ARTICLE | doi:10.20944/preprints202307.1139.v1
Subject: Biology And Life Sciences, Aging Keywords: telomeres; longevity; homosexuality; contraception; evolution
Online: 18 July 2023 (09:12:10 CEST)
The presence of homosexual behavior in the human population represents an evolutionary puzzle, as such behavior leads to obvious reproductive disadvantages. Recently, it was revealed that the length of telomeres inherited by offspring is determined, among other things, by the age of father. Older fathers pass longer telomeres to their children. The length of telomeres is generally considered as one of the factors determining the individual life span, which suggests that children of older fathers live longer. This phenomenon may provide a plausible explanation for the persistence of homosexuality among humans. Homosexuality is a partially inheritable trait. As homosexual males do not actively pursue reproductive sex, they are much likelier to become fathers later in life, if they reproduce at all. Through delayed reproduction, homosexual and bisexual subpopulations contribute to the increasing mean length of telomeres in population, which results in the gradually increasing life span. However, longer telomeres inherited from homosexual father are passed together with the genes predisposing to homosexual behavior, which helps to sustain a substantial pool of “gay genes” despite their reproductive disadvantage. The described effects are likely to be small but may results in a significant demographical shifts (increased longevity and sustained presence of homosexual sub-population) over multiple generations. The introduction of effective contraception (and the consequent serious increase of the mean age of fathering the children) may provide a similar mechanism for extending the mean telomere length in population, with consequences for longevity and general health.
ARTICLE | doi:10.20944/preprints202309.1569.v1
Subject: Biology And Life Sciences, Aging Keywords: longevity; healthspan; lifespan; nutraceuticals; C. elegans
Online: 22 September 2023 (11:43:17 CEST)
Aging is a complex process associated with tissue degeneration and an increased risk of age-related diseases. This study aimed to evaluate the impact of Terasen®, a nutraceutical containing standardized extracts of Euterpe oleracea, Myrciaria dubia, and purified oil of Bixa orellana and Astrocaryum aculeatum on the lifespan of Caenorhabditis elegans, a widely used model organism for aging research. The findings demonstrated that Terasen® exhibited significant antioxidant activity and influenced the feeding behavior of C. elegans, leading to a reduced pharyngeal pumping rate and a decreased number of offspring produced by treated individuals. Notably, Terasen® also displayed a remarkable ability to extend the lifespan of C. elegans. These findings suggest that Terasen® may possess promising anti-aging effects in vivo, warranting further investigation.
ARTICLE | doi:10.20944/preprints202309.1070.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: human longevity; single nucleotide polymorphisms; Sardinia
Online: 18 September 2023 (07:02:09 CEST)
Background. In the central-eastern region of the Mediterranean island of Sardinia more than two decades ago, a mountain area was identified where the population displays exceptional longevity, especially among men (the longevity Blue Zone, LBZ). This community was thoroughly investigated seeking to understand the underlying factors of this phenomenon. In the present study, 11 genetic markers previously associated with longevity in several long-lived populations were analyzed. Methods. APOE (rs429358 and rs7412), APOE promoter (rs449647, rs769446, and rs405509), ACE1 (rs1799752), IL6 ‒174G/C (rs1800795), TNFα ‒308G/A (rs1800629), FOXO3A (rs2802292), KLOTHO (rs9536314) and G6PD (c.563C→T) were investigated. PCR-based genotyping was performed following genomic DNA extraction from 150 nonagenarians living in the LBZ and 150 controls from a nearby area. Results. No significant deviation of the frequency of the analyzed markers was detected between the two groups except a weak association with the –174G>C gene variant of the IL-6 gene (p=0.040), a major modulator of the inflammatory response. Conclusions. The findings of this study do not support a significant association of known genetic variants on survival in the population of the Sardinian LBZ. Other genetic or epigenetic traits might play a role not yet identified.
SHORT NOTE | doi:10.20944/preprints202009.0401.v2
Subject: Biology And Life Sciences, Ecology, Evolution, Behavior And Systematics Keywords: life history; longevity; senescence; stochastic environments
Online: 26 July 2022 (08:51:22 CEST)
The world’s human population is reaching record longevities. Consequently, our societies are experiencing the impacts of prolonged longevity, such as increased retirement age. A major hypothesised influence on ageing patterns is resource limitation, formalised under calorie restriction theory. This theory predicts extended organismal longevity due to reduced calorie intake without malnutrition. However, several challenges face current calorie restriction (CR) research and, although several attempts have been made to overcome these challenges, there is still a lack of holistic understanding of how CR shapes organismal vitality. Here, we conduct a literature review of 222 CR peer-reviewed publications to summarise the state-of-the-art in the field. We use this summary to highlight challenges of CR research in our understanding of its impacts on longevity. Our review demonstrates that experimental research in this field is biased towards short-lived species (98.2% of studies examine species with <5 years of mean life expectancy) and lacks realism in key areas, such as stochastic environments or interactions with other environmental drivers such as temperature. We argue that only by considering a range of short- and long-lived species and by taking more realistic approaches can the impacts of CR on longevity be examined and validated in natural settings. We conclude by proposing experimental designs and study species that will allow the discipline to gain a much-needed understanding of how restricting caloric intake affects long-lived species in realistic settings. Through incorporating more experimental realism, we anticipate crucial insights that will ultimately shape the myriad of socio-bio-economic impacts of senescence in humans and other species across the Tree of Life.
