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Despite their biological importance, the role of stem cells in human aging remains to be elucidated. In this work, we applied a machine learning methodology to GTEx transcriptome data and assigned stemness scores to 17,382 healthy samples from 30 human tissues aged between 20 and 79 years. We found that ~60% of the studied tissues exhibit a significant negative correlation between the subject's age and stemness score. The only significant exception was the uterus, where we observed an increased stemness with age. Moreover, we observed that stemness is positively correlated with cell proliferation and negatively correlated with cellular senescence. Finally, we also observed a trend that hematopoietic stem cells derived from older individuals might have higher stemness scores. In conclusion, we assigned stemness scores to human samples and show evidence of a pan-tissue loss of stemness during human aging, which adds weight to the idea that stem cell deterioration may contribute to human aging.

GV1001, which mimics the activity of human telomerase reverse transcriptase, protects neural cells from amyloid beta (Aβ) toxicity and other stressors through extra-telomeric function, as noted in our prior in vitro studies. As per a recent phase II clinical trial, it improves cognitive function in patients with moderate to severe dementia. However, the underlying protective mechanisms remain unclear. This study aimed to investigate the effects of GV1001 on neurodegeneration, senescence, and survival in triple transgenic Alzheimer’s disease (3xTg-AD) mice. GV1001 (1 mg/kg) was subcutaneously injected into old 3xTg-AD mice thrice a week until the endpoint for sacrifice, and survival was analysed. Magnetic resonance imaging (MRI) and Prussian blue staining (PBS) were performed to evaluate entry of GV1001 entrance into the brain. Diverse molecular studies were performed to investigate the effect of GV1001 on neurodegeneration and cellular senescence in AD model mice, with a particular focus on BACE, amyloid beta1-42 (Aβ1-42), phosphorylated tau, volume of dentate gyrus, β-galactosidase positive cells, telomere length, telomerase activity, and ageing-associated proteins. GV1001 crossed the blood-brain barrier, as confirmed by assessing the status of ferrocenecarboxylic acid-conjugated GV1001 using magnetic resonance imaging and PBS. GV1001 increased the survival of 3xTg-AD mice. It decreased BACE and Aβ1-42 levels, neurodegeneration (i.e., reduced CA1, CA3 and dentate gyrus volume, decreased levels of senescence-associated β-galactosidase positive cells, and increased telomere length and telomerase activity), and levels of ageing-associated proteins. We suggest that GV1001 exerts anti-ageing effects in 3xTg-AD mice by reducing neurodegeneration and senescence, which contributes to improved survival.

Various immune pathways have been identified in the host, including TH1, TH2, TH3, TH9, TH17, TH22, TH1-like, and THαβ immune reactions. While TH2 and TH9 responses primarily target multicellular parasites, host immune pathways directed against viruses, intracellular microorganisms (such as bacteria, protozoa, and fungi), and extracellular microorganisms can employ programmed cell death mechanisms to initiate immune responses or execute effective strategies for pathogen elimination. The types of programmed cell death involved include apoptosis, autophagy, pyroptosis, ferroptosis, necroptosis, and NETosis. Specifically, apoptosis is associated with host anti-virus eradicable THαβ immunity, autophagy with host anti-virus tolerable TH3 immunity, pyroptosis with host anti-intracellular microorganism eradicable TH1 immunity, ferroptosis with host anti-intracellular microorganism tolerable TH1-like immunity, necroptosis with host anti-extracellular microorganism eradicable TH22 immunity, and NETosis with host anti-extracellular microorganism tolerable TH17 immunity.

