Predictive values of relative fat mass and body mass index on cardiovascular health in community-dwelling older adults: Results from the Longevity Check-up (Lookup) 7.

OBJECTIVES: To assess the predictive value of relative fat mass compared to body mass index for hypertension, diabetes, hyperlipidemia, and heightened cardiovascular risk in a cohort of community-dwelling older adults from the Longevity Check-up 7+ cohort. STUDY DESIGN: Retrospective cross-sectional study. MAIN OUTCOME MEASURES: Hyperlipidemia was defined as total cholesterol ≥200 mg/dL or ongoing lipid-lowering treatment. Diabetes was defined either as self-reported diagnosis or fasting blood glucose >126 mg/dL or a random blood glucose >200 mg/dL. Hypertension was defined as blood pressure ≥ 140/90 mmHg or requiring daily antihypertensive medications. Heightened cardiovascular risk was operationalized as having at least two of these conditions. RESULTS: Analyses were conducted in 1990 participants (mean age 73.2 ± 6.0 years; 54.1 % women). Higher proportions of men than women had hypertension and diabetes, while hyperlipidemia was more prevalent in women. Receiver operating curve analysis indicated relative fat mass was a better predictor of hypertension in women and diabetes in both sexes. Body mass index performed better in predicting hyperlipidemia in women. Relative fat mass thresholds of ≥27 % for men and ≥40 % for women were identified as optimal indicators of heightened cardiovascular risk and so were used to defined high adiposity. Moderate correlations were found between high adiposity or body mass index ≥25 kg/m2 and the presence of hypertension, hyperlipidemia and heightened cardiovascular risk, while a strong correlation was found with diabetes. Logistic regression analysis highlighted significant associations between high adiposity and increased odds of hypertension, diabetes, and heightened cardiovascular risk. CONCLUSIONS: Proposed cut-offs for relative fat mass were more reliable indices than the usual cut-offs for body mass index for identifying individuals at heightened cardiovascular risk. Our findings support the role of anthropometric measures in evaluating body composition and the associated metabolic and cardiovascular conditions in older adults.

Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?

Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.

Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.

Sarcopenia has a complex pathophysiology that encompasses metabolic dysregulation and muscle ultrastructural changes. Among the drivers of intracellular and ultrastructural changes of muscle fibers in sarcopenia, mitochondria and their quality control pathways play relevant roles. Mononucleated muscle stem cells/satellite cells (MSCs) have been attributed a critical role in muscle repair after an injury. The involvement of mitochondria in supporting MSC-directed muscle repair is unclear. There is evidence that a reduction in mitochondrial biogenesis blunts muscle repair, thus indicating that the delivery of functional mitochondria to injured muscles can be harnessed to limit muscle fibrosis and enhance restoration of muscle function. Injection of autologous respiration-competent mitochondria from uninjured sites to damaged tissue has been shown to reduce infarct size and enhance cell survival in preclinical models of ischemia-reperfusion. Furthermore, the incorporation of donor mitochondria into MSCs enhances lung and cardiac tissue repair. This strategy has also been tested for regeneration purposes in traumatic muscle injuries. Indeed, the systemic delivery of mitochondria promotes muscle regeneration and restores muscle mass and function while reducing fibrosis during recovery after an injury. In this review, we discuss the contribution of altered MSC function to sarcopenia and illustrate the prospect of harnessing mitochondrial delivery and restoration of MSCs as a therapeutic strategy against age-related sarcopenia.

Physical performance and negative events in very old adults: a longitudinal study examining the ilSIRENTE cohort.