BRIEF REPORT | doi:10.20944/preprints201911.0214.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: shark; genome; longevity; gigantism; positive selection
Online: 18 November 2019 (07:46:50 CET)
A previous study involving whole genome sequencing of the white shark suggested unique molecular evolution accounting for gigantism and the enhanced longevity of sharks including positive selection of dozens of protein-coding genes potentially involved in genome stability. We performed a reanalysis on some of the genes and identified serious flaws in their results. In this short article, we scrutinize one of the serious problems we identified, report other concerns, and point out a potential bias in analyzing iconic shark species in general.
REVIEW | doi:10.20944/preprints202102.0491.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: mTORC1; mTORC2; rapamycin; rapalog; aging; lifespan; longevity
Online: 22 February 2021 (15:34:25 CET)
Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) signaling promotes health and longevity in diverse model organisms. Over the past decade, excitement has built over the possibility that treatment with the mTORC1 inhibitor rapamycin can be utilized to treat or prevent age-related disease in humans. However, concerns over the side effects of rapamycin on immunity and metabolism have precluded the routine use of rapamycin as a geroprotective therapy. Here, we discuss the evidence that these negative side effects of rapamycin are largely mediated by off-target inhibition of a second mTOR Complex (mTORC2). Further, we discuss how intermittent treatment with rapamycin, specific dietary regimens, and new molecules may provide routes to the safer and more selective inhibition of mTORC1. We conclude that the time is ripe for the development of therapies based on the safe and selective inhibition of mTORC1 for the treatment or prevention of diseases of aging.
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: garlic; onion; antigenotoxicity; longevity; cytotoxicity; comet assay
Online: 25 March 2019 (10:09:47 CET)
This study aimed to evaluate the biological activities of two Allium species (Garlic and onion) as well as diallyl disulphide (DADS) and dipropyl disulphide (DPDS) as their representative bioactive compounds in a multi-assay experimental design. The genotoxic, antigenotoxic and lifespan effects of garlic, onion, DADS and DPDS were checked in Drosophila melanogaster and their cytotoxic, pro-apoptotic and DNA-clastogenic activities were analysed using HL60 tumoral cells. All compounds were non-genotoxic and antigenotoxic against H2O2-induced DNA damage with a positive dose-response effect and different inhibition percentages (the highest value: 95% for DADS) at all tested concentrations. Daily intake of Allium vegetables, DADS or DPDS had no positive effects on flies’ lifespan and healthspan. Garlic and DADS exerted the highest cytotoxic effects in a positive dose-dependent manner. Garlic and DADS exerted a DNA-internucleosomal fragmentation as an index of induced proapoptotic activity on HL60 cells. Allium vegetables and DADS were able to induce clastogenic strand breaks in the DNA of HL60 cells. This study showed the genomic safety of the assayed substances and their protective genetic effects against the hydrogen peroxide genotoxine. Long-term treatments during the whole life of Drosophila genetic model were beneficial only at low-median concentrations. The chemopreventive activity of garlic could be associated to its distinctive organosulphur DADS. We suggest that supplementary studies are needed to clarify the cell death pathway against garlic and DADS.
ARTICLE | doi:10.20944/preprints202310.1540.v1
Subject: Social Sciences, Demography Keywords: longevity; workforce; stochastic model; labor force participation; sustainable future
Online: 24 October 2023 (16:43:36 CEST)
The world population is aging, which along with recent shifts in the labor force participation (LFP), is having a significant longevity influence on state pension programs across the board, including Canada, Finland, Japan, and Germany. Except Japan, these countries have set their statutory re-tirement age at 65, but the impact of aging workforce and declined fertility rates create wonders on the estimate future trends in the LFP, as well as the length of retirement. In this study, we fit the LFP rates of these countries, representing continents from Asia, Europe and North America among the OECD countries, using the Lee-Carter and Cairns-Blake-Dowd (CBD) stochastic models. The es-timates are then used for the projection of future LFP rates (1989-2066), and by combining the mortality forecasts from the United Nations, we project the expected length of retirement (1989-2066). This study provided a novel comparison between the Lee-Carter and the CBD LFP models by fitting and forecasting the LFP rates of senior employees between 50- to 74-year-olds. The results revealed disparities between models that provided proof of the presence of model risk for longer retirement durations. The study findings emphasized the importance for decision-makers in pension industry to have awareness of potential risks and limits associated with the LFP models. The Lee-Carter model outperformed the CBD model even though the CBD model is known for its ac-curate prediction in higher ages. Population aging should be considered in any analysis of the long-term viability of pensions, together with the participation rate trends for a sustainable labor market future.
ARTICLE | doi:10.20944/preprints202307.2014.v1
Subject: Business, Economics And Management, Econometrics And Statistics Keywords: Longevity risk; stochastic mortality models; Lee-Carter; model selection
Online: 28 July 2023 (12:31:25 CEST)
Stochastic mortality models seek to forecast future mortality rates; thus, apparently the objective variable should be the mortality rate expressed in the original scale. However, the performance of stochastic mortality models - in terms, that is, of their goodness-of-fit and prediction accuracy - is often based on the logarithmic scale of the mortality rate. In this article, we examine whether the same forecast outcomes are obtained when the performance of mortality models is assessed based on the original and log scales of the mortality rate. We compare four different stochastic mortality models: the original Lee-Carter model, the Lee-Carter model with (log-)normal distribution, the Lee-Carter model with Poisson distribution and the median Lee-Carter model. We show that the preferred model will depend on the scale of the objective variable, the selection criteria measure and the range of ages analysed.