Neurodegenerative disorders, such as Alzheimer’s disease (AD), have the gradual onset of neurobiological changes preceding clinical diagnosis by decades. To elucidate how brain dysfunction proceeds in neurodegenerative disorders, we performed longitudinal characterization of behavioral, morphological, and transcriptomic changes in a tauopathy mouse model, P301S transgenic mice. P301S mice exhibited cognitive deficits as early as 3 months old, and deficits in social preference and social cognition at 5–6 months. They had a significant decrease of arborization in basal dendrites of hippocampal pyramidal neurons from 3 months and apical dendrites of PFC pyramidal neurons at 9 months. Transcriptomic analysis of genome-wide changes revealed the enrichment of synaptic gene upregulation at 3 months of age, while most of these synaptic genes were downregulated in PFC and hippocampus of P301S mice at 9 months. These time-dependent changes in gene expression may lead to progressive alterations of neuronal structure and function, resulting in the manifestation of behavioral symptoms in tauopathies.

The ability to accurately quantify biological age could help monitor and control healthy aging. Epigenetic clocks have emerged as promising tools for estimating biological age, yet they have been developed from heterogeneous bulk tissues, and are thus composites of two aging processes, one reflecting the change of cell-type composition with age and another reflecting the aging of individual cell-types. There is thus a need to dissect and quantify these two components of epigenetic clocks, and to develop epigenetic clocks that can yield biological age estimates at cell-type resolution. Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clock’s accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that these cell-type specific clocks yield improved estimates of chronological age in the corresponding cell and tissue-types. We find that neuron and glia specific clocks display biological age acceleration in Alzheimer’s Disease with the effect being strongest for glia in the temporal lobe. Moreover, CpGs from these clocks display a small but significant overlap with the causal DamAge-clock, mapping to key genes implicated in neurodegeneration. The hepatocyte clock is found accelerated in liver under various pathological conditions. In contrast, non-cell-type specific clocks do not display biological age-acceleration, or only do so marginally. In summary, this work highlights the importance of dissecting epigenetic clocks and quantifying biological age at cell-type resolution.

With aging, bone mass declines and the anabolic effects of skeletal loading diminish. While much research has focused on gene transcription, how bone ages and loses its mechanoresponsiveness at the protein level remains unclear. We developed a novel proteomics approach and performed a paired mass spectrometry and RNA-seq analysis on tibias from young-adult (5-month) and old (22-month) mice. We report the first correlation estimate between the bone proteome and transcriptome (Spearman ρ = 0.40), which is in line with other tissues but indicates that a relatively low amount of variation in protein levels is explained by the variation in transcript levels. Of 71 shared targets that differed with age, eight were associated with bone mineral density in previous GWAS, including understudied targets Asrgl1 and Timp2. We used complementary RNA in situ hybridization to confirm that Asrgl1 and Timp2 had reduced expression in osteoblasts/osteocytes in old bones. We also found evidence for reduced TGF-beta signaling with aging, in particular Tgfb2. Next, we defined proteomic changes following mechanical loading. At the protein level, bone differed more with age than with loading, and aged bone had fewer loading-induced changes. Overall, our findings underscore the need for complementary protein-level assays in skeletal biology research.

Purpose: The objective of this study was to investigate the senescent phenotypes of human corneal endothelial cells (hCEnCs) upon treatment with ultraviolet (UV)-A. Methods: We assessed cell morphology, senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation and expression of senescence markers (p16 and p21) in hCEnCs exposed to UV-A radiation, and senescent hCEnCs induced by ionizing radiation (IR) were used as positive controls. We performed RNA sequencing and proteomics analyses to compare gene and protein expression profiles between UV-A- and IR-induced senescent hCEnCs, and we also compared the results to non-senescent hCEnCs. Results: Cells exposed to 5 J/cm2 of UV-A or to IR exhibited typical senescent phenotypes, including enlargement, increased SA-β-gal activity, decreased cell proliferation and elevated expression of p16 and p21. RNA-Seq analysis revealed that 83.9% of the genes significantly upregulated and 82.6% of the genes significantly downregulated in UV-A-induced senescent hCEnCs overlapped with the genes regulated in IR-induced senescent hCEnCs. Proteomics also revealed that 93.8% of the proteins significantly upregulated in UV-A-induced senescent hCEnCs overlapped with those induced by IR. In proteomics analyses, senescent hCEnCs induced by UV-A exhibited elevated expression levels of several factors part of the senescence-associated secretory phenotype. Conclusions: In this study, where senescence was induced by UV-A, a more physiological stress for hCEnCs compared to IR, we determined that UV-A modulated the expression of many genes and proteins typically altered upon IR treatment, a more conventional method of senescence induction, even though UV-A also modulated specific pathways unrelated to IR.

