MiMIR: R-shiny application to infer risk factors and endpoints from Nightingale Health's 1H-NMR metabolomics data.

MOTIVATION: 1H-NMR metabolomics is rapidly becoming a standard resource in large epidemiological studies to acquire metabolic profiles in large numbers of samples in a relatively low-priced and standardized manner. Concomitantly, metabolomics-based models are increasingly developed that capture disease risk or clinical risk factors. These developments raise the need for user-friendly toolbox to inspect new 1H-NMR metabolomics data and project a wide array of previously established risk models. RESULTS: We present MiMIR (Metabolomics-based Models for Imputing Risk), a graphical user interface that provides an intuitive framework for ad hoc statistical analysis of Nightingale Health's 1H-NMR metabolomics data and allows for the projection and calibration of 24 pre-trained metabolomics-based models, without any pre-required programming knowledge. AVAILABILITY AND IMPLEMENTATION: The R-shiny package is available in CRAN or downloadable at https://github.com/DanieleBizzarri/MiMIR, together with an extensive user manual (also available as Supplementary Documents to the article). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

All-Microwave Leakage Reduction Units for Quantum Error Correction with Superconducting Transmon Qubits.

Minimizing leakage from computational states is a challenge when using many-level systems like superconducting quantum circuits as qubits. We realize and extend the quantum-hardware-efficient, all-microwave leakage reduction unit (LRU) for transmons in a circuit QED architecture proposed by Battistel et al. This LRU effectively reduces leakage in the second- and third-excited transmon states with up to 99% efficacy in 220 ns, with minimum impact on the qubit subspace. As a first application in the context of quantum error correction, we show how multiple simultaneous LRUs can reduce the error detection rate and suppress leakage buildup within 1% in data and ancilla qubits over 50 cycles of a weight-2 stabilizer measurement.

High-Fidelity Controlled-Z Gate with Maximal Intermediate Leakage Operating at the Speed Limit in a Superconducting Quantum Processor.

Simple tuneup of fast two-qubit gates is essential for the scaling of quantum processors. We introduce the sudden variant (SNZ) of the net zero scheme realizing controlled-Z (CZ) gates by flux control of transmon frequency. SNZ CZ gates realized in a multitransmon processor operate at the speed limit of transverse coupling between computational and noncomputational states by maximizing intermediate leakage. Beyond speed, the key advantage of SNZ is tuneup simplicity, owing to the regular structure of conditional phase and leakage as a function of two control parameters. SNZ is compatible with scalable schemes for quantum error correction and adaptable to generalized conditional-phase gates useful in intermediate-scale applications.

Basal cell carcinoma genetic susceptibility increases the rate of skin ageing: a Mendelian randomization study.

BACKGROUND: Onset of basal cell carcinoma (BCC) is connected to skin ageing, but it is unclear whether higher BCC genetic susceptibility drives skin ageing. OBJECTIVES: To investigate whether loci increasing genetic susceptibility to BCC also drive multiple features of skin ageing, independently of confounding factors, using Mendelian randomization. METHODS: A Mendelian randomization study was conducted in older adults from the Leiden Longevity Study (N = 604). A total of 25 BCC loci, selected based on a published genome-wide association study on BCC (P-value < 5 × 10-8 ), were used as genetic instruments for the calculation of a standardized (mean = 0, SD = 1) weighted BCC genetic risk score. Based on facial photographs, we determined perceived age, and skin wrinkling and pigmented spot grading. RESULTS: A higher BCC genetic risk score was associated with a higher perceived age (adjusted for chronological age and sex) of 0.88 years (95% CI: 0.44, 1.31; P-value = 7.1e-5 ), greater wrinkling by 0.14 grades (95% CI: 0.05, 0.23; P-value = 2.3e-3 ), and greater pigmented spots by 0.17 grades (95% CI: 0.08, 0.25; P-value = 1.1e-4 ). These findings were weakened but still present after exclusion of gene variants in MC1R and IRF4 which have potential pleiotropic effects. CONCLUSIONS: Mechanisms influenced by genetic loci increasing susceptibility to BCC also drive skin ageing suggesting shared biology and shared targets for interventions.

Four-month metacarpal bone mineral density loss predicts radiological joint damage progression after 1†year in patients with early rheumatoid arthritis: exploratory analyses from the IMPROVED study.

