Search

Aging is a major risk factor for multiple diseases, including cardiovascular diseases, neurodegenerative disorders, osteoarthritis, and cancer. It is accompanied by the dysregulation of stem cells and other differentiated cells, and the impairment of their microenvironment. Cell therapies to replenish the abovementioned cells provide a promising approach to restore tissue homeostasis and alleviate aging and aging-related chronic diseases. Importantly, by leveraging gene editing technologies, genetic enhancement, an enhanced strategy for cell therapy, can be developed to improve the safety and efficacy of transplanted therapeutic cells. In this review, we provide an overview and discussion of the current progress in the genetic enhancement field, including genetic modifications of mesenchymal stem cells, neural stem cells, hematopoietic stem cells, vascular cells, and T cells to target aging and aging-associated diseases. We also outline questions regarding safety and current limitations that need to be addressed for the continued development of genetic enhancement strategies for cell therapy to enable its further applications in clinical trials to combat aging-related diseases.

The thermodynamics of hydrogen bonds in aqueous and acidic solutions significantly impacts the kinetics and thermodynamics of acid reaction chemistry. We utilize in this work a multiscale approach, combining density functional theory (DFT) with classical molecular dynamics (MD) to model hydrogen bond thermodynamics in an acidic solution. Using thermodynamic cycles, we split the solution phase free energy into its gas phase counterpart plus solvation free energies. We validate this DFT/MD approach by calculating the aqueous phase hydrogen bond free energy between two water molecules (H

Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

Organismal aging exhibits wide-ranging hallmarks in divergent cell types across tissues, organs, and systems. The advancement of single-cell technologies and generation of rich datasets have afforded the scientific community the opportunity to decode these hallmarks of aging at an unprecedented scope and resolution. In this review, we describe the technological advancements and bioinformatic methodologies enabling data interpretation at the cellular level. Then, we outline the application of such technologies for decoding aging hallmarks and potential intervention targets and summarize common themes and context-specific molecular features in representative organ systems across the body. Finally, we provide a brief summary of available databases relevant for aging research and present an outlook on the opportunities in this emerging field. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Stem cell therapies, including stem cell transplantation and rejuvenation of stem cells in situ, are promising avenues for tackling a broad range of diseases. Stem cells can both self-renew and differentiate into other cell types, and play a significant role in the regulation of tissue homeostasis and regeneration after cell degeneration or injury. However, stem cell exhaustion or dysfunction increases with age and impedes the normal function of multiple tissues and systems. Thus, stem cell therapies could provide a solution to aging and age-associated diseases. Here, we discuss recent advances in understanding the mechanisms that regulate stem cell regeneration. We also summarize potential strategies for rejuvenating stem cells that leverage intrinsic and extrinsic factors. These approaches may pave the way toward therapeutic interventions aiming at extending both health and life span.

Hair loss affects millions of people at some time in their life, and safe and efficient treatments for hair loss are a significant unmet medical need. We report that topical delivery of quercetin (Que) stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in mice. We construct dynamic single-cell transcriptome landscapes over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1α in endothelial cells. Skin administration of a HIF-1α agonist partially recapitulates the pro-angiogenesis and hair-growing effects of Que. Together, these findings provide a molecular understanding for the efficacy of Que in hair regrowth, which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine, and suggest a route of pharmacological intervention that may promote hair regrowth.

The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying primate testicular aging remains largely elusive. Here, we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing the first single-nucleus transcriptomic atlas. Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir, disturbed meiosis and impaired spermiogenesis along the sequential continuum. Remarkably, Sertoli cell was identified as the cell type most susceptible to aging, given its deeply perturbed age-associated transcriptional profiles. Concomitantly, downregulation of the transcription factor Wilms’ Tumor 1 (WT1), essential for Sertoli cell homeostasis, was associated with accelerated cellular senescence, disrupted tight junctions, and a compromised cell identity signature, which altogether may help create a hostile microenvironment for spermatogenesis. Collectively, our study depicts in-depth transcriptomic traits of non-human primate (NHP) testicular aging at single-cell resolution, providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.

Metformin (MET) and nicotinamide riboside (NR) have both been reported to exert geroprotective effects in multiple species. However, the mechanism by which MET and NR regulate the aging program and delay aging in multiple tissues remains unclear. Here, we demonstrated that MET and NR attenuate aging features in human mesenchymal stem cells. Moreover, by systematically investigating the pathophysiological changes in different tissues from aged rats after oral administration of MET and NR, we showed that both MET and NR treatment alleviated various aging-related characteristics in multiple tissues, including inflammation, fibrosis, and protein aggregates. Consistently, MET or NR treatment partially rescued aging-related gene expression changes in aged rats. Collectively, we report that both MET and NR attenuate senescence phenotypes in human stem cells in vitro and in a variety of rodent tissues in vivo, thus providing a valuable resource and foundation for further evaluation of these two compounds against aging.

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of the complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.

The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s13238-021-00852-9.

Atomically thin MoS2 nanosheets are of interest due to unique electronic, optical, and catalytic properties that are absent in the bulk material. Methods to prepare nanosheets from bulk material th...

Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.

