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

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

Telomeres and aging: on and off the planet!

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

A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence.

Aging and senescence are characterized by pervasive transcriptional dysfunction, including increased expression of transposons and introns. Our aim was to elucidate mechanisms behind this increased expression. Most transposons are found within genes and introns, with a large minority being close to genes. This raises the possibility that transcriptional readthrough and intron retention are responsible for age-related changes in transposon expression rather than expression of autonomous transposons. To test this, we compiled public RNA-seq datasets from aged human fibroblasts, replicative and drug-induced senescence in human cells, and RNA-seq from aging mice and senescent mouse cells. Indeed, our reanalysis revealed a correlation between transposons expression, intron retention, and transcriptional readthrough across samples and within samples. Both intron retention and readthrough increased with aging or cellular senescence and these transcriptional defects were more pronounced in human samples as compared to those of mice. In support of a causal connection between readthrough and transposon expression, analysis of models showing induced transcriptional readthrough confirmed that they also show elevated transposon expression. Taken together, our data suggest that elevated transposon reads during aging seen in various RNA-seq dataset are concomitant with multiple transcriptional defects. Intron retention and transcriptional readthrough are the most likely explanation for the expression of transposable elements that lack a functional promoter.

A single-cell atlas of lung homeostasis reveals dynamic changes during development and aging.

Aging is a global challenge, marked in the lungs by function decline and structural disorders, which affects the health of the elderly population. To explore anti-aging strategies, we develop a dynamic atlas covering 45 cell types in human lungs, spanning from embryonic development to aging. We aim to apply the discoveries of lung's development to address aging-related issues. We observe that both epithelial and immune cells undergo a process of acquisition and loss of essential function as they transition from development to aging. During aging, we identify cellular phenotypic alternations that result in reduced pulmonary compliance and compromised immune homeostasis. Furthermore, we find a distinctive expression pattern of the ferritin light chain (FTL) gene, which increases during development but decreases in various types of lung cells during the aging process.

Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk.

BACKGROUND: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex. RESULTS: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02-5.61, P = 1.1E-03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status. CONCLUSIONS: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia.

Nonlinear DNA methylation trajectories in aging male mice.

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

Pregnancy is linked to faster epigenetic aging in young women.

A central prediction of evolutionary theory is that energy invested into reproduction comes at the expense of somatic maintenance and repair, accelerating biological aging. Supporting this prediction are findings that high fertility among women predicts shorter lifespan and poorer health later in life. However, biological aging is thought to begin before age-related health declines, limiting the applicability of morbidity and mortality for studying the aging process earlier in life. Here, we examine the relationship between reproductive history and biological aging in a sample of young (20 to 22yo) men and women from the Cebu Longitudinal Health and Nutrition Survey, located in the Philippines (n = 1,735). We quantify biological aging using six measures, collectively known as epigenetic clocks, reflecting various facets of cellular aging, health, and mortality risk. In a subset of women, we test whether longitudinal changes in gravidity between young and early-middle adulthood (25 to 31yo) are associated with changes in epigenetic aging during that time. Cross-sectionally, gravidity was associated with all six measures of accelerated epigenetic aging in women (n = 825). Furthermore, longitudinal increases in gravidity were linked to accelerated epigenetic aging in two epigenetic clocks (n = 331). In contrast, the number of pregnancies a man reported fathering was not associated with epigenetic aging among same-aged cohort men (n = 910). These effects were robust to socioecological, environmental, and immunological factors, consistent with the hypothesis that pregnancy accelerates biological aging and that these effects can be detected in young women in a high-fertility context.

Aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function.

DNA damage contributes to the aging of hematopoietic stem cells (HSCs), yet the underlying molecular mechanisms are not fully understood. In this study, we identified a heterogeneous functional role of microcephalin (MCPH1) in the nucleus and cytoplasm of mouse HSCs. In the nucleus, MCPH1 maintains genomic stability, whereas in the cytoplasm, it prevents necroptosis by binding with p-RIPK3. Aging triggers MCPH1 translocation from cytosol to nucleus, reducing its cytoplasmic retention and leading to the activation of necroptosis and deterioration of HSC function. Mechanistically, we found that KAT7-mediated lysine acetylation within the NLS motif of MCPH1 in response to DNA damage facilitates its nuclear translocation. Targeted mutation of these lysines inhibits MCPH1 translocation and, consequently, compromises necroptosis. The dysfunction of necroptosis signaling, in turn, improves the function of aged HSCs. In summary, our findings demonstrate that DNA damage-induced redistribution of MCPH1 promotes HSC aging and could have broader implications for aging and aging-related diseases.

Single-cell transcriptome atlas in C57BL/6 mice encodes morphological phenotypes in the aging kidneys.

