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Declines in physical performance and cognition are commonly observed in older adults. The geroscience paradigm posits that a set of processes and pathways shared among age-associated conditions may also serve as a molecular explanation for the complex pathophysiology of physical frailty, sarcopenia, and cognitive decline. Mitochondrial dysfunction, inflammation, metabolic alterations, declines in cellular stemness, and altered intracellular signaling have been observed in muscle aging. Neurological factors have also been included among the determinants of sarcopenia. Neuromuscular junctions (NMJs) are synapses bridging nervous and skeletal muscle systems with a relevant role in age-related musculoskeletal derangement. Patterns of circulating metabolic and neurotrophic factors have been associated with physical frailty and sarcopenia. These factors are mostly related to disarrangements in protein-to-energy conversion as well as reduced calorie and protein intake to sustain muscle mass. A link between sarcopenia and cognitive decline in older adults has also been described with a possible role for muscle-derived mediators (i.e., myokines) in mediating muscle–brain crosstalk. Herein, we discuss the main molecular mechanisms and factors involved in the muscle–brain axis and their possible implication in cognitive decline in older adults. An overview of current behavioral strategies that allegedly act on the muscle–brain axis is also provided. [ABSTRACT FROM AUTHOR]

The article presents the discussion on conducting a systematic review and meta-analysis for assessing the association between protein consumption and frailty in older adults. Topics include stratified analysis according to protein sources being conducted based on three cross-sectional studies providing the data; and based on animal protein digestibility and branched-chain amino acid content (BCAA), whereas the impact of vitamin D (vitD) on frailty.

Background: The present systematic review and meta-analysis investigated the cross-sectional and longitudinal associations between protein intake and frailty in older adults. Methods: We conducted a systematic review and meta-analysis of cross-sectional and longitudinal studies that investigated the association between protein intake and frailty in older adults. Cross-sectional, case-control, and longitudinal cohort studies that investigated the association between protein intake and frailty as a primary or secondary outcome in people aged 60+ years were included. Studies published in languages other than English, Italian, Portuguese, or Spanish were excluded. Studies were retrieved on 31 January 2022. Results: Twelve cross-sectional and five longitudinal studies that investigated 46,469 community-dwelling older adults were included. The meta-analysis indicated that absolute, bodyweight-adjusted, and percentage of protein relative to total energy consumption were not cross-sectionally associated with frailty. However, frail older adults consumed significantly less animal-derived protein than robust people. Finally, high protein consumption was associated with a significantly lower risk of frailty. Conclusions: Our pooled analysis indicates that protein intake, whether absolute, adjusted, or relative to total energy intake, is not significantly associated with frailty in older adults. However, we observed that frail older adults consumed significantly less animal protein than their robust counterparts. [ABSTRACT FROM AUTHOR]

Declining physical functioning covers a prominent span of later life and, as a modifiable driver to be leveraged, lifestyle plays a critical role. This research aimed to undertake a systematic review investigating the association between levels of coffee consumption and declining conditions of physical functioning during aging, such as sarcopenia, frailty, weakness, falls, and disability, while trying to explain the underlying mechanisms, both from a metabolic and social angle. The literature was reviewed from inception to May 2022 using different electronic databases, not excluding the grey literature. Two independent researchers assessed the eligibility of 28 retrieved articles based on inclusion criteria; only 10 met the eligibility requirements. Different levels of coffee consumption were considered as exposure(s) and comparator(s) according to PECO concepts, while middle age was an inclusion criterion (40+ years). No limitations were set on the tool(s) assessing physical functioning, type of dietary assessment(s), study setting, general health status, country, and observational study design (cohort, cross-sectional). The cross-sectional design outnumbered the longitudinal (90%, n = 9/10). The overall quality rating was judged poor (70%) to good (30%). It was found that higher exposure to coffee drinking is strongly associated with better physical functioning outcomes, and the findings showed consistency in the direction of association across selected reports. Countering physical decline is a considerable challenge in easing the burden of population aging. For preventive models that aim to allow a better lifestyle, it has to be kept in mind that increased coffee consumption does not lead to poor physical functioning. [ABSTRACT FROM AUTHOR]

Background: Low muscle strength is a powerful predictor of negative health‐related events and a key component of sarcopenia. The lack of normative values for muscle strength across ages hampers the practical appraisal of this parameter. The aim of the present study was to produce normative values for upper and lower extremity muscle strength across a wide spectrum of ages, in a large sample of community‐dwellers recruited in the Longevity check‐up (Lookup) 7+ project. Methods: Lookup 7+ is an ongoing project that started in June 2015 and conducted in unconventional settings (i.e. exhibitions, malls, and health promotion campaigns) across Italy with the aim of fostering the adoption of healthy lifestyles in the general population. Candidate participants are eligible for enrolment if they are 18+ years and provide written informed consent. Upper and lower extremity muscle strength is assessed by handgrip strength and five‐repetition chair‐stand [5 × sit‐to‐stand (STS)] tests, respectively. Cross‐sectional centile and normative values for handgrip strength and 5 × STS tests from age 18 to 80+ years were generated for the two genders. Smoothed normative curves for the two tests were constructed for men and women using the lambda‐mu‐sigma method. Results: From 1 June 2015 to 30 May 2019, 11 448 participants were enrolled. The mean age of participants was 55.6 years (standard deviation: 11.5 years; range: 18–98 years), and 6382 (56%) were women. Normative values for handgrip strength and the 5 × STS test, both absolute and normalized by body mass index, were obtained for men and women, stratified by age groups. Values of upper and lower extremity muscle strength across ages identified three periods in life: an increase to peak in young age and early adulthood (18–24 years), preservation through midlife (25–44 years), and a decline from midlife onwards (45+ years). Conclusions: Our study established age‐specific and gender‐specific percentile reference values for handgrip strength and the 5 × STS test. The normative curves generated can be used to interpret the assessment of muscle strength in everyday practice for the early detection of individuals with or at risk of sarcopenia. [ABSTRACT FROM AUTHOR]

