Papers by Anastasia Shindyapina
Distinct longevity mechanisms across and within species and their association with aging
Cell
In vivo cyclic induction of the FOXM1 transcription factor delays natural and progeroid aging phenotypes and extends healthspan
Nature Aging
Frontiers in Aging, 2022
Aging is characterized by increased mortality, functional decline, and exponential increases in t... more Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that expand with age in otherwise normal tissues. In the hematopoietic system, this phenomenon has generally been referred to as “clonal hematopoiesis of indeterminate potential” (CHIP) when it applies to a subset of clones in which mutations in driver genes of hematologic malignancies ...
The possibility that pace of development is tightly connected to aging is supported by the fact t... more The possibility that pace of development is tightly connected to aging is supported by the fact that the onset of reproduction is associated with lifespan and that many longevity interventions target growth and development. However, it has been unknown whether targeting development with pharmacological intervention can lead to a longer lifespan. To test this possibility, we subjected genetically diverse UMHET3 mice to the mTOR inhibitor rapamycin for the first 45 days of life and followed them up until death. Treated mice grew slower, with most of the deceleration occurring in the first week, and remained smaller for their entire lives. Their reproductive age was delayed but without affecting offspring numbers. The treatment was sufficient to extend the median lifespan by 10%, with the most effect in males, and to preserve better health as measured by frailty index, gait speed, and glucose and insulin tolerance tests. Mechanistically, the liver transcriptome of treated mice was youn...
Coronary artery disease (CAD) is one of the main and common types of cardio-vascular diseases, wh... more Coronary artery disease (CAD) is one of the main and common types of cardio-vascular diseases, which occurs as a result of atherosclerotic plaque formation in blood vessels during ageing. Increased levels of calcium deposition were detected in blood vessels of patients with CAD and linked to early CAD formation. Here, we hypothesized that these two processes are linked and possess common molecular basis, which is realized through regulation of target genes involved in calcification and CAD. To validate our hypothesis, we used a bioinformatics approach, in which micro- and mRNA data of blood samples from 12 patients with CAD were analyzed. Several high quality data sets were extracted from GEO database, analyzed by commercially available program TR GeneGo Metacore, statistically verified by J-express algorithms and analyzed using statistical methods implemented in R. Analysis of GEO data revealed patterns of differentially expressed microRNAs in patients with CAD. We have shown the i...
Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic ... more Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species. Our epigenetic maximum lifespan predictor corroborated the extended lifespan in growth hormone receptor knockout mice and rapamycin treated mice. Across dog breeds, epigenetic maximum lifespan correlates positively with breed lifespan but negatively with breed size. Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species. The epigenetic estimators of maximum lifespan and other life history traits will be useful for characterizing understudied species ...
While cancer is an age-related disease, most studies focus on genetically engineered younger mous... more While cancer is an age-related disease, most studies focus on genetically engineered younger mouse models. Here, we uncover how cancer develops as a consequence of the naturally aged immune system in mice. B-cell lymphoma frequently occurs in aged mice and is associated with increased cell size, splenomegaly, and a novel clonal B-cell population. Age-emergent B cells clonally expand outside of germinal centers driven by somatic mutations, activated c-Myc and hypermethylated promoters, and both genetically and epigenetically recapitulate human follicular and diffuse-large B-cell lymphomas. Mechanistically, mouse cancerous B cells originate from age-associated B cells, which are atypical memory B cells. Age-associated B cells secrete a spectrum of proinflammatory cytokines and activate paracrinally the expression of c-Myc in surrounding B cells. Although clonal B cells are a product of an aging microenvironment, they evolve being self-sufficient and support malignancy when transferred...
