Differences across the lifespan between females and males in the top 20 causes of disease burden globally: a systematic analysis of the Global Burden of Disease Study 2021.

BACKGROUND: Sex and gender shape health. There is a growing body of evidence focused on comprehensively and systematically examining the magnitude, persistence, and nature of differences in health between females and males. Here, we aimed to quantify differences in the leading causes of disease burden between females and males across ages and geographies. METHODS: We used the Global Burden of Disease Study 2021 to compare disability-adjusted life-year (DALY) rates for females and males for the 20 leading causes of disease burden for individuals older than 10 years at the global level and across seven world regions, between 1990 and 2021. We present absolute and relative differences in the cause-specific DALY rates between females and males. FINDINGS: Globally, females had a higher burden of morbidity-driven conditions with the largest differences in DALYs for low back pain (with 478·5 [95% uncertainty interval 346·3-632·8] more DALYs per 100 000 individuals among females than males), depressive disorders (348·3 [241·3-471·0]), and headache disorders (332·9 [48·3-731·9]), whereas males had higher DALY rates for mortality-driven conditions with the largest differences in DALYs for COVID-19 (with 1767·8 [1581·1-1943·5] more DALYs per 100 000 among males than females), road injuries (1012·2 [934·1-1092·9]), and ischaemic heart disease (1611·8 [1405·0-1856·3]). The differences between sexes became larger over age and remained consistent over time for all conditions except HIV/AIDS. The largest difference in HIV/AIDS was observed among those aged 25-49 years in sub-Saharan Africa with 1724·8 (918·8-2613·7) more DALYs per 100 000 among females than males. INTERPRETATION: The notable health differences between females and males point to an urgent need for policies to be based on sex-specific and age-specific data. It is also important to continue promoting gender-sensitive research, and ultimately, implement interventions that not only reduce the burden of disease but also achieve greater health equity. FUNDING: Bill & Melinda Gates Foundation.

Puzzling parrotfishes: Radiocarbon age validation and updated longevity estimates for western Atlantic species in support of sustainable fisheries management.

For management efforts to succeed in Caribbean fisheries, local fishers must support and be willing to comply with fishing regulations. This is more likely when fishers are included in a stock assessment process that utilizes robust scientific evidence, collected in collaboration with fishers, to evaluate the health of fish stocks. Caribbean parrotfishes are important contributors to coral reef ecosystem health while also contributing to local fisheries. Scientifically robust stock assessments require regional species-specific information on age-based key life history parameters, derived from fish age estimates. Evaluation of the accuracy of age estimation methods for fish species is a critical initial step in managing species for long-term sustainable harvest. The current study resulted from a collaborative research program between fish biologists and local fishers investigating age, growth, and reproductive biology of the seven parrotfish species landed in U.S. Caribbean fisheries; specifically, we validated age estimation for stoplight parrotfish Sparisoma viride and queen parrotfish Scarus vetula. This is the first study to directly validate age estimation for any parrotfish species through analysis of Δ14C from eye lens cores. Our age estimation validation results show that enumeration of opaque zones from thin sections of sagittal otoliths for a Sparisoma and a Scarus species provides accurate age estimates. The oldest stoplight parrotfish and queen parrotfish in the Δ14C age estimation validation series were 14 y and 16 y; while the oldest stoplight parrotfish and queen parrotfish we aged to-date using the Δ14C validated age estimation method were 20 y and 21 y, respectively. Fish longevity (maximum age attained/life span) is a key life history parameter used for estimation of natural mortality, survivorship, and lifetime reproductive output. Past reviews on parrotfishes from the Pacific and Atlantic concluded that most Caribbean/western Atlantic parrotfish species are relatively short-lived with estimated maximum ages ranging from 3-9 y. However, information from our collaborative research in the U.S. Caribbean combined with recently published age estimates for Brazilian parrotfish species indicate that many western Atlantic parrotfishes are relatively long-lived with several species attaining maximum ages in excess of 20 y.

Reducing childhood mortality extends mothers' lives.

During the twentieth century, childhood mortality was dramatically reduced globally, falling by more than 90% in the United States and much of Europe. Total fertility also fell, with the combined result that many parents who otherwise would have experienced the loss of a child were spared the trauma and negative health consequences that accompany such a loss. Here I use mathematical modeling to argue that the reduction in the frequency of child death that occurred in the twentieth century indirectly led to a substantial reduction in female mortality, resulting in an extension of female lifespan. I estimate that the reduction in maternal bereavement in the US during the twentieth century indirectly increased mean female lifespan after age 15 by approximately 1 year. I discuss implications for our understanding of the persistence of the sex gap in longevity and approaches to improving maternal health outcomes in countries that still face high levels of childhood mortality.

The evidence to date: implications of l-ascorbic acid in the pathophysiology of aging.