Aging-related transcriptome changes in various regions of the healthy human brain have been explored in previous works, however, a study to develop prediction models for age based on the expression levels of specific panels of transcripts is lacking. Moreover, studies that have assessed sexually dimorphic gene activities in the aging brain have reported discrepant results, suggesting that additional studies would be advantageous. The prefrontal cortex (PFC) region was previously shown to have a particularly large number of significant transcriptome alterations during healthy aging in a study that compared different regions in the human brain. We harmonized neuropathologically normal PFC transcriptome datasets obtained from the Gene Expression Omnibus (GEO) repository, ranging in age from 21 to 105 years, and found a large number of differentially regulated transcripts in the old and elderly, compared to young samples overall, and compared female and male-specific expression alterations. We assessed the genes that were associated with age by employing ontology, pathway, and network analyses. Furthermore, we applied various established (least absolute shrinkage and selection operator (Lasso) and Elastic Net (EN)) and recent (eXtreme Gradient Boosting (XGBoost) and Light Gradient Boosting Machine (LightGBM)) machine learning algorithms to develop accurate prediction models for chronological age and validated them. Studies to further validate these models in other large populations and molecular studies to elucidate the potential mechanisms by which the transcripts identified may be related to aging phenotypes would be advantageous.

Background: SARS-CoV-2 variants are constantly emerging with a variety of changes in the conformation of the spike protein, resulting in alterations of virus entry mechanisms. Solely omicron variants use the endosomal clathrin-mediated entry. Here, we investigate the influence of defined altered spike formations to study their impact on premature cellular senescence. Methods: In our study, in vitro infections of SARS-CoV-2 variants delta (B.1.617.2) and omicron (B.1.1.529) were analyzed by using human primary small alveolar epithelial cells and human ex vivo lung slices. We confirmed cellular senescence in human lungs of COVID-19 patients. Hence, global gene expression patterns of infected human primary alveolar epithelial cells were identified via mRNA sequencing. Results: Solely omicron variants of SARS-CoV-2 influenced the expression of cell cycle genes, highlighted by an increased p21 expression in human primary lung cells and human ex vivo lungs. Additionally, an upregulated senescence-associated secretory phenotype (SASP) was detected. Transcriptomic data indicate an increased gene expression of p16, and p38 in omicron-infected lung cells. Conclusions: Significant changes due to different SARS-CoV-2 infections in human primary alveolar epithelial cells with an overall impact on premature aging could be identified. A substantially different cellular response with an upregulation of cell cycle, inflammation- and integrin-associated pathways in omicron infected cells indicates premature cellular senescence.

Crucial for skin homeostasis, synthesis and degradation of extracellular matrix components are orchestrated by dermal fibroblasts. During aging, alterations of component expression, such as collagens and enzymes, lead to reduction of the mechanical cutaneous tension and defects of skin wound healing. The aim of this study was to better understand the molecular alterations underwent by fibroblasts during aging by comparing secretomic and proteomic signatures of fibroblasts from young (<35years) and aged (>55years) skin donors, in quiescence or TGF-stimulated conditions, using HLPC/MS. The comparison of the secretome from young and aged fibroblasts revealed that 16 proteins in resting condition, and 11 proteins after a 24h-lasting TGF-β1-treatment, were expressed in significant different ways between the two cell groups (fold change>2, p-value <0.05), with a 77% decrease in the number of secreted proteins in aged cells. Proteome comparison between young and aged fibroblasts identified a significant change of 63 proteins in resting condition, and 73 proteins in TGF-β1-stimulated condition, with a 67% increase in the number of proteins in aged fibroblasts. The majority of the differentially-expressed molecules belongs to the cytoskeleton-associated proteins and aging was characterized by an increase in Coronin 1C (CORO1C), and Filamin B (FLNB) expression in fibroblasts together with a decrease in Cofilin (CFL1), and Actin alpha cardiac muscle 1 (ACTC1) detection in aged cells, these proteins being involved in actin-filament polymerization and sharing co-activity in cell motility. Our present data reinforce knowledge about an age-related alteration in the synthesis of major proteins linked to the migratory and contractile functions of dermal human fibroblasts.