ARTICLE | doi:10.20944/preprints202302.0250.v1
Subject: Medicine And Pharmacology, Other Keywords: AI drug discovery; mTOR; rapalog; C. elegans; cancer; longevity
Online: 15 February 2023 (02:42:57 CET)
The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown their ability to slow aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in-silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We confirmed TKA001 binding in silico by molecular docking. TKA001 potently inhibits both TOR complex 1 and 2 downstream signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extended the lifespan of C. elegans, suggesting that TKA001 can slow aging in vivo.
ARTICLE | doi:10.20944/preprints202208.0445.v1
Subject: Business, Economics And Management, Economics Keywords: Adult children's education; parental longevity; truncated regression; emotional support.
Online: 26 August 2022 (04:18:44 CEST)
Background: Some developing countries, such as China, population is aging rapidly, meanwhile, the average years of schooling for residents is constantly increasing. However, the question of whether adult children’s education has an effect on the longevity of older parents, remains inadequately studied. Methods: This paper uses China Health and Retirement Longitudinal Survey (CHARLS) data to estimate the causal impact of adult children's education on their parents' longevity. Identification is achieved by using the truncated regression model and using historical education data as instrument variables for adult children’s education. Results: For every unit increase in adult children’s education, the father’s and mother’s longevity increased by 0.89 years and 0.75 years, respectively. Mechanism analysis shows that adult children's education has a significant positive impact on parents' emotional support, financial support and self-reported health. Further evidence shows that for every unit increase in adult children’s education, the father-in-law’s and mother-in-law’s longevity increased by 0.40 years and 0.46 years, respectively. Conclusions: It is conclusion that improving the level of adult children’s education can increase parents’ and parents-in-law’s longevity. Adult children’s education might contribute to the longevity of older parents by three channels that providing emotional, economic support and affecting parents’ health.
REVIEW | doi:10.20944/preprints201809.0171.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: NOX, sulfenylation, Nrf2, SKN-1, centenarians, extracellular matrix, longevity
Online: 10 September 2018 (12:59:22 CEST)
An accumulating body of evidence suggests that physiological reactive oxygen species (ROS) generated by NADPH oxidases act as a redox signal to re-establish homeostasis, a capacity that progressively declines during aging, but is maintained in long-lived animals to promote healthy aging. In the model organism Caenorhabditis elegans, ROS generated by dual oxidases (Duox) are important for extracellular matrix integrity, pathogen defense, oxidative stress resistance, and longevity. The Duox enzymatic activity is tightly regulated and under cellular control. Developmental molting cycles, pathogen infections, toxins, mitochondrial-derived ROS, drugs, and small GTPases (RHO-1) can activate Duox (BLI-3) to generate ROS, whereas NADPH oxidase inhibitors and negative regulators, such as MEMO-1, can inhibit Duox to generate ROS. Three mechanisms-of-action have been discovered for the Duox/BLI-3-generated ROS: 1) enzymatic activity to catalyze cross-linking of free tyrosine ethyl ester in collagen bundles to stabilize extracellular matrices, 2) high ROS bursts/levels to kill pathogens, and 3) Redox signaling activating downstream kinase cascades to transcription factors orchestrating oxidative stress- and immunity responses to re-establish homeostasis. Although Duox function at the cell surface is well established, recent genetic and biochemical data also suggests a novel role for Duoxs at the endoplasmic reticulum membrane to control redox signaling. Evidence underlying these mechanisms initiated by ROS from NADPH oxidases and their relevance for human aging are discussed in this review. Appropriately controlling NADPH oxidase activity for local and physiological redox signaling to maintain cellular homeostasis might be a therapeutic strategy to promote healthy aging.
ARTICLE | doi:10.20944/preprints201705.0020.v1
Subject: Business, Economics And Management, Finance Keywords: longevity risk; s-forwards; pricing; risk margin; solvency II
Online: 1 May 2017 (11:39:12 CEST)
Longevity risk constitutes an important risk factor for life insurance companies and it can be managed through longevity-linked securities. The market of longevity-linked securities is at present far from being complete and does not allow to find a unique pricing measure. We propose a method to estimate the maximum market price of longevity risk depending on the risk margin implicit within the calculation of the technical provisions as defined by Solvency II. The maximum price of longevity risk is determined for a survivor forward (S-forward), an agreement between two counterparties to exchange at maturity a fixed survival-dependent payment for a payment depending on the realized survival of a given cohort of individuals. The maximum prices determined for the S-forwards can be used to price other longevity-linked securities, such as q-forwards. The Cairns-Blake-Dowd model is used to represent the evolution of mortality over time, that combined with the information on the risk margin, enables us to calculate upper limits for the risk-adjusted survival probabilities, the market price of longevity risk and the S-forward prices. Numerical results can be extended for the pricing of other longevity-linked securities.