Dopaminergic nigrostriatal denervation and widespread intracellular α-synuclein accumulation are neuropathologic hallmarks of Parkinson's disease (PD). A constellation of peripheral processes, including metabolic and inflammatory changes, are thought to contribute to neurodegeneration. In the present study, we sought to obtain insight into the multifaceted pathophysiology of PD through the application of a multi-marker discovery approach. Fifty older adults aged 70+, 20 with PD and 30 age-matched controls were enrolled as part of the EXosomes in PArkiNson Disease (EXPAND) study. A panel of 68 circulating mediators of inflammation, neurogenesis and neural plasticity, and amino acid metabolism was assayed. Biomarker selection was accomplished through sequential and orthogonalized covariance selection (SO-CovSel), a multi-platform regression method developed to handle highly correlated variables organized in multi-block datasets. The SO-CovSel model with the best prediction ability using the smallest number of variables was built with seven biomolecules. The model allowed correct classification of 94.2 ± 3.1% participants with PD and 100% controls. The biomarker profile of older adults with PD was defined by higher circulating levels of interleukin (IL) 8, macrophage inflammatory protein (MIP)-1β, phosphoethanolamine, and proline, and by lower concentrations of citrulline, IL9, and MIP-1α. Our innovative approach allowed identifying and evaluating the classification performance of a set of potential biomarkers for PD in older adults. Future studies are warranted to establish whether these biomolecules could serve as biomarkers for PD as well as unveil new targets for interventions. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effects of a 6-month multicomponent exercise program (MCEP) on functional, cognitive, and hemodynamic parameters of older Type 2 diabetes mellitus (T2DM) patients. Moreover, additional analyses were performed to evaluate if T2DM patients present impaired adaptability in response to physical exercise when compared to nondiabetic volunteers. A total of 72 T2DM patients and 72 age-matched healthy volunteers (CG) were recruited and submitted to functional, cognitive, and hemodynamic evaluations before and after six months of a MCEP. The program of exercise was performed twice a week at moderate intensity. Results indicate T2DM and nondiabetic patients present an increase in mobility (i.e., usual walking speed) after the MCEP. However, improvements in maximal walking speed, transfer capacity, and executive function were only observed in the CG. On the other hand, only T2DM group reveals a marked decline in blood pressure. In conclusion, data of the current study indicate that a 6-month MCEP improves mobility and reduce blood pressure in T2DM patients. However, maximal walking speed, transfer capacity, and executive function were only improved in CG, indicating that T2DM may present impaired adaptability in response to physical stimulus. [ABSTRACT FROM AUTHOR]

The aim of this study was to carry out a literature review on the overall benefits of resistance training (RT) after stroke and undertake a critical analysis of the resistance exercise programs surveyed (rest interval between sets and exercises, number of sets, number of repetitions, intensity, duration of training, and weekly frequency). To obtain articles for the review, we searched PubMed, Google Scholar, and Physiotherapy Evidence Database (PEDro). Inclusion criteria were considered using the PICO (population, intervention, control/comparison, and outcome variables) model. The following characteristics were recorded for all articles: type of study, author, year of publication, participants (time after stroke, sample size, and age), benefits of RT, and structured resistance exercise programs. Positive effects of training were found on anxiety status, quality of life, muscle hypertrophy, cognitive function, strength, and muscle power. Only 5 studies described the main variables of RT in detail. Lack of control of some variables of RT may negatively affect the results of this practice. The findings of the present study may further inform health and physical conditioning professionals on the importance and necessity of using the main variables in the search for benefits for individuals with stroke. [ABSTRACT FROM AUTHOR]

Purpose:The present study aimed to investigate the association between hypertension and physical/functional capacities in community-dwelling older females. Materials and methods:Older female volunteers were dichotomized in two groups: hypertensive (n = 134) and normotensive (n = 244). Volunteers had their medical records reviewed and underwent evaluations of anthropometric data (weight, height and body mass index) and of physical and functional capacities. Results:The results showed that hypertensive older females presented higher values for age, weight, body mass index, and resting diastolic blood pressure than normotensive older females. Normotensive older females showed a higher performance in the one-leg stand test and six-minute walk test compared with hypertensive older females. Age, body mass index, maximal walking speed, performance in the Time Up and Go and six-minute walk test, and diagnosis of diabetes mellitus type II were factors associated with hypertension using the chi-square test. However, the multivariate regression analysis indicated that performance in the six-minute walk test was the only factor associated with hypertension. Conclusions:The patients with higher scores in the six-minute walk test, which is associated with aerobic capacity, show less odds to have clinical diagnosis of hypertension. However, hypertension was not associated with poor physical and functional capacity. [ABSTRACT FROM AUTHOR]

