Xiaolong Fu

The global surge in the population of people 60 years and older, including that in China, challenges healthcare systems with rising age‐related diseases. To address this demographic change, the Aging Biomarker Consortium (ABC) has launched the X-Age Project to develop a comprehensive aging evaluation system tailored to the Chinese population. Our goal is to identify robust biomarkers and construct composite aging clocks that capture biological age, defined as an individual’s physiological and molecular state, across diverse Chinese cohorts. This Perspective outlines the core objectives, methodological framework and key deliverables of the X-Age Project, including cohort recruitment, standardized sample collection, multimodal data acquisition and clock model development. By integrating interdisciplinary expertise, we aim to provide a practical and scalable platform for understanding aging complexity and heterogeneity, early detection of accelerated aging and evaluation of aging interventions.

Cochlear aging causes substantial hearing impairment in older adults, yet primate-specific mechanisms remain poorly characterized. Our comprehensive analysis combining single-cell and histopathological profiling in aging Macaca fascicularis demonstrates progressive cochlear degeneration featuring accelerated sensory hair cell loss, senescent spiral ganglion neurons with elevated neuroinflammation, and marked stria vascularis atrophy. We discovered that downregulation of transmembrane transport proteins, particularly SLC35F1, serves as a critical biomarker of hair cell aging. Functional validation through Slc35f1 knockdown in adult mice successfully recapitulated key aspects of age-related hearing loss, including hair cell degeneration and auditory function decline. Notably, we showed that long-term metformin administration at clinically relevant doses effectively delays cochlear aging in primates. These findings provide fundamental insights into the cellular and molecular basis of primate cochlear aging while establishing a foundation for developing targeted interventions against age-related hearing loss.

Cellular senescence is a hallmark of aging characterized by a permanent state of cell cycle arrest, accompanied by various molecular and cellular changes that disrupts tissue and organ homeostasis. This disruption contributes to the development and progression of numerous chronic diseases, including age-related hearing loss (ARHL), which is defined as a gradual and irreversible hearing impairment resulting from cochlear aging. Among the many changes associated with biological aging, ARHL ranks among the top three chronic conditions affecting older individuals, leading to communication difficulties, social isolation, depression, and cognitive decline. Notably, targeting cellular senescence has shown significant promise in extending lifespan; however, the relationship between age-related diseases, particularly ARHL, remains to be fully elucidated. In this discussion, we explore the hallmarks of cellular senescence, and highlights its impacts on peripheral presbycusis.

Age-related hearing loss (ARHL) is among the most prevalent and complex disorders in older adults. However, the pathogenesis of ARHL remains poorly understood. Using a single-cell transcriptomic landscape of mouse cochlea at five time points (1, 2, 5, 12 and 15 months), we found that the levels of human antigen R (HuR)-a classical RNA-binding protein-increase with age. Here we show that HuR is specifically transported from the nucleus to the cytoplasm in hair cells in both aging mice and nonhuman primates. HuR overexpression in cochlea could successfully alleviate ARHL in aged mice. Meanwhile, HuR deficiency led to premature hearing dysfunction characterized by degeneration of stereocilia and the subsequent loss of hair cells. RNA immunoprecipitation sequencing analysis revealed that HuR can bind to messenger RNAs that enable stereocilia maintenance, including Gnai3. Adeno-associated virus-mediated Gnai3 overexpression partially rescues the hearing defects in HuR-deficient mice. Taken together, these findings indicate that HuR is a potential therapeutic target for ARHL.

Presbycusis, also known as age‐related hearing loss (ARHL), is a progressive auditory impairment and ranks among the most prevalent sensory disorders in the elderly population. It is primarily caused by damage to hair cells, degeneration of spiral ganglion neurons, and atrophy of the stria vascularis, which are integral components of the cochlea. While extensive research has been devoted to hair cells and spiral ganglion neurons, this review focuses on the critical role of the stria vascularis in ARHL. The primary function of the stria vascularis is to maintain the endocochlear potential, which is essential for hearing. This review presents an overview of the research concerning the stria vascularis in ARHL, particularly focusing on the application of single‐cell transcriptomics to elucidate its role. Furthermore, this review explores relevant signaling pathways and therapeutic strategies for ARHL. By enhancing the understanding of the stria vascularis in ARHL, this review aims to pave the way for personalized treatment and improved strategies for protection and prevention.

Aminoglycoside antibiotic‐induced sensorineural hearing loss (SNHL) is a common sensory disorder that requires the development of prophylactic and therapeutic interventions. Lycium barbarum glycopeptide (LBGP) is a peptidoglycan isolated and purified from Lycium barbarum polysaccharides that exhibit significant anti‐inflammatory, antioxidant, and neuroprotective effects, but the role of LBGP in aminoglycoside‐induced SNHL has not been well investigated. Here it is shown that LBGP can protect against neomycin‐induced hearing impairment and alleviate oxidative stress in a neomycin‐induced SNHL mouse model. Moreover, it is further found that inhibition of tryptophan hydroxylase (Tph)‐mediated serotonin (5‐HT) biosynthesis plays a key role in the mechanism of action of LBGP in treating neomycin‐induced hearing loss. Systemic delivery of 5‐HT increased neomycin‐induced apoptosis of cochlear hair cells and spiral ganglion neurons, and pharmacological Tph2 inhibition with P‐chlorophenylalanine or Tph2 knock down by AAV‐ie‐ Tph2 effectively attenuated neomycin‐induced hearing dysfunction. Collectively, these results provide a promising strategy for the prevention of SNHL by using natural plant extract which is more available and exhibits lower side effects compared with other otoprotective drugs, and identify Tph2 as a potential pharmacological target for the treatment of aminoglycoside‐induced ototoxicity.

Centrosomal proteins (Cep), as crucial scaffolding molecules, play a pivotal role in the biogenesis of centrioles and the regulation of the cell cycle. To date, mutation in Cep135 has been reported to be closely associated with multiple morphological abnormalities of the flagella (MMAF) in humans. However, the specific mechanism of Cep135 in spermatogenesis and its detailed role in male infertility remains largely unexplored. In this study, we present compelling evidence that Cep135 functions as a pathogenic gene responsible for oligoasthenoteratozoospermia (OAT) and male infertility in mice. By selectively deleting Cep135 in premeiotic germ cells using Stra8-Cre mice crossed with Cep135^flox/flox mice, we observed that Cep135 knockdown produced abnormal sperm morphology, germ cell apoptosis and consequentlybecame complete infertility, but did not impact premeiosis. Scanning and transmission electron microscopy revealed defects in acrosome, flagellum, and head-to-tail connections during spermatogenesis. Proteomic analysis further indicated that CEP135 deletion led to a significant reduction in proteins mainly associated with acrosome formation, sperm heads, sperm flagellum and microtubule assembly. Additionally, CEP135 interacts with spermatogenic proteins SPATA6 and AKAP3, regulating their expression and stability. Deficiency in CEP135 or its interacting proteins resulted in ciliary shortening. In conclusion, our study profoundly unveils the central role of Cep135 in spermatogenesis and male fertility. This discovery not only deepens our comprehension of spermatogenesis but also furnishes a solid theoretical foundation and experimental evidence that can guide the formulation of therapeutic and preventive strategies for male infertility.