Advances in Gerontology最新文献

We have studied the concentration of vitamins A (retinol) and E (α-tocopherol) in the tissues of the bank vole (Myodes (Clethrionomys) glareolus) and common shrew (Sorex araneus) inhabiting the northern periphery of its natural habitat. The distribution of vitamin A in the common shrew and bank vole tissues is similar: the highest concentration is found in the liver, and the lowest level is found in the heart. Age-related differences in the retinol concentration are detected in the kidneys of the two species, as well as in the skeletal muscle of the shrew. A significantly lower vitamin E concentration is found in all organs of young shrews before wintering, compared to adult overwintered animals, while in the bank vole no such age-related differences are found. Interspecies differences in the levels of vitamins A and E in the liver of overwintered animals are revealed. The results obtained show that the concentration of vitamins A and E in the tissues of the bank vole and the common shrew is determined by metabolic processes and the ecological characteristics of the species. The level of vitamins in the common shrew depends largely on age.

Parkinson’s disease (PD) is a neurodegenerative disease, the main predisposing factor of which is aging. Today, the majority of people suffering from PD are over 65 years of age. This disease leads to motor and nonmotor deficits, significantly reducing the quality and length of life. One of the symptoms of nonmotor manifestations is a decrease in cognitive function, including impaired memory and learning ability. Fear is a response to a threatening situation that is always real and well defined. Fear memory is a form of memory that remains stable throughout the life of an organism. Using neurotoxic and genetic models of laboratory animals, it is possible to reproduce the symptoms of the disease to decipher the pathological features, genetic factors, and mechanisms underlying PD. In addition, disease modeling makes it possible to study the mechanisms of fear memory for a given disease with assessment of the response of fear conditioning to a given context or sound/light as the conditioned signal (contextual and signal response to fear conditioning), and the conditioned response of passive avoidance. The cognitive and motor symptoms of PD refer to different brain regions. The structures that play a critical role in fear-memory mechanisms are the hippocampus and the amygdala. The hippocampus is responsible for “creating context” and the amygdala is responsible for “creating fear,” and as a result of the convergence of signals, a fear-memory trace is formed. Using mice and rat models of PD, experimental evidence has been obtained for the significant contribution of the hippocampus and amygdala to the mechanisms of fear-memory impairment. In addition, deficits in fear memory in Parkinson-like conditions correlate with α-syn neuropathology (alpha-synuclein deposits) in the hippocampus and amygdala. Dysfunction of the nigrostriatal system through the mechanisms of neuroinflammation and oxidative stress also causes the impairment of fear memory. Thus, the mechanism of fear-memory deficit in PD may be a change in information processing in the hippocampus/prefrontal cortex/amygdala networks due to identified impairment in synaptic plasticity, the development of neuroinflammation, oxidative stress, and α-syn-neuropathology.

Studying the mechanisms of age-related changes in vascular reactions and applying the acquired knowledge in clinics can help reduce complications and mortality from diseases of the cardiovascular system, the frequency of which increases with age. This study is important because with aging, endothelial dysfunction increases and cerebral circulation disorders caused by the occurrence of ischemic foci are observed. One of the main elements in the regulation of vascular tone, along with many important mechanisms, is potassium ion channels. In this work, we study age-related changes in the role of calcium-activated potassium channels (BK_Ca) in the acetylcholine-mediated dilation of cerebral arteries in Wistar rats, since their contribution to vasodilation in aging is poorly understood. Using intravital microphotography (×470), we compare the responses of pial arteries to acetylcholine chloride (ACh, 10^–7 M, 5 min) in the absence and against the background of BK_Ca blockade with tetraethylammonium chloride (TEA, 2 mM, 5 min) in Wistar rats 4, 6, 9, 18 and 24 months old. Changes in the contribution of BK_Ca to vascular dilation are assessed by changes in the number of dilations of the pial arteries upon exposure to ACh after BK_Ca blockade, measuring the width of vessels in 3 separate groups of arteries: small (with a diameter of less than 20 μm), medium (20–40 μm), and large (more than 40 μm). It has been shown that ACh-induced dilation depends on the initial diameter of the arteries. The inhibition of BK_Ca activity in 4-month-old rats reduces the number of ACh-induced dilations in all groups of arteries studied. Compared to 4-month-old rats, in 6- and 18-month-old rats the contribution of BK_Ca channels to the dilation of small arteries is reduced, in 9- and 24-month-old rats the contribution of BK_Ca channels to the dilation of medium arteries is increased; the contribution of BK_Ca to the dilation of large arteries decreases starting from 6 months of age. Dilation of the pial arteries of Wistar rats at the age of 4–24 months depends on the initial diameter of the vessel. BK_Ca play a significant role in the ACh-mediated dilation of these vessels. Age-related impairments in the contribution of these channels to the ACh-mediated dilation of pial arteries develop gradually, have a wave-like course and depend on the diameter of the arteries. The identified disturbances in the functional activity of BK_Ca can serve as therapeutic targets for the creation of new technologies for the treatment of age-related lesions of cerebral vessels.

