Host and environmental factors shape upper airway microbiota and respiratory health across the human lifespan.

Our understanding of the normal variation in the upper respiratory tract (URT) microbiota across the human lifespan and how these relate to host, environment, and health is limited. We studied the microbiota of 3,104 saliva (<10 year-olds)/oropharynx (≥10 year-olds) and 2,485 nasopharynx samples of 3,160 Dutch individuals 0-87 years of age, participating in a cross-sectional population-wide study (PIENTER-3) using 16S-rRNA sequencing. The microbiota composition was strongly related to age, especially in the nasopharynx, with maturation occurring throughout childhood and adolescence. Clear niche- and age-specific associations were found between the microbiota composition and host/environmental factors and health outcomes. Among others, social interaction, sex, and season were associated with the nasopharyngeal microbial community. By contrast, the oral microbiota was more related to antibiotics, tobacco, and alcohol use. We present an atlas of the URT microbiota across the lifespan in association with environment and health, establishing a baseline for future research.

Highly regenerative species-specific genes improve age-associated features in the adult Drosophila midgut.

BACKGROUND: The remarkable regenerative abilities observed in planarians and cnidarians are closely linked to the active proliferation of adult stem cells and the precise differentiation of their progeny, both of which typically deteriorate during aging in low regenerative animals. While regeneration-specific genes conserved in highly regenerative organisms may confer regenerative abilities and long-term maintenance of tissue homeostasis, it remains unclear whether introducing these regenerative genes into low regenerative animals can improve their regeneration and aging processes. RESULTS: Here, we ectopically express highly regenerative species-specific JmjC domain-encoding genes (HRJDs) in Drosophila, a widely used low regenerative model organism. Surprisingly, HRJD expression impedes tissue regeneration in the developing wing disc but extends organismal lifespan when expressed in the intestinal stem cell lineages of the adult midgut under non-regenerative conditions. Notably, HRJDs enhance the proliferative activity of intestinal stem cells while maintaining their differentiation fidelity, ameliorating age-related decline in gut barrier functions. CONCLUSIONS: These findings together suggest that the introduction of highly regenerative species-specific genes can improve stem cell functions and promote a healthy lifespan when expressed in aging animals.

Suicide-related internet use among mental health patients who died by suicide in the UK: a national clinical survey with case-control analysis.

Background: Suicide-related internet use (SRIU) has been shown to be linked to suicide. However, there is limited research on SRIU among mental health patients, who are at 4 to 7 times increased risk of suicide compared to the general population. This study aims to address this gap by exploring the prevalence of SRIU among mental health patients who died by suicide in the UK and describing their characteristics. Methods: The study was carried out as part of the National Confidential Inquiry into Suicide and Safety in Mental Health (NCISH). Data were collected on sociodemographic, clinical, suicide characteristics and engagement in SRIU of patients who died by suicide between 2011 and 2021. The study utilised a case-control design to compare patients who engaged in suicide-related internet use with those who did not. Findings: The presence or absence of SRIU was known for 9875/17,347 (57%) patients; SRIU was known to be present in 759/9875 (8%) patients. The internet was most often used to obtain information on suicide methods (n = 523/759, 69%) and to visit pro-suicide websites (n = 250/759, 33%) with a significant overlap between the two (n = 152/759, 20%). Engaging in SRIU was present across all age groups. The case-control element of the study showed patients who were known to have engaged in SRIU were more likely to have been diagnosed with autism spectrum disorder (OR = 2.13, 95% CI: 1.43-3.18), have a history of childhood abuse (OR = 1.70, 95% CI: 1.36-2.13) and to have received psychological treatment (OR = 1.43, 95% CI: 1.18-1.74) than controls. Additionally, these patients were more likely to have died on or near a salient date (OR = 2.11, 95% CI: 1.61-2.76), such as a birthday or anniversary. Interpretation: The findings affirm SRIU as a feature of suicide among patients of all ages and highlight that clinicians should inquire about SRIU during assessments. Importantly, as the most common type of SRIU can expand knowledge on suicide means, clinicians need to be aware of the association between SRIU and choice of methods. This may be particularly relevant for patients approaching a significant calendar event. Funding: The Healthcare Quality Improvement Partnership.