AIM: To assess whether in early (rheumatoid) arthritis (RA) patients, metacarpal bone mineral density (BMD) loss after 4 months predicts radiological progression after 1 year of antirheumatic treatment. METHODS: Metacarpal BMD was measured 4 monthly during the first year by digital X-ray radiogrammetry (DXR-BMD) in patients participating in the IMPROVED study, a clinical trial in 610 patients with recent onset RA (2010 criteria) or undifferentiated arthritis, treated according to a remission (disease activity score<1.6) steered strategy. With Sharp/van der Heijde progression ≥0.5 points after 1 year (yes/no) as dependent variable, univariate and multivariate logistic regression analyses were performed. RESULTS: Of 428 patients with DXR-BMD results and progression scores available, 28 (7%) had radiological progression after 1 year. Independent predictors for radiological progression were presence of baseline erosions (OR (95% CI) 6.5 (1.7 to 25)) and early DXR-BMD loss (OR (95% CI) 1.5 (1.1 to 2.0)). In 366 (86%) patients without baseline erosions, early DXR-BMD loss was the only independent predictor of progression (OR (95% CI) 2.0 (1.4 to 2.9)). CONCLUSIONS: In early RA patients, metacarpal BMD loss after 4 months of treatment is an independent predictor of radiological progression after 1 year. In patients without baseline erosions, early metacarpal BMD loss is the main predictor of radiological progression.

Genetic reincarnation of workers as queens in the Eastern honeybee Apis cerana.

Thelytokous parthenogenesis, or the asexual production of female offspring, is rare in the animal kingdom, but relatively common in social Hymenoptera. However, in honeybees, it is only known to be ubiquitous in one subspecies of Apis mellifera, the Cape honeybee, A. mellifera capensis. Here we report the appearance of queen cells in two colonies of the Eastern honeybee Apis cerana that no longer contained a queen or queen-produced brood to rear queens from. A combination of microsatellite genotyping and the timing of the appearance of these individuals excluded the possibility that they had been laid by the original queen. Based on the genotypes of these individuals, thelytokous production by natal workers is the most parsimonious explanation for their existence. Thus, we present the first example of thelytoky in a honeybee outside A. mellifera. We discuss the evolutionary and ecological consequences of thelytoky in A. cerana, in particular the role thelytoky may play in the recent invasions by populations of this species.

Inheritance of thelytoky in the honey bee Apis mellifera capensis.

Asexual reproduction via thelytokous parthenogenesis is widespread in the Hymenoptera, but its genetic underpinnings have been described only twice. In the wasp Lysiphlebus fabarum and the Cape honey bee Apis mellifera capensis the origin of thelytoky have each been traced to a single recessive locus. In the Cape honey bee it has been argued that thelytoky (th) controls the thelytoky phenotype and that a deletion of 9 bp in the flanking intron downstream of exon 5 (tae) of the gemini gene switches parthenogenesis from arrhenotoky to thelytoky. To further explore the mode of inheritance of thelytoky, we generated reciprocal backcrosses between thelytokous A. m. capensis and the arrhenotokous A. m. scutellata. Ten genetic markers were used to identify 108 thelytokously produced offspring and 225 arrhenotokously produced offspring from 14 colonies. Patterns of appearance of thelytokous parthenogenesis were inconsistent with a single locus, either th or tae, controlling thelytoky. We further show that the 9 bp deletion is present in the arrhenotokous A. m. scutellata population in South Africa, in A. m. intermissa in Morocco and in Africanized bees from Brazil and Texas, USA, where thelytoky has not been reported. Thus the 9 p deletion cannot be the cause of thelytoky. Further, we found two novel tae alleles. One contains the previously described 9 bp deletion and an additional deletion of 7 bp nearby. The second carries a single base insertion with respect to the wild type. Our data are consistent with the putative th locus increasing reproductive capacity.

Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women.

BACKGROUND: Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. OBJECTIVE: To study associations between the d3-GHR polymorphism and symptomatic OA. METHODS: In the GARP (Genetics, osteoARthritis and Progression) study, we compared the d3-GHR polymorphism between OA patients and controls. GARP patients were genotyped for seven single nucleotide polymorphisms encompassing the d3-GHR gene, using rs4590183 as proxy for d3-GHR (pairwise r(2)=1). Binary logistic regression models with robust SEs were performed, stratified by sex. For replication, rs4590183 was tested in three additional cohorts. Fixed- and random-effects combined analyses were performed. RESULTS: In female GARP patients with severe familial OA, d3-GHR was associated with OA (adjusted OR 1.36 (95% CI 1.01 to 1.83), p=0.043), independently of age and body mass index. Combined analysis of all studies showed suggestive evidence for association between d3-GHR and OA (OR=1.17 (95% CI 1.04 to 1.30), p=0.008). Evidence was strongest in hip OA cases, without any evidence for heterogeneity. CONCLUSIONS: In women, the d3-GHR polymorphism was associated with symptomatic OA, especially at the hip site.

Why acquiesce? Worker reproductive parasitism in the Eastern honeybee (Apis cerana).

Most societies are vulnerable to rogue individuals that pursue their own interests at the expense of the collective entity. Societies often protect themselves from selfish behaviour by 'policing', thereby enforcing the interests of the collective over those of individuals. In insect societies, for example, selfish workers can activate their ovaries and lay eggs, exploiting the collective brood rearing system for individual benefit. Policing, usually in the form of oophagy of worker-laid eggs, controls selfish behaviour. Importantly, once an effective system of policing has evolved, the incentive for personal reproduction is lost, and 'reproductive acquiescence' in which ovary activation is rare or absent is predicted to evolve. Studies of social Hymenoptera have largely supported the prediction of worker 'acquiescence'; workers of most species where policing is well developed have inactive ovaries. However, the eastern honeybee Apis cerana appears to be an exception. A. cerana colonies are characterized by highly efficient policing, yet about 5% of workers have active ovaries, even when a queen is present. This suggests that the evolution of acquiescence is incomplete in A. cerana. We regularly sampled male eggs and pupae from four A. cerana colonies. Workers had high levels of ovary activation overall (11.7%), and 3.8% of assignable male eggs and 1.1% of assignable male pupae were worker-laid. We conclude that workers with active ovaries lay their eggs, but these rarely survive to pupation because of intense policing. We then used our findings as well as previously published data on A. cerana and A. mellifera to redo the meta-analysis on which reproductive acquiescence theory is based. Including data on both species did not affect the relationship between effectiveness of policing and levels of worker reproduction. Their inclusion did, however, seriously weaken the relationship between relatedness among workers and levels of worker reproduction. Our work thus suggests that relatedness among workers does not affect the probability that workers will attempt to reproduce, but that it is coercion by peers that limits worker reproduction.

Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.

AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic ß-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to type 2 diabetes in humans. METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for type 2 diabetes susceptibility in up to 25 000 people (8148 with type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*104) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*104) but again not in men (P = 0.34). CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific type 2 diabetes susceptibility gene.

1H-NMR metabolomics-based surrogates to impute common clinical risk factors and endpoints.

BACKGROUND: Missing or incomplete phenotypic information can severely deteriorate the statistical power in epidemiological studies. High-throughput quantification of small-molecules in bio-samples, i.e. 'metabolomics', is steadily gaining popularity, as it is highly informative for various phenotypical characteristics. Here we aim to leverage metabolomics to impute missing data in clinical variables routinely assessed in large epidemiological and clinical studies. METHODS: To this end, we have employed ∼26,000 1H-NMR metabolomics samples from 28 Dutch cohorts collected within the BBMRI-NL consortium, to create 19 metabolomics-based predictors for clinical variables, including diabetes status (AUC5-Fold CV = 0·94) and lipid medication usage (AUC5-Fold CV = 0·90). FINDINGS: Subsequent application in independent cohorts confirmed that our metabolomics-based predictors can indeed be used to impute a wide array of missing clinical variables from a single metabolomics data resource. In addition, application highlighted the potential use of our predictors to explore the effects of totally unobserved confounders in omics association studies. Finally, we show that our predictors can be used to explore risk factor profiles contributing to mortality in older participants. INTERPRETATION: To conclude, we provide 1H-NMR metabolomics-based models to impute clinical variables routinely assessed in epidemiological studies and illustrate their merit in scenarios when phenotypic variables are partially incomplete or totally unobserved. FUNDING: BBMRI-NL, X-omics, VOILA, Medical Delta and the Dutch Research Council (NWO-VENI).

Over-prescription of short-acting ß2-agonists for asthma in South Africa: Results from the SABINA III study.

Background: Asthma medication prescription trends, including those of short-acting ß2 -agonists (SABAs), are not well documented for South Africa (SA). Objectives: To describe demographics, disease characteristics and asthma prescription patterns in the SA cohort of the SABA use IN Asthma (SABINA) III study. Methods: An observational, cross-sectional study conducted at 12 sites across SA. Patients with asthma (aged ≥12 years) were classified by investigator-defined asthma severity, guided by the Global Initiative for Asthma (GINA) 2017 recommendations, and practice type (primary/ specialist care). Data were collected using electronic case report forms. Results: Overall, 501 patients were analysed - mean (standard deviation) age, 48.4 (16.6) years; 68.3% female - of whom 70.6% and 29.4% were enrolled by primary care physicians and specialists, respectively. Most patients were classified with moderate-to-severe asthma (55.7%; GINA treatment steps 3 - 5), were overweight or obese (70.7%) and reported full healthcare reimbursement (55.5%). Asthma was partly controlled/uncontrolled in 60.3% of patients, with 46.1% experiencing ≥1 severe exacerbations in the 12 months before the study visit. Overall, 74.9% of patients were prescribed ≥3 SABA canisters in the previous 12 months (over-prescription); 56.5% were prescribed ≥10 SABA canisters. Additionally, 27.1% of patients reported purchasing SABA over-the-counter (OTC); among patients with both SABA purchase and prescriptions, 75.4% and 51.5% already received prescriptions for ≥3 and ≥10 SABA canisters, respectively, in the preceding 12 months. Conclusion: SABA over-prescription and OTC purchase were common in SA, demonstrating an urgent need to align clinical practices with the latest evidence-based recommendations and regulate SABA OTC purchase to improve asthma outcomes. Study synopsis: What the study adds. This study provides valuable insights into asthma medication prescription patterns, particularly SABAs, across SA. Collection of this real-world data in patients treated in primary and specialty care demonstrates that SABA over-prescription and SABA OTC purchase are common, even in patients with mild asthma. These findings will enable clinicians and policymakers to make targeted changes to optimise asthma outcomes across the country Implications of the findings. SABA over-prescription represents a major public health concern in SA. Healthcare providers and policymakers will need to work together to promote educational initiatives aimed at patients, pharmacists and physicians, align clinical practices with the latest evidence-based recommendations, improve access to affordable medications and regulate SABA purchase without prescription.

A mixture model with random-effects components for classifying sibling pairs.

In healthy aging research, typically multiple health outcomes are measured, representing health status. The aim of this paper was to develop a model-based clustering approach to identify homogeneous sibling pairs according to their health status. Model-based clustering approaches will be considered on the basis of linear mixed effect model for the mixture components. Class memberships of siblings within pairs are allowed to be correlated, and within a class the correlation between siblings is modeled using random sibling pair effects. We propose an expectation-maximization algorithm for maximum likelihood estimation. Model performance is evaluated via simulations in terms of estimating the correct parameters, degree of agreement, and the ability to detect the correct number of clusters. The performance of our model is compared with the performance of standard model-based clustering approaches. The methods are used to classify sibling pairs from the Leiden Longevity Study according to their health status. Our results suggest that homogeneous healthy sibling pairs are associated with a longer life span. Software is available for fitting the new models.

Intrinsic electrical and thermal properties from single crystals of Na24Si136.

The observation of intrinsic structural, electrical, and thermal properties from measurements on single-crystal specimens of clathrate-II Na24Si136 is reported, revealing metallic conduction in agreement with electronic structure calculations. Low-temperature heat capacity measurements corroborate a substantial electronic density of states at the Fermi level, and reveal an Einstein-like mode that can be attributed to Na guest "rattling". The large thermal conductivity of Na24Si136, compared to literature data for other intermetallic clathrates, can be understood in terms of the predominant electronic contribution for the fully filled Na24Si136 composition.

Protecting quantum entanglement from leakage and qubit errors via repetitive parity measurements.

Protecting quantum information from errors is essential for large-scale quantum computation. Quantum error correction (QEC) encodes information in entangled states of many qubits and performs parity measurements to identify errors without destroying the encoded information. However, traditional QEC cannot handle leakage from the qubit computational space. Leakage affects leading experimental platforms, based on trapped ions and superconducting circuits, which use effective qubits within many-level physical systems. We investigate how two-transmon entangled states evolve under repeated parity measurements and demonstrate the use of hidden Markov models to detect leakage using only the record of parity measurement outcomes required for QEC. We show the stabilization of Bell states over up to 26 parity measurements by mitigating leakage using postselection and correcting qubit errors using Pauli-frame transformations. Our leakage identification method is computationally efficient and thus compatible with real-time leakage tracking and correction in larger quantum processors.

Noise improves collective decision-making by ants in dynamic environments.

