von sechs Wochen in unterschiedlichen ontogenetischen Stadien untersucht. Ausserdem wurde das Wachstum der verschiedenen Stadien bestimmt und O2- und pCO2-Konzentration in der Eihülle wurden gemessen. Die Ergebnisse unterstützen die Hypothese, dass Energiebudgets bei adulten Cephalopoden nicht signifikant durch chronisch erhöhten Seewasser pCO2 beeinflusst werden. Allerdings zeigte sich eine höhere Sensitivität bei frühen Entwicklungsstadien in Form einer verringerten Expression von ionenregulatorischen und metabolischen Genen begleitet durch eine signifikante Verzögerung in Wachstum und Entwicklung. Diese erhöhte Sensitivität bei frühen Entwicklungsstadien kann durch zwei Hauptgründe erklärt werden. Der Erste steht im Zusammenhang mit der Entwicklung ionenregulatorischer Epithelien. Ähnlich wie bei Fischen und Crustaceen ist auch bei Cephalopoden die Kieme eines der wichtigsten ionenregulatorischen Organe. Während der Larvalentwicklung entstehen rudimentäre Kiemenanlagen im 20. Entwicklungsstadium und differenzieren sich im Laufe der weiteren Ontogenese bis hin zum Schlüpfling. Diese späte Differenzierung legt nahe, dass die Fähigkeit zum Gasaustausch und die volle ionenregulatorische Kapazität erst nach dem Verlassen der schützenden Eikapsel erreicht werden. Das Fehlen ionenregulatorischer Strukturen wie man sie in adulten Tieren vorfindet, kann ein möglicher Grund für eine erhöhte Sensitivität bei frühen Entwicklungsstadien sein. Der Zweite Grund für eine höhere Empfindlichkeit bei Embyonalstadien kann durch die ovipare Entwicklung bei Cephalopoden erklärt werden. In der finalen Entwicklungsphase im Ei sind Cephalopodenembryos bereits unter Kontrollbedingungen sehr geringen O2 Konzentrationen (0,3 kPa) ausgesetzt. Dies liegt an den steigenden metabolischen Raten und der Eischale, die eine Diffusionsbarriere für gelöste Gase darstellt. Diese Arbeit zeigt ferner, dass Anstiege des pCO2 im Seewasser additiv zum bereits hohen pCO2 in der Perivittellinflüssigkeit (PVF) sind. Der fast lineare Anstieg des PVF pCO2 ist notwendig, um den Diffusionsgradienten von respiratorischem CO2 aus dem Ei aufrecht zu erhalten. Aufgrund dieser Erkenntnis kann geschlossen werden, dass Anstiege des Umgebungs-pCO2 einen größeren Stressor für Embryonalstadien (im Ei) darstellen als für Juvenile oder Adulte. Trotz fehlender adult-typischer ionenregulatorischer Organe (Kiemen, Nieren und Darm) bei frühen Entwicklungsstadien zeigt diese Arbeit zum ersten Mal, dass Cephalopodenembryos konvergente Säure-Base regulatorische Strukturen zu Fischen entwickelt haben. Ionocyten auf der Haut und dem Dottersack sind für den Säure-Base-relevanten Ionentransport verantwortlich bevor die Kiemenepithelien voll differenziert und funktional sind. Säure-Base Regulation ist bereits für die frühen Entwicklungsstadien aufgrund der zuvor genannten extremen hypercapnischen Bedingungen in der Eikapsel von großer Wichtigkeit. Epidermale Ionocyten wurden anhand von in situ Hybridisierung, immunohistochemischen und „vital dye“-Färbungen charakterisiert. Ähnlich wie bei Fischen scheinen Zellen, die reich an NHE3 sind, Natrium im Austausch gegen Protonen aufzunehmen. Der Einsatz von NHE-Proteinen kann als energetisch günstigere Variante der Protonenexkretion in marinen Organismen verstanden werden. Darüber hinaus zeigen in vivo elektrophysiologische Techniken, dass die Sekretion von Säureequivalenten tatsächlich über den Dottersack und die Haut stattfindet. Diese Arbeit trägt signifikant zu unserem mechanistischen Verständnis der Hyperkapnietoleranz bei marinen Organismen bei. Sie zeigt, dass Cephalopoden, die im Kontext der Ozeanversauerung als tolerant identifiziert wurden, Mechanismen besitzen, um aktiv ihren Säure-Base Haushalt zu regulieren. Ferner besitzen Cephalopoden in allen Phasen ihrer Ontogenie signifikante Säure-Base regulatorische Kapazitäten und spezialisierte Organe, die auf eine konvergente Evolution mit Teleosteern hindeuten

Acoustically evoked potentials in two cephalopods inferred using the auditory brainstem response (ABR) approach

It is still a matter of debate whether cephalopods can detect sound frequencies above 400 Hz. So far there is no proof for the detection of underwater sound above 400 Hz via a physiological approach. The controversy of whether cephalopods have a sound detection ability above 400 Hz was tested using the auditory brainstem response (ABR) approach, which has been successfully applied in fish, crustaceans, amphibians, reptiles and birds. Using ABR we found that auditory evoked potentials can be obtained in the frequency range 400 to 1500 Hz (Sepiotheutis lessoniana) and 400 to 1000 Hz (Octopus vulgaris), respectively. The thresholds of S. lessoniana were generally lower than those of O. vulgaris

Mussel larvae modify calcifying fluid carbonate chemistry to promote calcification