BACKGROUND: Declining physical performance in old age is associated with a wide range of negative health-related outcomes. However, it is unclear which physical capabilities should be prioritized to obtain prognostic information in older adults. AIMS: To examine the associations between the performance on several physical function tests and falls, disability, and death in a well-characterized sample of very old Italian adults. METHODS: This was a prospective cohort study of older adults who lived in the mountain community of the Sirente geographic area in Central Italy. Physical performance was assessed using isometric handgrip strength (IHG), walking speed (WS) at a usual and fast pace, 5-time sit-to-stand test (5STS), and sit-to-stand power measures. Appendicular skeletal muscle mass was estimated from calf circumference using a validated equation. History of falls, incident falls, and disability status according to basic Activities of Daily Living (ADLs) were recorded over two years. Survival status was obtained from the participants' general practitioners and was confirmed by the National Death Registry over 10 years from enrolment. Linear, binary, and Cox regressions were performed to evaluate the association between physical performance measures and health outcomes. RESULTS: The mean age of the 255 participants was 84.2 ± 5.1 years, and 161 (63.1%) were women. Logistic regression indicated that IHG was significantly associated with incident ADL disability, whereas specific sit-to-stand muscle power was an independent predictor of death. No significant associations were observed between physical function and falls. CONCLUSIONS: Our findings indicate selective associations between physical function tests and the occurrence of negative events in very old adults, with poor IHG predicting disability and specific sit-to-stand muscle power being longitudinally associated with death.

Mitochondrial Quantity and Quality in Age-Related Sarcopenia.

Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation.

Differential profiles of serum cytokines in Parkinson's disease according to disease duration.

OBJECTIVE: Neurodegeneration and neuroinflammation are two intertwined mechanisms contributing to the pathophysiology of Parkinson's disease. Whether circulating biomarkers reflecting those two processes differ according to disease duration remains to be established. The present study was conducted to characterize the biomarkers individuals with PD with short (≤5 years) or long disease duration (>5 years). METHODS: We consecutively enrolled 104 patients with Parkinson's disease and evaluated them using validated clinical scales (MDS-UPDRS, Hoehn and Yahr staging, MMSE). Serum samples were assayed for the following biomarkers: neurofilament light chain (NfL), brain-derived neurotrophic factor (BDNF), interleukin (IL-) 1ß, 4, 5, 6, 10, 17, interferon-γ, and tumor necrosis factor α. RESULTS: Mean age of participants was 66.0 ± 9.6 years and 45 (34%) were women. The average disease duration was 8 ± 5 years (range 1 to 19 years). Patients with short disease duration (≤ 5 years) showed a pro-inflammatory profile, with significantly higher levels of pro-inflammatory IL-1ß and lower concentrations of IL-5, IL-10 and IL-17 (p < 0.05). NfL serum levels showed a positive correlation with disease duration and age (respectively rho = 0.248, p = 0.014 and rho = 0.559, p < 0.001) while an opposite pattern was detected for BDNF (respectively rho -0,187, p = 0.034 and rho = -0.245, p = 0.014). CONCLUSIONS: Our findings suggest that a pro-inflammatory status may be observed in PD patients in the early phases of the disease, independently from age.

Functional hypothalamic amenorrhea: gut microbiota composition and the effects of exogenous estrogen administration.

Functional hypothalamic amenorrhea (FHA) is characterized by estrogen deficiency that significantly impacts metabolic, bone, cardiovascular, mental, and reproductive health. Given the importance of environmental factors such as stress and body composition, and particularly considering the importance of estrogens in regulating the gut microbiota, some changes in the intestinal microenvironment are expected when all of these factors occur simultaneously. We aimed to assess whether the gut microbiota composition is altered in FHA and to determine the potential impact of hormonal replacement therapy (HRT) on the gut microbiota. This prospective observational study included 33 patients aged 18-34 yr with FHA and 10 age-matched healthy control women. Clinical, hormonal, and metabolic evaluations were performed at baseline for the FHA group only, whereas gut microbiota profile was assessed by 16S rRNA gene amplicon sequencing for both groups. All measurements were repeated in patients with FHA after receiving HRT for 6 mo. Gut microbiota alpha diversity at baseline was significantly different between patients with FHA and healthy controls (P < 0.01). At the phylum level, the relative abundance of Fusobacteria was higher in patients with FHA after HRT (P < 0.01), as was that of Ruminococcus and Eubacterium at the genus level (P < 0.05), which correlated with a decrease in circulating proinflammatory cytokines. FHA is a multidimensional disorder that is interconnected with dysbiosis through various mechanisms, particularly involving the gut-brain axis. HRT appears to induce a favorable shift in the gut microbiota in patients with FHA, which is also associated with a reduction in the systemic inflammatory status.NEW & NOTEWORTHY Our study marks the first comprehensive analysis of gut microbiota composition in FHA and the impact of HRT on it, along with biochemical, anthropometric, and psychometric aspects. Our results indicate distinct gut microbiota composition in patients with FHA compared with healthy individuals. Importantly, HRT prompts a transition toward a more beneficial gut microbiota profile and reduced inflammation. This study validates the concept of FHA as a multifaceted disorder interlinked with dysbiosis, particularly involving the gut-brain axis.

