As the global population ages, age-related hearing loss has emerged as a significant public health challenge. This irreversible, progressive hearing decline not only severely impairs auditory function but also leads to social isolation, cognitive decline, and an increased risk of Alzheimer's disease. The primary cause of this condition is cochlear aging, yet our understanding of its molecular regulation remains limited. This gap is largely due to two factors: the reliance on rodent models, whose cochlear structures differ significantly from primates, and the scarcity of human cochlear samples, which restricts the clinical relevance of research.

On June 20, 2025, a collaborative research team led by Dr. Guanghui Liu from the Institute of Zoology, Chinese Academy of Sciences (CAS), Professor Renjie Chai from Southeast University, Professor Si Wang from Xuanwu Hospital Capital Medical University, and Dr. Jing Qu from the Institute of Zoology, CAS, published a pioneering study in Nature Aging. Titled "Single-Cell Profiling Identifies Hair Cell SLC35F1 Deficiency as a Signature of Primate Cochlear Aging," the paper presents the first cellular and molecular map of primate cochlear aging.

It identifies the downregulation of the hair cell transmembrane transporter SLC35F1 as a core molecular hallmark driving cochlear aging and demonstrates the protective effects of metformin, a drug traditionally used for type 2 diabetes, on cochlear health. This work bridges the gap from mechanistic discovery to clinically translatable intervention strategies, offering new therapeutic targets for age-related hearing loss.

The research team overcame technical challenges in primate cochlear dissection and single-cell dissociation, employing a multidimensional analysis approach to elucidate the key biological features of cochlear aging. At the tissue level, detailed staining and phenotypic characterization revealed core pathological changes, including hair cell loss, accelerated spiral ganglion neuron aging, exacerbated inflammatory damage, stria vascularis atrophy, and impaired transmembrane transport function.

At the cellular and molecular levels, the team innovatively combined single-nucleus RNA sequencing with artificial intelligence to create the first high-throughput, high-precision molecular map of primate cochlear aging. This map captured rare hair cell and spiral ganglion neuron subpopulations, revealing significant age-related transcriptional disruptions, with the specific downregulation of SLC35F1 in hair cells identified as a key molecular signature.

To explore the role of SLC35F1, the researchers knocked down Slc35f1 in hair cell lines, inducing significant apoptosis and suggesting that its silencing accelerates hair cell loss. Using AAV vector delivery technology, they specifically knocked down Slc35f1 in mouse hair cells, replicating key pathological features of age-related hearing loss, including the accumulation of aging markers, disordered hair cell cilia, hair cell loss, and hearing function decline. These findings confirmed SLC35F1's crucial role in maintaining hair cell homeostasis and provided new molecular insights into the pathogenesis of age-related hearing loss.

Building on previous research showing metformin's anti-aging effects in elderly primates, the team explored its protective effects on aged primate cochleae. After 3.3 years of treatment, elderly cynomolgus monkeys receiving clinical doses of metformin exhibited significant cochlear rejuvenation: reduced hair cell loss and stria vascularis atrophy, and a lower proportion of aging spiral ganglion neurons. Transcriptomic analysis revealed that metformin's protective effects stemmed from dual mechanisms: downregulating inflammation-related genes and upregulating key genes involved in sound perception and neural signaling.

This study is the first to systematically parse the cellular and molecular trajectories of primate cochlear aging, revealing key susceptible cell types and their specific aging drivers (such as SLC35F1) and confirming metformin's significant anti-aging effects in primate models. It deepens our understanding of primate auditory degeneration, provides key biomarkers for early warning of age-related hearing loss, and lays a theoretical and experimental foundation for developing innovative targeted therapies. This work paves the way for potential clinical interventions to prevent and treat age-related hearing loss.

Hair cell loss and reduced SLC35F1 expression in aged cynomolgus monkeys: Young group (left), Aged group (right). (Image by LIU Guanghui's lab)