Cell type-specific aging clocks to quantify aging and rejuvenation in regenerative regions of the brain

Aging manifests as progressive dysfunction culminating in death. The diversity of cell types is a challenge to the precise quantification of aging and its reversal. Here we develop a suite of 'aging clocks' based on single cell transcriptomic data to characterize cell type-specific aging and rejuvenation strategies. The subventricular zone (SVZ) neurogenic region contains many cell types and provides an excellent system to study cell-level tissue aging and regeneration. We generated 21,458 single-cell transcriptomes from the neurogenic regions of 28 mice, tiling ages from young to old. With these data, we trained a suite of single cell-based regression models (aging clocks) to predict both chronological age (passage of time) and biological age (fitness, in this case the proliferative capacity of the neurogenic region). Both types of clocks perform well on independent cohorts of mice. Genes underlying the single cell-based aging clocks are mostly cell-type specific, but also include a few shared genes in the interferon and lipid metabolism pathways. We used these single cell-based aging clocks to measure transcriptomic rejuvenation, by generating single cell RNA-seq datasets of SVZ neurogenic regions for two interventions - heterochronic parabiosis (young blood) and exercise. Interestingly, the use of aging clocks reveals that both heterochronic parabiosis and exercise reverse transcriptomic aging in the niche, but in different ways across cell types and genes. This study represents the first development of high-resolution aging clocks from single cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.

Physiological Mechanisms Regulating Lens Transport

The transparency and refractive properties of the lens are maintained by the cellular physiology provided by an internal microcirculation system that utilizes spatial differences in ion channels, transporters and gap junctions to establish standing electrochemical and hydrostatic pressure gradients that drive the transport of ions, water and nutrients through this avascular tissue. Aging has negative effects on lens transport, degrading ion and water homeostasis, and producing changes in lens water content. This alters the properties of the lens, causing changes in optical quality and accommodative amplitude that initially result in presbyopia in middle age and ultimately manifest as cataract in the elderly. Recent advances have highlighted that the lens hydrostatic pressure gradient responds to tension transmitted to the lens through the Zonules of Zinn through a mechanism utilizing mechanosensitive channels, multiple sodium transporters respond to changes in hydrostatic pressure to restore equilibrium, and that connexin hemichannels and diverse intracellular signaling cascades play a critical role in these responses. The mechanistic insight gained from these studies has advanced our understanding of lens transport and how it responds and adapts to different inputs both from within the lens, and from surrounding ocular structures.

The Rise and the Death of Senescent Cells: From Mechanisms to Interventions

Aging is at the root of age-related diseases and therapies targeting basic age-associated mechanisms have the potential to extend healthy lifespan. A common feature of older organisms is the accumulation of senescent cells – cells that have irreversibly lost the capacity to undergo replication. Senescent cells are characterized by an irreversible cell cycle arrest and by the Senescence-Associated Secretory Phenotype (SASP), which include many tissue remodeling and pro-inflammatory factors. Senescent cells are intermittently present during embryogenesis and in young organisms. On the contrary senescent cells accumulate and persist in aging tissues. Significantly, these persistent senescent cells can drive low-grade chronic inflammation, and their genetic or pharmacological elimination is sufficient to delay a number of diseases and to improve health span. Here, I will discuss the mechanisms by which senescent cells can promote tissue aging and dysfunction and the potential of targeting senescent cells to delay human aging.

Cell Senescence as a Mediator of Age-Dependent Brain Inflammation

Cellular senescence and inflammation are interconnected causes and consequences of tissue aging. Here, we implemented orthogonal approaches to study their interaction in steady-state mature and aged mouse brain. Using single cell sequencing, we identified a putative senescent microglial population, which increased in abundance with age and was characterized by increased expression of p16 and chemotactic senescence associated secretory phenotype (SASP) factors. Using p16-INK-ATTAC transgenic mice to eliminate p16ink4a-positive senescent cells and mass cytometry, we show that p16ink4a-positive cell targeting reduced the abundance of activated inflammatory cells in the aged female brain. Age-dependent declines in executive cognitive function were improved following transgenic p16ink4a-positive cell targeting, and executive function robustly correlated with inflammatory brain cell composition in females. Collectively, our findings demonstrate fundamental differences in the age- and sex-dependent brain inflammatory landscape and implicate p16ink4a-positive senescent cell targeting as a therapeutic strategy to attenuate age-related inflammation and cognitive decline.

Inverse correlation between urethral length and continence before and after native tissue pelvic floor reconstruction

Urethral length was evaluated retrospectively in patients with prolapse undergoing anterior native-tissue repair. Effects of age, prolapse stage, defect pattern, urodynamic and clinical stress test findings, and tension-free vaginal tape (TVT) surgery indication were analyzed using Mann–Whitney and Wilcoxon tests and linear and logistic regression. Of 394 patients, 61% had stage II/III and 39% had stage IV prolapse; 90% of defects were central (10% were lateral). Median pre- and postoperative urethral lengths were 14 and 22 mm (p < 0.01). Preoperative urethral length was greater with lateral defects [p < 0.01, B 6.38, 95% confidence interval (CI) 4.67–8.08] and increased stress incontinence risk (p < 0.01, odds ratio 1.07, 95% CI 1.03–1.12). Postoperative urethral length depended on prolapse stage (p < 0.01, B 1.61, 95% CI 0.85–2.38) and defect type (p = 0.02, B – 1.42, 95% CI – 2.65 to – 0.2). Postoperatively, TVT surgery was indicated in 5.1% of patients (median 9 months), who had longer urethras than those without this indication (p = 0.043). Native-tissue prolapse repair including Kelly plication increased urethral length, reflecting re-urethralization, particularly with central defects. The functional impact of urethral length in the context of connective tissue aging should be examined further.