REVIEW | doi:10.20944/preprints202306.1728.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: nicotinamide riboside; vitamin B3 derivative; efficacy; safety; healthy aging; longevity
Online: 25 June 2023 (10:43:10 CEST)
NAD+ is known classically as a metabolite that participates in catabolic and anabolic pathways throughout the metabolism that is taught to students in introductory biochemistry courses. However, non-classical studies starting over a decade ago found that NAD+ is also involved in higher order functions, in part because of its involvement in the activation of SIRTs and the support of the mitochondrial unfolded protein response. Many studies since have suggested that NAD+ is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes, Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including NAR and NMN. Together, these studies show that this system has value as a dietary supplement to improve general health overall, as well as mitigating specific disease conditions. Accordingly, many are now recommending the consumption of materials in this system as dietary supplements. Nicotinamide riboside (NAR) appears to have special value in this regard. It appears to be better tolerated than other molecules in this system, as well as better pharmacodynamics and greater potency. Unfortunately, NAR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Indeed, HPLC analyses of many commercial samples of NAR shows that they contain substantial amounts of material that are not, in fact, NAR. In some of these commercial preparations, NAR is a minority component. Therefore, more stable derivatives of NAR that are easily converted upon consumption into NAR are therefore desired. Recently work related to prebiotic chemistry provided the borate derivative of NAR. NARB is considerably more stable than NAR itself. However, immediately upon consumption, the borate dissociates from NARB, and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NAR left behind is expected to behave pharmacologically in ways identical to NAR itself. This review provides a comprehensive summary (through Q1 of 2023) of literature that makes the case for the consumption of NAR as a dietary supplement. It then summarizes the challenges of delivering quality NAR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NAR-borate in these processes.
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: nitric oxide; nitrates; dietary potassium nitrate; Drosophila melanogaster; longevity; lifespan
Online: 29 January 2021 (14:20:31 CET)
The recently defined and yet rather new topic of Healthy aging is gathering more attention on the global stage. With world’s population getting older - it is rapidly becoming very important to develop and maintain functional abilities in older age and develop mechanisms to protect senior population from chronic diseases. One of the most effective components, as well as, one may call - process involved in, and strongly associated with aging is recently discovered and Nobel prize awarded - nitric oxide as a signaling molecule, which followed by later discoveries showed to have a positive metabolic, immune and anti-inflammatory effects. One of the most debated topics of the last decade in the scientific community is nitrates, one of the pathways involved in nitric oxide production. Thus, the objective of this study was to evaluate effect of different potassium nitrate concentrate supplementation on Drosophila melanogaster longevity. 0,5-3% potassium nitrate medium was analyzed on the life span and motor function in different groups consisting of 100 females fruit flies each. In this assay, female fly species supplemented with potassium nitrate diet showed life span increase by 18.6% and 5.1% with 1% and 2% KNO3- respectively with a positive impact on locomotor function. In conclusion, we found that low concentration of potassium nitrate medium increased lifespan and locomotor function in Drosophila melanogaster.
ARTICLE | doi:10.20944/preprints202310.0508.v1
Subject: Biology And Life Sciences, Aging Keywords: C15:0; pentadecanoic acid; rapamycin; metformin; acarbose; longevity; essential fatty acid
Online: 9 October 2023 (10:53:44 CEST)
Pentadecanoic acid (C15:0) is an essential odd-chain saturated fatty acid with broad activities relevant to protecting cardiometabolic, immune, and liver health. C15:0 activates AMPK and inhibits mTOR, both of which are core components of the human longevity pathway. To assess the potential for C15:0 to enhance processes associated with longevity and healthspan, we used human cell-based molecular phenotyping assays to compare C15:0 with three longevity-enhancing candidates: acarbose, metformin, and rapamycin. C15:0 (n=36 activities in 10 of 12 cell systems) and rapamycin (n=32 activities in 12 of 12 systems) had the most clinically relevant, dose-dependent activities. At their optimal doses, C15:0 (17 µM) and rapamycin (9 µM) shared 24 activities across 10 cell systems, including anti-inflammatory (e.g., lowered MCP-1, TNFɑ, IL-10, IL-17A/F), antifibrotic, and anticancer activities, which are further supported by previously published in vitro and in vivo studies. Paired with prior demonstrated abilities for C15:0 to target longevity pathways, hallmarks of aging, aging rate biomarkers, and core components of type 2 diabetes, heart disease, cancer, and nonalcoholic fatty liver disease, our results support C15:0 as an essential nutrient with activities equivalent to, or surpassing, leading longevity-enhancing candidate compounds.
COMMUNICATION | doi:10.20944/preprints202301.0334.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: serotonin; pcpa; cystamine; dinophilida; invertebate models; aging; maternal serotonin; lifespan longevity
Online: 18 January 2023 (10:22:43 CET)
Serotonin (5-HT) is crucial molecule in animal kingdom. It is involved in control of multiple processes. It might act via transmembrane receptors or via postranslational protein modification (serotonylation). D. gyrociliatus is a marine worm-like invertebrate with quite short lifespan. In this study lifetime experiments were performed. We incubated freshly laid eggs, adult females lifelong in HTP, PCPA and cystamine. Every week we monitored the survived individuals. This was lifelong (about 5 moth) monitoring. The survival analysis demonstrated that PCPA and cystamine reduce lifespan longevity drastically and even in F1 offsprings from mothers with reduced level of serotonin. HTP incubation to the contary extended mean lifespan longevity up to 22 % even in F1 offsprings from mothers with extended levels of serotonin. Thus, our results demonstrated that serotonin impacts lifespan longevity and moreover the level of serotonin in mother organism affects offspring lifespan longevity.
