Abstract
The progressive decline of cell function and integrity, manifesting clinically as increased vulnerability to adverse outcomes and death, is core to biological aging. Mitochondrial dysfunction, oxidative stress, altered intercellular communication (including chronic low-grade inflammation), genomic instability, telomere attrition, loss of proteostasis, altered nutrient sensing, epigenetic alterations, and stem cell exhaustion have been proposed as hallmarks of aging. These “aging pillars” are not mutually exclusive, making the matter intricate and leaving numerous unanswered questions. The characterization of circulating extracellular vesicles (EVs) has recently allowed specific secretory phenotypes associated with aging to be identified. As such, EVs may serve as novel biomarkers for capturing the complexity of aging. Besides the mitochondrial–lysosomal axis, EV trafficking has been proposed as an additional layer in mitochondrial quality control. Indeed, disruption of the mitochondrial–lysosomal axis coupled with abnormal EV secretion may play a role in the pathogenesis of aging and several disease conditions. Here, we discuss (1) the mechanisms of EV generation; (2) the relationship between the mitochondrial–lysosomal axis and EV trafficking in the setting of mitochondrial quality control; and (3) the prospect of using EVs as aging biomarkers and as delivery systems for therapeutics against age-related conditions.
Highlights
Aging is marked by multiple biological disarrangements that increase the risk of developing several chronic diseases and functional decline, which both contribute to negative health-related events [1,2]
Mitochondrial-derived vesicles (MDVs) are generated in cells lacking autophagy-related gene (Atg) 5, Beclin-1 or Rab9 as well as after silencing of dynamin-related protein 1 (DRP1) [72]. These findings indicate that MDV delivery to lysosomes for degradation complements mitophagy for mitochondrial quality control (MQC)
multivesicular bodies (MVBs) can follow two alternative fates: some are delivered to lysosomes for degradation, promoting clearance of cellular waste, while others fuse with the plasma membrane to release intraluminal vesicles (ILVs) into the extracellular space as exosomes [94]
Summary
Aging is marked by multiple biological disarrangements that increase the risk of developing several chronic diseases (e.g., cardiovascular disease, diabetes, cancer, and neurodegeneration) and functional decline, which both contribute to negative health-related events (e.g., poor quality of life, morbidity, disability, loss of independence, institutionalization, death) [1,2]. Such a scenario well depicts the urge of untangling the determinants of aging for devising strategies able to extend healthspan and foster active aging. A new generation of clinical trials is highly sought after to validate this hypothesis in humans
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