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.

Targeted degradation, having emerged as a powerful and promising strategy in drug discovery in the past two decades, has provided a solution for many once undruggable targets involved in various diseases. While earlier targeted degradation tools, as exemplified by PROteolysis-TArgeting Chimera (PROTAC), focused on harnessing the ubiquitin-proteasome system, novel approaches that aim to utilize autophagy, a potent, lysosome-dependent degradation pathway, have also surfaced recently as promising modalities. In this review, we first introduce the mechanisms that establish selectivity in autophagy, which provides the rationales for autophagy-based targeted degradation; we also provide an overview on the panoply of cellular machinery involved in this process, an arsenal that could be potentially harnessed. On this basis, we propose four strategies for designing autophagy-based targeted degraders, including Tagging Targets, Directly Engaging Targets, Initiating Autophagy at Targets, and Phagophore-Tethering to Targets. We introduce the current frontiers in this field, including AUtophagy-TArgeting Chimera (AUTAC), Targeted Protein Autophagy (TPA), AUTOphagy-TArgeting Chimera (AUTOTAC, not to be confused with AUTAC), AuTophagosome TEthering Compound (ATTEC), and other experimental approaches as case studies for each strategy. Finally, we put forward a workflow for generating autophagy-based degraders and some important questions that may guide and inspire the process.

Cardiac aging constitutes a significant risk factor for cardiovascular diseases prevalent among the elderly population. Urgent attention is required to prioritize preventive and management strategies for age-related cardiovascular conditions to safeguard the well-being of elderly individuals. In response to this critical challenge, the Aging Biomarker Consortium (ABC) of China has formulated an expert consensus on cardiac aging biomarkers. This consensus draws upon the latest scientific literature and clinical expertise to provide a comprehensive assessment of biomarkers associated with cardiac aging. Furthermore, it presents a standardized methodology for characterizing biomarkers across three dimensions: functional, structural, and humoral. The functional dimension encompasses a broad spectrum of markers that reflect diastolic and systolic functions, sinus node pacing, neuroendocrine secretion, coronary micro-circulation, and cardiac metabolism. The structural domain emphasizes imaging markers relevant to concentric cardiac remodeling, coronary artery calcification, and epicardial fat deposition. The humoral aspect underscores various systemic (N) and heart-specific (X) markers, including endocrine hormones, cytokines, and other plasma metabolites. The ABC’s primary objective is to establish a robust foundation for assessing cardiac aging, thereby furnishing a dependable reference for clinical applications and future research endeavors. This aims to contribute significantly to the enhancement of cardiovascular health and overall well-being among elderly individuals.

Macrophages are widely distributed in various metabolic tissues/organs and play an essential role in the immune regulation of metabolic homeostasis. Macrophages have two major functions: adaptive defenses against invading pathogens by triggering inflammatory cytokine release and eliminating damaged/dead cells via phagocytosis to constrain inflammation. The pro-inflammatory role of macrophages in insulin resistance and related metabolic diseases is well established, but much less is known about the phagocytotic function of macrophages in metabolism. In this review, we review our current understanding of the ontogeny, tissue distribution, and polarization of macrophages in the context of metabolism. We also discuss the Yin-Yang functions of macrophages in the regulation of energy homeostasis. Third, we summarize the crosstalk between macrophages and gut microbiota. Lastly, we raise several important but remain to be addressed questions with respect to the mechanisms by which macrophages are involved in immune regulation of metabolism.

Aging is a natural but relentless process of physiological decline, leading to physical frailty, reduced ability to respond to physical stresses (resilience) and, ultimately, organismal death. Cellular senescence, a self-defensive mechanism activated in response to intrinsic stimuli and/or exogenous stress, is one of the central hallmarks of aging. Senescent cells cease to proliferate, while remaining metabolically active and secreting numerous extracellular factors, a feature known as the senescence-associated secretory phenotype. Senescence is physiologically important for embryonic development, tissue repair, and wound healing, and prevents carcinogenesis. However, chronic accumulation of persisting senescent cells contributes to a host of pathologies including age-related morbidities. By paracrine and endocrine mechanisms, senescent cells can induce inflammation locally and systemically, thereby causing tissue dysfunction, and organ degeneration. Agents including those targeting damaging components of the senescence-associated secretory phenotype or inducing apoptosis of senescent cells exhibit remarkable benefits in both preclinical models and early clinical trials for geriatric conditions. Here we summarize features of senescent cells and outline strategies holding the potential to be developed as clinical interventions. In the long run, there is an increasing demand for safe, effective, and clinically translatable senotherapeutics to address healthcare needs in current settings of global aging.