In modern conditions of constant adverse effects on living organisms, such as environmental pollution or global climate change, the study of deeply conserved mechanisms that contribute to the adaptation of animals to such conditions is of particular relevance. The influence of stress suffered at early stages of development on the formation of fitness and the endocrine status of adults has been repeatedly shown in various species of mammals. However, similar studies on arthropods have not previously been carried out, and one of the key differences between the ontogeny of holometabolous insects from mammals is metamorphosis, including the formation of a pupa and the histolysis of tissues and organs with the subsequent formation of new structures from its products and imaginal discs, which are formed in early ontogenesis. As a result, an almost new organism, an imago, is formed. Are the metabolic changes that occurred in the insect’s body under the influence of unfavorable external influences before the imaginal moult preserved, or does metamorphosis “erase” them? To answer this question, the effect of heat stress experienced by the larvae of Drosophila melanogaster on such signs of adult fitness as longevity, response to acute heat stress, and resistance to it is studied. The study results show that early mortality is reduced due to larval stress in both D. melanogaster males and females, although no changes in the maximum lifespan are recorded. At the same time, early stress leads to a decrease in resistance to acute heat stress and a corresponding drop in alkaline-phosphatase activity in both sexes. Thus, we can conclude that heat stress experienced by D. melanogaster during the larval stage is not “reset” by metamorphosis, and causes significant changes in the fitness of adult individuals.

The authors try to consider the current situation with experimental gerontological research aimed at finding means to slow down aging and prolong life (geroprotectors/anti-aging drugs). The importance of correct defining aging as a set of age-related changes in the body, leading to an increase in the probability of its death, is emphasized, as well as the importance of attention to which lifespan (average, maximum, median, species-specific) changes under the influence of geroprotectors. It is noted that prolonging the life of non-aging animals with an exponential survival curve can hardly be considered a geroprotective effect. It is emphasized that the rate of aging and lifespan are not always strictly related, so the impact on one of these two indicators does not necessarily affect the second. The methodological aspects of works devoted to the study of the influence of diet restriction/modification on aging and lifespan are analyzed. The need for correct selection of a control group of animals in experimental gerontological studies is noted. According to the authors, such animals should not have any pathologies or genetic defects in order to exclude the possible influence of the studied factors on such abnormalities, and not on the aging process per se. In this regard, the authors do not consider antibiotics or drugs/vaccines against COVID-19 to be geroprotective, although the former led to the most significant increase of average lifespan in the 20th century, and the latter offset its decline in recent years caused by this infection. It is noted that the current situation in experimental gerontology makes it very desirable to have a thorough discussion on the question of what can still be considered geroprotectors/anti-aging drugs. It is proposed to organize such a discussion in the journal Advances in Gerontology.

Transcription regulation is required for correct differential gene expression, which determines the development and function of all cells in the organism throughout the lifespan, ensuring adaptability to continuously changing environments. Altered transcriptional regulation causes gene function rearrangements, which alter the phenotype, including aging rate and lifespan. In this regard, there has recently been a great interest in the application of technologies based on the “rejuvenation” of the transcriptome due to the modification of regulatory mechanisms that determine the level and pattern of gene expression. To develop such an approach to slowing down aging and prolonging life, it is important to understand how the transcription of individual genes and the entire transcriptome changes with age, as well as how the transcriptional machinery of the cell and mechanisms of transcription regulation are related to the aging process and longevity control. Addressing these issues in the review, we discuss the prospects of using transcription regulation as a strategy for extending life and improving its quality.

Age is a main risk factor for age-related macular degeneration (AMD), a complex multifactorial neurodegenerative retinal disease that is becoming the leading cause of vision loss in people over 55 years in developed countries. The risk of developing and rate of progression of AMD, as well as response to therapy, depend on the interaction of multiple genetic and environmental factors. In advanced stage, AMD is classified into dry atrophic (dry) or neovascular (wet) form. Intravitreal injection of anti-vascular endothelial growth factor agents is currently the first-line therapy for neovascular AMD. Unfortunately, therapy for dry AMD is still challenging, owing to an insufficient knowledge of the exact pathogenetic mechanisms. Considering the heterogeneity of AMD and the complexity of influencing age-dependent physiological processes, aging and immune disorders, the most realistic seems to be the further development of antiangiogenic therapy with an expansion of the range of targets, prolongation of their action and improvement of the delivery system. The neuroprotective potential of exogenous neurotrophins for retinal neurons has been proven; however, in order to develop effective drugs for the dry form of AMD based on them, it is necessary to resolve the issue of ways to effectively deliver them to the retina. In this review we discuss the current data on the AMD pathophysiology with focus on the role of vascular growth factors and neurotrophins.