ARTICLE | doi:10.20944/preprints201806.0198.v1
Subject: Computer Science And Mathematics, Probability And Statistics Keywords: quantile regression; quantile time series; demographics; mortality; longevity; modelling mortality projection
Online: 12 June 2018 (15:05:09 CEST)
This paper has three objectives, the first is to present a detailed overview in the form of a tutorial for the developments of several key quantile time series modelling approaches. The second objective is to develop a general framework to represent such quantile models in a unifying manner in order to easily develop extensions and connections between existing models that can then be developed to further extend these models in practice. In this regard, the core theme of the paper is to provide perspectives to a general audience of core components that go into construction of a quantile time series model and then to explore each of these core components in detail. The paper is not addressing the concerns of estimation of these models, as there is existing literature on these aspects in many settings, we provide references to relevant works on these aspects in several classes of model. Instead, the focus is rather to provide a unified framework to construct such models for practitioners, therefore the focus is instead on the properties of the models and links between such models from a constructive perspective. The third objective is to compare and discuss the application of the different quantile time series models on several sets of interesting demographic and mortality based time series data sets of relevance to life insurance analysis. The exploration included detailed mortality, fertility, births and morbidity data in several countries with more detailed analysis of regional data in England, Wales and Scotland.
ARTICLE | doi:10.20944/preprints201612.0035.v1
Subject: Business, Economics And Management, Economics Keywords: inflation risk; investment returns; life annuity; longevity risk; post-retirement benefits
Online: 7 December 2016 (10:27:23 CET)
Building a social security system to ensure Singapore residents have peace of mind in funding for retirement has been at the top of Singapore Government’s policy agenda over the last decade. Implementation of the Lifelong Income For the Elderly (LIFE) scheme in 2009 clearly shows that the government spares no effort in improving its pension scheme to boost its residents’ income after retirement. Despite the recent modifications to the LIFE scheme, Singapore residents must still choose between two plans: the Standard and Basic plans. To enhance the flexibility of the LIFE scheme while maintaining its simplicity, we propose some plan modifications such that scheme members do not face a dichotomy of plan choices. Instead, they select two age parameters: the Payout Age and the Life-annuity Age. This paper provides an actuarial framework for determining members’ payouts and bequests based on the proposed age parameters. We analyze the net cash receipts and internal rate of return (IRR) for various plan-parameter configurations. This information helps members make their plan choices. To address cost-of-living increases we propose to extend the plan to accommodate an annual step-up of monthly payouts. By deferring the Payout Age from 65 to 68, members can enjoy an annual increase of about 2% of the payouts for the same first-year monthly benefits.
REVIEW | doi:10.20944/preprints202311.0227.v1
Subject: Biology And Life Sciences, Aging Keywords: apolipoprotein E; Alzheimer’s disease; methylation; dementia; epigenetics; tau protein; amyloid-β; longevity
Online: 3 November 2023 (10:00:30 CET)
Sporadic Alzheimer’s disease (AD) derives from an interplay among environmental factors and genetic variants, while epigenetic modifications have been expected to affect the onset and progression of its complex etiopathology. Heterozygous carriers of the apolipoprotein E gene (APOE)4 allele have a 4-fold increased risk of developing AD, while APOE 4/4-carriers have a 12-fold increased risk in comparison with the APOE 3-carriers. The main longevity factor is the homozygous APOE ε3/ε3 genotype. In the present narrative review article, we summarized and described the role of APOE epigenetics in aging and AD pathophysiology. It is not fully understood how APOE variants may increase or decrease AD risk, but this gene is known to affect amyloid- and tau-mediated neurodegeneration directly or indirectly, also by affecting lipid metabolism and inflammation. For sporadic AD, epigenetic regulatory mechanisms may control and influence APOE expression in response to external insults. Diet, a major environmental factor, has been significant associated with physical exercise, cognitive function, and the methylation level of several cytosine-phosphate-guanine (CpG) dinucleotides sites of APOE.
REVIEW | doi:10.20944/preprints202309.0509.v1
Subject: Biology And Life Sciences, Food Science And Technology Keywords: Microalgae; Antioxidants; Wellness; Longevity; Health benefits; Natural antioxidants; Sustainable production; Bioactive compounds
Online: 7 September 2023 (11:17:39 CEST)
In recent times, there has been a revolutionary surge in antioxidant research, with a focus on harnessing microalgae to enhance wellness and extend human longevity. Microalgae, a diverse group of unicellular photosynthetic organisms, have emerged as promising sources of natural antioxidants due to their ability to synthesize various bioactive compounds, including carotenoids, polyphenols, and tocopherols. These antioxidants play a pivotal role in scavenging free radicals and reducing oxidative stress, known contributors to aging and chronic diseases. This review provides an overview of recent advancements in understanding microalgae's antioxidant potential, covering their biochemical composition, extraction techniques, and purification methods. Moreover, it delves into compelling in vitro and in vivo studies showcasing microalgae-derived antioxidants' protective effects against oxidative damage, inflammation, cardiovascular diseases, and neurodegenerative disorders. The sustainable cultivation of microalgae in controlled environments further supports the potential for large-scale production and commercialization of their antioxidant compounds. As microalgae continue to revolutionize antioxidant research, they hold immense promise in developing novel preventive and therapeutic strategies to promote human health and wellbeing.