Identification of biomarkers of brown adipose tissue aging highlights the role of dysfunctional energy and nucleotide metabolism pathways

Brown adipose tissue function declines during aging and may contribute to the onset of metabolic disorders such as diabetes and obesity. Only limited understanding of the mechanisms leading to the metabolic impairment of brown adipocytes during aging exists. To this end, interscapular brown adipose tissue samples were collected from young and aged mice for quantification of differential gene expression and metabolite levels. To identify potential processes involved in brown adipocyte dysfunction, metabolite concentrations were correlated to aging and significantly changed candidates were subsequently integrated with a non-targeted proteomic dataset and gene expression analyses. Our results include novel age-dependent correlations of polar intermediates in brown adipose tissue. Identified metabolites clustered around three biochemical processes, specifically energy metabolism, nucleotide metabolism and vitamin metabolism. One mechanism of brown adipose tissue dysfunction may be linked to mast cell activity, and we identify increased histamine levels in aged brown fat as a potential biomarker. In addition, alterations of genes involved in synthesis and degradation of many metabolites were mainly observed in the mature brown adipocyte fraction as opposed to the stromal vascular fraction. These findings may provide novel insights on the molecular mechanisms contributing to the impaired thermogenesis of brown adipocytes during aging.

A unique adipocyte progenitor population promotes age-related adiposity

The average fat mass in adults increases dramatically with age, and older people often suffer from visceral obesity and related adverse metabolic disorders. Unfortunately, how aging leads to fat accumulation is poorly understood. It is known that fat cell (adipocyte) turnover is very low in young mice, similar to that in young humans. Here, we find that mice mimic age-related fat expansion in humans. In vivo lineage tracing shows that massive adipogenesis (the generation of new adipocytes), especially in the visceral fat, is triggered during aging. Thus, in contrast to most types of adult stem cells that exhibit a reduced ability to proliferate and differentiate, the adipogenic potential of adipocyte progenitor cells (APCs) is unlocked by aging. In vivo transplantation and 3D imaging of transplants show that APCs in aged mice cell-autonomously gain high adipogenic capacity. Single-cell RNA sequencing analyses reveal that aging globally remodels APCs. Herein, we identify a novel committed preadipocyte population that is age-specific (CP-A), existing both in mice and humans, with a global activation of proliferation and adipogenesis pathways. CP-A cells display high proliferation and adipogenesis activity, both in vivo and in vitro. Macrophages may regulate the remodeling of APCs and the generation of CP-A cells during aging. Together, these findings define a new fundamental mechanism involved in fat tissue aging and offer prospects for preventing and treating age-related metabolic disorders.

Key miRNAs in Modulating Aging and Longevity: A Focus on Signaling Pathways and Cellular Targets

: Aging is a multifactorial procedure accompanied by gradual deterioration of most biological procedures of cells. MicroRNAs (miRNAs) are a class of short non-coding RNAs that post-transcriptionally regulate the expression of mRNAs through sequence-specific binding, and contributing to many crucial aspects of cell biology. Several miRNAs are expressed differently in various organisms through aging. The function of miRNAs in modulating aging procedures has been disclosed recently with the detection of miRNAs that modulate longevity in the invertebrate model organisms, through the IIS pathway. In these model organisms, several miRNAs have been detected to both negatively and positively regulate lifespan via commonly aging pathways. miRNAs modulate age-related procedures and disorders in different mammalian tissues by measuring their tissue-specific expression in older and younger counterparts, including heart, skin, bone, brain, and muscle tissues. Moreover, several miRNAs have been contributed to modulating senescence in different human cells, and the roles of these miRNAs in modulating cellular senescence have allowed illustrating some mechanisms of aging. The review discusses the available data on miRNAs through the aging process and we highlight the roles of miRNAs as aging biomarkers and regulators of longevity in cellular senescence, tissue aging, and organism lifespan.

Antioxidant Effects of Caffeic Acid Lead to Protection of Drosophila Intestinal Stem Cell Aging

The dysfunction or exhaustion of adult stem cells during aging is closely linked to tissue aging and age-related diseases. Circumventing this aging-related exhaustion of adult stem cells could significantly alleviate the functional decline of organs. Therefore, identifying small molecular compounds that could prevent the age-related decline of stem cell function is a primary goal in anti-aging research. Caffeic acid (CA), a phenolic compound synthesized in plants, offers substantial health benefits for multiple age-related diseases and aging. However, the effects of CA on adult stem cells remain largely unknown. Using the Drosophila midgut as a model, this study showed that oral administration with CA significantly delayed age-associated Drosophila gut dysplasia caused by the dysregulation of intestinal stem cells (ISCs) upon aging. Moreover, administering CA retarded the decline of intestinal functions in aged Drosophila and prevented hyperproliferation of age-associated ISC by suppressing oxidative stress-associated JNK signaling. On the other hand, CA supplementation significantly ameliorated the gut hyperplasia defect and reduced environmentally induced mortality, revealing the positive effects of CA on tolerance to stress responses. Taken together, our findings report a crucial role of CA in delaying age-related changes in ISCs of Drosophila.