Understanding mollusk calcification sensitivity to ocean acidification (OA) requires a better knowledge of calcification mechanisms. Especially in rapidly calcifying larval stages, mechanisms of shell formation are largely unexplored—yet these are the most vulnerable life stages. Here we find rapid generation of crystalline shell material in mussel larvae. We find no evidence for intracellular CaCO3 formation, indicating that mineral formation could be constrained to the calcifying space beneath the shell. Using microelectrodes we show that larvae can increase pH and [CO32−] beneath the growing shell, leading to a ~1.5-fold elevation in calcium carbonate saturation state (Ωarag). Larvae exposed to OA exhibit a drop in pH, [CO32−] and Ωarag at the site of calcification, which correlates with decreased shell growth, and, eventually, shell dissolution. Our findings help explain why bivalve larvae can form shells under moderate acidification scenarios and provide a direct link between ocean carbonate chemistry and larval calcification rate

ElevatedpCO2drives lower growth and yet increased calcification in the early life history of the cuttlefish Sepia officinalis (Mollusca: Cephalopoda)

Ocean acidification is an escalating environmental issue and associated changes in the ocean carbonate system have implications for many calcifying organisms. The present study followed the growth of Sepia officinalis from early-stage embryos, through hatching, to 7-week-old juveniles. Responses of cuttlefish to elevated pCO(2) (hypercapnia) were investigated to test the impacts of near-future and extreme ocean acidification conditions on growth, developmental time, oxygen consumption, and yolk utilization as proxies for individual fitness. We further examined gross morphological characteristics of the internal calcareous cuttlebone to determine whether embryonically secreted shell lamellae are impacted by environmental hypercapnia. Embryonic growth was reduced and hatching delayed under elevated pCO(2), both at environmentally relevant levels (0.14 kPa pCO(2) similar to predicted ocean conditions in 2100) and extreme conditions (0.40 kPa pCO(2)). Comparing various metrics from control and intermediate treatments generally showed no significant difference in experimental measurements. Yet, results from the high pCO(2) treatment showed significant changes compared with controls and revealed a consistent general trend across the three treatment levels. The proportion of animal mass contributed by the cuttlebone increased in both elevated pCO(2) treatments. Gross cuttlebone morphology was affected under such conditions and cuttlebones of hypercapnic individuals were proportionally shorter. Embryonic shell morphology was maintained consistently in all treatments, despite compounding hypercapnia in the perivitelline fluid; however, post-hatching, hypercapnic animals developed denser cuttlebone laminae in shorter cuttlebones. Juvenile cuttlefish in acidified environments thus experience lower growth and yet increased calcification of their internal shell. The results of this study support recent findings that early cuttlefish life stages are more vulnerable towards hypercapnia than juveniles and adults, which may have negative repercussions on the biological fitness of cuttlefish hatchlings in future oceans

Evolution of extreme stomach pH in bilateria inferred from gastric alkalization mechanisms in basal deuterostomes

The stomachs of most vertebrates operate at an acidic pH of 2 generated by the gastric H+/K+-ATPase located in parietal cells. The acidic pH in stomachs of vertebrates is believed to aid digestion and to protect against environmental pathogens. Little attention has been placed on whether acidic gastric pH regulation is a vertebrate character or a deuterostome ancestral trait. Here, we report alkaline conditions up to pH 10.5 in the larval digestive systems of ambulacraria (echinoderm + hemichordate), the closest relative of the chordate. Microelectrode measurements in combination with specific inhibitors for acid-base transporters and ion pumps demonstrated that the gastric alkalization machinery in sea urchin larvae is mainly based on direct H+ secretion from the stomach lumen and involves a conserved set of ion pumps and transporters. Hemichordate larvae additionally utilized HCO 3- transport pathways to generate even more alkaline digestive conditions. Molecular analyses in combination with acidification experiments supported these findings and identified genes coding for ion pumps energizing gastric alkalization. Given that insect larval guts were also reported to be alkaline, our discovery raises the hypothesis that the bilaterian ancestor utilized alkaline digestive system while the vertebrate lineage has evolved a strategy to strongly acidify their stomachs

Acidified seawater impacts sea urchin larvae pH regulatory systems relevant for calcification

Calcifying echinoid larvae respond to changes in seawater carbonate chemistry with reduced growth and developmental delay. To date, no information exists on how ocean acidification acts on pH homeostasis in echinoderm larvae. Understanding acid–base regulatory capacities is important because intracellular formation and maintenance of the calcium carbonate skeleton is dependent on pH homeostasis. Using H+-selective microelectrodes and the pH-sensitive fluorescent dye BCECF, we conducted in vivo measurements of extracellular and intracellular pH (pHe and pHi) in echinoderm larvae. We exposed pluteus larvae to a range of seawater CO2 conditions and demonstrated that the extracellular compartment surrounding the calcifying primary mesenchyme cells (PMCs) conforms to the surrounding seawater with respect to pH during exposure to elevated seawater pCO2. Using FITC dextran conjugates, we demonstrate that sea urchin larvae have a leaky integument. PMCs and spicules are therefore directly exposed to strong changes in pHe whenever seawater pH changes. However, measurements of pHi demonstrated that PMCs are able to fully compensate an induced intracellular acidosis. This was highly dependent on Na+ and HCO3−, suggesting a bicarbonate buffer mechanism involving secondary active Na+-dependent membrane transport proteins. We suggest that, under ocean acidification, maintained pHi enables calcification to proceed despite decreased pHe. However, this probably causes enhanced costs. Increased costs for calcification or cellular homeostasis can be one of the main factors leading to modifications in energy partitioning, which then impacts growth and, ultimately, results in increased mortality of echinoid larvae during the pelagic life stage

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions