Exploring Patterns of Human Mortality and Aging: A Reliability Theory Viewpoint.

The most important manifestation of aging is an increased risk of death with advancing age, a mortality pattern characterized by empirical regularities known as mortality laws. We highlight three significant ones: the Gompertz law, compensation effect of mortality (CEM), and late-life mortality deceleration and describe new developments in this area. It is predicted that CEM should result in declining relative variability of mortality at older ages. The quiescent phase hypothesis of negligible actuarial aging at younger adult ages is tested and refuted by analyzing mortality of the most recent birth cohorts. To comprehend the aging mechanisms, it is crucial to explain the observed empirical mortality patterns. As an illustrative example of data-directed modeling and the insights it provides, we briefly describe two different reliability models applied to human mortality patterns. The explanation of aging using a reliability theory approach aligns with evolutionary theories of aging, including idea of chronic phenoptosis. This alignment stems from their focus on elucidating the process of organismal deterioration itself, rather than addressing the reasons why organisms are not designed for perpetual existence. This article is a part of a special issue of the journal that commemorates the legacy of the eminent Russian scientist Vladimir Petrovich Skulachev (1935-2023) and his bold ideas about evolution of biological aging and phenoptosis.

Actuarial Aging Rates in Human Cohorts.

Aging rate is an important characteristic of human aging. Attempts to measure aging rates through the Gompertz slope parameter lead to a conclusion that actuarial aging rates were stable during the most of the 20th century, but recently demonstrate an increase over time in the majority of studied populations. These findings were made using cross-sectional mortality data rather than by the analysis of mortality of real birth cohorts. In this study we analyzed historical changes of actuarial aging rates in human cohorts. The Gompertz parameters were estimated in the age interval 50-80 years using data on one-year cohort age-specific death rates from the Human Mortality Database (HMD). Totally, data for 2,294 cohorts of men and women from 76 populations were analyzed. Changes of the Gompertz slope parameter in the studied cohorts revealed two distinct patterns for actuarial aging rate. In higher mortality Eastern European countries actuarial aging rates showed continuous decline from the 1910 to 1940 birth cohort. In lower mortality Western European countries, Australia, Canada, Japan, New Zealand, and USA actuarial aging rates declined from the 1910th to approximately 1930th cohort and then increased. Overall, in 50 out of 76 populations (68%) actuarial aging rate demonstrated decreasing pattern of change over time. Compensation effect of mortality (CEM) was tested for the first time in human cohorts and the cohort species-specific lifespan was estimated. CEM was confirmed using cohort data and human cohort species-specific lifespan estimates were similar to the estimates obtained for the cross-sectional data published earlier.

On the Commentary by Anatoly I. Mikhalsky Published in Biochemistry (Moscow), Vol. 88, No. 1, pp. 162-163 (2023).

Caution is needed in using cohort data when studying age-related mortality dynamics, because mortality depends not only on age, but also on the changing living conditions over time. A hypothesis is proposed for further testing that the actuarial aging rate may even decrease in more recent birth cohorts of people due to improved living conditions.

Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Association with Symptom Severity.

Recent studies provide some evidence for the contribution of antibody-mediated autoimmune mechanisms to the nature of fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Much attention was paid to the autoantibodies (AAb) targeting G protein-coupled receptors as natural components of the immune system. However, the natural AAb network is much more extensive, and has not been previously investigated in these disorders. The enzyme immunoassays ELI-Viscero-Test and ELI-Neuro-Test were used to determine changes in serum content of 33 natural AAb to neural, organ-specific and non-tissue-specific autoantigens (a) in 11 ME/CFS patients with comorbid FM; (b) in 11 ME/CFS patients without FM; (c) in 11 healthy controls. Individual AAb profiles and their correlation with some clinical symptoms were analyzed. Both patients with ME/CFS(-)FM and ME/CFS(+)FM were characterized by more frequent and pronounced deviations in the immunoreactivity to GABA-receptors than healthy controls. Although the level of other natural AAb did not differ between study groups, AAb correlation signatures were altered in patients compared to healthy controls. Both in patients and healthy controls the level of natural AAb to various neural and tissue-specific antigens correlated with the severity of fatigue, bodily pain, depression, anxiety, physical and mental health-related quality of life. Notably, widely different correlation patterns were observed between study groups. Findings from this pilot study provide some evidence that the homeostasis of autoimmune relationships, which are possibly a physiological part of our immune system, may be altered in FM and ME/CFS. The correlation of disease-induced perturbations in individual AAb profiles with some clinical symptoms may arise from the immune system's ability to reflect qualitative and quantitative changes in antigenic composition of the body.

Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease. Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or "healthy but tired" (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria. ß2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999). In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed. An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.

New Clinical Phenotype of the Post-Covid Syndrome: Fibromyalgia and Joint Hypermobility Condition.

