Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice.

Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1's neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity.

Evolution of T cells in the cancer-resistant naked mole-rat.

Naked mole-rats (NMRs) are best known for their extreme longevity and cancer resistance, suggesting that their immune system might have evolved to facilitate these phenotypes. Natural killer (NK) and T cells have evolved to detect and destroy cells infected with pathogens and to provide an early response to malignancies. While it is known that NMRs lack NK cells, likely lost during evolution, little is known about their T-cell subsets in terms of the evolution of the genes that regulate their function, their clonotypic diversity, and the thymus where they mature. Here we find, using single-cell transcriptomics, that NMRs have a large circulating population of γδT cells, which in mice and humans mostly reside in peripheral tissues and induce anti-cancer cytotoxicity. Using single-cell-T-cell-receptor sequencing, we find that a cytotoxic γδT-cell subset of NMRs harbors a dominant clonotype, and that their conventional CD8 αßT cells exhibit modest clonotypic diversity. Consistently, perinatal NMR thymuses are considerably smaller than those of mice yet follow similar involution progression. Our findings suggest that NMRs have evolved under a relaxed intracellular pathogenic selective pressure that may have allowed cancer resistance and longevity to become stronger targets of selection to which the immune system has responded by utilizing γδT cells.

Association of 8-hydroxy-2'-deoxyguanosine with motoric cognitive risk in elderly Chinese people: RUGAO longevity and aging cross-sectional study.

BACKGROUND: Motor cognitive risk syndrome (MCR) represents a critical pre-dementia and disability state characterized by a combination of objectively measured slow walking speed and subjective memory complaints (SMCs). This study aims to identify risk factors for MCR and investigate the relationship between plasma levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and MCR among Chinese community-dwelling elderly populations. METHODS: A total of 1312 participants were involved in this study based on the data of the Rugao Longevity and Aging Study (RuLAS). The MCR was characterized by SMCs and slow walking speed. The SCCs were defined as a positive answer to the question 'Do you feel you have more problems with memory than most?' in a 15-item Geriatric Depression Scale. Slow walking speed was determined by one standard deviation or more below the mean value of the patient's age and gender group. The plasma of 8-OHdG were measured by a technician in the biochemistry laboratory of the Rugao People's Hospital during the morning of the survey. RESULTS: The prevalence of MCR was found to be 7.9%. After adjusting for covariates, significant associations with MCR were observed in older age (OR 1.057; p = 0.018), history of cerebrovascular disease (OR 2.155; p = 0.010), and elevated 8-OHdG levels (OR 1.007; p = 0.003). CONCLUSIONS: This study indicated the elevated plasma 8-OHdG is significantly associated with increased MCR risk in the elderly, suggesting its potential as a biomarker for early detection and intervention in MCR. This finding underscores the importance of monitoring oxidative DNA damage markers in predicting cognitive and motor function declines, offering new avenues for research and preventive strategies in aging populations.

Sensor-Based Quantitative Assessment of Children's Fine Motor Competence: An Instrumented Version of the Placing Bricks Test.

The assessment of fine motor competence plays a pivotal role in neuropsychological examinations for the identification of developmental deficits. Several tests have been proposed for the characterization of fine motor competence, with evaluation metrics primarily based on qualitative observation, limiting quantitative assessment to measures such as test durations. The Placing Bricks (PB) test evaluates fine motor competence across the lifespan, relying on the measurement of time to completion. The present study aims at instrumenting the PB test using wearable inertial sensors to complement PB standard assessment with reliable and objective process-oriented measures of performance. Fifty-four primary school children (27 6-year-olds and 27 7-year-olds) performed the PB according to standard protocol with their dominant and non-dominant hands, while wearing two tri-axial inertial sensors, one per wrist. An ad hoc algorithm based on the analysis of forearm angular velocity data was developed to automatically identify task events, and to quantify phases and their variability. The algorithm performance was tested against video recordings in data from five children. Cycle and Placing durations showed a strong agreement between IMU- and Video-derived measurements, with a mean difference <0.1 s, 95% confidence intervals <50% median phase duration, and very high positive correlation (ρ > 0.9). Analyzing the whole population, significant differences were found for age, as follows: six-year-olds exhibited longer cycle durations and higher variability, indicating a stage of development and potential differences in hand dominance; seven-year-olds demonstrated quicker and less variable performance, aligning with the expected maturation and the refined motor control associated with dominant hand training during the first year of school. The proposed sensor-based approach allowed the quantitative assessment of fine motor competence in children, providing a portable and rapid tool for monitoring developmental progress.

