No abstract

Physical frailty and sarcopenia (PF&S) share multisystem derangements, including variations in circulating amino acids and chronic low-grade inflammation. Gut microbiota balances inflammatory responses in several conditions and according to nutritional status. Therefore, an altered gut-muscle crosstalk has been hypothesized in PF&S. We analyzed the gut microbial taxa, systemic inflammation, and metabolic characteristics of older adults with and without PF&S. An innovative multi-marker analytical approach was applied to explore the classification performance of potential biomarkers for PF&S. Thirty-five community dwellers aged 70+, 18 with PF&S, and 17 nonPF&S controls were enrolled. Sequential and Orthogonalized Covariance Selection (SO-CovSel), a multi-platform regression method developed to handle highly correlated variables, was applied. The SO-CovSel model with the best prediction ability using the smallest number of variables was built using seven mediators. The model correctly classified 91.7% participants with PF&S and 87.5% nonPF&S controls. Compared with the latter group, PF&S participants showed higher serum concentrations of aspartic acid, lower circulating levels of concentrations of threonine and macrophage inflammatory protein 1α, increased abundance of Oscillospira and Ruminococcus microbial taxa, and decreased abundance of Barnesiellaceae and Christensenellaceae. Future investigations are warranted to determine whether these biomediators are involved in PF&S pathophysiology and may, therefore, provide new targets for interventions.

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.

(1) Background: Several factors have been suggested to be associated with the physiopathology of frailty in older adults, and nutrition (especially protein intake) has been attributed fundamental importance in this context. The objective of this study was to conduct a systematic review and meta-analysis to investigate the relationship between protein intake and frailty status in older adults. (2) Methods: A search of scientific studies was conducted in the main databases (Medline, Scopus, Cochrane library), and in the reference lists of selected articles. The search terms included synonyms and Medical Subject Headings and involved the use of Boolean operators which allowed the combination of words and search terms. Observational studies—cross-sectional and longitudinal—that met the eligibility criteria were included in the review. Article selection and data extraction were performed by two independent reviewers. Meta-analyses with random effects were performed. Publication bias was measured using the Strengthening the Reporting of Observational Studies in Epidemiology instrument. (3) Results: In the final sample, 10 articles, seven cross-sectional and three longitudinal, were included in the present study. Overall, studies investigated a total of 50,284 older adults from three different continents between 2006 and 2018. Four cross-sectional studies were included in the meta-analyses. The results demonstrated that a high protein intake was negatively associated with frailty status in older adults (odds ratio: 0.67, confidence interval = 0.56 to 0.82, p = 0.0001). (4) Conclusions: Our findings suggest that a high consumption of dietary protein is inversely associated with frailty in older adults.

Oxidative stress develops as a response to injury and reflects a breach in the cell’s antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell’s homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer’s and Parkinson’s disease) and Down syndrome, the most frequent progeroid syndrome.

One of the most widely conserved hallmarks of aging is a decline in functional capabilities. Mobility loss is particularly burdensome due to its association with negative health outcomes, loss of independence and disability, and the heavy impact on quality of life. Recently, a new condition, physical frailty and sarcopenia, has been proposed to define a critical stage in the disabling cascade. Physical frailty and sarcopenia are characterized by weakness, slowness, and reduced muscle mass, yet with preserved ability to move independently. One of the strategies that have shown some benefits in combatting mobility loss and its consequences for older adults is physical activity. Here, we describe the opportunities and challenges for the development of physical activity interventions in people with physical frailty and sarcopenia. The aim of this article is to review age-related physio(patho)logical changes that impact mobility in old age and to provide recommendations and procedures in accordance with the available literature.

(1) Background: The present work aims to conduct a systematic review and meta-analysis of observational studies, in order to investigate the association of relative protein intake and physical function in older adults; (2) Methods: Observational studies, that investigated the association between protein intake and physical function in older adults, were retrieved from MEDLINE, SCOPUS, CINAHL, AgeLine, EMBASE, and Cochrane-CENTRAL. Two independent researchers conducted study selection and data extraction; (3) Results: Very high protein intake (≥1.2 g/kg/day) and high protein intake (≥1.0 g/kg/day) groups showed better lower limb physical functioning and walking speed (WS) performance, respectively, in comparison to individuals who present relative low protein (<0.80 g/kg/day) intake. On the other hand, relative high protein intake does not seem to propitiate a better performance on isometric handgrip (IHG) and chair rise in comparison to relative low protein intake. In addition, there were no significant differences in the physical functioning of high and middle protein intake groups; (4) Conclusions: In conclusion, findings of the present study indicate that a very high (≥1.2 g/kg/day) and high protein intake (≥1.0 g/kg/day) are associated with better lower-limb physical performance, when compared to low protein (<0.80 g/kg/day) intake, in community-dwelling older adults. These findings act as additional evidence regarding the potential need to increase protein guidelines to above the current recommendations. However, large randomized clinical trials are needed to confirm the addictive effects of high-protein diets (≥1.0 g/kg/day) in comparison to the current recommendations on physical functioning. All data are available in the Open ScienceFramework.

Physical frailty and sarcopenia (PF&S) are hallmarks of aging that share a common pathogenic background. Perturbations in protein/amino acid metabolism may play a role in the development of PF&S. In this initial report, 68 community-dwellers aged 70 years and older, 38 with PF&S and 30 non-sarcopenic, non-frail controls (nonPF&S), were enrolled as part as the “BIOmarkers associated with Sarcopenia and Physical frailty in EldeRly pErsons” (BIOSPHERE) study. A panel of 37 serum amino acids and derivatives was assayed by UPLC-MS. Partial Least Squares–Discriminant Analysis (PLS-DA) was used to characterize the amino acid profile of PF&S. The optimal complexity of the PLS-DA model was found to be three latent variables. The proportion of correct classification was 76.6 ± 3.9% (75.1 ± 4.6% for enrollees with PF&S; 78.5 ± 6.0% for nonPF&S). Older adults with PF&S were characterized by higher levels of asparagine, aspartic acid, citrulline, ethanolamine, glutamic acid, sarcosine, and taurine. The profile of nonPF&S participants was defined by higher concentrations of α-aminobutyric acid and methionine. Distinct profiles of circulating amino acids and derivatives characterize older people with PF&S. The dissection of these patterns may provide novel insights into the role played by protein/amino acid perturbations in the disabling cascade and possible new targets for interventions.