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While the average human life span continues to increase, there is little evidence that this is leading to a contemporaneous increase in "healthy years" experienced by our aging population. Consequently, many scientists focus their research on understanding the process of aging and trialing interventions that can promote healthspan. The 2021 Midwest Aging Consortium consensus statement is to develop and further the understanding of aging and age-related disease using the wealth of expertise across universities in the Midwestern United States. This report summarizes the cutting-edge research covered in a virtual symposium held by a consortium of researchers in the Midwestern United States, spanning topics such as senescence biomarkers, serotonin-induced DNA protection, immune system development, multisystem impacts of aging, neural decline following severe infection, the unique transcriptional impact of calorie restriction of different fat depots, the pivotal role of fasting in calorie restriction, the impact of peroxisome dysfunction, and the influence of early life trauma on health. The symposium speakers presented data from studies conducted in a variety of common laboratory animals as well as less-common species, including Caenorhabditis elegans, Drosophila, mice, rhesus macaques, elephants, and humans. The consensus of the symposium speakers is that this consortium highlights the strength of aging research in the Midwestern United States as well as the benefits of a collaborative and diverse approach to geroscience. [ABSTRACT FROM AUTHOR]

Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging‐related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence‐related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12‐week structured exercise program drives significant improvements in several performance‐based and self‐reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16,p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence‐related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence‐related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first‐in‐human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise. [ABSTRACT FROM AUTHOR]

To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a nontranslational stimulus and/or have been performed over a relatively short time frame. Although it has been shown that satellite cell depletion throughout adulthood does not drive skeletal muscle loss in sedentary mice, it remains unknown how satellite cells participate in skeletal muscle adaptation to long-term physical activity. The current study was designed to determine whether reduced satellite cell content throughout adulthood would influence the transcriptome-wide response to physical activity and diminish the adaptive response of skeletal muscle. We administered vehicle or tamoxifen to adult Pax7-diphtheria toxin A (DTA) mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 mo. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume, and the size of muscle proprioceptors (spindle fibers). Furthermore, satellite cell participation was necessary for optimal muscle fiber hypertrophy but not adaptations in fiber type distribution in response to lifelong physical activity. Transcriptome-wide analysis of the plantaris and soleus revealed that satellite cell function is muscle type specific; satellite cell-dependent myonuclear accretion was apparent in oxidative muscles, whereas initiation of G protein-coupled receptor (GPCR) signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long-term physical activity. These findings suggest that satellite cells play a role in preserving physical function during aging and influence muscle adaptation during sustained periods of physical activity. [ABSTRACT FROM AUTHOR]

The eukaryotic initiation factor 4E (eIF4E) is a major mRNA cap-binding protein that has a central role in translation initiation. Ser209 is the single phosphorylation site within eIF4E and modulates its activity in response to MAPK pathway activation. It has been reported that phosphorylation of eIF4E at Ser209 promotes translation of key mRNAs, such as cyclin D1, that regulate ribosome biogenesis. We hypothesized that phosphorylation at Ser209 is required for skeletal muscle growth in response to a hypertrophic stimulus by promoting ribosome biogenesis. To test this hypothesis, wild-type (WT) and eIF4E knocked-in (KI) mice were subjected to synergist ablation to induce muscle hypertrophy of the plantaris muscle as the result of mechanical overload; in the KI mouse, Ser209 of eIF4E was replaced with a nonphosphorylatable alanine. Contrary to our hypothesis, we observed no difference in the magnitude of hypertrophy between WT and KI groups in response to 14 days of mechanical overload induced by synergist ablation. Similarly, the increases in cyclin D1 protein levels, ribosome biogenesis, and translational capacity did not differ between WT and KI groups. Based on these findings, we conclude that phosphorylation of eIF4E at Ser209 is dispensable for skeletal muscle hypertrophy in response to mechanical overload. [ABSTRACT FROM AUTHOR]

