Spatial transcriptomic profiling reveals senescence-sensitive spots in the spleens of aged mice. [IMAGE: LIU GUANGHUI’S LAB]

In an innovative study that could reshape our understanding of aging, a team of Chinese scientists from the Chinese Academy of Sciences (CAS) and BGI Research has uncovered the intricate mechanisms by which immunoglobulins influence the aging process. Published in the prestigious journal Cell, their research not only charts a high-precision map of aging across various organs but also reveals the dual-edged sword of immunoglobulins in systemic aging.

The researchers constructed a detailed spatial transcriptomic landscape, dubbed Gerontological Geography (GG), which exposes the common threads of tissue structural disorder and loss of cellular identity as hallmarks of aging. This landscape is a significant step forward, pinpointing the epicenters of aging within multiple organs and uncovering the accumulation of immunoglobulins as a key aging characteristic and driver.

The quest for systemic biomarkers and key drivers of aging has been a long-standing puzzle in the field of gerontology. This study, a collaborative effort between Liu Guanghui’s team from CAS’s Institute of Zoology, Gu Ying’s team from BGI Research, Zhang Weiqi’s team from CAS’s Beijing Institute of Genomics, and Qu Jing’s team from CAS’s Institute of Zoology, has provided compelling answers.

By meticulously analyzing millions of spatial spots across nine organs in male mice, the team created high-precision spatial transcriptomic maps. These maps detailed the spatial distribution of over 70 cell types, offering a vivid picture of aging’s spatial characteristics. By using a novel method called organizational structure entropy (OSE) analysis, they discovered that increased spatial structural disorder and loss of cellular identity are universal signs of systemic aging, suggesting that spatial structural damage may be a primary cause of organ functional decline during aging.

The team also identified senescence-sensitive spots (SSS), which are structural regions in different tissues more susceptible to aging’s effects. They found that areas closer to SSS exhibit higher tissue structural entropy and greater loss of cellular identity, indicating that SSS could be the nucleus of organ aging. Notably, in immune organs, plasma cells, which are responsible for antibody synthesis, and cells with specific structures and functions, are the main components of the SSS microenvironment. The expression levels of immunoglobulin-related genes in these cells increase around SSS.

The study further discovered that immunoglobulin G (IgG) accumulates in multiple tissues and organs during aging in humans and mice, suggesting that IgG levels could serve as a new biomarker for aging. Moreover, IgG was found to directly induce aging in human and mouse macrophages and microglia, releasing inflammatory factors. Intriguingly, injecting IgG into young mice induced aging in multiple tissues and organs, demonstrating its potent aging effects.

In a promising development, the team developed an intervention strategy using antisense oligonucleotides (ASO) to reduce IgG content in mouse tissues, thereby delaying the aging of multiple organs.

This study is the first to map the spatial transcriptome of pan-organ aging in mammals, revealing tissue structural disorder and loss of cellular identity as key aging hallmarks and precisely locating the core regions and microenvironmental characteristics of aging sensitivity. The Immunoglobulin-associated Senescence Phenotype (IASP) proposed by the study expands the frontiers of aging science and opens new avenues for delaying aging and preventing related diseases.

The co-corresponding authors of the paper are Liu Guangui from CAS’s Institute of Zoology, Gu Ying from BGI Research, Zhang Weiqi from CAS’s Beijing Institute of Genomics, and Qu Jing from CAS’s Institute of Zoology. The co-first authors include Ma Shuai, Ji Zhejun, Zhang Bin, Geng Lingling, Cai Yusheng, Nie Chao, Li Jiaming, Zuo Yuesheng, Sun Yuzhe, and Xu Gang.

For more information, please contact:

Professor Liu Guanghui

E-mail: ghliu@ioz.ac.cn

Institute of Zoology,

Chinese Academy of Sciences

Source: Institute of Zoology,

Chinese Academy of Sciences