Longevity as a Responsibility: Constructing Healthy Aging by Enacting within Contexts over the Entire Lifespan.

Studying aging now requires going beyond the bio-psycho-social model and incorporating a broader multidisciplinary view capable of capturing the ultimate complexity of being human that is expressed as individuals age. Current demographic trends and the lengthening of life expectancies allow the observation of long-lived individuals in full health. These super-agers are no longer an exception. Indeed, individuals can have a good quality of life even over age 70 and living with chronic or neurodegenerative diseases. This change is driven in part by the cohort effect observed in people who are about to age today (e.g., better schooling, more advanced health conditions, and technologization) but more so by the gradual overcoming of ageist views. An aged person is no longer seen as a quitter but rather as one empowered to direct their own trajectory of potentially healthy longevity. According to this vision, this article proposes a situated lifespan perspective for the study of aging that integrates pedagogical models of developmental ecology with psychological theories of optimal experience to understand the individual motivational perspective on aging. At the same time, it does not disregard analyzing the daily and cultural contexts in which everyone situates and that guide aging trajectories. Nor does it forget that aging people are body-mind (embodied) organisms that, with contexts and through motivations, seize opportunities for action (affordances) to evolve in an optimal way during their lifespan. This theoretical reflection sheds new light on the aging process and on future trends in healthy longevity research.

An Introductory Guide to Using Bloomington Drosophila Stock Center and FlyBase for Aging Research.

Studies on numerous species have demonstrated strikingly conserved mechanisms that determine the aging process, from yeasts to worms, flies, zebrafish, mice, and humans. The fruit fly Drosophila melanogaster is an excellent model organism for studying the biological basis of normal aging and etiology of age-related diseases. Since its inception in 1967, the Bloomington Drosophila Stock Center (BDSC) has grown into the largest collection of documented D. melanogaster strains (currently > 91,000). This paper aims to briefly review conserved mechanisms of aging and provides a guide to help users understand the organization of stock listings on the BDSC website and familiarize themselves with the search functions on BDSC and FlyBase, with an emphasis on using genes in conserved pathways as examples to find stocks for aging studies.

The ZcVg3 Gene Regulates the Reproduction and Lifespan of Female Zeugodacus cucurbitae (Coquillett) Mediated by Short-Term High Temperatures.

Zeugodacus cucurbitae (Coquillett) is a significant pest affecting fruit and vegetables in tropical and subtropical regions, and its development and reproduction are enhanced after exposure to short-term high-temperature stress at 45 °C. Vitellogenin (Vg) is an essential precursor of yolk protein formation in eggs and plays a vital role in the ovarian development of insects. Interfering with the Z. cucurbitae vitellogenin receptor (ZcVgR) gene in short-term high-temperature conditions decreases the fecundity of female adults, while the transcription level of the ZcVg3 gene increases. To elucidate the reproductive function of the ZcVg3 gene and the synergistic relationship among the ZcVgs genes under short-term high temperatures, this study injected siRNA to interfere with the ZcVg3 gene after subjecting Z. cucurbitae to a 1 h treatment at 45 °C and 25 °C. The expression of the ZcVg3 gene was suppressed, leading to the upregulation of the ZcVg1 and ZcVg2 genes, and the expression of the ZcVgR gene was initially decreased and then increased. Silencing the ZcVg3 gene after a 1 h treatment at 45 °C resulted in a reduction of approximately 84.7% and 75.9% in the fecundity and spawning days of female adults compared to the control. The development rate of their ovaries and the ovarian diameter significantly decreased, and their lifespan was reduced by 71%. The ZcVg3 gene plays a crucial role in the reproduction of Z. cucurbitae in short-term high-temperature conditions. The results of this study provide potential targets for the development of RNAi-based techniques for the control of Z. cucurbitae.

Co-analysis of methylation platforms for signatures of biological aging in the domestic dog reveals previously unexplored confounding factors.