Senescence-associated ß-galactosidase staining over the lifespan differs in a short- and a long-lived fish species.

During the aging process, cells can enter cellular senescence, a state in which cells leave the cell cycle but remain viable. This mechanism is thought to protect tissues from propagation of damaged cells and the number of senescent cells has been shown to increase with age. The speed of aging determines the lifespan of a species and it varies significantly in different species. To assess the progress of cellular senescence during lifetime, we performed a comparative longitudinal study using histochemical detection of the senescence-associated beta-galactosidase as senescence marker to map the staining patterns in organs of the long-lived zebrafish and the short-lived turquoise killifish using light- and electron microscopy. We compared age stages corresponding to human stages of newborn, childhood, adolescence, adult and old age. We found tissue-specific but conserved signal patterns with respect to organ distribution. However, we found dramatic differences in the onset of tissue staining. The stained zebrafish organs show little to no signal at newborn age followed by a gradual increase in signal intensity, whereas the organs of the short-lived killifish show an early onset of staining already at newborn stage, which remains conspicuous at all age stages. The most prominent signal was found in liver, intestine, kidney and heart, with the latter showing the most prominent interspecies divergence in onset of staining and in staining intensity. In addition, we found staining predominantly in epithelial cells, some of which are post-mitotic, such as the intestinal epithelial lining. We hypothesize that the association of the strong and early-onset signal pattern in the short-lived killifish is consistent with a protective mechanism in a fast growing species. Furthermore, we believe that staining in post-mitotic cells may play a role in maintaining tissue integrity, suggesting different roles for cellular senescence during life.

Ergosterol promotes neurite outgrowth, inhibits amyloid-beta synthesis, and extends longevity: In vitro neuroblastoma and in vivo Caenorhabditis elegans evidence.

AIMS: Alzheimer's disease (AD), the most common neurodegenerative disorder associated with aging, is characterized by amyloid-ß (Aß) plaques in the hippocampus. Ergosterol, a mushroom sterol, exhibits neuroprotective activities; however, the underlying mechanisms of ergosterol in promoting neurite outgrowth and preventing Aß-associated aging have never been investigated. We aim to determine the beneficial activities of ergosterol in neuronal cells and Caenorhabditis elegans (C. elegans). MATERIALS AND METHODS: The neuritogenesis and molecular mechanisms of ergosterol were investigated in wild-type and Aß precursor protein (APP)-overexpressing Neuro2a cells. The anti-amyloidosis properties of ergosterol were determined by evaluating in vitro Aß production and the potential inhibition of Aß-producing enzymes. Additionally, AD-associated transgenic C. elegans was utilized to investigate the in vivo attenuating effects of ergosterol. KEY FINDINGS: Ergosterol promoted neurite outgrowth in Neuro2a cells through the upregulation of the transmembrane protein Teneurin-4 (Ten-4) mRNA and protein expressions, phosphorylation of the extracellular signal-regulated kinases (ERKs), activity of cAMP response element (CRE), and growth-associated protein-43 (GAP-43). Furthermore, ergosterol enhanced neurite outgrowth in transgenic Neuro2A cells overexpressing either the wild-type APP (Neuro2a-APPwt) or the Swedish mutant APP (Neuro2a-APPswe) through the Ten-4/ERK/CREB/GAP-43 signaling pathway. Interestingly, ergosterol inhibited Aß synthesis in Neuro2a-APPwt cells. In silico analysis indicated that ergosterol can interact with the catalytic sites of ß- and γ-secretases. In Aß-overexpressing C. elegans, ergosterol decreased Aß accumulation, increased chemotaxis behavior, and prolonged lifespan. SIGNIFICANCE: Ergosterol is a potential candidate compound that might benefit AD patients by promoting neurite outgrowth, inhibiting Aß synthesis, and enhancing longevity.

