Small Extracellular Vesicles in Young Plasma Reverse Age-Related Functional Decline by Improving Mitochondrial Energy Metabolism

Background

In recent years, research on heterochronic parabiosis has revealed significant regenerative effects of young blood on elderly tissues. However, the specific regenerative mechanisms are not fully understood. This paper demonstrates that small extracellular vesicles (sEVs) from young mouse plasma can counteract existing aging at the molecular, mitochondrial, cellular, and physiological levels. Young sEVs, administered intravenously into elderly mice, extended their lifespan, reduced aging phenotypes, and improved age-related functional decline in various tissues. Quantitative proteomics analysis showed significant changes in the proteome of aged tissues treated with young sEVs, and these changes were closely related to metabolic processes. Mechanistic studies revealed that young sEVs mainly stimulated the expression of PGC-1α through their miRNA cargo both in vivo and in vitro, thereby improving mitochondrial function and reducing mitochondrial defects. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related functional decline at least in part by stimulating the expression of PGC-1α and enhancing mitochondrial energy metabolism.

Source Introduction

This paper was jointly authored by scholars including Xiaorui Chen, Yang Luo, Qing Zhu, and Jingzi Zhang, affiliated with institutions such as the Reproductive Medicine Center and Department of Andrology at Nanjing Drum Tower Hospital, the School of Life Sciences at Nanjing University, and the First Affiliated Hospital of Nanjing Medical University. The article was published in the June 2024 issue of the journal “Nature Aging.”

Detailed Research Process

Experimental Procedure and Subjects

The experimental procedure of this paper can be divided into the following steps: 1. Extraction and Purification of sEVs: Researchers first extracted and purified sEVs from the plasma of young (2 months) and aged (20 months) mice. The presence and characteristics of sEVs were verified using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). 2. Effects of sEVs on Lifespan and Frailty Index of Aged Mice: The purified young sEVs were administered intravenously to aged mice once a week until death, and their effects on lifespan were analyzed using Kaplan-Meier survival curves. Results showed that young sEVs extended the median lifespan of aged mice by 12.42%. 3. Systemic Physiological Effects of Long-term and Short-term sEVs Treatment: The long-term and short-term effects of sEVs were assessed through a series of behavioral experiments and physiological tests, including cognitive function, sperm quality, metabolic health, cardiac performance, bone density, and brain volume. 4. Effects of sEVs on Mitochondrial Function in Aged Mice: Detailed measurements were conducted on the mitochondrial ATP production rate, respiratory complex activity, mtDNA copy number, and changes in mitochondrial quality and morphology after sEVs treatment. 5. Mechanism Study of miRNA Cargo in sEVs: Through small RNA deep sequencing and literature review, miRNAs with significant variations in plasma sEVs among different age groups were identified. Functional validation experiments confirmed the role of these miRNAs in regulating PGC-1α expression.

Major Research Results

1. Lifespan Extension and Frailty Index Improvement: Elderly mice injected with young sEVs showed significantly extended lifespans and reduced frailty index scores, appearing healthier.
2. Improvement in Systemic Multi-Organ Functions: Notable improvements were observed in sperm quality and fertility, metabolic health, cardiac function, bone density, and brain volume.
3. Enhanced Mitochondrial Function: Young sEVs significantly increased the ATP production rate and respiratory complex activity, mtDNA copy number, and improved mitochondrial quality and morphology.
4. Key Role of miRNA Cargo: The miRNA content in plasma sEVs differed significantly between age groups. miR-144-3p, miR-149-5p, and miR-455-3p were more abundant in young sEVs, and these miRNAs were shown to improve mitochondrial energy metabolism by enhancing PGC-1α expression.

Conclusion and Value

The study concludes that young sEVs reverse the aging phenotype, extend lifespan, and improve multi-organ functions in elderly mice by carrying specific miRNAs that activate PGC-1α expression. This finding highlights the crucial role of sEVs as a non-cell-autonomous mechanism in regulating the aging process, potentially providing new strategies for anti-aging and related disease treatments.

Research Highlights

1. Extraction and Purification Technology for sEVs: The research team successfully extracted, purified, and identified sEVs from young and aged mice, laying the experimental foundation.
2. Comprehensive Physiological Function Evaluation: Multiple experimental methods were used to comprehensively evaluate the long-term and short-term effects of sEVs treatment on various systems in elderly mice, confirming their significant anti-aging effects.
3. Discovery and Mechanism of miRNA Cargo: The key role of miRNA cargo in young sEVs was thoroughly analyzed and experimentally validated for their function in anti-aging through PGC-1α regulation.

Other Important Information

In addition, this paper underscores the critical role of sEVs in the regenerative effects of young plasma, providing a novel non-cellular approach to understanding and addressing aging. In the future, sEVs may play a significant role in anti-aging treatments and disease prevention.

This paper comprehensively demonstrates the potential of sEVs in young plasma to delay aging and promote regeneration, opening new research directions and providing important references for understanding anti-aging mechanisms and developing therapeutic approaches.