Chronological age reveals the number of years an individual has lived since birth. By contrast, biological age varies between individuals of the same chronological age at a rate reflective of physiological decline. Differing rates of physiological decline are related to longevity and result from genetics, environment, behavior, and disease. The creation of methylation biological age predictors is a long-standing challenge in aging research due to the lack of individual pre-mortem longevity data. The consistent differences in longevity between domestic dog breeds enable the construction of biological age estimators which can, in turn, be contrasted with methylation measurements to elucidate mechanisms of biological aging. We draw on three flagship methylation studies using distinct measurement platforms and tissues to assess the feasibility of creating biological age methylation clocks in the dog. We expand epigenetic clock building strategies to accommodate phylogenetic relationships between individuals, thus controlling for the use of breed standard metrics. We observe that biological age methylation clocks are affected by population stratification and require heavy parameterization to achieve effective predictions. Finally, we observe that methylation-related markers reflecting biological age signals are rare and do not colocalize between datasets.

Ranking Age-at-Death Distributions Using Dominance: Robust Evaluation of United States Mortality Trends, 2006-2021.

Diverging mortality trends at different ages motivate the monitoring of lifespan inequality alongside life expectancy. Conclusions are ambiguous when life expectancy and lifespan inequality move in the same direction or when inequality measures display inconsistent trends. We propose using nonparametric dominance analysis to obtain a robust ranking of age-at-death distributions. Application to U.S. period life tables for 2006-2021 reveals that, until 2014, more recent years generally dominate earlier years, implying improvement if longer lifespans that are less unequally distributed are considered better. Improvements were more pronounced for non-Hispanic Black and Hispanic individuals than for non-Hispanic White individuals. Since 2014, for all subpopulations-particularly Hispanics-earlier years often dominate more recent years, indicating worsening age-at-death distributions if shorter and more unequal lifespans are considered worse. Dramatic deterioration of the distributions in 2020-2021 during the COVID-19 pandemic is most evident for Hispanic individuals.

Trends in socioeconomic inequalities in life expectancy and lifespan variation in Chile.

Background: Socioeconomic disparities in life expectancy are well-documented in various contexts, including Chile. However, there is a lack of research examining trends in life expectancy inequalities and lifespan variation over time. Addressing these gaps can provide crucial insights into the dynamics of health inequalities. Methods: This study utilizes data from census records, population surveys, and death certificates to compare the life expectancy and the lifespan variation at age 26 of individuals according to their rank in the distribution of years of education within their own birth cohort. The analysis spans three periods (1991, 2002, and 2017) and focuses on two educational groups: individuals in the first (lowest) quintile and tenth (highest) decile of educational attainment. Changes in life expectancy are disaggregated by major causes of death to elucidate their contributions to overall trends. Results: Consistent with existing literature, our findings confirm that individuals with lower education levels experience lower life expectancy and higher lifespan variation compared to their more educated counterparts. Notably, by 2017, life expectancy for individuals in the lowest quintile of education has caught up with that of the top decile in 1991, albeit with contrasting trends between genders. Among women, the gap has reduced, while it has increased for males. Moreover, lifespan variation decreased (increased) over time for individuals in the tenth decile (first quintile). The leading causes of death that explain the increase in life expectancy in women and men in the tenth decile as well as women in the first quintile are cardiovascular, cancer, respiratory and digestive diseases. In the case of males in the first quintile, few gains have been made in life expectancy resulting from cancer and a negative contribution is associated with digestive conditions. Conclusions: This study underscores persistent socioeconomic disparities in life expectancy in Chile, emphasizing the importance of ongoing monitoring of health inequalities across different demographic segments. The gender-specific and educational gradient trends highlight areas for targeted interventions aimed at reducing health disparities and improving overall population health outcomes. Further research is warranted to delve into specific causes of death driving life expectancy differentials and to inform evidence-based policy interventions.

Luspatercept enhances hemoglobin levels in a Chinese boy with congenital sideroblastic anemia: A case report.