The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3; also called Machado-Joseph disease, MJD) is a trinucleotide repeat disorder caused by expansion of the CAG repeats in the ATXN3 gene. Here, we applied a CRISPR/Cas9-mediated approach using homologous recombination to achieve a one-step genetic correction in SCA3-specific induced pluripotent stem cells (iPSCs). The genetic correction reversed disease-associated phenotypes during cerebellar region-specific differentiation. In addition, we observed spontaneous ataxin-3 aggregates specifically in mature cerebellar neurons differentiated from SCA3 iPSCs rather than in SCA3 pan-neurons, SCA3 iPSCs or neural stem cells, suggesting that SCA3 iPSC-derived disease-specific and region-specific cerebellar neurons can provide unique cellular models for studying SCA3 pathogenesis in vitro. Importantly, the genetically corrected cerebellar neurons did not display typical SCA3 aggregates, suggesting that genetic correction can subsequently reverse SCA3 disease progression. Our strategy can be applied to other trinucleotide repeat disorders to facilitate disease modeling, mechanistic studies and drug discovery.

China and the world are facing severe population aging and an increasing burden of age-related diseases. Aging of the brain causes major age-related brain diseases, such as neurodegenerative diseases and stroke. Identifying biomarkers for the effective assessment of brain aging and establishing a brain aging assessment system could facilitate the development of brain aging intervention strategies and the effective prevention and treatment of aging-related brain diseases. Thus, experts from the Aging Biomarker Consortium (ABC) have combined the latest research results and practical experience to recommend brain aging biomarkers and form an expert consensus, aiming to provide a basis for assessing the degree of brain aging and conducting brain-aging-related research with the ultimate goal of improving the brain health of elderly individuals in both China and the world.

Organoids-on-chips is opening up new frontier of research in biomedical field by combining organoids and organs-on-chips technology. The integrative technology offers great opportunities to maximize the potentials of organoids with higher fidelity, thus building advanced organ model systems in a physiologically relevant manner. In this review, we highlight the key features of organoids-on-chips and how this integrative technology could be used to build organoids in higher fidelity under controlled cellular microenvironment. We then introduce the recent progress of organoids-on-chips and their applications in biomedical research. We also discuss the opportunities and challenges of the nascent field of organoids-on-chips that lie ahead to accelerate their utility in disease research, drug testing, and regenerative medicine.

The majority of cancer patients are among aged population, suggesting an urgent need to advance our knowledge on complicated relationship between aging and cancer. It has been hypothesized that metabolic changes during aging could act as a driver for tumorigenesis. Given the fact that mitochondrial DNA (mtDNA) mutations are common in both tumors and aged tissues, it is interesting to contemplate possible role of age-related mtDNA mutations in tumorigenesis. MtDNA encodes genes essential for mitochondrial metabolism, and mtDNA mutates at a much higher rate than nuclear genome. Random drifting of somatic mtDNA mutations, as a result of cell division or mitochondrial turnover during aging, may lead to more and more cells harboring high-frequency pathogenic mtDNA mutations, albeit at different loci, in single-cells. Such mutations can induce metabolic reprogramming, nuclear genome instability and immune response, which might increase the likelihood of tumorigenesis. In this review, we summarize current understanding of how mtDNA mutations accumulate with aging and how these mutations could mechanistically contribute to tumor origin. We also discuss potential prevention strategies for mtDNA mutation-induced tumorigenesis, and future works needed in this direction.

Skeletal stem cells (SSCs) were originally discovered in the bone marrow stroma. They are capable of self-renewal and multilineage differentiation into osteoblasts, chondrocytes, adipocytes, and stromal cells. Importantly, these bone marrow SSCs localize in the perivascular region and highly express hematopoietic growth factors to create the hematopoietic stem cell (HSC) niche. Thus, bone marrow SSCs play pivotal roles in orchestrating osteogenesis and hematopoiesis. Besides the bone marrow, recent studies have uncovered diverse SSC populations in the growth plate, perichondrium, periosteum, and calvarial suture at different developmental stages, which exhibit distinct differentiation potential under homeostatic and stress conditions. Therefore, the current consensus is that a panel of region-specific SSCs collaborate to regulate skeletal development, maintenance, and regeneration. Here, we will summarize recent advances of SSCs in long bones and calvaria, with a special emphasis on the evolving concept and methodology in the field. We will also look into the future of this fascinating research area that may ultimately lead to effective treatment of skeletal disorders.

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.

Aging of the vasculature, which is integral to the functioning of literally all human organs, serves as a fundamental physiological basis for age-related alterations as well as a shared etiological mechanism for various chronic diseases prevalent in the elderly population. China, home to the world’s largest aging population, faces an escalating challenge in addressing the prevention and management of these age-related conditions. To meet this challenge, the Aging Biomarker Consortium of China has developed an expert consensus on biomarkers of vascular aging (VA) by synthesizing literature and insights from scientists and clinicians. This consensus provides a comprehensive assessment of biomarkers associated with VA and presents a systemic framework to classify them into three dimensions: functional, structural, and humoral. Within each dimension, the expert panel recommends the most clinically relevant VA biomarkers. For the functional domain, biomarkers reflecting vascular stiffness and endothelial function are high-lighted. The structural dimension encompasses metrics for vascular structure, microvascular structure, and distribution. Additionally, proinflammatory factors are emphasized as biomarkers with the humoral dimension. The aim of this expert consensus is to establish a foundation for assessing the extent of VA and conducting research related to VA, with the ultimate goal of improving the vascular health of the elderly in China and globally.