Fibromyalgia can be defined as a chronic pain condition, affecting the musculoskeletal system, etiology and pathophysiology of which is sufficiently understudied. Despite the fact that many authors consider this entity to be a manifestation of central sensitization, and not an autoimmune disease, the high prevalence of fibromyalgia in patients with post-COVID-19 conditions requires taking a fresh look at the causes of the disease development. During the patient examination, the authors identified a combination of symptoms that occurs so often, that they can be carefully described as a clinical pattern. These manifestations include young age, female gender, joint hypermobility, the onset of pain after COVID-19, physical traumatization of one particular tendon and the development of the fibromyalgia pain syndrome during the next several weeks. As well as an increase in the titer of antinuclear antibodies and some other systemic inflammation factors. It can be assumed with great caution that local damage to the connective tissue in patients with joint hypermobility, having COVID-19 as a trigger factor can lead to the development of fibromyalgia syndrome. This article presents three clinical cases that illustrated this hypothesis.

CVD-Synthesis of N-CNT Using Propane and Ammonia.

N-CNT is a promising material for various applications, including catalysis, electronics, etc., whose widespread use is limited by the significant cost of production. CVD-synthesis using a propane-ammonia mixture is one of the cost-effective processes for obtaining carbon nanomaterials. In this work, the CVD-synthesis of N-CNT was conducted in a traditional bed reactor using catalyst: (Al0,4Fe0,48Co0,12)2O3 + 3% MoO3. The synthesized material was characterized by XPS spectroscopy, ASAP, TEM and SEM-microscopy. It is shown that the carbon material contains various morphological structures, including multiwalled carbon nanotubes (MWCNT), bamboo-like structures, spherical and irregular sections. The content of structures (bamboo-like and spherical structure) caused by the incorporation of nitrogen into the carbon nanotube structure depends on the synthesis temperature and the ammonia content in the reaction mixture. The optimal conditions for CVD-synthesis were determined: the temperature range (650-700 °C), the composition (C3H8/NH3 = 50/50%) and flow rate of the ammonia-propane mixture (200 mL/min).

Intensification of Dry Reforming of Methane on Membrane Catalyst: Confirmation and Development of the Hypothesis.

This article presents an analysis of kinetic studies of dry methane reforming (DRM) in a reactor with a membrane catalyst (RMC) in the modes of a contactor with "diffusion" and "forced" mass transfer. Comparison of the specific rate constants of the methane dissociation reaction in membrane and traditional reactors confirmed the phenomenon of intensification of dry methane reforming in a membrane catalyst (MC). It has been experimentally established that during DRM, a temperature gradient arises in the channels of the pore structure of the membrane catalyst, characterized by a decrease in temperature towards the inner volume of the MC, and initiates the phenomenon of thermal slip. The features of this phenomenon are highlighted and must be considered in the analysis of kinetic data. The main provisions of the hypothesis explaining the effect of intensification by the occurrence of thermal slip in the channels of the pore structure of the MC are formulated. The proposed hypothesis, based on thermal slip, explains the difference in rate constants of traditional and membrane catalysts, and substantiates the phenomenological scheme of DRM stages in a reactor with a membrane catalyst.

A Novel Integrated Biomarker for Evaluation of Risk and Severity of Coronary Atherosclerosis, and Its Validation.

OBJECTIVE: To assess the feasibility of a combination of biochemical and imaging parameters for estimation of risk and severity of coronary atherosclerosis (CA), and to verify the created integrated biomarker (i-BIO) on independent cohort. METHODS: Two cohorts of patients admitted to the hospital for coronary angiography and ultrasound carotid dopplerography were enrolled into the study (n = 205 and n = 216, respectively). The extent of CA was assessed by Gensini Score (GS). RESULTS: According to GS, participants were distributed as follows: atherosclerosis-free (GS = 0), CA of any stage (GS > 0), subclinical CA (GS < 35), severe CA (GS ≥ 35). Based on the analysis of mathematical models, including biochemical and imaging parameters, we selected and combined the most significant variables as i-BIO. The ability of i-BIO to detect the presence and severity of CA was estimated using ROC-analysis with cut-off points determination. Risk of any CA (GS > 0) at i-BIO > 4 was 7.3 times higher than in those with i-BIO ≤ 4; risk of severe CA (GS ≥ 35) at i-BIO ≥ 9 was 3.1 times higher than at i-BIO < 9. Results on the tested cohort confirmed these findings. CONCLUSIONS: The i-BIO > 4 detected CA (GS > 0) with sensitivity of 87.9%, i-BIO ≥ 9 excluded patients without severe CA (GS < 35), specificity 79.8%. Validation of i-BIO confirmed the feasibility of i-BIO > 4 to separate patients with any CA with sensitivity 76.2%, and of i-BIO ≥ 9 to exclude atherosclerosis-free subjects with specificity of 84.0%.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown etiology, sharing a similar clinical presentation with the increasingly recognized post-COVID syndrome. We performed the first cross-sectional study of ME/CFS in a community population in Russia. Then we described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders. Of the cohort of 76 individuals who suggested themselves as suffering from ME/CFS, 56 were diagnosed with ME/CFS by clinicians according to ≥1 of the four most commonly used case definitions. Of the cohort of 14 individuals with post-COVID-19 syndrome, 14 met the diagnostic criteria for ME/CFS. The severity of anxiety/depressive symptoms did not correlate with the severity of fatigue either in ME/CFS or in post-COVID ME/CFS. Still, a positive correlation was found between the severity of fatigue and 20 other symptoms of ME/CFS related to the domains of "post-exertional exhaustion", "immune dysfunction", "sleep disturbances", "dysfunction of the autonomic nervous system", "neurological sensory/motor disorders" and "pain syndromes". Immunological abnormalities were identified in 12/12 patients with ME/CFS according to the results of laboratory testing. The prevalence of postural orthostatic tachycardia assessed in the active orthostatic test amounted to 37.5% in ME/CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02). There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group. Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified laser doppler flowmetry pattern corresponded to the hyperemic form of microcirculation disorders usually observed in acute inflammatory response or in case of systemic vasoconstriction failure.