Purpose. The present study aimed to investigate the impact of a 6-month multicomponent exercise program (MCEP) on physical function and cognitive parameters of normotensive (NTS) and hypertensive (HTS) older patients and verify if age can influence the adaptations in response to the exercise. Methods. A total of 218 subjects, 101 NTS and 117 HTS, were recruited and underwent functional and cognitive evaluations before and after six months of a MCEP. The program of exercise was performed twice a week, for 26 weeks. The physical exercises were thought to mimic the activities of daily living and, therefore, aggregated functional and walking exercises. Exercise sessions were performed at moderate intensity. Results. Data indicated that HTS and NST patients showed a similar increase in the performance of walking speed test and one-leg stand test after the MCEP. Regarding age, results did not show differences in the magnitude of adaptations between old and young HTS and NTS patients. Conclusions. Data of the present study indicated that a 6-month MCEP was able to increase equally balance and mobility in NTS and HTS patients. Moreover, data demonstrated that aging did not seem to impair the capacity to adapt in response to exercise in both groups. [ABSTRACT FROM AUTHOR]

Inflammatory markers are increased systematically and locally (e.g., skeletal muscle) in stroke patients. Besides being associated with cardiovascular risk factors, proinflammatory cytokines seem to play a key role in muscle atrophy by regulating the pathways involved in this condition. As such, they may cause severe decrease in muscle strength and power, as well as impairment in cardiorespiratory fitness. On the other hand, physical exercise (PE) has been widely suggested as a powerful tool for treating stroke patients, since PE is able to regenerate, even if partially, physical and cognitive functions. However, the mechanisms underlying the beneficial effects of physical exercise in poststroke patients remain poorly understood. Thus, in this study we analyze the candidate mechanisms associated with muscle atrophy in stroke patients, as well as the modulatory effect of inflammation in this condition. Later, we suggest the two strongest anti-inflammatory candidate mechanisms, myokines and the cholinergic anti-inflammatory pathway, which may be activated by physical exercise and may contribute to a decrease in proinflammatory markers of poststroke patients. [ABSTRACT FROM AUTHOR]

Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components—in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions. [ABSTRACT FROM AUTHOR]

Mitochondria serve as a hub for a multitude of vital cellular processes. To ensure an efficient deployment of mitochondrial tasks, organelle homeostasis needs to be preserved. Mitochondrial quality control (MQC) mechanisms (i.e., mitochondrial dynamics, biogenesis, proteostasis, and autophagy) are in place to safeguard organelle integrity and functionality. Defective MQC has been reported in several conditions characterized by chronic low-grade inflammation. In this context, the displacement of mitochondrial components, including mitochondrial DNA (mtDNA), into the extracellular compartment is a possible factor eliciting an innate immune response. The presence of bacterial-like CpG islands in mtDNA makes this molecule recognized as a damaged-associated molecular pattern by the innate immune system. Following cell death-triggering stressors, mtDNA can be released from the cell and ignite inflammation via several pathways. Crosstalk between autophagy and apoptosis has emerged as a pivotal factor for the regulation of mtDNA release, cell's fate, and inflammation. The repression of mtDNA-mediated interferon production, a powerful driver of immunological cell death, is also regulated by autophagy–apoptosis crosstalk. Interferon production during mtDNA-mediated inflammation may be exploited for the elimination of dying cells and their conversion into elements driving anti-tumor immunity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mitochondria are intracellular organelles involved in a myriad of activities. To safeguard their vital functions, mitochondrial quality control (MQC) systems are in place to support organelle plasticity as well as physical and functional connections with other cellular compartments. In particular, mitochondrial interactions with the endosomal compartment support the shuttle of ions and metabolites across organelles, while those with lysosomes ensure the recycling of obsolete materials. The extrusion of mitochondrial components via the generation and release of mitochondrial-derived vesicles (MDVs) has recently been described. MDV trafficking is now included among MQC pathways, possibly operating via mitochondrial–lysosomal contacts. Since mitochondrial dysfunction is acknowledged as a hallmark of aging and a major pathogenic factor of multiple age-associated conditions, the analysis of MDVs and, more generally, of extracellular vesicles (EVs) is recognized as a valuable research tool. The dissection of EV trafficking may help unravel new pathophysiological pathways of aging and diseases as well as novel biomarkers to be used in research and clinical settings. Here, we discuss (1) MQC pathways with a focus on mitophagy and MDV generation; (2) changes of MQC pathways during aging and their contribution to inflamm-aging and progeroid conditions; and (3) the relevance of MQC failure to several disorders, including neurodegenerative conditions (i.e., Parkinson's disease, Alzheimer's disease) and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson's disease as a prototypical geroscience condition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]