It is postulated that testosterone-induced skeletal muscle hypertrophy is driven by myonuclear accretion as the result of satellite cell fusion. To directly test this hypothesis, we utilized the Pax7-DTA mouse model to deplete satellite cells in skeletal muscle followed by testosterone administration. Pax7-DTA mice (6 mo of age) were treated for 5 days with either vehicle [satellite cell replete (SC+)] or tamoxifen [satellite cell depleted (SC-)]. Following a washout period, a testosterone propionate or sham pellet was implanted for 21 days. Testosterone administration caused a significant increase in muscle fiber crosssectional area in SC+ and SC- mice in both oxidative (soleus) and glycolytic (plantaris and extensor digitorum longus) muscles. In SC+ mice treated with testosterone, there was a significant increase in both satellite cell abundance and myonuclei that was completely absent in testosterone-treated SC- mice. These findings provide direct evidence that testosterone-induced muscle fiber hypertrophy does not require an increase in satellite cell abundance or myonuclear accretion. Listen to a podcast about this Rapid Report with senior author E. E. Dupont-Versteegden (https://ajpcell.podbean.com/e/podcast-on-paperthat- shows-testosterone-induced-skeletal-muscle-hypertrophydoes- not-need-muscle-stem-cells/). [ABSTRACT FROM AUTHOR]

Background: Progressive resistance training (PRT) is consistently shown to improve muscle strength in older adults. The efficacy of PRT to improve muscle fatigue in older adults with demonstrated mobility limitations remains unclear.Methods: Mobility-limited (Short Physical Performance Battery [SPPB] ≤ 9) older adults (age 70-92 years) were recruited for this study and randomized to either PRT or home-based flexibility (FLEX) 3 d/wk for 12 weeks. Muscle fatigue and strength outcomes were assessed at baseline and 12 weeks. The primary outcome was torque capacity, a composite measure of strength and fatigue, defined as the sum of peak torques from an isokinetic fatigue test.Results: Seventy participants were randomized (mean [SD] age 78.9 [5.4] years; 60% female; mean [SD] SPPB 7.5 [1.6]). At follow-up, the PRT group improved significantly in torque capacity, mean between-group difference (95% confidence interval) 466.19 (138.4, 793.97) Nm (p = .006), and maximal strength 127.3 (60.96, 193.61) Nm (p = .0003), when compared with FLEX group. Neither group demonstrated significant changes in muscle fatigue or torque variability.Conclusion: Twelve weeks of PRT improved torque capacity, as well as strength in mobility-limited older adults. These results demonstrate PRT improves multiple age-related muscular impairments. [ABSTRACT FROM AUTHOR]

Background: Nutritional supplementation and physical activity have been shown to positively influence muscle mass and strength in older adults. The efficacy of long-term nutritional supplementation in combination with physical activity in older adults remains unclear.Methods: Mobility-limited (short physical performance battery [SPPB] ≤9) and vitamin D insufficient (serum 25(OH) D 9-24 ng/mL) older adults were recruited for this study. All subjects participated in a physical activity program. Subjects were randomized to consume a daily nutritional supplement (150 kcal, 20 g whey protein, 800 IU vitamin D, 119 mL beverage) or placebo (30 kcal, nonnutritive, 119 mL). In a prespecified secondary analysis, we examined total-body composition (dual energy X-ray absorptiometry), thigh composition (computed tomography), and muscle strength, power, and quality before and after the 6-month intervention.Results: One hundred and forty-nine subjects were randomized into the study [mean (standard deviation, SD) age 78.5 (5.4) years; 46.3% female; mean (SD) short physical performance battery 7.9 (1.2); mean (SD) vitamin D 18.7 (6.4) ng/mL]. After the intervention period both groups demonstrated improvements in muscle strength, body composition, and thigh composition. Nutritional supplementation lead to further losses of intermuscular fat (p = .049) and increased normal muscle density (p = .018).Conclusions: Six months of physical activity resulted in improvements in body composition, subcutaneous fat, intermuscular fat, and strength measures. The addition of nutritional supplementation resulted in further declines in intermuscular fat and improved muscle density compared to placebo. These results suggest nutritional supplementation provides additional benefits to mobility-limited older adults undergoing exercise training. ClinicalTrials.gov Identifier: NCT01542892. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to compare the effects of high and low velocity knee extension training on changes in muscle strength and mobility status in high-functioning older adults. Methods Twenty-six (16 female, 10 male) older adults (mean age of 65) were randomized to either 6 weeks of low velocity resistance training (LVRT) performed at 75°/s or high velocity resistance training (HVRT) performed at 240°/s. Both groups performed 3 sets of knee extension exercises at maximal effort, 3 times a week. Muscle strength was assessed through a range of testing velocities on an isokinetic dynamometer. Mobility status was assessed with the short physical performance battery (SPPB) and myosin heavy chain (MyHC) transcript levels were quantified via qRT-PCR. Results From baseline to post-training, there were several significant ( P < 0.05) differences in muscle strength and functional characteristics in LVRT (n = 13) and HVRT (n = 13) groups. From baseline to post-training, MyHC-α mRNA and MyHC-IIa mRNA showed a significant ( P < 0.05) increase within HVRT but MyHC-IIx mRNA did not change significantly. Our results demonstrate HVRT provides a greater number of muscular enhancements when compared to LVRT, particularly under conditions of high velocity muscle contraction. Conclusion HVRT is emerging as the optimal training stimulus for the older adult. The present study demonstrates, in addition to increased strength and functional outcomes, HVRT elicits a potentially therapeutic (i.e., slow to fast) transcriptional response in MyHC. [ABSTRACT FROM AUTHOR]