An experimental study was performed on the application of the digital image correlation (DIC) technique to characterize aircraft components for which accurate time information is required. This study builds an aircraft external measurement system based on Stereo DIC. This system obtains real-time satellite time information from a GPS clock source and transmits it to a trigger unit. A camera acquires this information and displays it on the image. This solves the problem that some closed laboratories can use only computer time and cannot obtain accurate satellite time when using camera measurements. Moreover, we verify the reliability and accuracy of this approach, finding an average angular accuracy of better than 0.02 degrees and a relative error of less than 1%. Using the binocular Stereo DIC system, the accuracy of the measurements is clarified for specific conditions. Furthermore, we use this system to measure simulated aircraft landing gear, which moves at an angular velocity of 52.4 °/ s over a distance of 5 m with a wide field of view of 16.8°. The satellite time information acquired by the camera and the time information of the captured time targets are highly stable. The system’s reliability is demonstrated for use in practical engineering, contributing to the engineering application of Stereo DIC for external aircraft measurements.

Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.

SUMMARYWhether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process are largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. Activation of ERVs was also observed in organs of aged primates and mice, as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.In briefLiu and colleagues uncover the ways in which de-repression of human endogenous retrovirus triggers cellular senescence and tissue aging; the findings provide fresh insights into therapeutic strategies for alleviating aging.HighlightsDerepression of the endogenous retrovirus contributes to programmed agingUpregulation of HERVK triggers the innate immune response and cellular senescenceExtracellular HERVK retrovirus-like particles induce senescence in young cellsEndogenous retrovirus serves as a potential target to alleviate agingsGraphical abstract

In this paper, the fatigue energy dissipation of Gravity Casting (GC) and Laser-based Powder Bed Fusion (LPBF) AlSi10Mg alloys under cyclic loading are investigated. The increase in surface temperature related to the energy dissipation effect is decoupled and used to predict the fatigue limits of GC and LPBF AlSi10Mg alloys as being 55.8% UTS and 33.9% UTS, respectively. The energy dissipation rate is obtained by solving the one-dimensional thermal diffusion problem. This energy dissipation is separated into related and unrelated fatigue damage using polynomial function fitting. The energy dissipation related to fatigue damage for LPBF specimens is observed to be higher than that of GC specimens, which indicates worse fatigue performance. The fatigue damage entropy is employed to predict the fatigue life of both GC and LPBF AlSi10Mg alloys, which has a good agreement with the results of a traditional fatigue experiment.

Regeneration plays an instrumental role in biological development and damage repair by constructing and replacing cells, tissues, and organs. Since regenerative capacity declines with age, promoting regeneration is heralded as a potential strategy for delaying aging. On this premise, mechanisms that regulate regeneration have been extensively studied across species and in different tissues. However, an open and comprehensive database collecting and standardizing the abundant data generated in regeneration research, such as high-throughput sequencing data, remains to be developed. In this work, we constructed Regeneration Roadmap to systematically and comprehensively collect such information over 2.38 million data entries across 11 species and 36 tissues, including regeneration-related genes, bulk and single-cell transcriptomics, epigenomics, and pharmacogenomics data. In this database, users can explore regulatory and expression changes of regeneration-associated genes in different species and tissues. Regeneration Roadmap provides the research community with a long-awaited and valuable data resource featuring convenient computing and visualizing tools, which is publicly available at https://ngdc.cncb.ac.cn/regeneration/index.

Various leg exoskeletons have been designed for gait rehabilitation. The transparency of these exoskeletons is crucial to their effectiveness in gait training. The weight and inertia of an exoskeleton are two important factors affecting its transparency. In this study, using a light-weight leg exoskeleton C-ALEX, we conducted a series of experiments to explore the effect of exoskeleton weight and inertia on the natural walking of twelve healthy subjects. They walked in C-ALEX under three levels of mass added to the leg: (i) no added mass, (ii) 1.8 kg, and (iii) 3.6 kg, and three different setups of C-ALEX: (i) freewalking without C-ALEX, (ii) with C-ALEX, and (iii) with C-ALEX compensating for the weight of the added mass. The result shows that increasing exoskeleton mass increases step length, decreases step height, and reduces maximum knee flexion. After weight compensation, the step height, and the maximum knee flexion partially restored, but the step length did not, implying that the inertia is responsible for the change in step length. The study demonstrates that compensating for weight alone cannot eliminate the changes due to exoskeleton mass. On the other hand, reducing the overall mass of the exoskeleton can better preserve the natural gait of the subjects.

A transparent PEMFC with a single straight channel was designed to study liquid water transport in the cathode channel. The pressure-drop between the inlet and outlet of the channel was measured and used as a diagnostic signal to monitor liquid water accumulation and removal. This method was non-destructive for the fuel cell, and is capable of monitoring the water droplet buildup and removal in the channel on-line directly, and giving real-time liquid water buildup information. The proper velocity for liquid water removal can be determined according to the pressure-drop curve, which was very helpful to design a flow field and to optimize fuel cell operation. Under the study conditions, and to ensure liquid water discharge, the gas velocity should not lower than 2, 3 and 5 m s−1 for 600, 1000 and 1200 mA cm−2, respectively. The results were further verified by visualization in a transparent PEMFC.

The mobility of water droplets and water films inside a straight micro-channel of a proton exchange membrane fuel cell was simulated to study the effects of the hydrophilic/hydrophobic properties on water behavior. The volume-of-fluid model in the FLUENT package was used to keep track of the deformation of the liquid–gas interface. The results show that the water moved faster on a hydrophobic surface. But a hydrophobic channel side-wall was a disadvantage for the gas diffusion when the MEA had a hydrophilic surface. A hydrophilic channel side-wall with a hydrophobic MEA surface could avoid water accumulation on the MEA surface. The water and gas distribution under this condition was advantageous for water discharge and gas diffusion.