Assessment of Hearing and Vestibular Functions in a Post-COVID-19 Patient: A Clinical Case Study.

SARS-CoV-2 infection may cause such complications as post-COVID-19 syndrome, which includes chronic fatigue, myalgia, arthralgia, as well as a variety of neurological manifestations, e.g., neuropathy of small fibers, hearing and vestibular dysfunction, and cognitive impairment. This clinical case describes a 41-year-old patient suffering from post-COVID-19 syndrome and chronic fatigue syndrome. A detailed examination was performed, including an in-depth study of peripheral and central hearing and vestibular functions, as well as small nerve fibers length and density in the skin and cornea of the eye. Contrary to expectations, no peripheral nervous system dysfunction was detected, despite the presence of dizziness and gait instability in the patient. Hearing tests (gap detection test and dichotic test) showed central auditory processing disorders. The evaluated lesion in the processing of temporal and verbal auditory information can be a significant factor contributing to additional overload of the neural activity and leading to chronic fatigue when performing daily activities in patients with CFS and post-COVID-19 complications.

Protective Effects of Familial Longevity Decrease With Age and Become Negligible for Centenarians.

It is known that biological relatives of long-lived individuals demonstrate lower mortality and longer life span compared to relatives of shorter-lived individuals, and at least part of this advantage is likely to be genetic. Less information, however, is available about effects of familial longevity on age-specific mortality trajectories. We compared mortality patterns after age 50 years for 10 045 siblings of US centenarians and 12 308 siblings of shorter-lived individuals (died at age 65 years). Similar comparisons were made for sons and daughters of longer-lived parents (both parents lived 80 years and more) and shorter-lived parents (both parents lived less than 80 years) within each group of siblings. Although relatives of longer-lived individuals have lower mortality at younger ages compared to relatives of shorter-lived individuals, this mortality advantage practically disappears by age 100 years. To validate this observation further, we analyzed the survival of 3 408 US centenarians born in 1890-1897 with known information on maternal and paternal life span. We found using the Cox proportional hazards model that both maternal and paternal longevity (life span 80+ years) is not significantly associated with survival after age 100 years. The results are compatible with the predictions of reliability theory of aging suggesting higher initial levels of system redundancy (reserves) in individuals with protective familial/genetic background and hence lower initial mortality. Heterogeneity hypothesis is another possible explanation for the observed phenomena.

Trends in Human Species-Specific Lifespan and Actuarial Aging Rate.

The compensation effect of mortality (CEM) was tested and species-specific lifespan was estimated using data on one-year age-specific death rates from the Human Mortality Database (HMD). CEM was confirmed using this source of the data and human species-specific lifespan estimates were obtained, which were similar to the estimates published before. Three models (Gompertz-Makeham, Gompertz-Makeham with mean-centered age, and Gompertz) produced similar estimates of the species-specific lifespan. These estimates demonstrated some increase over time. Attempts to measure aging rates through the Gompertz slope parameter led to the conclusion that actuarial aging rates were stable during most of the 20th century, but recently demonstrated an increase over time in the majority (74%) of studied populations. This recent phenomenon is most likely caused by more rapid historical decline of mortality at the younger adult age groups compared to the older age groups, thus making the age gradient in mortality steeper over time. There is no biomedical reason to believe that human aging rates accelerated recently, so that the actuarial aging rate is probably not a good measure of true aging rate (rate of functional loss). Therefore, better measures of aging rate need to be developed.

Formation of Molybdenum Blue Nanoparticles in the Organic Reducing Area.

