Of all recognized modalities that may be utilized for the prevention and/or intervention of aging, exercise is the most accessible, effective, and multifactorial modality known to improve health and treat chronic disease [
77,
78]. Interestingly, it is high-intensity, strenuous exercise that has been reported to be effective for treating numerous chronic diseases ranging from diabetes and heart disease to cerebrovascular and pulmonary disease [
77,
79] and may even be a more favorable intervention compared to pharmacological agents in specific cases such as stroke [
80]. The interest in exercise as a means for prevention and/or intervention is not a new concept; however, more recently, interest in its efficacy and evidence for its pluripotency has led to the now global initiative known as “Exercise is Medicine
® (EIM)” from leading agencies, associations, and centers such as the American College of Sports Medicine, the American Medical Association, and the Centers for Disease Control, as well as enjoying support from the Surgeon General of the United States. This initiative aims to incorporate physical activity assessment and exercise prescription into disease prevention and to translate evidence-based, scientifically-proven health benefits of exercise into the current and future healthcare system [
78]. It is well-accepted that regular physical exercise, which includes resistance exercise loading, provides the most conclusive evidence for preserving, and even restoring, function and skeletal muscle mass with aging [
7,
81,
82,
83,
84,
85]. It is chronic resistance exercise loading, or training, that is unique in promoting restoration or improvements in skeletal muscle performance (i.e., strength, work capacity, fatigue resistance, etc.) and skeletal muscle mass [
83,
84], as evidence for these findings exist in both human [
57,
71,
83] and animal studies [
66]; yet, little evidence exists for improving skeletal muscle quality in various populations, including aged populations [
7,
59]. There are numerous human studies that have suggested that resistance exercise training is beneficial in countering distinct components of musculoskeletal health and aging [
71,
83,
84]; however, no translational study has shown that resistance exercise training can restore musculoskeletal health with aging to youthful states entirely. The limitations of human intervention studies are noted in that small populations, subject adherence, and lack of overall control with respect to the biomechanical loading parameters is customary. For these reasons and with these limitations in mind, fundamental, in vivo animal models that are valid and representative of the human exposure–response relationship with respect to aging and exercise are an essential tool for investigating and quantifying these phenomena due to the exquisite control they allow over the biomechanical loading exposure as well as providing a means to evaluate, characterize, and quantify the integrated skeletal muscle response systematically. Interestingly, only recently have investigations begun to question and quantify the impact age-specific RTET imparts on skeletal muscle quality and whether this specific and sensitive outcome metric (i.e., “biomarker”) is modifiable with aging [
13,
38,
66,
86]. Initial studies by Cutlip and colleagues provided a basis for investigating non-injurious SSC RTET exposure in a validated, fundamental rodent model of aging, which quantified the adaptive and maladaptive response in young and old skeletal muscle, respectively [
13]. These reports provided evidence that a general SSC RTET employed 3 days per week over a 1-month period repeatedly resulted in skeletal muscle performance decrements with no improvements in skeletal muscle quality in old rodents (i.e., 30 months of age). More recently, Rader and colleagues have conducted follow-up work that extended from those initial findings and have reported that when SSC RTET was implemented in old rodents that included both the 3 days per week RTET group and compared this with a 2 days per week RTET group over a 1-month period, the old rodents that underwent 2 days per week RTET adapted and were indistinguishable from their younger counterparts and, notably, had their skeletal muscle quality restored to that of a youthful state [
66]. In a subsequent investigation from this same group, both the mode (i.e., isometric contractions alone, utilized as a minimalistic RTET approach) as well as repetition number was studied. With regards to both the utilization of isometric contractions in age-dependent RTET and/or reducing the number of SSC repetitions (i.e., compared with the previous stated study), neither the isometric contraction RTET nor the reduced SSC repetition protocols were successful in restoring skeletal muscle performance, skeletal muscle mass, and skeletal muscle quality [
86]. In these fundamental in vivo studies, it has been established that skeletal muscle quality is modifiable with increasing age; yet, these data suggest that the RTET prescription or mechanical loading paradigm must be precisely prescribed in order to achieve these benefits (i.e., increased function, skeletal muscle mass, skeletal muscle quality, etc.) for all outcomes predicted, particularly in aged populations. Also, these studies emphasize that there is a very narrow “window” involving both the specificity and sensitivity of these physical/mechanical loading variables with respect to an RTET exposure–response relationship with aging, and that particularly frequency of exposure, rather than mode or repetition number, may be the more precise variable for consideration when designing and implementing age-specific RTET in aged populations [
66,
85] when skeletal muscle performance, skeletal muscle mass, and skeletal muscle quality are the focal outcomes for positively affecting, and restoring, health-span. Thus, when considered in total, the fundamental evidence from SSC RTET suggests that the utility of this mode of exercise is efficacious and applicable for translational approaches in aging populations. Importantly, these studies continue to emphasize that the understanding and discernment of the biomechanical loading envelope (i.e., the mechanical factors responsible for the exercise or protocol “prescription”) is imperative, just as is the intimate knowledge and expertise required for the dosing of a pharmacological agent when prescribed for a particular pathophysiological condition, disorder, or disease.