L-Ascorbic acid, commonly known as vitamin C, has been used not only for disease prevention and in complementary and alternative medicine, but also for anti-aging purposes. However, the scientific evidence is not yet sufficient. Here, we review the physiological functions of vitamin C and its relationship with various pathological conditions, including our previous findings, and discuss the prospects of its application in healthy longevity. In summary, vitamin C levels are associated with lifespan in several animal models. Furthermore, clinical studies have shown that the blood vitamin C levels are lower in middle-aged and older adults than in younger adults. Lower blood vitamin C levels have also been observed in various pathological conditions such as chronic kidney disease and chronic obstructive pulmonary disease in the elderly. These observations suggest the implications of vitamin C in age-related pathological mechanisms owing to its physiological functions.

Lactobacillus paracasei subsp. paracasei 2004 improves health and lifespan in Caenorhabditis elegans.

Recent research has highlighted the importance of the gut microbiome in regulating aging, and probiotics are interventions that can promote gut health. In this study, we surveyed several novel lactic acid bacteria to examine their beneficial effect on organismal health and lifespan in C. elegans. We found that animals fed some lactic acid bacteria, including L. acidophilus 1244 and L. paracasei subsp. paracasei 2004, grew healthy. Supplementation with the lactic acid bacterial strains L. acidophilus 1244 or L. paracasei subsp. paracasei 2004 significantly improved health, including food consumption, motility, and resistance to oxidative stressor, hydrogen peroxide. Our RNA-seq analysis showed that supplementation with L. paracasei subsp. paracasei 2004 significantly increased the expression of daf-16, a C. elegans FoxO homolog, as well as genes related to the stress response. Furthermore, daf-16 deletion inhibited the longevity effect of L. paracasei subsp. paracasei 2004 supplementation. Our results suggest that L. paracasei subsp. paracasei 2004 improves health and lifespan in a DAF-16-dependent manner.

Naturally occurring viruses of Drosophila reduce offspring number and lifespan.

Drosophila remains a pre-eminent insect model system for host-virus interaction, but the host range and fitness consequences of the drosophilid virome are poorly understood. Metagenomic studies have reported approximately 200 viruses associated with Drosophilidae, but few isolates are available to characterize the Drosophila immune response, and most characterization has relied on injection and systemic infection. Here, we use a more natural infection route to characterize the fitness effects of infection and to study a wider range of viruses. We exposed laboratory Drosophila melanogaster to 23 naturally occurring viruses from wild-collected drosophilids. We recorded transmission rates along with two components of female fitness: survival and the lifetime number of adult offspring produced. Nine different viruses transmitted during contact with laboratory D. melanogaster, although for the majority, rates of transmission were less than 20%. Five virus infections led to a significant decrease in lifespan (D. melanogaster Nora virus, D. immigrans Nora virus, Muthill virus, galbut virus and Prestney Burn virus), and three led to a reduction in the total number of offspring. Our findings demonstrate the utility of the Drosophila model for community-level studies of host-virus interactions, and suggest that viral infection could be a substantial fitness burden on wild flies.

Timing of TORC1 inhibition dictates Pol III involvement in Caenorhabditis elegans longevity.

Organismal growth and lifespan are inextricably linked. Target of Rapamycin (TOR) signalling regulates protein production for growth and development, but if reduced, extends lifespan across species. Reduction in the enzyme RNA polymerase III, which transcribes tRNAs and 5S rRNA, also extends longevity. Here, we identify a temporal genetic relationship between TOR and Pol III in Caenorhabditis elegans, showing that they collaborate to regulate progeny production and lifespan. Interestingly, the lifespan interaction between Pol III and TOR is only revealed when TOR signaling is reduced, specifically in adulthood, demonstrating the importance of timing to control TOR regulated developmental versus adult programs. In addition, we show that Pol III acts in C. elegans muscle to promote both longevity and healthspan and that reducing Pol III even in late adulthood is sufficient to extend lifespan. This demonstrates the importance of Pol III for lifespan and age-related health in adult C. elegans.

Validity of claims-based definition of number of remaining teeth in Japan: Results from the Longevity Improvement and Fair Evidence Study.