Investigation of stair ascending and descending activities on the lifespan of hip implants.

Total hip arthroplasty (THA) surgeries among young patients are on the increase, so it is crucial to predict the lifespan of hip implants correctly and produce solutions to improve longevity. Current implants are designed and tested against walking conditions to predict the wear rates. However, it would be reasonable to include the additional effects of other daily life activities on wear rates to predict convergent results to clinical outputs. In this study, 14 participants are recruited to perform stair ascending (AS), descending (DS), and walking activities to obtain kinematic and kinetic data for each cycle using marker based Qualisys motion capture (MOCAP) system. AnyBody Modeling System using the Calibrated Anatomical System Technique (CAST) full body marker set are performed Multibody simulations. The 3D generic musculoskeletal model used in this study is a marker-based full-body motion capture model (AMMR,2.3.1 MoCapModel) consisting of the upper extremity and the Twente Lower Extremity Model (TLEM2). The dynamic wear prediction model detailing the intermittent and overall wear rates for CoCr-on-XLPE bearing couple is developed to investigate the wear mechanism under 3D loading for AS, DS, and walking activities over 5 million cycles (Mc) by using finite element modelling technique. The volumetric wear rates of XLPE liner under AS, DS, and walking activities over 5-Mc are predicted as 27.43, 23.22, and 18.84 mm3/Mc respectively. Additionally, the wear rate was predicted by combining stair activities and gait cycles based on the walk-to-stair ratio. By adding the effect of stair activities, the volumetric wear rate of XLPE is predicted as 22.02 mm3/Mc which is equivalent to 19.41% of walking. In conclusion, in this study, the effect of including other daily life activities is demonstrated and evidence is provided by matching them to the clinical data as opposed to simulator test results of implants under ISO 14242 boundary conditions.

It is time to explore the impact of length of gestation and fetal health on the human lifespan.

A recently proposed principal law of lifespan (PLOSP) proposes to extend the whole human lifespan by elongating different life stages. As the preborn stage of a human being, gestation is the foundation for the healthy development of the human body. The antagonistic pleiotropy (AP) theory of aging states that there is a trade-off between early life fitness and late-life mortality. The question is whether slower development during the gestation period would be associated with a longer lifespan. Among all living creatures, the length of the gestation period is highly positively correlated to the length of the lifespan, although such a correlation is thought to be influenced by the body sizes of different species. While examining the relationship between lifespan length and body size within the same species, dogs exhibit a negative correlation between lifespans and body sizes, while there is no such correlation among domestic cats. For humans, most adverse gestational environments shorten the period of gestation, and their impacts are long-term. While many issues remain unsolved, various developmental features have been linked to the conditions during the gestation period. Given that the length of human pregnancies can vary randomly by as long as 5 weeks, it is worth investigating whether a slow steady healthy gestation over a longer period will be related to a longer and healthier lifespan. This article discusses the potential benefits, negative impacts, and challenges of the relative elongation of the gestation period.

Telomeres and aging: on and off the planet!

Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.

Feeding Drosophila gut microbiomes from young and old flies modifies the microbiome.

