Research on the Impact of Nutritional Signals on the Lifespan of Mice

Background and Motivation

In recent years, the intensification of global aging has posed unprecedented challenges to medicine, socio-economics, and philosophy. By 2050, the global population aged 65 and above is expected to grow from 5% at the beginning of the 20th century to 17%, approximately 2 billion people. Although progress is anticipated in the prevention and management of age-related diseases, the comprehensive disease problems caused by the physiological decline of multiple organs in the elderly population are difficult to control through the treatment of single symptoms and diseases. Therefore, to intervene in age-related systemic physical decline and health deterioration, we need to deeply understand the processes that cause cellular and organ functions to degrade with age. Using genetic and pharmacological approaches in model organisms, researchers have discovered that the aging process is regulatable and that lifespan can be shortened or extended by modulating the functions of certain proteins.

Among these, the mechanistic target of rapamycin complex 1 (mTORC1) regulates cellular anabolic processes by receiving growth factor and nutritional signals. Under conditions of mTORC1 signal inhibition, the lifespan of various organisms can be significantly extended. However, the relationship between mTORC1 signal activation and lifespan shortening becomes complicated in more advanced model organisms like mice due to the emergence of other pathologies. Although mutations in certain genes lead to mTORC1 signal activation, early-onset specific diseases limit the study of overall aging mechanisms.

Source of Research

This study was conducted by Ana Ortega-Molina, Cristina Lebrero-Fernández, Alba Sanz, and others, primarily from the Spanish National Cancer Research Centre (CNIO) and the National Institute on Aging (NIA). The paper was published in Nature Aging on April 25, 2024.

Research Process and Details

Subjects and Methods

The study utilized a gene knock-in model expressing active mutant forms of RagC in mice, with mutations (such as s74n) believed to cause moderate mTORC1 signal upregulation. The research included the following steps:

1. Gene Editing and Model Establishment: Constructing a mouse model with RagC mutations using gene editing technology, where these mice exhibited moderately upregulated mTORC1 signals.
2. Cell and Tissue Analysis: Evaluating the impact of mutations on pathology and physiological activity by detecting mTORC1 signal activity and downstream molecules, such as the phosphorylation levels of s6k1 and tfeb, in different tissues of the mice.
3. Behavioral and Physiological Assessment: Including mouse maze experiments, rotarod tests, measuring skin thickness and bone density to evaluate the physical and physiological changes of the mice with age.
4. Inflammation and Aging Indicators Measurement: Measuring inflammatory factors in the blood of mice, and the activity of β-galactosidase (sa-β-gal) in kidneys and liver, as well as evaluating aging markers in organs such as cdkn1a (p21) and γ-H2AX expression.
5. Transcriptome Analysis: Analyzing gene expression changes in the kidneys and liver of old and young mice through RNA sequencing to further reveal gene regulatory networks.
6. Drug and Cell Experiments: Including rapamycin administration experiments to observe its impact on the lifespan of elderly mutant mice and bone marrow transplantation experiments to evaluate the independent effects of bone marrow cells.

Research Results

Major findings include:

1. Shortened Lifespan and Pathological Manifestations: RagC mutant mice had significantly shortened lifespans by approximately 30%. These mice exhibited various aging markers: decreased neuromuscular coordination, thinner cortices, lower bone density, and elevated blood pressure.
2. Increased Inflammation and Cellular Aging: The key pathological features of RagC mutant mice included glandular damage and significant myeloid inflammation, characterized by increased expression of inflammatory molecules and abnormal activation of myeloid cells. Additionally, aging markers like Sa-β-gal activity and p21 expression were increased in organs such as the kidneys.
3. Bone Marrow Transplantation Experiments: Bone marrow cells were found not to be the direct factors leading to shortened lifespans, but the organ damage and associated myeloid inflammatory response present in mutant mice were.
4. Limitations of Rapamycin Therapy: Although rapamycin significantly extended the lifespan of wild-type mice, it did not have a similar effect on RagC mutant mice, suggesting that in the presence of mutations, the chronic damage caused by increased nutritional signals may be irreversible.
5. Inflammation Inhibition Prolonging Lifespan: Targeting myeloid cells with anti-Gr1 antibodies reduced the inflammatory burden and extended the lifespan of RagC mutant mice.

Conclusions and Significance

Based on the research results, moderately increased nutritional signals through the mTORC1 pathway promoted chronic inflammation and damage in multiple organs, thereby shortening the lifespan of mice. The study demonstrated a “two-step” aging-promoting process: the interaction between organ damage and myeloid inflammation, which can be partially alleviated by inhibiting myeloid inflammation. The findings provide new insights into the relationship between nutritional signals, mTORC1, and aging, and suggest that controlling myeloid inflammation might delay aging-related health decline.

Research Highlights

1. First Discovery: It was first discovered that moderately increased nutritional signals could affect the lifespan of mice through the mTORC1 pathway.
2. Key Finding: The importance of myeloid inflammation in the nutritional signal-induced aging-promoting process.
3. Therapeutic Potential: Showed the potential of extending lifespan by inhibiting the inflammatory response of myeloid cells, especially neutrophils.

Comprehensive Evaluation

This study reveals the important link between nutritional signals and shortened lifespan, points out the critical role of myeloid inflammation in this process, and suggests the possibility of extending lifespan by controlling myeloid inflammation. This provides new ideas for understanding the aging process and potential intervention strategies.