Molybdenum blue dispersions were synthesized by reducing an acidic molybdate solution with glucose, hydroquinone and ascorbic acid. The influence of the H/Mo molar ratio on the rate of formation of molybdenum particles was established. For each reducing agent, were determined the rate constant and the order of the particle formation and were established the conditions for the formation of aggregative stable dispersion with the maximum concentration of particles. The dispersed phase is represented by toroidal molybdenum oxide nanoclusters, which was confirmed by the results of UV/Vis, FTIR, XPS spectroscopy and DLS.

Transport Reagents through the Pore Structure of a Membrane Catalyst under Isothermal and Non-Isothermal Conditions.

The article presents the results of an experimental comparison of methane transport in the pore structure of a membrane catalyst under isothermal and non-isothermal Knudsen diffusion conditions. It is shown that under the conditions of non-isothermal Knudsen diffusion in the pore structure of the membrane catalyst, there is a coupling of dry reforming of the methane (DRM) and gas transport, which leads to the intensification of this process. The reasons for the intensification are changes in the mechanism of gas transport, an increase in the rate of mass transfer, and changes in the mechanism of some stages of the DRM. The specific rate constant of the methane dissociation reaction on a membrane catalyst turned out to be an order of magnitude (40 times) higher than this value on a traditional (powder) catalyst.

Molybdenum-Tungsten Blue Nanoparticles as a Precursor for Ultrafine Binary Carbides.

Herein, we demonstrate a promising method for the synthesis of ultrafine carbide particles using dispersions of molybdenum-tungsten nanoparticles. Dispersions of molybdenum-tungsten blue nanoparticles with different initial molar ratios of molybdenum/tungsten were synthesized through the reduction of molybdate and tungstate ions by ascorbic acid in an acidic medium (pH = 1.0-2.5). Molybdenum-tungsten blue nanoparticles were characterized by ultraviolet-visual (UV-VIS), infrared (FTIR), and X-ray photoelectron (XPS) spectroscopies; transmission electronic microscopy (TEM); and dynamic light scattering (DLS). We demonstrated that molybdenum-tungsten blue nanoparticles belong to toroidal polyoxometalate clusters (λmax = 680-750 nm) with a predominant particle size of 4.0 nm. Molybdenum-tungsten blue dispersions were shown to be monodispersed systems with a small particle size and long-term stability (>30 days) and are suitable for further catalytic applications.

Simple Synthesis of Molybdenum Carbides from Molybdenum Blue Nanoparticles.

In recent years, much attention has been paid to the development of a new flexible and variable method for molybdenum carbide (Mo2C) synthesis. This work reports the applicability of nano-size clusters of molybdenum blue to molybdenum carbide production by thermal treatment of molybdenum blue xerogels in an inert atmosphere. The method developed made it possible to vary the type (glucose, hydroquinone) and content of the organic reducing agent (molar ratio R/Mo). The effect of these parameters on the phase composition and specific surface area of molybdenum carbides and their catalytic activity was investigated. TEM, UV-VIS spectroscopy, DTA, SEM, XRD, and nitrogen adsorption were performed to characterize nanoparticles and molybdenum carbide. The results showed that, depending on the synthesis conditions, variants of molybdenum carbide can be formed: α-Mo2C, η-MoC, or γ-MoC. The synthesized samples had a high specific surface area (7.1-203.0 m2/g) and meso- and microporosity. The samples also showed high catalytic activity during the dry reforming of methane. The proposed synthesis method is simple and variable and can be successfully used to obtain both Mo2C-based powder and supports catalysts.

Small Fiber Neuropathy in Sarcoidosis.

Sarcoidosis (SC) is a granulomatous disease of an unknown origin. The most common SC-related neurological complication is a small fiber neuropathy (SFN) that is often considered to be the result of chronic inflammation and remains significantly understudied. This study aimed to identify the clinical and histological correlates of small fiber neuropathy in sarcoidosis patients. The study was performed in 2018-2019 yy and included 50 patients with pulmonary sarcoidosis (n = 25) and healthy subjects (n = 25). For the clinical verification of the SFN, the "Small Fiber Neuropathy Screening List" (SFN-SL) was used. A punch biopsy of the skin was performed followed by enzyme immunoassay analysis with PGP 9.5 antibodies. Up to 60% of the sarcoidosis patients reported the presence of at least one complaint, and it was possible that these complaints were associated with SFN. The most frequent complaints included dysfunctions of the cardiovascular and musculoskeletal systems and the gastrointestinal tract. A negative, statistically significant correlation between the intraepidermal nerve fiber density (IEND) and SFN-SL score was revealed. In patients with pulmonary sarcoidosis, small fiber neuropathy might develop as a result of systemic immune-mediated inflammation. The most common symptoms of this complication were dysautonomia and mild sensory dysfunction.