Sex- and age-specific normative values of lower extremity muscle power in Italian community-dwellers.

BACKGROUND: Muscle power is associated with health-related parameters. Simple equations were validated to estimate lower extremity muscle power measures based on the time to complete the five-repetition sit-to-stand test. The present study was conducted to provide lower extremity muscle power estimates and produce centile values in a large and relatively unselected population across a wide age spectrum. METHODS: Data were from the Longevity Check-up 7+ (Lookup 7+) project, an ongoing initiative conducted in unconventional settings (e.g., exhibitions, shopping centres and health promotion campaigns) across Italy to foster adoption of healthy lifestyles. Absolute, relative, allometric and specific muscle power measures of the lower extremities were estimated using validated formulas. Cross-sectional centile and normative values for muscle power measures from 18 to 81+ years were produced for the two sexes. Smoothed normative curves for men and women were constructed using the lambda-mu-sigma method. RESULTS: From 1 June 2015 to 31 October 2021, 13 515 participants were enrolled of whom 12 864 were eligible for the present study. Mean age was 55.9 years (standard deviation: 14.8 years; range: 18-98 years), and 7217 (56.%) were women. Absolute, relative, allometric and specific muscle power declined significantly with age. Specific patterns of decline were observed according to sex and muscle power parameter. Absolute muscle power peaked at 41-50 and 31-40 years in men and women, respectively. Afterwards, a decline rate of approximately 12% per decade was observed, regardless of sex. Relative muscle power showed the largest reduction with age, such that it was 40.6% and 46.4% smaller in men and women older than 80, respectively, compared with those aged 18-30 years. Age-related changes in allometric and specific muscle power measures were similar between men and women. CONCLUSIONS: Data from the Lookup 7+ project indicate that lower extremity muscle power estimated using simple equations is significantly associated with age. Sex-specific patterns of decline in absolute and relative muscle power were observed with age. Allometric and specific muscle power declined at a similar rate in men and women.

Lower Adherence to a Mediterranean Diet Is Associated with High Adiposity in Community-Dwelling Older Adults: Results from the Longevity Check-Up (Lookup) 7+ Project.

High adiposity impacts health and quality of life in old age, owing to its association with multimorbidity, decreased physical performance, and frailty. Whether a high adherence to a Mediterranean diet (Medi-Diet) is associated with reduced body adiposity in older adults is unclear. The present study was conducted to assess the prevalence of high adiposity in a large sample of community-dwelling older adults. We also explored the relationship between whole-body adiposity estimated through relative fat mass (RFM) and Medi-Diet adherence. Data were obtained from the Longevity Check-up 7+ (Lookup7+) project database. RFM was estimated from anthropometric and personal parameters using a validated equation. RFM was categorized as high if ≥40% in women and ≥30% in men. Information on diet was collected using a food frequency questionnaire, while Medi-Diet adherence was assessed through a modified version of the Medi-Lite scoring system. Analyses were conducted in 2092 participants (mean age 73.1 ± 5.9 years; 53.4% women). Mean RFM was 39.6 ± 5.14% in women and 29.0 ± 3.6% in men. High adiposity was found in 971 (46.4%) participants and was more frequent in those with a low (54.2%) or moderate (46.4%) Medi-Diet adherence compared with the high-adherence group (39.7%, p < 0.001). Logistic regression indicated that older adults with high Medi-Diet adherence were less likely to have a high RFM. Other factors associated with a greater risk of having high adiposity were older age, female sex, and physical inactivity. Our findings support an association between healthy lifestyles, including a greater adherence to a Mediterranean-style diet, and lower body adiposity in older adults.