L Dorokhov YL, Shindyapina AV, Sheshukova EV, Komarova TV. Metabolic Methanol: Molecular Pathways... more L Dorokhov YL, Shindyapina AV, Sheshukova EV, Komarova TV. Metabolic Methanol: Molecular Pathways and Physiological Roles. Physiol Rev 95: 603–644, 2015; doi:10.1152/physrev.00034.2014.—Methanol has been historically considered an exogenous product that leads only to pathological changes in the human body when consumed. However, in normal, healthy individuals, methanol and its short-lived oxidized product, formaldehyde, are naturally occurring compounds whose functions and origins have received limited attention. There are several sources of human physiological methanol. Fruits, vegetables, and alcoholic beverages are likely the main sources of exogenous methanol in the healthy human body. Metabolic methanol may occur as a result of fermentation by gut bacteria and metabolic processes involving S-adenosyl methionine. Regardless of its source, low levels of methanol in the body are maintained by physiological and metabolic clearance mechanisms. Although human blood contains small amo...
Multi-omic rejuvenation and lifespan extension upon exposure to youthful circulation
SUMMARYHeterochronic parabiosis (HPB) is known for its functional rejuvenation effects across sev... more SUMMARYHeterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on the biological age of organisms and their long-term health remains unknown. Here, we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the biological age of blood and liver based on epigenetic analyses across several clock models on two independent platforms; remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a comprehensive multi-omic rejuvenation effect. In addition, old HPB mice showed transcriptome changes opposite to aging, but akin to several lifespan-extending interventions. Altogether, we reveal that long-te...
ABSTRACTAging is often perceived as a degenerative process caused by random accrual of cellular d... more ABSTRACTAging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosin...
Communications Medicine, 2021
Background Epidemiological studies revealed that the elderly and those with comorbidities are mos... more Background Epidemiological studies revealed that the elderly and those with comorbidities are most affected by COVID-19, but it is important to investigate shared genetic mechanisms between COVID-19 risk and aging. Methods We conducted a multi-instrument Mendelian Randomization analysis of multiple lifespan-related traits and COVID-19. Aging clock models were applied to the subjects with different COVID-19 conditions in the UK-Biobank cohort. We performed a bivariate genomic scan for age-related COVID-19 and Mendelian Randomization analysis of 389 immune cell traits to investigate their effect on lifespan and COVID-19 risk. Results We show that the genetic variation that supports longer life is significantly associated with the lower risk of COVID-19 infection and hospitalization. The odds ratio is 0.31 (P = 9.7 × 10−6) and 0.46 (P = 3.3 × 10−4), respectively, per additional 10 years of life. We detect an association between biological age acceleration and future incidence and sever...
COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greate... more COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is highly contagious and often leads to severe viral pneumonia with respiratory failure and death in the elderly and subjects with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in Italy, Spain, South Korea, and China, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its majo...
Epidemiological studies have revealed that the elderly and those with co-morbidities are most sus... more Epidemiological studies have revealed that the elderly and those with co-morbidities are most susceptible to COVID-19. To understand the genetic link between aging and the risk of COVID-19, we conducted a multi-instrument Mendelian randomization analysis and found that the genetic variation that leads to a longer lifespan is significantly associated with a lower risk of COVID-19 infection. The odds ratio is 0.32 (95% CI: 0.18 to 0.57; P = 1.3 × 10-4) per additional 10 years of life, and 0.62 (95% CI: 0.51 to 0.77; P = 7.2 × 10-6) per unit higher log odds of surviving to the 90th percentile age. On the other hand, there was no association between COVID-19 susceptibility and healthspan (the lifespan free of the top seven age-related morbidities). To examine the relationship at the phenotypic level, we applied various biological aging clock models and detected an association between the biological age acceleration and future incidence and severity of COVID-19 infection for all subjects...
