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.

Systemic inflammation and mitochondrial dysfunction are involved in neurodegeneration in Parkinson’s disease (PD). Extracellular vesicle (EV) trafficking may link inflammation and mitochondrial dysfunction. In the present study, circulating small EVs (sEVs) from 16 older adults with PD and 12 non-PD controls were purified and characterized. A panel of serum inflammatory biomolecules was measured by multiplex immunoassay. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers (adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2)) were quantified in purified sEVs by immunoblotting. Relative to controls, PD participants showed a greater amount of circulating sEVs. Levels of CD9 and CD63 were lower in the sEV fraction of PD participants, whereas those of CD81 were similar between groups. Lower levels of ATP5A, NDUFS3, and SDHB were detected in sEVs from PD participants. No signal was retrieved for UQCRC2, MTCOI, or NDUFB8 in either participant group. To identify a molecular signature in circulating sEVs in relationship to systemic inflammation, a low level-fused (multi-platform) partial least squares discriminant analysis was applied. The model correctly classified 94.2% ± 6.1% PD participants and 66.7% ± 5.4% controls, and identified seven biomolecules as relevant (CD9, NDUFS3, C-reactive protein, fibroblast growth factor 21, interleukin 9, macrophage inflammatory protein 1β, and tumor necrosis factor alpha). In conclusion, a mitochondrial signature was identified in circulating sEVs from older adults with PD, in association with a specific inflammatory profile. In-depth characterization of sEV trafficking may allow identifying new biomarkers for PD and possible targets for personalized interventions.

Aims Cognitive dysfunction is a prevalent condition among patients with heart failure, and is independently associated with disability and mortality. Angiotensin-converting enzyme (ACE)-inhibitors might increase cerebral blood flow in subjects with heart failure. Our aim was to assess whether starting treatment with ACE-inhibitors might improve cognition in patients with heart failure. Methods and results Analyses involved 12 081 subjects, 1220 of whom had a verified diagnosis of heart failure, enrolled in a multi-centre pharmaco-epidemiology survey. None of these participants received ACE-inhibitors before hospitalization. Among participants with heart failure, cognitive performance improved in 30% of 446 participants who started ACE-inhibitors, but only in 22% of remaining patients (P=0.001). Among participants without heart failure, cognition improved in 19% of those receiving ACE-inhibitors, and in 18% of untreated patients (P=0.765). Use of ACE-inhibitors among patients with heart failure was associated with improving cognition (odds ratio=1.57; 95% CI 1.18–2.08) also in the multivariable regression modelling, independently of baseline or discharge blood pressure levels. The probability of improving cognitive performance was higher for dosages above the median values, as compared with lower doses (odds ratios=1.90 and 1.42; P for trend=0.001), and increased with duration of treatment (odds ratios for the lower, middle, and upper tertiles=1.25, 1.34, and 1.59; P for trend=0.007). Conclusion Treatment with ACE-inhibitors might selectively improve cognitive performance in patients with heart failure. However, up-titration of these agents might be required to yield the greatest benefit.