It is becoming increasingly evident that the myriad of microbes in the gut, within cells and attached to body parts (or roots of plants), play crucial roles for the host. Although this has been known for decades, recent developments in molecular biology allow for expanded insight into the abundance and function of these microbes. Here we used the vinegar fly, Drosophila melanogaster, to investigate fitness measures across the lifetime of flies fed a suspension of gut microbes harvested from young or old flies, respectively. Our hypothesis was that flies constitutively enriched with a 'Young microbiome' would live longer and be more agile at old age (i.e. have increased healthspan) compared to flies enriched with an 'Old microbiome'. Three major take home messages came out of our study: (1) the gut microbiomes of young and old flies differ markedly; (2) feeding flies with Young and Old microbiomes altered the microbiome of recipient flies and (3) the two different microbial diets did not have any effect on locomotor activity nor lifespan of the recipient flies, contradicting our working hypothesis. Combined, these results provide novel insight into the interplay between hosts and their microbiomes and clearly highlight that the phenotypic effects of gut transplants and probiotics can be complex and unpredictable.

Endocrine Regulation of Aging in the Fruit Fly Drosophila melanogaster.

The past few decades have witnessed increasing research clarifying the role of endocrine signaling in the regulation of aging in both vertebrates and invertebrates. Studies using the model organism fruit fly Drosophila melanogaster have largely advanced our understanding of evolutionarily conserved mechanisms in the endocrinology of aging and anti-aging. Mutations in single genes involved in endocrine signaling modify lifespan, as do alterations of endocrine signaling in a tissue- or cell-specific manner, highlighting a central role of endocrine signaling in coordinating the crosstalk between tissues and cells to determine the pace of aging. Here, we review the current landscape of research in D. melanogaster that offers valuable insights into the endocrine-governed mechanisms which influence lifespan and age-related physiology.

Microbiome composition as a potential predictor of longevity in rabbits.

BACKGROUND: Longevity and resilience are two fundamental traits for more sustainable livestock production. These traits are closely related, as resilient animals tend to have longer lifespans. An interesting criterion for increasing longevity in rabbit could be based on the information provided by its gut microbiome. The gut microbiome is essential for regulating health and plays crucial roles in the development of the immune system. The aim of this research was to investigate if animals with different longevities have different microbial profiles. We sequenced the 16S rRNA gene from soft faeces from 95 does. First, we compared two maternal rabbit lines with different longevities; a standard longevity maternal line (A) and a maternal line (LP) that was founded based on longevity criteria: females with a minimum of 25 parities with an average prolificacy per parity of 9 or more. Second, we compared the gut microbiota of two groups of animals from line LP with different longevities: females that died/were culled with two parities or less (LLP) and females with more than 15 parities (HLP). RESULTS: Differences in alpha and beta diversity were observed between lines A and LP, and a partial least square discriminant analysis (PLS-DA) showed a high prediction accuracy (> 91%) of classification of animals to line A versus LP (146 amplicon sequence variants (ASV)). The PLS-DA also showed a high prediction accuracy (> 94%) to classify animals to the LLP and HLP groups (53 ASV). Interestingly, some of the most important taxa identified in the PLS-DA were common to both comparisons (Akkermansia, Christensenellaceae R-7, Uncultured Eubacteriaceae, among others) and have been reported to be related to resilience and longevity. CONCLUSIONS: Our results indicate that the first parity gut microbiome profile differs between the two rabbit maternal lines (A and LP) and, to a lesser extent, between animals of line LP with different longevities (LLP and HLP). Several genera were able to discriminate animals from the two lines and animals with different longevities, which shows that the gut microbiome could be used as a predictive factor for longevity, or as a selection criterion for these traits.

A diet of oxidative stress-adapted bacteria improves stress resistance and lifespan in C. elegans via p38-MAPK.

Organisms across taxa face stresses including variable temperature, redox imbalance, and xenobiotics. Successfully responding to stress and restoring homeostasis are crucial for survival. Aging is associated with a decreased stress response and alterations in the microbiome, which contribute to disease development. Animals and their microbiota share their environment; however, microbes have short generation time and can rapidly evolve and potentially affect host physiology during stress. Here, we leverage Caenorhabditis elegans and its simplified bacterial diet to demonstrate how microbial adaptation to oxidative stress affects the host's lifespan and stress response. We find that worms fed stress-evolved bacteria exhibit enhanced stress resistance and an extended lifespan. Through comprehensive genetic and metabolic analysis, we find that iron in stress-evolved bacteria enhances worm stress resistance and lifespan via activation of the mitogen-activated protein kinase pathway. In conclusion, our study provides evidence that understanding microbial stress-mediated adaptations could be used to slow aging and alleviate age-related health decline.

