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Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial

Xiaorui Chen¹, Yang Luo¹, Qing Zhu¹

¹Center for Reproductive Medicine and Department of Andrology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, China.

|April 16, 2024

Abstract:

Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes and ameliorates age-associated functional declines in multiple tissues. Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.

Insights

Young small extracellular vesicles (sEVs) reverse aging in mice by improving mitochondrial function and extending lifespan. This study highlights sEVs as a key factor in age-related rejuvenation and metabolic enhancement.

Area of Science:

Gerontology and Molecular Biology
Extracellular Vesicle Biology
Mitochondrial Medicine

Background:

Heterochronic parabiosis shows young blood rejuvenates aged tissues, but mechanisms are unclear.
Aging involves molecular, cellular, and physiological decline.
Small extracellular vesicles (sEVs) are implicated in intercellular communication.

Purpose of the Study:

To investigate the rejuvenating effects of young plasma-derived sEVs on aged mice.
To elucidate the molecular mechanisms underlying sEV-mediated rejuvenation.
To assess the impact of young sEVs on lifespan and age-associated dysfunction.

Main Methods:

Intravenous injection of young mouse plasma-derived sEVs into aged mice.
Assessment of molecular, mitochondrial, cellular, and physiological parameters.
Quantitative proteomic analysis and miRNA profiling of sEVs and tissues.
In vitro and in vivo studies on PGC-1α expression and mitochondrial function.

Main Results:

Young sEVs extended lifespan and mitigated senescence in aged mice.
sEV treatment ameliorated age-associated functional declines across multiple tissues.
Proteomic analysis revealed metabolic process alterations post-sEV treatment.
Young sEVs stimulated PGC-1α expression via miRNA cargoes, enhancing mitochondrial function.

Conclusions:

Young plasma-derived sEVs possess significant rejuvenating properties.
sEVs reverse aging phenotypes by enhancing mitochondrial energy metabolism through PGC-1α.
This study identifies young sEVs as a promising therapeutic strategy for age-related decline.

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