BACKGROUND: Secondary healthcare data use has been increasing in the dental research field. The validity of the number of remaining teeth assessed from Japanese dental claims data has been reported in several studies, but has not been tested in the general population in Japan. OBJECTIVES: To evaluate the validity of the number of remaining teeth assessed from Japanese dental claims data and assess its predictability against subsequent health deterioration. METHODS: We used the claims data of residents of a municipality that implemented oral health screening programs. Using the number of teeth in the screening records as the reference standard, we assessed the validity of the claims-based number of teeth by calculating the mean differences. In addition, we assessed the association between the claims-based number of teeth and pneumococcal disease (PD) or Alzheimer's disease (AD) in adults aged ≥65 years using Cox proportional hazards analyses. RESULTS: Of the 10,154 participants, the mean number of teeth assessed from the claims data was 20.9, that in the screening records was 20.5, and their mean difference was 0.5. During the 3-year follow-up, PD or AD onset was observed in 10.4% (3,212/30,838) and 5.3% (1,589/30,207) of participants, respectively. Compared with participants with ≥20 teeth, those with 1-9 teeth had a 1.29 (95% confidence interval [CI]: 1.17-1.43) or 1.19 (95% CI: 1.04-1.36) times higher risk of developing PD or AD, respectively. CONCLUSION: High validity of the claims-based number of teeth was observed. In addition, the claims-based number of teeth was associated with the risk of PD and AD.

Energetic cost of biosynthesis is a missing link between growth and longevity in mammals.

The comparative studies of aging have established a negative correlation between Gompertz postnatal growth constant and maximum lifespan across mammalian species, but the underlying physiological mechanism remains unclear. This study shows that the Gompertz growth constant can be decomposed into two energetic components, mass-specific metabolic rate and the energetic cost of biosynthesis, and that after controlling the former as a confounder, the negative correlation between growth constant and lifespan still exists due to a 100-fold variation in the latter, revealing that the energetic cost of biosynthesis is a link between growth and longevity in mammals. Previously, the energetic cost of biosynthesis has been thought to be a constant across species and therefore was not considered a contributor to the variation in any life history traits, such as growth and lifespan. This study employs a recently proposed model based on energy conservation to explain the physiological effect of the variation in this energetic cost on the aging process and illustrates its role in linking growth and lifespan. The conventional life history theory suggested a tradeoff between growth and somatic maintenance, but the findings in this study suggest that allocating more energy to biosynthesis may enhance the somatic maintenance and extend lifespan and, hence, reveal a more complex nature of the tradeoff.

Association between plasma metal exposure and health span in very elderly adults: a prospective cohort study with mixture statistical approach.

BACKGROUND: Metals have been linked to a diverse spectrum of age-related diseases; however, the effects of metal exposure on health span remains largely unknown. This cohort study aims to determine the association between plasma metal and health span in elder adults aged ≥ 90 years. METHODS: The plasma concentrations of seven metals were measured at baseline in 300 elder adults. The end of the health span (EHS) was identified as the occurrence of one of eight major morbidities or mortality events. We used Cox regression to assess hazard ratios (HR). The combined effects of multiple metal mixtures were estimated using grouped-weighted quantile sum (GWQS), quantile g-computation (Q-gcomp), and Bayesian kernel machine regression (BKMR) methods. RESULTS: The estimated HR for EHS with an inter-quartile range (IQR) increment for selenium (Se) was 0.826 (95% confidence interval [CI]: 0.737-0.926); magnesium (Mg), 0.806 (95% CI: 0.691-0.941); iron (Fe), 0.756 (95% CI: 0.623-0.917), and copper (Cu), 0.856 (95% CI: 0.750-0.976). The P for trend of Se, Mg, and Fe were all < 0.05. In the mixture analyses, Q-gcomp showed a negative correlation with EHS (P = 0.904), with the sum of the negative coefficients being -0.211. CONCLUSION: Higher plasma Se, Mg, and Fe reduced the risk of premature end of health span, suggesting that essential metal elements played a role in health maintenance in elder adults.

[Exploring a definition of healthy longevity in Chinese population based on Delphi method].

Objective: To explore a definition of healthy longevity in the Chinese population based on the Delphi method. Methods: Through a comprehensive literature review and expert consultation, the dimensions in the definition of healthy longevity were identified, and a preliminary list of questions was created. Experts in clinical medicine, public health, basic research, and the elderly care service industry, who had been working in the field of geriatric health for at least 5 years, were invited to participate in the Delphi survey from August to December 2022. The survey questionnaires were administered via email in two rounds, and experts were asked to select the optimal options from the provided questions. The active coefficients were expressed by the response rate, and a consensus was reached when the largest number of experts agreed for single-choice questions and more than 70% agreed for multiple-choice questions. Results: In the two rounds, the active coefficients were 96.00% (24/25) and 79.17% (19/24), respectively, and a consensus was finally reached on nine items, including age, physical health, common metabolic indicators, mental health, cognitive function, functional ability, social activity, self-rated health, and subjective well-being. Following discussions among the research team and experts, a final definition of healthy longevity was determined. Healthy longevity could refer to a state of good physical, psychological, cognitive function and social adaptation, as well as subjective well-being, in individuals aged 90 and above. Specifically, individuals with healthy longevity should be free from diseases associated with high disability rates and mortality, such as stroke, cancer, and Parkinson's disease. They should also maintain reasonable levels of common non-communicable disease indicators, such as blood pressure and blood glucose, and exhibit favorable mental health and cognitive function using validated measurement tools. In addition, individuals with healthy longevity should engage in social interactions with friends and relatives, care for family members, and go out to do things. Meanwhile, with the ability to complete the visual and hearing functions of daily life and communication, and the ability to complete basic activities such as walking, eating, bathing, toileting, dressing, continence of urination, and bowel movement independently, they could rate themselves to be in good health and experience a relatively high level of life satisfaction. Conclusion: A definition of healthy longevity in the Chinese population is established through the two-round Delphi consultation.