C57BL/6 mice are frequently utilized as murine models with the desired genetic background for altertion in multiple research contexts. So far, there is still a lack of comprehensive kidney morphology and single-cell transcriptome atlas at all stages of growth of C57BL/6 mice. To provide an interactive set of reference standards for the scientific community, we performed the current study to investigate the kidney's development throughout the capillary-loop stage until senescence. Eight groups, with five to six mice each, represented embryonic stage (embryos 18.5 days), suckling period (1 day after birth), juvenile stage (1 month old), adulthood (containing 3 months old, 6 months old and 10 months old), reproductive senescence stage (20 months old), and post-senescence stage (30 months old), respectively. With age, the thickness of the glomerular basement membrane (GBM) was increased. Notably, GBM knobs appeared at three months and became frequent with age. Using single-cell transcriptome data, we evaluated how various biological process appear in particular cell types and investigated the potential mechanism of formation of GBM konbs. In conclusion, having access to detailed kidney morphology and single-cell transcriptome maps from C57BL/6 mice at various developmental stages of C57BL/6 mice would be a novel and major resource for biological research and testing of prospective therapeutic approaches.

[Postnatal epigenome-mediated aging control and global trends].

The epigenome can adequately regulate the on/off states of genes in response to external environmental factors and stress. In recent years, it has been observed that the epigenome, which is modulated through DNA methylation, histone modifications, and chromatin remodeling, changes with age. Alterations in the epigenome lead to the loss of cell-specific epigenome/identity, which in turn triggers a decline in tissue function. In mammals, postnatal epigenomic variations are not only caused by metabolic diseases, such as diabetes or DNA damage, but also by social stress and infectious diseases. Unlike Genome-Wide Association Studies (GWAS), dynamically changing epigenomes, along with their cellular roles, need to be established as objective biomarkers in conjunction with various biological signals, such as walking speed, brain waves, and clinical data. The biological age/aging clock, determined by methylated DNA, has attracted attention, and calorie restriction not only slows the progression of aging, but also seems to suppress it. However, as indicated by gene expression analysis in aging mice, aging is not a linear model, but is represented by nonlinear dynamic changes. Consequently, the development of experimental models and analytical methods that enhance temporal resolution through time-series analysis, tailored to spatial resolution, such as cell distribution and organ specificity, is progressing. Moreover, in recent years, in addition to anti-aging efforts targeting epigenomic variations, global attention has increasingly focused on research and development aimed at rejuvenating treatments, thus leading to the birth of many biotech companies. Aging Hallmarks such as inflammation, stem cells, metabolism, genomic instability, and autophagy, interact closely with the epigenome. Various postnatal and reversible epigenomic controls of aging, including Yamanaka factors (OKSM and OSK), are now entering a new phase. In the future, the development of aging control using diverse modalities, such as mRNA, artificial peptides, and genome editing, is expected, along with an improved molecular understanding of aging and identification of useful biomarkers.

Translating genetic findings to epigenetics: identifying the mechanisms associated with aging after high-radiation exposure on earth and in space.

Purpose: Exposure to radiation is a health concern within and beyond the Earth's atmosphere for aircrew and astronauts in their respective austere environments. The biological effects of radiation exposure from a multiomics standpoint are relatively unexplored and stand to shed light on tailored monitoring and treatment for those in these career fields. To establish a reference variable for genetic damage, biological age seems to be closely associated with the effect of radiation. Following a genetic-based study, this study explores the epigenetic landscape of radiation exposure along with its associative effects on aging processes. Methods: We imported the results of the genetics-based study that was a secondary analysis of five publicly available datasets (noted as Data1). The overlap of these genes with new data involving methylation data from two datasets (noted as Data2) following similar secondary analysis procedures is the basis of this study. We performed the standard statistical analysis on these datasets along with supervised and unsupervised learning to create preranked gene lists used for functional analysis in Ingenuity Pathway Analysis (IPA). Results: There were 664 genes of interest from Data1 and 577 genes from Data2. There were 40 statistically significant methylation probes within 500 base pairs of the gene's transcription start site and 10 probes within 100 base pairs, which are discussed in depth. IPA yielded 21 significant pathways involving metabolism, cellular development, cell death, and diseases. Compared to gold standards for gestational age, we observed relatively low error and standard deviation using newly identified biomarkers. Conclusion: We have identified 17 methylated genes that exhibited particular interest and potential in future studies. This study suggests that there are common trends in oxidative stress, cell development, and metabolism that indicate an association between aging processes and the effects of ionizing radiation exposure.

ARDS and aging: TYMS emerges as a promising biomarker and therapeutic target.