REVIEW | doi:10.20944/preprints202205.0217.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: longevity; aging; cancer; complex systems; non-equilibrium thermodynamics; biological phase transition; ferroptosis
Online: 17 May 2022 (03:16:18 CEST)
From the formalism of the thermodynamics of irreversible processes and the theory of complex systems, characterization of longevity and aging and its relationship with the emergence and evolution of cancer was carried out. It was found that: 1. The rate of entropy production can be used as an index of robustness, plasticity, the aggressiveness of cancer, and as a measure of biological age; 2. The aging process, as well as the evolution of cancer, goes through what we have called “biological phase transition”; 3. The process of metastasis, which occurs through epithelial-mesenchymal transition (EMT), appears as a phase transition far from thermodynamic equilibrium and exhibits Shilnikov chaos-like dynamic behavior. This dynamic guarantees the robustness of the process and, in turn, its unpredictability; 4. It was shown that as the ferroptosis process is strengthened, the complexity of the dynamics associated with the emergence and evolution of cancer decreases. The theoretical framework developed contributes to a better understanding of the biophysical-chemical phenomena of longevity and aging and their relationship with cancer.
REVIEW | doi:10.20944/preprints202105.0054.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Anopheles mosquito; Body size; Fecundity; Gonotrophic cycle; Immature stage; Insecticide; Longevity; Temperature
Online: 5 May 2021 (12:41:25 CEST)
The rearing temperature of the immature stages can have a significant impact on the life-history traits and the ability of adult mosquitoes to transmit diseases. This review assessed published evidence of the effects of temperature on the immature stages, life-history traits, insecticide susceptibility, and expression of enzymes in the adult Anopheles mosquito. Original articles published through 31 March 2021 were systematically retrieved from Scopus, Google Scholar, Science Direct, PubMed, ProQuest and Web of Science databases. After applying eligibility criteria, 29 studies were included. The review revealed that immature stages of Anopheles arabiensis were more tolerant (in terms of survival) to a higher temperature than An. funestus and An. quadriannulatus. Higher temperatures resulted in smaller larval size and decreased hatching and pupation time. The development rate and survival of Anopheles stephensi were significantly reduced at a higher temperature than a lower temperature. Increasing temperatures decreased the longevity, body size, length of the gonotrophic cycle and fecundity of Anopheles mosquitoes. Anopheles mosquitoes exposed at 18° or 30 °C had a higher risk of dying compared to those exposed at 25 °C. Increasing temperature also significantly increased NOS expression and decreased insecticide toxicity. Both extreme low and high temperatures affect Anopheles mosquito development and survival. Climate change could have diverse effects on Anopheles mosquitoes. There seems to be inconclusive evidence of the effects of temperature on the development and survival of Anopheles species, and more studies are needed to clarify this relationship.
REVIEW | doi:10.20944/preprints202011.0734.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: abscisic acid; after-ripening; desiccation tolerance; dormancy; germination; gibberellins; LAFL; longevity; seeds
Online: 30 November 2020 (14:41:46 CET)
Desiccation tolerance appeared as the key adaptation feature of photoautotrophic organisms for survival in terrestrial habitats. During the further evolution, vascular plants developed complex anatomy structures and molecular mechanisms to maintain the hydrated state of cell environment, which essentially increased their ability to sustain water deficit and dehydration. However, the role of the genes encoding the mechanisms behind this adaptive feature in the higher vascular plants is restricted to the dehydration protection of spores, seeds and pollen, whereas the mature vegetative stages became sensitive to desiccation. During maturation, orthodox seeds lose up to 95% of their water and successfully enter dormancy. This feature allows seeds maintaining their viability even under strongly fluctuating environmental conditions. The mechanisms behind the desiccation tolerance are activated at the late seed maturation stage and are associated with the accumulation of late embryogenesis abundant proteins (LEA proteins), small heat shock proteins (sHSP), non-reducing oligosaccharides, and antioxidants of different chemical nature. The main regulators of maturation and desiccation tolerance onset are abscisic acid and protein DOG1, which control the network of transcription factors, among which are LEC1, LEC2, FUS3, ABI3, ABI5, AGL67, PLATZ1, PLATZ2. This network is complemented by epigenetic regulation of gene expression by methylation of DNA, post-translational modifications of histones and chromatin remodeling impact on seed desiccation tolerance and longevity. Moreover, orthodox seeds are able to maintain desiccation tolerance during germination up to the stage of radicle protrusion. This time point is critical in the process of seed development, as the seeds lose desiccation tolerance at this moment.
ARTICLE | doi:10.20944/preprints202309.0839.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Ageing; ARIP; Biological Ageing; Inflamm-ageing; INFLA-score; Lymphocyte subsets; Longevity; Semi-supercentenarian
Online: 13 September 2023 (07:22:24 CEST)
In this paper, we present demographic, clinical, anamnestic, cognitive, and functional data, as well as haematological, haematochemical, immunological and genetic parameters of an exceptional individual: Antonino Turturici, a semi-supercentenarian who held the title of the oldest living Italian centenarian from December 28, 2020, to September 23, 2021. The purpose of this study is to offer fresh insights into extreme phenotypes, with a particular focus on immune-inflammatory parameters. To the best of our knowledge, this study represents the first phenotypic investigation of a semi-supercentenarian, illustrating both indicators of age-related immune phenotype (ARIP) recognized as significant gauges of biological ageing and INFLA-score, a metric designed to assess the cumulative impact of inflammatory markers. The aim of this study was, indeed, to advance our understanding of the role of immune-inflammatory responses in achieving extreme longevity. The results bolster the idea that the immune system can play a role in promoting extreme longevity. However, this does not exclude the involvement of other body systems or organs in achieving extreme longevity.