Association of Physical Activity and Exercise with Physical Performance and Muscle Mass in Older Adults: Results from the Longevity Check-Up (Lookup) 7+ Project.

Regular engagement in physical activity (PA) or physical exercise (PE) is effective at improving physical performance and body composition in older adults. Less is known about the benefits that may be obtained through combining PA with PE and whether the effects of activity habits differ between men and women. This study cross-sectionally investigated the association of PA and/or PE with physical performance and anthropometric measures in a large and relatively unselected sample of older adults enrolled in the Longevity Check-up (Lookup) 7+ project. Participants were individuals 65 years and older living in the community who were recruited in unconventional settings across Italy. Adherence to PA or PE was operationalized as involvement in light walking or various types of exercise, respectively, at least twice weekly for a minimum of 30 min per session throughout the last 12 months. Physical performance measures included handgrip strength and five-time sit-to-stand (5STS) tests. Lower-limb muscle power and appendicular skeletal muscle mass (ASM) were estimated through validated equations. We analyzed data of 4119 participants, of whom 2222 (53.4%) were women. The mean age was 72.8 ± 5.8 years in men and 72.1 ± 5.4 years in women. Regular engagement in PA + PE was reported by 139 (7.3%) men and 100 (4.5%) women. Results indicated that regular walking activity and/or PE were significantly associated with better physical performance and greater ASM with sex-specific patterns. Associations were also influenced by the type of activity, physical performance assessment tool, and anthropometric parameters. Men engaged in PA + PE performed better on the 5STS test and had greater handgrip strength, ASM, and relative and specific muscle power than those practicing either PA or PE. In women, the combination of PA and PE was associated with greater handgrip strength. The findings of this study indicate that older adults regularly practicing PA + PE had better physical performance than those who only engaged in either modality. In men, the combination of PA and PE was also associated with greater ASM.

Mitophagy in human health, ageing and disease.

Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities. Preclinical and clinical studies have shown that impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. Strategies to boost mitophagy have been successfully tested in model organisms, and, recently, some have been translated into clinics. In this Review, we describe the basic mechanisms of mitophagy and how mitophagy can be assessed in human blood, the immune system and tissues, including muscle, brain and liver. We outline mitophagy's role in specific diseases and describe mitophagy-activating approaches successfully tested in humans, including exercise and nutritional and pharmacological interventions. We describe how mitophagy is connected to other features of ageing through general mechanisms such as inflammation and oxidative stress and forecast how strengthening research on mitophagy and mitophagy interventions may strongly support human health.

Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.

Mitophagy is crucial for maintaining mitochondrial quality. However, its assessment in vivo is challenging. The endosomal-lysosomal system is a more accessible pathway through which subtypes of extracellular vesicles (EVs), which also contain mitochondrial constituents, are released for disposal. The inclusion of mitochondrial components into EVs occurs in the setting of mild mitochondrial damage and during impairment of lysosomal function. By releasing mitochondrial-derived vesicles (MDVs), cells limit the unload of mitochondrial damage-associated molecular patterns with proinflammatory activity. Both positive and negative effects of EVs on recipient cells have been described. Whether this is due to the production of EVs other than those containing mitochondria, such as MDVs, holding specific biological functions is currently unknown. Evidence on the existence of different MDV subtypes has been produced. However, their characterization is not always pursued, which would be relevant to exploring the dynamics of mitochondrial quality control in health and disease. Furthermore, MDV classification may be instrumental in understanding their biological roles and promoting their implementation as biomarkers in clinical studies.

Adherence to aerobic training combined with high protein intake is associated with low blood pressure in Italian older adults: a cross-sectional study.