Nonlinear DNA methylation trajectories in aging male mice.

Although DNA methylation data yields highly accurate age predictors, little is known about the dynamics of this quintessential epigenomic biomarker during lifespan. To narrow the gap, we investigate the methylation trajectories of male mouse colon at five different time points of aging. Our study indicates the existence of sudden hypermethylation events at specific stages of life. Precisely, we identify two epigenomic switches during early-to-midlife (3-9 months) and mid-to-late-life (15-24 months) transitions, separating the rodents' life into three stages. These nonlinear methylation dynamics predominantly affect genes associated with the nervous system and enrich in bivalently marked chromatin regions. Based on groups of nonlinearly modified loci, we construct a clock-like classifier STageR (STage of aging estimatoR) that accurately predicts murine epigenetic stage. We demonstrate the universality of our clock in an independent mouse cohort and with publicly available datasets.

Linking fine root lifespan to root chemical and morphological traits-A global analysis.

Fine root lifespan is a critical trait associated with contrasting root strategies of resource acquisition and protection. Yet, its position within the multidimensional "root economics space" synthesizing global root economics strategies is largely uncertain, and it is rarely represented in frameworks integrating plant trait variations. Here, we compiled the most comprehensive dataset of absorptive median root lifespan (MRL) data including 98 observations from 79 woody species using (mini-)rhizotrons across 40 sites and linked MRL to other plant traits to address questions of the regulators of MRL at large spatial scales. We demonstrate that MRL not only decreases with plant investment in root nitrogen (associated with more metabolically active tissues) but also increases with construction of larger diameter roots which is often associated with greater plant reliance on mycorrhizal symbionts. Although theories linking organ structure and function suggest that root traits should play a role in modulating MRL, we found no correlation between root traits associated with structural defense (root tissue density and specific root length) and MRL. Moreover, fine root and leaf lifespan were globally unrelated, except among evergreen species, suggesting contrasting evolutionary selection between leaves and roots facing contrasting environmental influences above vs. belowground. At large geographic scales, MRL was typically longer at sites with lower mean annual temperature and higher mean annual precipitation. Overall, this synthesis uncovered several key ecophysiological covariates and environmental drivers of MRL, highlighting broad avenues for accurate parametrization of global biogeochemical models and the understanding of ecosystem response to global climate change.

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?

Improving epilepsy diagnosis across the lifespan: approaches and innovations.

Epilepsy diagnosis is often delayed or inaccurate, exposing people to ongoing seizures and their substantial consequences until effective treatment is initiated. Important factors contributing to this problem include delayed recognition of seizure symptoms by patients and eyewitnesses; cultural, geographical, and financial barriers to seeking health care; and missed or delayed diagnosis by health-care providers. Epilepsy diagnosis involves several steps. The first step is recognition of epileptic seizures; next is classification of epilepsy type and whether an epilepsy syndrome is present; finally, the underlying epilepsy-associated comorbidities and potential causes must be identified, which differ across the lifespan. Clinical history, elicited from patients and eyewitnesses, is a fundamental component of the diagnostic pathway. Recent technological advances, including smartphone videography and genetic testing, are increasingly used in routine practice. Innovations in technology, such as artificial intelligence, could provide new possibilities for directly and indirectly detecting epilepsy and might make valuable contributions to diagnostic algorithms in the future.

Storylines of family medicine VII: family medicine across the lifespan.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'VII: family medicine across the lifespan', authors address the following themes: 'Family medicine maternity care', 'Seeing children as patients brings joy to work', 'Family medicine and the care of adolescents', 'Reproductive healthcare across the lifespan', 'Men's health', 'Care of older adults', and 'Being with dying'. May readers appreciate the range of family medicine in these essays.