BACKGROUND: Congenital sideroblastic anemia (CSA) is a rare and heterogeneous group of genetic disorders. Conventional treatment include pyridoxine (vitamin B6) and allogeneic hematopoietic stem cell transplantation (allo-HSCT), and can alleviate anemia in the majority of cases. Nevertheless, some CSA cases remain unresponsive to pyridoxine or are unable to undergo allo-HSCT. Novel management approaches is necessary to be developed. To explore the response of luspatercept in treating congenital sideroblastic anemia. CASE SUMMARY: We share our experience in luspatercept in a 4-year-old male patient with CSA. Luspatercept was administered subcutaneously at doses of 1.0 mg/kg/dose to 1.25 mg/kg/dose every 3 wk, three consecutive doses, evaluating the hematological response. Luspatercept leading to a significant improvement in the patient's anemia. The median hemoglobin during the overall treatment with three doses of luspatercept was 90 (75-101) g/L, the median absolute reticulocyte count was 0.0593 (0.0277-0.1030) × 1012/L, the median serum ferritin was 304.3 (234.4-399) ng/mL, and the median lifespan of mature red blood cells was 80 (57-92) days. Notably, no adverse reactions, such as headaches, dizziness, vomiting, joint pain, or back pain, were observed during the treatment period. CONCLUSION: We believe that luspatercept might emerge as a viable therapeutic option for the maintenance treatment of CSA or as a bridging treatment option before hematopoietic stem cell transplantation.

Timut Pepper Extract Slows Age-Dependent Decline of Mobility and Collagen Loss and Promotes Longevity.

Investigations into human longevity are increasingly focusing on healthspan enhancement, not just lifespan extension. Lifestyle modifications and nutritional choices, including food supplements, can significantly affect aging and general health. Phytochemicals in centenarians' diets, such as those found in Timut pepper, a Nepalese spice with various medicinal properties, may contribute to their longevity. Similarly, Sichuan pepper, a related species, has demonstrated anti-inflammatory and neuroprotective activities. With the broader purpose of uncovering a novel treatment to address aging and its comorbidities, this study aims to investigate the potential lifespan- and healthspan-promoting effects of Timut pepper using the model organism Caenorhabditis elegans. We show that Timut pepper extract extends C. elegans' lifespan at different maintenance temperatures and increases the proportion of active nematodes in their early adulthood. In addition, we show that Timut pepper extract enhances speed and distance moved as the nematodes age. Finally, Timut pepper extract assures extracellular matrix homeostasis by slowing the age-dependent decline of collagen expression.

Comparing the lifespan of virgin artificial urinary sphincters in radiated patients: transcorporal vs. standard placement.

PURPOSE: To compare the lifespan of first transcorporal cuff (TC) placement of an artificial urinary sphincter (AUS) versus standard placement (SP) in patients with prior radiotherapy (RT) for prostate cancer (PCa). METHODS: We reviewed first (virgin) AUS placements from two high-volume care centers between 1/2011 and 1/2021, including PCa patients with RT history. AUS lifespan was assessed via the hazard ratio of device explantation and/or revision within a ten-year timeframe for the TC vs. SP approaches. Chi-square, Fisher's exact, and t-tests compared clinicodemographic variables. Kaplan-Meier curve compared TC and SP lifespan. RESULTS: 85/314 men with AUS met inclusion criteria, with 38.8% (33/85) in the TC group and 61.2% (52/85) in the SP group. Median ages were 69.8 (IQR = 65.2-73.6) and 67.1 (61.6-72.9), respectively, p = 0.17. Over a median follow up of 51.9 (15.8-86.1) and 80.4 (28.1-128.3) months for the TC and SP, overall, 12 (36.4%) TC devices were removed (four [12.1%] due to mechanical failures; eight [24.2%] erosions, and two [6.1%] infections) vs. 29 (55.8%) in the SP group (14 [26.9%] mechanical failures; 11 [21.1%] erosions, and five [9.6%] infections). No statistically significant differences were observed between the two approaches, with HR = 0.717, 95% CI 0.37-1.44, p = 0.35. The calculated device survival probabilities for the TC vs. SP at one, five, and 10 years were 78.8% vs. 76.9%, 69.3% vs. 58.7%, and 62.1% vs. 46.7%, respectively. CONCLUSIONS: TC cuff insertion for the first AUS implantation in pre-radiated patients showed to be comparable to SP when it comes to device survival, with comparable complication rates. Current guidance for approach selection is primarily based on patient selection and surgeon preference.