BACKGROUND: Lifestyle habits have a key role in cardiometabolic health. The effects of combined aerobic training (AT) and high protein intake (HPI) on cardiometabolic parameters in older adults are not well established. AIMS: To investigate the association of AT and HPI with blood pressure (BP), blood glucose, and total blood cholesterol levels in a sample of Italian older adults enrolled in the Longevity Check-up 7 + (Lookup 7 +) study. METHODS: Lookup 7 + is an ongoing project started in June 2015 and conducted in unconventional settings (e.g., exhibitions, malls, health promotion campaigns) across Italy with the aim of fostering adoption of healthy lifestyles in the general population. For the present investigation, analyses were conducted in participants 65 + years and with body mass index values ≥ 18.5 kg/m2 (n = 3219). Systolic (SBP) and diastolic BP (DBP), blood glucose, and total blood cholesterol were measured. Protein intake was estimated using a 12-item food frequency questionnaire. HPI was operationalized as a daily protein intake ≥ 0.8 g/kg of body weight. AT was operationalized as the practice of running and/or swimming for 60 + minutes at least twice weekly during the previous year. RESULTS: The mean age of the 3219 participants was 72.7 ± 5.7 years, and 55.2% were women. Adherence to AT combined with a HPI was negatively and independently associated with SPB (ß: - 4.976; 95% confidence interval: - 9.8 to - 0.08). No other significant associations were observed. DISCUSSION AND CONCLUSIONS: Our results indicate that AT combined with HPI was negatively associated with SBP in a large and relatively unselected sample of Italian older adults living in the community. These findings need confirmation by ad hoc designed studies.

Muscle power-related parameters in middle-aged and older Brazilian women: a cross-sectional study.

The present study was conducted to provide normative values for lower-limb muscle power estimated through equations based on the 5 times sit-to-stand (5STS) test in Brazilian older women. In addition, we investigated the association between muscle power parameters and age. The study followed a cross-sectional design. Participants were community-dwelling women. Candidates were considered eligible if they were 18 years or older, lived independently, and possessed sufficient physical and cognitive abilities to perform all measurements required by the protocol. The 5STS test was performed as fast as possible using a standard protocol. Absolute, relative, and allometric muscle power measures were estimated using 5STS-based equations. Two thousand four-hundred seventy-one women participated in the present study. Results indicated that muscle power-related parameters decreased linearly with age. Women 60-69 years showed a marginal reduction in absolute (- 5.2%), relative (- 7.9%), and allometric (- 4.0%) muscle power. A larger reduction was observed in those 70-79 years and reached » of loss in participants ≥ 80, in comparison to middle-aged participants. Pearson's correlation and linear regression analyses indicated that power-related parameters were negatively associated with age. In conclusion, data of the present study provide normative values for lower-limb muscle power parameters according to 5STS-based equations. We observed that muscle power-related parameters declined with age, such that participants 60-69, 70-79, and ≥ 80 years displayed lower absolute and relative muscle power compared middle-aged women. A later decline was observed in allometric muscle power. Relative muscle power declined to a greater extent than other parameters, suggesting a possible window of opportunity for interventions.

Combined Aerobic Training and Mediterranean Diet Is Not Associated with a Lower Prevalence of Sarcopenia in Italian Older Adults.

Previous studies found a lower prevalence of sarcopenia in older adults engaged in regular aerobic training (AT) or with greater adherence to a Mediterranean (MED) diet. However, the effect of their combination on sarcopenia indices is unknown. The present study tested the association between AT plus a MED diet and the presence of sarcopenia and its defining elements in a sample of Italian older adults enrolled in the Longevity Check-up 7+ (Lookup 7+) project. Analyses were conducted in participants 65+ years, with a body mass index of at least 18.5 kg/m2, engaged in regular AT, and without missing information for the variables of interest. MED diet adherence was evaluated via a modified version of the MEDI-LITE score and categorized as low, moderate, or high. The presence of sarcopenia was established by handgrip strength and appendicular skeletal muscle mass (ASM) values below sex-specific cut-points recommended by the European Working Group on Sarcopenia in Older People 2. Data from 491 older adults were analyzed for the present study. The mean age was 72.7 ± 5.7 years, and 185 (37.7%) were women. MED diet adherence was low in 59 (12.0%) participants, moderate in 283 (57.6%), and high in 149 (30.3%). Sarcopenia was identified in 26 participants (5.3%), with no differences across MED diet adherence groups. The results of binary logistic regression showed no significant associations between AT plus adherence to a MED diet and dynapenia, low ASM, or sarcopenia. The findings of the present study indicate that the combination of AT with a MED diet is not associated with a lower probability of sarcopenia or its defining elements in Italian older adults enrolled in Lookup 7+. Further research is warranted to establish whether exercise frequency, volume, intensity, and length of engagement in AT impact the association between MED diet and sarcopenia.