Skeletal muscle in individuals with CP also contains lower amounts of mtDNA, potentially indicating fewer mitochondria in CP skeletal muscle compared with typically developing muscle. We compared skeletal muscle samples from children with cerebral palsy (CP) and typically developing children and observed evidence of reduced mtDNA and OXPHOS protein content in CP skeletal muscle, indicating reduced mitochondrial abundance. Cerebral palsy (CP) muscle contains fewer energy-generating organelles than typically developing muscle. [Extracted from the article]

Background: The tetracycline-responsive system (Tet-ON/OFF) has proven to be a valuable tool for manipulating gene expression in an inducible, temporal, and tissue-specific manner. The purpose of this study was to create and characterize a new transgenic mouse strain utilizing the human skeletal muscle α-actin (HSA) promoter to drive skeletal muscle-specific expression of the reverse tetracycline transactivator (rtTA) gene which we have designated as the HSA-rtTA mouse. Methods: To confirm the HSA-rtTA mouse was capable of driving skeletal muscle-specific expression, we crossed the HSA-rtTA mouse with the tetracycline-responsive histone H2B-green fluorescent protein (H2B-GFP) transgenic mouse in order to label myonuclei. Results: Reverse transcription-PCR confirmed skeletal muscle-specific expression of rtTA mRNA, while single-fiber analysis showed highly effective GFP labeling of myonuclei in both fast- and slow-twitch skeletal muscles. Pax7 immunohistochemistry of skeletal muscle cross-sections revealed no appreciable GFP expression in satellite cells. Conclusions: The HSA-rtTA transgenic mouse allows for robust, specific, and inducible gene expression across muscles of different fiber types. The HSA-rtTA mouse provides a powerful tool to manipulate gene expression in skeletal muscle. [ABSTRACT FROM AUTHOR]

Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole‐body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi‐weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7‐ or 28 days prior to euthanization. Senescence‐associated β‐Galactosidase positive (SA β‐Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β‐Gal+ cells were also CD11b+ in young and old mice 7‐ and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β‐Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti‐inflammatory macrophages. SA β‐Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q‐treated old mice, muscle regenerated following injury to a greater extent compared to vehicle‐treated old mice, having larger fiber cross‐sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice. [ABSTRACT FROM AUTHOR]

Background: The Lifestyle Interventions and Independence for Elders (LIFE) clinical trial demonstrated that a structured program of physical activity (PA) reduced mobility-disability in older adults by up to 28%. It remains unknown whether the benefits of LIFE PA can be translated to older adults at risk for mobility-disability in real-world community-based settings. To address this knowledge gap, we conducted the ENhancing independence using Group-based community interventions for healthy AGing in Elders (ENGAGE) pilot study and examined the safety, feasibility, and preliminary effectiveness of translating LIFE PA to a community-based senior center.Methods: Forty older adults with severe lower extremity functional limitations (age: 76.9 ± 7.3 years; body mass index: 32.7 ± 8 kg/m2; 85% female; short physical performance battery score: 6.3 ± 2.2) were randomized to 24 weeks of PA or a health education control intervention.Results: Community-based PA was safe (serious adverse events: PA vs health education, 0:2; nonserious adverse events: PA vs health education, 3:1) and participants successfully adhered to the PA intervention (65.2%). Compared to health education, PA participants who attended ≥25% of scheduled visits had meaningful and sustained short physical performance battery improvements at follow-up (between group short physical performance battery score differences: ~0.7 units).Conclusions: ENGAGE has demonstrated the preliminary safety, feasibility, and effectiveness of LIFE PA in a real-world community-based setting. Larger-scale translational studies are needed to further disseminate the benefits of LIFE PA to vulnerable older adults in a variety of community-based settings. [ABSTRACT FROM AUTHOR]