The impact of vitamin D3 deficiency on the risk and prognosis of numerous chronic diseases has been actively studied for years. Recent research demonstrates that vitamin D is not merely involved in controlling calcium– phosphorus metabolism, but can also enhance insulin sensitivity, and decrease the incidence of type-2 diabetes mellitus (T2DM), obesity, and the autoimmune destruction of pancreatic β cells. The influence of vitamin D3 on some cardiometabolic risk factors and cardiovascular disease (CVD) is described. Thus, it seems quite relevant to study the role of vitamin D3 in the development of arterial-wall changes in the case of T2DM and insulin resistance (IR) and their relationship with the biology of telomeres. The study is aimed at investigating the relationship between vitamin D3 deficiency and vascular-wall condition by the telomere biology in patients with varying insulin sensitivity. The cross-sectional study involves 305 patients (106 men and 199 women) aged 51.5 ± 13.3 SU. All patients undergo laboratory and instrumental tests; the morphofunctional state of the vascular wall is studied. The telomere length and telomerase activity are determined using polymerase chain reaction. Altogether 18 out of 248 patients (7.2%) are found to have normal vitamin D3 levels (above 30 ng/mL). Vitamin D3 insufficiency or deficiency is determined in 92.8% of subjects. The increase in the vitamin D3 deficiency is accompanied by an increased level of fasting glucose, HbA1c and its elevated concentration, HOMA index, glucose disorders up to T2DM, and higher vascular stiffness. Telomerase activity in the group with vitamin D3 deficiency is significantly lower than in the groups with vitamin D3 insufficiency and normal concentrations. Multiple linear regression analysis shows that they are independently associated with vitamin D3 in T2DM (B = 1.43; st. OR 0.106; p = 0.0001), vascular stiffness (B = 0.075; st. OR 2.11; p = 0.017), fasting glucose (B = 0.169; st. OR 1.62; p = 0.004), HbA1c level (B = 0.062; st. OR 7.4; p = 0.001) and the presence of “short” telomeres (B = 0.09; st. OR 1.154; p = 0.001). Receiver-operating characteristic (ROC) analysis reveals relationships between the BMI (0.634, p = 0.001), duration of T2DM (0.651, p = 0.022), high intima-media thickness (0.614, p = 0.004), vascular stiffness (0.605, p < 0.001), HbA1c (0.588, p = 0.022), and the presence of vitamin D3 deficiency. In persons with varying insulin sensitivity, from insulin resistance to T2DM, it is advisable to assess the vitamin D3 levels for effective prevention of arterial-wall changes in addition to traditional CVD risk factors. Vitamin D3 deficiency requires the active prevention of metabolic disorders and vascular changes.

Describing mortality dynamics using average indicators without considering variability can yield average results, impeding the analysis of survival-curve patterns during periods of significant mortality spikes, especially at the oldest or youngest ages. Therefore, instead of the generally accepted Gompertz method, other methods are increasingly used, which rely on comparisons of various demographic indicators. In humans, chronic phenoptosis, in contrast to age-independent acute phenoptosis, manifests as a rectangularization of the survival curve with a simultaneous increase in the life expectancy at birth due to the advancement of social, scientific, and technological progress. Rectangularization is difficult to notice solely by examining the optimal coefficients in the Gompertz—Makeham equation, primarily because of the inevitable calculation errors. This can be avoided by calculating demographic indicators based on the spread of the life expectancy: Keyfitz entropy, Gini coefficient, and coefficient of variation of lifespan. We examine several sub-Gompertzian models of mortality growth with age, which describe the aging of nematodes and insects. Within the sub-Gompertzian model of aging, the increase in mortality with age in invertebrates is quantified as a rectangularization of the survival function estimated by these demographic indicators. On the other hand, the increasing rectangularization of the survival function with the development of scientific and technological progress, demonstrated by a decrease in the Keyfitz entropy, along with a simultaneous increase in the life expectancy in humans, also aligns well with the hypothesis of an age-dependent increase in mortality in mammals overall. Calculations on aging models demonstrate the effectiveness of using Keyfitz entropy and the Gini coefficient as important demographic indicators. The use of these indicators seems preferable, especially for nematodes, where the sub-Gompertzian model of aging is applicable, and for vertebrates, primarily mammals, with certain restrictions, the Gompertz–Makeham law is applicable. Approaches that consider dynamic age-related shifts in improved survival, such as studying imbalances in lifespan, enhance our understanding of the mechanisms of aging. This, in turn, will contribute to the development of more accurate methods for assessing the effects of biologically active substances used in gerontology, such as anti-aging drugs and geroprotectors.

Many organs undergo negative changes during aging that affect their functions and ability to regenerate. In particular, the kidneys become more susceptible to acute injury and are more likely to develop chronic kidney disease with age. One of the reasons for this may be a decrease in the number of resident renal progenitor cells. This review addresses age-related changes that occur in the kidneys at the histological and molecular levels, including those related to the cell cycle, mitochondrial function, oxidative stress, and chronic inflammation. We described the available studies on resident renal stem cells, their niches, morphology, possible markers, and the dynamics of their numbers during the aging process. The reasons for the age-related decline in renal regenerative potential are considered based on molecular and cellular mechanisms.