Are sit-to-stand and isometric handgrip tests comparable assessment tools to identify dynapenia in sarcopenic people?

Sarcopenia is a neuromuscular disease characterized by the simultaneous existence of reduced muscle strength and muscle atrophy. The current recommendations for the diagnosis of sarcopenia suggest dynapenia be operationalized using either isometric handgrip strength (IHG) or sit-to-stand (STS) tests. However, specific associations between each of these assessment tools and sarcopenia-related parameters have been observed. In addition, important neuromuscular and biomechanical aspects differ between IHG and STS. This scenario has important clinical implications and calls for detailed studies to refine the current recommendations for sarcopenia identification. The present communication presents evidence to foster a constructive debate on the matter.

Diet for the prevention and management of sarcopenia.

Sarcopenia is a geriatric condition characterized by a progressive loss of skeletal muscle mass and strength, with an increased risk of adverse health outcomes (e.g., falls, disability, institutionalization, reduced quality of life, mortality). Pharmacological remedies are currently unavailable for preventing the development of sarcopenia, halting its progression, or impeding its negative health outcomes. The most effective strategies to contrast sarcopenia rely on the adoption of healthier lifestyle behaviors, including adherence to high-quality diets and regular physical activity. In this review, the role of nutrition in the prevention and management of sarcopenia is summarized. Special attention is given to current "blockbuster" dietary regimes and agents used to counteract age-related muscle wasting, together with their putative mechanisms of action. Issues related to the design and implementation of effective nutritional strategies are discussed, with a focus on unanswered questions on the most appropriate timing of nutritional interventions to preserve muscle health and function into old age. A brief description is also provided on new technologies that can facilitate the development and implementation of personalized nutrition plans to contrast sarcopenia.

The contribution of mitochondrial DNA alterations to aging, cancer, and neurodegeneration.

Mitochondrial DNA (mtDNA) is as a double-stranded molecule existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. An accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and humans, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.

Inflammatory, mitochondrial, and senescence-related markers: Underlying biological pathways of muscle aging and new therapeutic targets.

The maintenance of functional health is pivotal for achieving independent life in older age. The aged muscle is characterized by ultrastructural changes, including loss of type I and type II myofibers and a greater proportion of cytochrome c oxidase deficient and succinate dehydrogenase positive fibers. Both intrinsic (e.g., altered proteostasis, DNA damage, and mitochondrial dysfunction) and extrinsic factors (e.g., denervation, altered metabolic regulation, declines in satellite cells, and inflammation) contribute to muscle aging. Being a hub for several cellular activities, mitochondria are key to myocyte viability and mitochondrial dysfunction has been implicated in age-associated physical decline. The maintenance of functional organelles via mitochondrial quality control (MQC) processes is, therefore, crucial to skeletal myofiber viability and organismal health. The autophagy-lysosome pathway has emerged as a critical step of MQC in muscle by disposing organelles and proteins via their tagging for autophagosome incorporation and delivery to the lysosome for clearance. This pathway was found to be altered in muscle of physically inactive older adults. A relationship between this pathway and muscle tissue composition of the lower extremities as well as physical performance was also identified. Therefore, integrating muscle structure and myocyte quality control measures in the evaluation of muscle health may be a promising strategy for devising interventions fostering muscle health.