A mechanistic analysis of metformin's biphasic effects on lifespan and healthspan in C. elegans: Elixir in youth, poison in elder.

Aging, a complex biological process influenced by genetic, environmental, and pharmacological factors, presents a significant challenge in understanding its underlying mechanisms. In this study, we explored the divergent impacts of metformin treatment on the lifespan and healthspan of young and old C. elegans, demonstrating a intriguing "elixir in youth, poison in elder" phenomenon. By scrutinizing the gene expression changes in response to metformin in young (day 1 of adulthood) and old (days 8) groups, we identified nhr-57 and C46G7.1 as potential modulators of age-specific responses. Notably, nhr-57 and C46G7.1 exhibit contrasting regulation patterns, being up-regulated in young worms but down-regulated in old counterparts following metformin treatment. Functional studies employing knockdown approaches targeting nhr-57, a gene under the control of hif-1 with a documented protective function against pore-forming toxins in C. elegans, and C46G7.1, unveiled their critical roles in modulating lifespan and healthspan, as well as in mediating the biphasic effects of metformin. Furthermore, deletion of hif-1 retarded the influence of metformin, implicating the involvement of hif-1/nhr-57 in age-specific drug responses. These findings underscored the necessity of deciphering the mechanisms governing age-related susceptibility to pharmacological agents to tailor interventions for promoting successful aging.

Multi-generation effects of lead (Pb) on two Daphnia species.

Two monophyletic Daphnia species (Daphnia magna and D. similis) were exposed to a sub-lethal concentration of Pb (50 µg/L) for nine generations under two food regimes (usual and restricted) and analyzed for acetylcholinesterase (AChE) activity, first reproduction delay, lifespan, and net reproductive rate (R0) at the subcellular, individual, and population levels, respectively. In the sixth generation, Pb-acclimated neonates were moved to clean media for three more generations to check for recovery. The net reproductive rate (R0) of D. magna was not affected by Pb. However, Pb stimulated reproduction, reduced lifespan, and decreased AChE activity. First reproduction delay and lifespan did not improve during the recovery process, suggesting a possible genetic adaptation. Food restriction reduced R0, lifespan, delayed hatching, and increased AChE activity; the opposite outcomes were observed for D. similis. The full recovery shown by R0 suggests the physiological acclimation of D. similis. Under food restriction, the animals exhibited a reduction of R0 and lifespan, delayed first reproduction, and increased AChE activity; however, there was no effect of Pb. The recovery process under food restriction showed that D. similis might not cope with Pb exposure, indicating a failed recovery. Such outcomes indicate that one model species' sensitivity may not represent another's sensitivity.

Allostatic interoceptive overload across psychiatric and neurological conditions.

Emerging theories emphasize the crucial role of allostasis (anticipatory and adaptive regulation of the body's biological processes) and interoception (integration, anticipation, and regulation of internal bodily states) in adjusting physiological responses to environmental and bodily demands. This review explores the disruptions in integrated allostatic interoceptive mechanisms in psychiatric and neurological disorders, including anxiety, depression, Alzheimer's disease, and frontotemporal dementia. We assess the biological mechanisms associated with allostatic interoception, including whole-body cascades, brain structure and function of the allostatic interoceptive network, heart-brain interactions, respiratory-brain interactions, the gut-brain-microbiota axis, peripheral biological processes (inflammatory, immune), and epigenetic pathways. These processes span psychiatric and neurological conditions and call for developing dimensional and trans-nosological frameworks. We synthesize new pathways to understand how allostatic interoceptive processes modulate interactions between environmental demands and biological functions in brain disorders. We discuss current limitations of the framework and future transdisciplinary developments. This review opens a new research agenda for understanding how allostatic interoception involves brain predictive coding in psychiatry and neurology, allowing for better clinical application and the development of new therapeutic interventions.

