Abstract 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.
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.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.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).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 Background A reduction in skeletal muscle stem cell (satellite cell) content with advancing age is thought to directly contribute to the progressive loss of skeletal muscle mass and function with aging (sarcopenia). However, we reported that the depletion of satellite cells throughout adulthood did not affect the onset or degree of sarcopenia observed in sedentary old mice. The current study was designed to determine if lifelong physical activity would alter the requirements for satellite cells during aging. Methods We administered vehicle or tamoxifen to adult (5 months old) female Pax7-DTA mice for 5 consecutive days to effectively deplete satellite cells. Following a 2-month washout period, mice were assigned to physically active (free access to a running wheel) or sedentary (locked running wheel) conditions. Thirteen months later, at a mean age of 20 months, mice were sacrificed for subsequent analysis. Results Satellite cell depletion throughout adulthood negatively impacted physical function and limited muscle fiber hypertrophy in response to lifelong physical activity. To further interrogate these findings, we performed transcriptome-wide analyses on the hind limb muscles that experienced hypertrophic growth (plantaris and soleus) in response to lifelong physical activity. Our findings demonstrate that satellite cell function is muscle type-specific; fusion with fibers is apparent in oxidative muscles, while initiation of Gα i2 signaling appears to require satellite cells in glycolytic muscles to induce muscle growth.. Conclusions These findings suggest that satellite cells, or their secretory products, are viable therapeutic targets to preserve physical function with aging and promote muscle growth in older adults who regularly engage in physical activity.
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. 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. 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. 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.
Sarcopenia is a debilitating age-related skeletal muscle wasting syndrome associated with poor quality of life, disability and death. Despite its profound personal and societal impacts, there are currently no approved pharmacological therapies for the treatment of sarcopenia. Thus, we must rely on lifestyle factors, such as exercise, to counter age-related declines in muscle mass and function. Exercise intervention and high levels of intense physical activity have been shown to be protective against several parameters of age-related muscle pathophysiology (Mackey et al. 2007; Sonjak et al. 2019). While encouraging, these findings are limited to a small segment of the population that regularly participate in strenuous physical activity. Long-term structured physical activity intervention has also been shown to improve clinically meaningful outcomes, such as major mobility disability (Pahor et al. 2014). However, the extent to which commonly adopted levels of habitual physical activity mediate key features of skeletal muscle ageing has yet to be examined. This type of work is particularly meaningful as it can guide exercise prescription and future public health initiatives, making the recent publication from Soendenbroe and colleagues in this issue of The Journal of Physiology a valuable contribution to the fields of skeletal muscle and exercise physiology. The authors investigated the health-promoting effects of lifelong physical activity by examining measures of muscle function and muscle fibre physiology (with a focus on satellite cells and muscle fibre innervation) between groups of young, elderly lifelong recreational exercisers, and elderly sedentary men. The authors found that while recreational exercise did not influence measures of muscle size, it had a positive effect on measures of muscle function (fatigue resistance) under challenged conditions. This finding is clinically relevant, as maintaining adequate levels of muscle strength is essential to remain functionally independent during ageing. It seems possible that more intense and/or structured exercise may be required to provide the anabolic stimulus necessary to influence muscle fibre size and overall muscle mass. It may also be that the protective effects of recreational activity are more related to the preservation of muscle mass and not detectable until later in life. Interestingly, the authors found that even modest levels of physical activity are sufficient to mitigate the loss of satellite cells during ageing. While the direct contribution of satellite cell content to sarcopenia remains unclear, recent evidence in mice shows higher satellite cell content is an important contributing factor to the adaptive response to exercise (Englund et al. 2021). Therefore, older adults with higher satellite cell content may respond more favourably to exercise intervention or physical rehabilitation. The authors went on to analyse the effects of recreational exercise on muscle fibre innervation with microscopy and antibody-based techniques but did not detect protective effects. On the other hand, the expression levels of β and γ acetylcholine receptors suggest a positive effect of exercise on muscle fibre innervation, at least at the transcriptional level. This is a valuable study that has advanced our understanding for how recreational exercise influences consequential measures of muscle function and physiology. Importantly, even modest levels of recreational exercise have therapeutic effects, preserving muscle function and satellite cell content during ageing. Future studies may aim to leverage more exploratory omics-based approaches to identify additional cellular and molecular processes positively influenced by recreational activity, which has the potential to reveal new druggable targets to counter sarcopenia. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. Sole author. No funding was received for this work.
Abstract 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 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.