Alpha-ketoglutarate supplementation in long-lived Drosophila melanogaster: Impact on lifespan and metabolic responses.

Studies on antiaging remedies in insect models sometimes show discrepancies in results. These discrepancies could be explained by different responses of short- and long-lived strains on the antiaging remedies. The purpose of the study was to test whether life-prolonging effects of alpha-ketoglutarate (AKG), observed in nematodes and fruit flies, would be reproduced in long-lived Drosophila melanogaster flies. Lifespan was assayed in flies kept in demographic cages. Fecundity, proportion of flies capable of negative geotaxis, starvation resistance, time of heat coma onset, levels of triacyglycerols, body glucose, glycogen, activities of glutamate dehydrogenase, catalase, glutathione-S-transferase, hexokinase, phosphofructokinase, pyruvate kinase, lactate, and glutamate dehydrogenases were assessed. Dietary AKG did not affect fly lifespan on the diet with 5% yeast and 5% sucrose (5Y:5S) and on the diet with 9% yeast and 1% sucrose (9Y:1S), but increased lifespan on the low-protein diet (1Y:9S). Twenty-five-day-old female flies fed a 5Y:5S diet with 10 mM AKG for 3 weeks, did not differ from the control group (without AKG) in climbing activity, resistance to heat stress, and starvation. The levels of glucose and glycogen were unaffected but the levels of triacylglycerols were lower in AKG-fed female flies. No differences in activities of glycolytic enzymes, NADPH-producing enzymes, glutamate dehydrogenase, oxygen consumption, and levels of oxidative stress markers were observed between the control and AKG-fed flies. However, AKG-fed flies had lower activities of catalase and glutathione-S-transferase. These results suggest that potential antiaging remedies, such as AKG, may not extend lifespan in long-living organisms despite influencing several metabolic parameters.

Targeting Aging and Longevity with Exogenous Nucleotides (TALENTs): Rationale, Design, and Baseline Characteristics from a Randomized Controlled Trial in Older Adults.

Nucleotides (NTs), important biomolecules involved in numerous cellular processes, have been proposed as potential candidates for anti-aging interventions. However, whether nucleotides can act as an anti-aging supplement in older adults remains unclear. TALENTs is a randomized, double-blinded, placebo-controlled trial that evaluates the efficacy and safety of NTs as an anti-aging supplement in older adults by exploring the effects of NTs on multiple dimensions of aging in a rigorous scientific setting. Eligible community-dwelling adults aged 60-70 years were randomly assigned equally to two groups: nucleotides intervention group and placebo control group. Comprehensive geriatric health assessments were performed at baseline, 2-months, and 4-months of the intervention. Biological specimens were collected and stored for age-related biomarker testing and multi-omics sequencing. The primary outcome was the change from baseline to 4 months on leukocyte telomere length and DNA methylation age. The secondary aims were the changes in possible mechanisms underlying aging processes (immunity, inflammatory profile, oxidative stress, gene stability, endocrine, metabolism, and cardiovascular function). Other outcomes were changes in physical function, body composition and geriatric health assessment (including sleep quality, cognitive function, fatigue, frailty, and psychology). In the RCT, 301 participants were assessed for eligibility and 122 were enrolled. Participants averaged 65.65 years of age, and were predominately female (67.21%). All baseline characteristics were well-balanced between groups, as expected due to randomization. The majority of participants were pre-frailty and had at least one chronic condition. The mean scores for physical activity, psychological, fatigue and quality of life were within the normal range. However, nearly half of the participants still had room for improvement in cognitive level and sleep quality. This TALENTs trial will represent one of the most comprehensive experimental clinical trials in which supplements are administered to elderly participants. The findings of this study will contribute to our understanding of the anti-aging effects of NTs and provide insights into their potential applications in geriatric healthcare.

Synthetic soldiers: Turning T cells into immortal warriors.

The creation of synthetic T cell states has captivated the field of cell-based therapies. Wang et al. (https://doi.org/10.1084/jem.20232368) describe how disruption of BCOR and ZC3H12A unleashes anti-tumor T cells with unprecedented lifespan and killer instinct. Are we witnessing the birth of immortal super-soldiers in medicine?

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.