Background: Acute Respiratory Distress Syndrome (ARDS) is a common condition in the intensive care unit (ICU) with a high mortality rate, yet the diagnosis rate remains low. Recent studies have increasingly highlighted the role of aging in the occurrence and progression of ARDS. This study is committed to investigating the pathogenic mechanisms of cellular and genetic changes in elderly ARDS patients, providing theoretical support for the precise treatment of ARDS. Methods: Gene expression profiles for control and ARDS samples were obtained from the Gene Expression Omnibus (GEO) database, while aging-related genes (ARGs) were sourced from the Human Aging Genomic Resources (HAGR) database. Differentially expressed genes (DEGs) were subjected to functional enrichment analysis to understand their roles in ARDS and aging. The Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning pinpointed key modules and marker genes, with ROC curves illustrating their significance. The expression of four ARDS-ARDEGs was validated in lung samples from aged mice with ARDS using qRT-PCR. Gene set enrichment analysis (GSEA) investigated the signaling pathways and immune cell infiltration associated with TYMS expression. Single-nucleus RNA sequencing (snRNA-Seq) explored gene-level differences among cells to investigate intercellular communication during ARDS onset and progression. Results: ARDEGs are involved in cellular responses to DNA damage stimuli, inflammatory reactions, and cellular senescence pathways. The MEmagenta module exhibited a significant correlation with elderly ARDS patients. The LASSO, RRF, and XGBoost algorithms were employed to screen for signature genes, including CKAP2, P2RY14, RBP2, and TYMS. Further validation emphasized the potential role of TYMS in the onset and progression of ARDS. Immune cell infiltration indicated differential proportion and correlations with TYMS expression. SnRNA-Seq and cell-cell communication analysis revealed that TYMS is highly expressed in endothelial cells, and the SEMA3 signaling pathway primarily mediates cell communication between endothelial cells and other cells. Conclusion: Endothelial cell damage associated with aging could contribute to ARDS progression by triggering inflammation. TYMS emerges as a promising diagnostic biomarker and potential therapeutic target for ARDS.

Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice.

An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process ("the mitochondrial hypothesis of aging"). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower - not higher - than in wildtype, thus apparently invalidating the "mitochondrial hypothesis of aging". We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wildtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + carnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly, even during active oxidative phosphorylation (as would be ongoing physiologically), higher ROS rates were seen in the mtDNA-mutator mitochondria than in wildtype. Thus, when examined under physiological conditions, mitochondrial ROS production rates are indeed increased in mtDNA-mutator mitochondria. While this does not prove the validity of the mitochondrial hypothesis of aging, it may no longer be said to be negated in this respect. This paper is dedicated to the memory of Professor Vladimir P. Skulachev.

AgeMeta: Quantitative Gene Expression Database of Mammalian Aging.

AgeMeta is a database that provides systemic and quantitative description of mammalian aging at the level of gene expression. It encompasses transcriptomic changes with age across various tissues of humans, mice, and rats, based on a comprehensive meta-analysis of 122 publicly available gene expression datasets from 26 studies. AgeMeta provides an intuitive visual interface for quantification of aging-associated transcriptomics at the level of individual genes and functional groups of genes, allowing easy comparison among various species and tissues. Additionally, all the data in the database can be downloaded and analyzed independently. Overall, this work contributes to the understanding of the complex network of biological processes underlying mammalian aging and supports future advancements in this field. AgeMeta is freely available at: https://age-meta.com/.

Calculating Aging: Analysis of Survival Curves in the Norm and Pathology, Fluctuations in Mortality Dynamics, Characteristics of Lifespan Distribution, and Indicators of Lifespan Variation.

The article describes the history of studies of survival data carried out at the Research Institute of Physico-Chemical Biology under the leadership of Academician V. P. Skulachev from 1970s until present, with special emphasis on the last decade. The use of accelerated failure time (AFT) model and analysis of coefficient of variation of lifespan (CVLS) in addition to the Gompertz methods of analysis, allows to assess survival curves for the presence of temporal scaling (i.e., manifestation of accelerated aging), without changing the shape of survival curve with the same coefficient of variation. A modification of the AFT model that uses temporal scaling as the null hypothesis made it possible to distinguish between the quantitative and qualitative differences in the dynamics of aging. It was also shown that it is possible to compare the data on the survival of species characterized by the survival curves of the original shape (i.e., "flat" curves without a pronounced increase in the probability of death with age typical of slowly aging species), when considering the distribution of lifespan as a statistical random variable and comparing parameters of such distribution. Thus, it was demonstrated that the higher impact of mortality caused by external factors (background mortality) in addition to the age-dependent mortality, the higher the disorder of mortality values and the greater its difference from the calculated value characteristic of developed countries (15-20%). For comparison, CVLS for the Paraguayan Ache Indians is 100% (57% if we exclude prepuberty individuals as suggested by Jones et al.). According to Skulachev, the next step is considering mortality fluctuations as a measure for the disorder of survival data. Visual evaluation of survival curves can already provide important data for subsequent analysis. Thus, Sokolov and Severin [1] found that mutations have different effects on the shape of survival curves. Type I survival curves generally retains their standard convex rectangular shape, while type II curves demonstrate a sharp increase in the mortality which makes them similar to a concave exponential curve with a stably high mortality rate. It is noteworthy that despite these differences, mutations in groups I and II are of a similar nature. They are associated (i) with "DNA metabolism" (DNA repair, transcription, and replication); (ii) protection against oxidative stress, associated with the activity of the transcription factor Nrf2, and (iii) regulation of proliferation, and (or these categories may overlap). However, these different mutations appear to produce the same result at the organismal level, namely, accelerated aging according to the Gompertz's law. This might be explained by the fact that all these mutations, each in its own unique way, either reduce the lifespan of cells or accelerate their transition to the senescent state, which supports the concept of Skulachev on the existence of multiple pathways of aging (chronic phenoptosis).