Heritability of human lifespan is 23-33% as evident from twin studies. Genome-wide association st... more Heritability of human lifespan is 23-33% as evident from twin studies. Genome-wide association studies explored this question by linking particular alleles to lifespan traits. However, genetic variants identified so far can explain only a small fraction of lifespan heritability in humans. Here, we report that the burden of rarest protein-truncating variants (PTVs) in two large cohorts is negatively associated with human healthspan and lifespan, accounting for 0.4 and 1.3 years of their variability, respectively. In addition, longer-living individuals possess both fewer rarest PTVs and less damaging PTVs. We further estimated that somatic accumulation of PTVs accounts for only a small fraction of mortality and morbidity acceleration and hence is unlikely to be causal in aging. We conclude that rare damaging mutations, both inherited and accumulated throughout life, contribute to the aging process, and that burden of ultra-rare variants in combination with common alleles better explain apparent heritability of human lifespan.
Scientific Reports, 2019
Studies of breast cancer therapy have examined the improvement of bispecific trastuzumab/pertuzum... more Studies of breast cancer therapy have examined the improvement of bispecific trastuzumab/pertuzumab antibodies interacting simultaneously with two different epitopes of the human epidermal growth factor receptor 2 (HER2). Here, we describe the creation and production of plant-made bispecific antibodies based on trastuzumab and pertuzumab plant biosimilars (bi-TPB-PPB). Using surface plasmon resonance analysis of bi-TPB-PPB antibodies binding with the HER2 extracellular domain, we showed that the obtained Kd values were within the limits accepted for modified trastuzumab and pertuzumab. Despite the ability of bi-TPB-PPB antibodies to bind to Fcγ receptor IIIa and HER2 oncoprotein on the cell surface, a proliferation inhibition assay did not reveal any effect until α1,3-fucose and β1,2-xylose in the Asn297-linked glycan were removed. Another approach to activating bi-TPB-PPB may be associated with the use of disulfiram (DSF) a known aldehyde dehydrogenase 2 (ALDH2) inhibitor. We found...
Genome-wide association studies often explore links between particular genes and phenotypes of in... more Genome-wide association studies often explore links between particular genes and phenotypes of interest. Known genetic variants, however, are responsible for only a small fraction of human lifespan variation evident from genetic twin studies. To account for the missing longevity variance, we hypothesized that the cumulative effect of deleterious variants may affect human longevity. Here, we report that the burden of rarest protein-truncating variants (PTVs) negatively impacts both human healthspan and lifespan in two large independent cohorts. Longer-living subjects have both fewer rarest PTVs and less damaging PTVs. In contrast, we show that the burden of frequent PTVs and rare non-PTVs is less deleterious, lacking association with longevity. The combined effect of rare PTVs is similar to that of known variants associated with longer lifespan and accounts for 1 − 2 years of lifespan variability. We further find that somatic accumulation of PTVs accounts for a minute fraction of mor...
In vivo cyclic induction of the FOXM1 transcription factor delays natural and progeroid aging phenotypes and extends healthspan
Nature Aging
The possibility that pace of development is tightly connected to aging is supported by the fact t... more The possibility that pace of development is tightly connected to aging is supported by the fact that the onset of reproduction is associated with lifespan and that many longevity interventions target growth and development. However, it has been unknown whether targeting development with pharmacological intervention can lead to a longer lifespan. To test this possibility, we subjected genetically diverse UMHET3 mice to the mTOR inhibitor rapamycin for the first 45 days of life and followed them up until death. Treated mice grew slower, with most of the deceleration occurring in the first week, and remained smaller for their entire lives. Their reproductive age was delayed but without affecting offspring numbers. The treatment was sufficient to extend the median lifespan by 10%, with the most effect in males, and to preserve better health as measured by frailty index, gait speed, and glucose and insulin tolerance tests. Mechanistically, the liver transcriptome of treated mice was youn...
Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic ... more Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species. Our epigenetic maximum lifespan predictor corroborated the extended lifespan in growth hormone receptor knockout mice and rapamycin treated mice. Across dog breeds, epigenetic maximum lifespan correlates positively with breed lifespan but negatively with breed size. Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species. The epigenetic estimators of maximum lifespan and other life history traits will be useful for characterizing understudied species ...
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Papers by Anastasia Shindyapina