REVIEW | doi:10.20944/preprints202104.0384.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: Aging; cellular clocks; reprogramming; development; epigenetics; DNA methylation; telomeres; transposable elements; longevity; regeneration
Online: 14 April 2021 (14:15:26 CEST)
Multicellular life evolved from simple unicellular organisms that could replicate indefinitely being essentially ageless. At this point, life split into 2 fundamentally different cell types: the immortal germline representing an unbroken lineage of cell division with no intrinsic endpoint and the mortal soma which ages and dies. In this review, we describe the germline as clock-free and the soma as clock-bound and discuss aging with respect to 3 DNA-based cellular clocks (telomeric, DNA methylation, and transposable element). The ticking of these clocks corresponds to the stepwise progressive limitation of growth and regeneration of somatic cells that we term, somatic restriction. Somatic restriction acts in opposition to strategies that ensure continued germline replication and regeneration. We thus consider the plasticity of aging as a process not fixed to the pace of chronological time but one that can speed up or slow down depending on the rate of intrinsic cellular clocks. We further describe how germline factor reprogramming might be used to slow the rate of aging and potentially reverse it by causing the clocks to tick backwards. Therefore, reprogramming may eventually lead to therapeutic strategies to treat degenerative diseases by altering aging itself, the one condition common to us all.
REVIEW | doi:10.20944/preprints202012.0554.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: microbiome; vectorial capacity; density; competence; biting; extrinsic incubation period; longevity; mosquito; symbiosis; pathogen transmission
Online: 22 December 2020 (10:49:13 CET)
Microbiome research has gained considerable interest due to the emerging evidence of its impact on human and animal health. Similar to higher organisms, the gut-associated microbiota of mosquitoes affect host fitness and other phenotypes. It is now well established that microbes can alter pathogen transmission in mosquitoes, either positively or negatively, and avenues are being explored to exploit microbes for vector control. However, less attention has been paid to how microbiota affect phenotypes that impact vectorial capacity. Several mosquito and pathogen components, such as vector density, biting rate, survival, vector competence and pathogen extrinsic incubation period all influence pathogen transmission. Interestingly, the mosquito gut-associated microbes can impact each of these components, and therefore ultimately modulate vectorial capacity. Promisingly, this expands the options available to exploit microbes for vector control by also targeting parameters that affect vectorial capacity. However, there are still many knowledge gaps in the biology of the mosquito – microbe symbiosis that need to be addressed in order to understand these interactions more thoroughly and exploit them efficiently. Here, we review current evidence of the impacts of the microbiome on aspects of vectorial capacity highlighting opportunities for novel vector control strategies and areas where further studies are required.
Subject: Biology And Life Sciences, Plant Sciences Keywords: medicinal plants; bioactive molecules; phenolic compounds; Oxidative stress; Antioxidants; chronic disorders; health maintenance; longevity
Online: 3 June 2019 (09:58:55 CEST)
Plants and its corresponding botanical preparations have been used for centuries due to their remarkable potentialities in both treatment and prevention of numerous affections. Hundreds of biologically active constituents are present in each whole plant matrice, working in synergism and conferring both its own protection against invaders and even providing promissory bioactive effects for human beings. The worldwide population has devoted increasing attention and preference by medicinal plants use for health promotion and disease prevention, and more recently for oxidative-stress related disorders protection. Indeed, oxidative stress-related disorders, like cardiovascular and (neuro) degenerative disorders, and even cancer have raised exponentially. Although oxidative stress is in itself intrinsic to our own metabolism, allarming sources of free radicals are daily affecting us. In fact, plant-derived bioactives present a broad spectrum of biological effects, and its antioxidant, anti-inflammatory and more recently anti-aging effects have been considered a hot topic among the medical and scientific community. Nonetheless, and although its numerous biological effects, it should not also be forgotten that some bioactive molecules are prone to oxidation and can even exert pro-oxidant effects. In this sense, the objective of the present review is to provide a detailed overview on plant-derived bioactives in oxidative stress-related disorders. Specifically, the role of phytochemicals as antioxidants and pro-oxidant agents is carefully addressed, as is its therapeutic relevance in disease prevention. Finally, an eye-opening look in overall evidence in humans is also ensured.
REVIEW | doi:10.20944/preprints202211.0320.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: aging; longevity; supplements; geroprotectors; SIRT1; NAD+; NMN; resveratrol; nutraceuticals; age-related diseases; flavonoids; senolytics; healthspan
Online: 17 November 2022 (02:51:11 CET)
Disrupted biological function, manifesting through the hallmarks of aging, poses as one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease of nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds to restore youthful NAD+ levels. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NMN supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.