Epigenetic age estimation of wild mice using faecal samples.

Age is a key parameter in population ecology, with a myriad of biological processes changing with age as organisms develop in early life then later senesce. As age is often hard to accurately measure with non-lethal methods, epigenetic methods of age estimation (epigenetic clocks) have become a popular tool in animal ecology and are often developed or calibrated using captive animals of known age. However, studies typically rely on invasive blood or tissue samples, which limit their application in more sensitive or elusive species. Moreover, few studies have directly assessed how methylation patterns and epigenetic age estimates compare across environmental contexts (e.g. captive or laboratory-based vs. wild animals). Here, we built a targeted epigenetic clock from laboratory house mice (strain C57BL/6, Mus musculus) using DNA from non-invasive faecal samples, and then used it to estimate age in a population of wild mice (Mus musculus domesticus) of unknown age. This laboratory mouse-derived epigenetic clock accurately predicted adult wild mice to be older than juveniles and showed that wild mice typically increased in epigenetic age over time, but with wide variation in epigenetic ageing rate among individuals. Our results also suggested that, for a given body mass, wild mice had higher methylation across targeted CpG sites than laboratory mice (and consistently higher epigenetic age estimates as a result), even among the smallest, juvenile mice. This suggests wild and laboratory mice may display different CpG methylation levels from very early in life and indicates caution is needed when developing epigenetic clocks on laboratory animals and applying them in the wild.

The Causality between Human Immunoglobulin G (IgG) N-Glycosylation and Aging: A Mendelian Randomization Study.

BACKGROUND: Immunoglobulin G (IgG) N-glycosylation is considered a potential biomarker for aging and various pathological conditions. However, whether these changes in IgG N-glycosylation are a consequence or a contributor to the aging process remains unclear. This study aims to investigate the causality between IgG N-glycosylation and aging using Mendelian randomization (MR) analysis. METHODS: We utilized genetic variants associated with IgG N-glycosylation traits, the frailty index (FI), and leukocyte telomere length (LTL) from a previous genome-wide association study (GWAS) on individuals of European ancestry. Two-sample and multivariable MR analyses were conducted, employing the inverse-variance weighted (IVW) method. Sensitivity analyses were performed to assess potential confounding factors. RESULTS: Using the IVW method, we found suggestive evidence of a causal association between GP14 and FI (ß 0.026, 95% CI 0.003 to 0.050, p = 0.027) and LTL (ß -0.020, 95% CI -0.037 to -0.002, p = 0.029) in the two-sample MR analysis. In the multivariable MR analysis, suggestive evidence was found for GP23 and FI (ß -0.119, 95% CI -0.219 to -0.019, p = 0.019) and GP2 and LTL (ß 0.140, 95% CI 0.020 to 0.260, p = 0.023). CONCLUSIONS: In conclusion, our results supported a potentially causal effect of lower GP23 levels on an advanced aging state. Additional verification is required to further substantiate the causal relationship between glycosylation and aging.

Expression of TLR2, IL-1ß, and IL-10 Genes as a Possible Factor of Successful or Pathological Aging in Nonagenarians.

The expression of the gene of pattern recognition receptor TLR2, proinflammatory cytokine IL-1ß, and anti-inflammatory cytokine IL-10 was analyzed in the peripheral blood of nonagenarians (n=219; mean age 92.1 years, 77 men and 142 women) in comparison with healthy young donors (n=24; mean age 22.5 years, 16 women and 8 men). Nonagenarians were interviewed, medical records were analyzed, and a comprehensive geriatric assessment was performed according to the Clinical Guidelines on Frailty. The level of gene expression was determined by real-time PCR. The participation of inflammatory mechanisms in the immunosenescence was revealed. It was shown that increased expression of IL1B and TLR2 genes is associated with the development of frailty in nonagenarians and can be a factor of pathological aging. Increased expression of IL10 gene can be considered as a factor of successful aging in nonagenarians.