Cross-sectional Average Length of Life Entropy ( H CAL ): International Comparisons and Decompositions.

Keyfitz and Leser's life table entropy was proposed to serve as a relative inequality in mortality measure. Entropy considers the variation around the age at death relative to the length of lifespan in a population, allowing comparisons across time and populations. It is used widely in period and cohort applications. Here, we propose extending this measure and present an index that incorporates the history of survival of all cohorts present at a given time, namely the cross-sectional average length of life entropy, or CAL-entropy ( H CAL ). We decompose cross-population differences of CAL-entropy into the contribution of longevity and lifespan variation, and the change of those differences across time. Our illustrations show that populations are converging regarding lifespan inequality. Lifespan variation holds a noticeable share in the CAL-entropy gap among selected European populations. Longevity held once a pronounced share in CAL-entropy differences and their change, but its influence has receded over the years. The US demonstrates a unique trend where it performs worse across time compared to the selected European populations, and lifespan variation has played a major role in this process. This study signals the importance of lifespan variation in reducing inequality in mortality among developed and longevous populations.

Age-Based Developmental Biomarkers in Eye Movements: A Retrospective Analysis Using Machine Learning.

This study aimed to identify when and how eye movements change across the human lifespan to benchmark developmental biomarkers. The sample size comprised 45,696 participants, ranging in age from 6 to 80 years old (M = 30.39; SD = 17.46). Participants completed six eye movement tests: Circular Smooth Pursuit, Horizontal Smooth Pursuit, Vertical Smooth Pursuit, Horizontal Saccades, Vertical Saccades, and Fixation Stability. These tests examined all four major eye movements (fixations, saccades, pursuits, and vergence) using 89 eye-tracking algorithms. A semi-supervised, self-training, machine learning classifier was used to group the data into age ranges. This classifier resulted in 12 age groups: 6-7, 8-11, 12-14, 15-25, 26-31, 32-38, 39-45, 46-53, 54-60, 61-68, 69-76, and 77-80 years. To provide a descriptive indication of the strength of the self-training classifier, a series of multiple analyses of variance (MANOVA) were conducted on the multivariate effect of the age groups by test set. Each MANOVA revealed a significant multivariate effect on age groups (p < 0.001). Developmental changes in eye movements across age categories were identified. Specifically, similarities were observed between very young and elderly individuals. Middle-aged individuals (30s) generally showed the best eye movement metrics. Clinicians and researchers may use the findings from this study to inform decision-making on patients' health and wellness and guide effective research methodologies.

The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity.

Dietary restriction (DR) protocols frequently employ intermittent fasting. Following a period of fasting, meal consumption increases lipogenic gene expression, including that of NADPH-generating enzymes that fuel lipogenesis in white adipose tissue (WAT) through the induction of transcriptional regulators SREBP-1c and CHREBP. SREBP-1c knockout mice, unlike controls, did not show an extended lifespan on the DR diet. WAT cytoplasmic NADPH is generated by both malic enzyme 1 (ME1) and the pentose phosphate pathway (PPP), while liver cytoplasmic NADPH is primarily synthesized by folate cycle enzymes provided one-carbon units through serine catabolism. During the daily fasting period of the DR diet, fatty acids are released from WAT and are transported to peripheral tissues, where they are used for beta-oxidation and for phospholipid and lipid droplet synthesis, where monounsaturated fatty acids (MUFAs) may activate Nrf1 and inhibit ferroptosis to promote longevity. Decreased WAT NADPH from PPP gene knockout stimulated the browning of WAT and protected from a high-fat diet, while high levels of NADPH-generating enzymes in WAT and macrophages are linked to obesity. But oscillations in WAT [NADPH]/[NADP+] from feeding and fasting cycles may play an important role in maintaining metabolic plasticity to drive longevity. Studies measuring the WAT malate/pyruvate as a proxy for the cytoplasmic [NADPH]/[NADP+], as well as studies using fluorescent biosensors expressed in the WAT of animal models to monitor the changes in cytoplasmic [NADPH]/[NADP+], are needed during ad libitum and DR diets to determine the changes that are associated with longevity.