ARTICLE | doi:10.20944/preprints202103.0620.v1
Subject: Medicine And Pharmacology, Veterinary Medicine Keywords: risk factors; longevity, death; euthanasia; retirement; longitudinal; TeamMate; working dogs; herding dogs; working farm dogs
Online: 25 March 2021 (14:24:34 CET)
Working farm dogs are essential to many livestock farmers. Little is known about factors that influence dogs’ risk of being lost from work. This paper explores risk factors for farm dogs being lost through death, euthanasia and retirement. All enrolled dogs were working and minimum 18 months old. Five data collection rounds were done over four years. Data about dogs were collected from owners and dogs were given physical examinations by veterinarians. Dogs that were lost from work were counted and owner-reported reasons for loss were recorded. Multivariable logistic regression modelling was used to investigate risk factors for loss. Of 589 dogs, 81 were lost from work. Of these, 59 dogs died or were euthanized and 22 were retired. Farm dogs tended to reach high ages, with 38% being 10 years or older when last examined. Acute injury or illness was the most commonly owner-reported reason for loss. Age group (P < 0.0001) and lameness (P = 0.04, OR = 1.8) significantly affected dogs’ risk being lost. These results expand our knowledge about factors that affect health, welfare and work in farm dogs. Further investigation into reasons for lameness may help improve health and welfare in working farm dogs.
ARTICLE | doi:10.20944/preprints201910.0252.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: ferric ammonium citrate; deferoxamine; 2,2′-bipyridine; iron homeostasis; ISC; mitochondrial clearance; longevity; starvation; Parkinson’s disease
Online: 22 October 2019 (05:01:43 CEST)
Lifespan extension was recently achieved in Caenorhabditis elegans nematodes by mitochondrial stress and mitophagy, triggered via iron depletion. Conversely in man, deficient mitophagy due to Pink1/Parkin mutations triggers iron accumulation in patient brain and limits survival. We now aimed to identify murine fibroblast factors, which adapt their mRNA expression to acute iron manipulation, relate to mitochondrial dysfunction and may influence survival. After iron depletion, expression of the plasma membrane receptor Tfrc with its activator Ireb2, the mitochondrial membrane transporter Abcb10, the heme-release factor Pgrmc1, the heme-degradation enzyme Hmox1, the heme-binding cholesterol metabolizer Cyp46a1, as well as the mitophagy regulators Pink1 and Parkin showed a negative correlation to iron levels. After iron overload, these factors did not change expression. Conversely, a positive correlation of mRNA levels with both conditions of iron availability was observed for the endosomal factors Slc11a2 and Steap2, as well as for the iron-sulfur-cluster (ISC)-containing factors Ppat, Bdh2 and Nthl1. Positive correlation only after iron depletion was observed for the iron export factor Slc40a1, mitochondrial iron transporters Slc25a28, Abcb7 and Abcb8, mitochondrial ISC-containing factors Glrx5, Nfu1, Bola1 and Abce1, cytosolic Aco1 and Tyw5, as well as nuclear Dna2, Elp3, Pold1 and Prim2. The latter are regulators of nucleotide synthesis and DNA quality control, which have known importance for growth and lifespan. The only Pink1-/- triggered transcript modulation was the reduced expression of the ISC-containing ribosomal factor Abce1. These mammalian findings support previous fly data that Pink1 influences co-translational quality control via Abce1, as well as mitophagy. Our findings provide the first systematic survey how iron dosage triggers homeostatic transcriptional regulations and elucidate how iron deprivation results in mitophagy.
REVIEW | doi:10.20944/preprints202011.0728.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: mitochondrial permeability transition; aging; longevity; aging-driven degenerative disease; Reactive Oxygen Species; mitophagy; autophagy; Parkinson’s disease
Online: 30 November 2020 (12:53:43 CET)
The activity of the mitochondrial Permeability Transition Pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging Reactive Oxygen Species, Ca2+ and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either, inhibit, or accelerate aging, retards, or enhance the progression of aging-driven degenerative diseases, and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s Diseases. The Increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.
ARTICLE | doi:10.20944/preprints201907.0144.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: longevity; life expectancy; CODAS syndrome; Perrault syndrome; protease target substrates; respiratory complex assembly; oxidative stress; glutathione pathway; lysosomal degradation; fidelity protein synthesis
Online: 10 July 2019 (10:18:22 CEST)
Research on healthy ageing shows that lifespan reductions are often caused by mitochondrial dysfunction. Thus, it is very interesting that the deletion of mitochondrial matrix peptidase LonP1 was observed to abolish embryogenesis, while deletion of the mitochondrial matrix peptidase ClpP prolonged survival. To unveil the targets of each enzyme, we documented the global proteome of LonP1+/- mouse embryonal fibroblasts (MEF), for comparison with ClpP-/- depletion. Proteomic profiles of LonP1+/- MEF generated by label-free mass spectrometry were further processed with the STRING webserver Heidelberg for protein interactions. ClpP was previously reported to degrade Eral1 as a chaperone involved in mitoribosome assembly, so ClpP deficiency triggers accumulation of mitoribosomal subunits and inefficient translation. LonP1+/- MEF also showed Eral1 accumulation, but no systematic effect on mitoribosomal subunits. In contrast to ClpP-/- profiles, several components of the respiratory complex I membrane arm were accumulated, whereas the upregulation of numerous innate immune defense components was similar. Overall, LonP1 as opposed to ClpP appears to have no effect on translational machinery, instead it shows enhanced respiratory dysfunction; this agrees with reports on the human CODAS syndrome caused by LonP1 mutations.