Recruitment via pheromone trails by ants is arguably one of the best-studied examples of self-organization in animal societies. Yet it is still unclear if and how trail recruitment allows a colony to adapt to changes in its foraging environment. We study foraging decisions by colonies of the ant Pheidole megacephala under dynamic conditions. Our experiments show that P. megacephala, unlike many other mass recruiting species, can make a collective decision for the better of two food sources even when the environment changes dynamically. We developed a stochastic differential equation model that explains our data qualitatively and quantitatively. Analysing this model reveals that both deterministic and stochastic effects (noise) work together to allow colonies to efficiently track changes in the environment. Our study thus suggests that a certain level of noise is not a disturbance in self-organized decision-making but rather serves an important functional role.

Genomic studies in ageing research: the need to integrate genetic and gene expression approaches.

Genome-wide and hypothesis-based approaches to the study of ageing and longevity have been dominated by genetic investigations. To identify essential mechanisms of a complex trait such as ageing in higher species, a holistic understanding of interacting pathways is required. More information on such interactions is expected to be obtained from global gene expression analysis if combined with genetic studies. Genetic sequence variation often provides a functional gene marker for the trait, whereas a gene expression profile may provide a quantitative biomarker representing complex cellular pathway interactions contributing to the trait. Thus far, gene expression studies have associated multiple pathways to ageing including mitochondrial electron transport and the oxidative stress response. However, most of the studies are underpowered to detect small age-changes. A systematic survey of gene expression changes as a function of age in human individuals and animal models is lacking. Well designed gene expression studies, especially at the level of biological processes, will provide hypotheses on gene-environmental interactions determining biological ageing rate. Cross-sectional studies monitoring the profile as a chronological marker of ageing must be integrated with prospective studies indicating which profiles represent biomarkers preceding and predicting physiological decline and mortality. New study designs such as the Leiden Longevity Study, including two generations of subjects from longevity families, aim to achieve these combined approaches.

Factors affecting the dynamics of the honeybee (Apis mellifera) hybrid zone of South Africa.

Hybrid zones are found wherever two populations distinguishable on the basis of heritable characters overlap spatially and temporally and hybridization occurs. If hybrids have lower fitness than the parental types a tension zone may emerge, in which there is a barrier to gene flow between the two parental populations. Here we discuss a hybrid zone between two honeybee subspecies, Apis mellifera capensis and A. m. scutellata and argue that this zone is an example of a tension zone. This tension zone is particularly interesting because A. m. capensis can be a lethal social parasite of A. m. scutellata. However, despite its parasitic potential, A. m. capensis appears to be unable to increase its natural range unassisted. We propose three interlinked mechanisms that could maintain the South African honeybee hybrid zone: (1) low fitness of intercrossed and genetically mixed colonies arising from inadequate regulation of worker reproduction; (2) higher reproductive success of A. m. scutellata via both high dispersal rates into the hybrid zone and increased competitiveness of males, countered by (3) the parasitic nature of A. m. capensis.

Short telomere length is associated with impaired cognitive performance in European ancestry cohorts.

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (ß=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (ß=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (ß=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (ß=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (ß=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (ß=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (ß=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

C. elegans DAF-12, Nuclear Hormone Receptors and human longevity and disease at old age.

In Caenorhabditis elegans, DAF-12 appears to be a decisive checkpoint for many life history traits including longevity. The daf-12 gene encodes a Nuclear Hormone Receptor (NHR) and is member of a superfamily that is abundantly represented throughout the animal kingdom, including humans. It is, however, unclear which of the human receptor representatives are most similar to DAF-12, and what their role is in determining human longevity and disease at old age. Using a sequence similarity search, we identified human NHRs similar to C. elegans DAF-12 and found that, based on sequence similarity, Liver X Receptor A and B are most similar to C. elegans DAF-12, followed by the Pregnane X Receptor, Vitamin D Receptor, Constitutive Andosteron Receptor and the Farnesoid X Receptor. Their biological functions include, amongst others, detoxification and immunomodulation. Both are processes that are involved in protecting the body from harmful environmental influences. Furthermore, the DAF-12 signalling systems seem to be functionally conserved and all six human NHRs have cholesterol derived compounds as their ligands. We conclude that the DAF-12 signalling system seems to be evolutionary conserved and that NHRs in man are critical for body homeostasis and survival. Genomic variations in these NHRs or their target genes are prime candidates for the regulation of human lifespan and disease at old age.