Senescent cells contribute to tissue aging and underlie the pathology of chronic diseases. The benefits of eliminating senescent cells have been demonstrated in several disease models, and the efficacy of senolytic drugs is currently being tested in humans. Exercise training has been shown to reduce cellular senescence in several tissues; however, the mechanisms responsible remain unclear. We found that myocyte-derived factors significantly extended the replicative lifespan of fibroblasts, suggesting that myokines mediate the anti-senescence effects of exercise. A number of proteins within myocyte-derived factors were identified by mass spectrometry. Among these, pigment epithelium-derived factor (PEDF) exerted inhibitory effects on cellular senescence. Eight weeks of voluntary running increased Pedf levels in skeletal muscles and suppressed senescence markers in the lungs. The administration of PEDF reduced senescence markers in multiple tissues and attenuated the decline in respiratory function in the pulmonary emphysema mouse model. We also showed that blood levels of PEDF inversely correlated with the severity of COPD in patients. Collectively, these results strongly suggest that PEDF contributes to the beneficial effects of exercise, potentially suppressing cellular senescence and its associated pathologies.

Observational studies in preclinical models demonstrate age-related declines in circadian functions. We hypothesized that age would be associated with declines in function of cell-autonomous circadian clocks in human tissue. Accordingly, we cultured adipose progenitor cells (APCs) from previously collected white-adipose tissue biopsies from abdominal subcutaneous depots of young (Age: 23.4 ± 2.1 yrs) vs. older female participants (Age: 70.6 ± 5.9 yrs). Using an in vitro model, we compared rhythmic gene expression profiles of core clock components, as an indicator of circadian oscillatory function. We observed consistent circadian rhythmicity of core clock components in young and older-APCs. Expression analysis showed increased levels of some components in older-APCs (CLOCK, CRY1, NR1D1) vs. young. We also investigated resveratrol (RSV), a well-known longevity-enhancing effector, for its effects on rhythmic clock gene expression profiles. We found that RSV resulted in gained rhythmicity of some components (CLOCK and CRY), loss of rhythmicity in others (PER2, CRY2), and altered some rhythmic parameters (NR1D1 and NR1D2), consistent in young and older-APCs. The observation of detectable circadian rhythmicity retained in vitro suggests that the oscillatory function of the cell-autonomous core clock in APCs is preserved at this stage of the aging process. RSV impacts core clock gene expression in APCs, implicating its potential as a therapeutic agent for longevity by targeting the core clock.

According to birth certificates, the life of a child begins once their body comes out of the mother’s womb. But when does their organismal life begin? Science holds a palette of answers—depending on how one defines a human life. In 1984, a commission on the regulatory framework for human embryo experimentation opted not to answer this question, instead setting a boundary, 14 days post-fertilization, beyond which any experiments were forbidden. Recently, as the reproductive technologies developed and the demand for experimentation grew stronger, this boundary may be set aside leaving the ultimate decision to local oversight committees. While science has not come closer to setting a zero point for human life, there has been significant progress in our understanding of early mammalian embryogenesis. It has become clear that the 14-day stage does in fact possess features, which make it a foundational time point for a developing human. Importantly, this stage defines the separation of soma from the germline and marks the boundary between rejuvenation and aging. We explore how different levels of life organization emerge during human development and suggest a new meaning for the 14-day stage in organismal life that is grounded in recent mechanistic advances and insights from aging studies.