Myonuclei gained during exercise-induced skeletal muscle hypertrophy may be long-lasting and could facilitate future muscle adaptability after deconditioning, a concept colloquially termed "muscle memory." The evidence for this is limited, mostly due to the lack of a murine exercise-training paradigm that is nonsurgical and reversible. To address this limitation, we developed a novel progressive weightedwheel- running (PoWeR) model of murine exercise training to test whether myonuclei gained during exercise persist after detraining. We hypothesized that myonuclei acquired during training-induced hypertrophy would remain following loss of muscle mass with detraining. Singly housed female C57BL/6J mice performed 8 wk of PoWeR, while another group performed 8 wk of PoWeR followed by 12 wk of detraining. Age-matched sedentary cage-dwelling mice served as untrained controls. Eight weeks of PoWeR yielded significant plantaris muscle fiber hypertrophy, a shift to a more oxidative phenotype, and greater myonuclear density than untrained mice. After 12 wk of detraining, the plantaris muscle returned to an untrained phenotype with fewer myonuclei. A finding of fewer myonuclei simultaneously with plantaris deconditioning argues against a muscle memory mechanism mediated by elevated myonuclear density in primarily fasttwitch muscle. PoWeR is a novel, practical, and easy-to-deploy approach for eliciting robust hypertrophy in mice, and our findings can inform future research on the mechanisms underlying skeletal muscle adaptive potential and muscle memory. [ABSTRACT FROM AUTHOR]

Older adults are encouraged to engage in multicomponent physical activity, which includes aerobic and muscle-strengthening activities. The current work is an extension of the Vitality, Independence, and Vigor in the Elderly 2 (VIVE2) study – a 6-month multicenter, randomized, placebo-controlled trial of physical activity and nutritional supplementation in community dwelling 70-year-old seniors. Here, we examined whether the magnitude of changes in muscle size and quality differed between major lower-extremity muscle groups and related these changes to functional outcomes. We also examined whether daily vitamin-D-enriched protein supplementation could augment the response to structured physical activity. Forty-nine men and women (77 ± 5 yrs) performed brisk walking, muscle-strengthening exercises for the lower limbs, and balance training 3 times weekly for 6 months. Participants were randomized to daily intake of a nutritional supplement (20 g whey protein + 800 IU vitamin D), or a placebo. Muscle cross-sectional area (CSA) and radiological attenuation (RA) were assessed in 8 different muscle groups using single-slice CT scans of the hip, thigh, and calf at baseline and after the intervention. Walking speed and performance in the Short Physical Performance Battery (SPPB) were also measured. For both CSA and RA, there were muscle group × time interactions (P < 0.01). Significant increases in CSA were observed in 2 of the 8 muscles studied, namely the knee extensors (1.9%) and the hip adductors (2.8%). For RA, increases were observed in 4 of 8 muscle groups, namely the hip flexors (1.1 HU), hip adductors (0.9 HU), knee extensors (1.2 HU), and ankle dorsiflexors (0.8 HU). No additive effect of nutritional supplementation was observed. While walking speed (13%) and SPPB performance (38%) improved markedly, multivariate analysis showed that these changes were not associated with the changes in muscle CSA and RA after the intervention. We conclude that this type of multicomponent physical activity program results in significant improvements in physical function despite relatively small changes in muscle size and quality of some, but not all, of the measured lower extremity muscles involved in locomotion. • The effects of physical activity on muscle size (CSA) and density (RA) of multiple lower extremity muscles were studied • Structured physical activity resulted in small changes in CSA and RA of several, but not all, lower extremity muscles • Marked improvements in physical function were noted that could not be explained by changes in CSA or RA • A protein- and vitamin D-enriched nutritional supplement did not enhance muscle-specific adaptations to this program [ABSTRACT FROM AUTHOR]