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AIM: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models "typical" brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain. METHODS: Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry. RESULTS: At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age. CONCLUSIONS: Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.
Assuntos
Envelhecimento , Hipocampo , Mitocôndrias , Animais , Cobaias , Mitocôndrias/metabolismo , Envelhecimento/metabolismo , Hipocampo/metabolismo , Masculino , Respiração Celular/fisiologia , Doença de Alzheimer/metabolismo , Modelos Animais de DoençasRESUMO
Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a transcription factor that serves as a master regulator of anti-inflammatory agents, phase I xenobiotic, and phase II antioxidant enzymes, all of which provide a cytoprotective role during disease progression. We hypothesized that oral administration of a purported phytochemical Nrf2-activator, PB125®, would increase long bone strength in aging Hartley guinea pigs, a model prone to musculoskeletal decline. Male (N = 56) and female (N = 56) guinea pigs were randomly assigned to receive daily oral treatment with either PB125® or vehicle control. Animals were treated for a consecutive 3-months (starting at 2-months of age) or 10-months (starting at 5-months of age) and sacrificed at 5-months or 15-months of age, respectively. Outcome measures included: (1) ANY-maze™ enclosure monitoring, (2) quantitative microcomputed tomography, and (3) biomechanical testing. Treatment with PB125® for 10 months resulted in increased long bone strength as determined by ultimate bending stress in female Hartley guinea pigs. In control groups, increasing age resulted in significant effects on geometric and structural properties of long bones, as well as a trending increase in ultimate bending stress. Furthermore, both age and sex had a significant effect on the geometric properties of both cortical and trabecular bone. Collectively, this work suggests that this nutraceutical may serve as a promising target and preventive measure in managing the decline in bone mass and quality documented in aging patients. Auxiliary to this main goal, this work also capitalized upon 5 and 15-month-old male and female animals in the control group to characterize age- and sex-specific differences on long bone geometric, structural, and material properties in this animal model.
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Fator 2 Relacionado a NF-E2 , Osteoartrite , Animais , Feminino , Cobaias , Masculino , Osso e Ossos , Fator 2 Relacionado a NF-E2/farmacologia , Fator 2 Relacionado a NF-E2/uso terapêutico , Osteoartrite/prevenção & controle , Microtomografia por Raio-X , Modelos Animais de DoençasRESUMO
The development of high-resolution respirometry (HRR) has greatly expanded the analytical scope to study mitochondrial respiratory control relative to specific tissue/cell types across various metabolic states. Specifically, the Oroboros Oxygraph 2000 (O2k) is a common tool for measuring rates of mitochondrial respiration and is the focus of this perspective. The O2k platform is amenable for answering numerous bioenergetic questions. However, inherent variability with HRR-derived data, both within and amongst users, can impede progress in bioenergetics research. Therefore, we advocate for several vital considerations when planning and conducting O2k experiments to ultimately enhance transparency and reproducibility across laboratories. In this perspective, we offer guidance for best practices of mitochondrial preparation, protocol selection, and measures to increase reproducibility. The goal of this perspective is to propagate the use of the O2k, enhance reliability and validity for both new and experienced O2k users, and provide a reference for peer reviewers.
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Fosforilação Oxidativa , Consumo de Oxigênio , Reprodutibilidade dos Testes , Respiração Celular , Mitocôndrias/metabolismoRESUMO
Impaired mitochondrial function and disrupted proteostasis contribute to musculoskeletal dysfunction. However, few interventions simultaneously target these two drivers to prevent musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) activates a transcriptional programme promoting cytoprotection, metabolism, and proteostasis. We hypothesized daily treatment with a purported Nrf2 activator, PB125, in Hartley guinea pigs, a model of musculoskeletal decline, would attenuate the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis and preserve musculoskeletal function. We treated 2- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical compound PB125. Longitudinal assessments of voluntary mobility were measured using Any-MazeTM open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in soleus muscles was measured using high resolution respirometry. In both sexes, PB125 (1) increased electron transfer system capacity; (2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and (3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial and cytosolic subfractions of the soleus. These effects were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, treatment with PB125 contributed to maintenance of skeletal muscle mitochondrial respiration and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these documented effects of PB125 are also accompanied by slowed progression of other aspects of musculoskeletal dysfunction. KEY POINTS: Aside from exercise, there are no effective interventions for musculoskeletal decline, which begins in the fifth decade of life and contributes to disability and cardiometabolic diseases. Targeting both mitochondrial dysfunction and impaired protein homeostasis (proteostasis), which contribute to the age and disease process, may mitigate the progressive decline in overall musculoskeletal function (e.g. gait, strength). A potential intervention to target disease drivers is to stimulate nuclear factor erythroid 2-related factor 2 (Nrf2) activation, which leads to the transcription of genes responsible for redox homeostasis, proteome maintenance and mitochondrial energetics. Here, we tested a purported phytochemical Nrf2 activator, PB125, to improve mitochondrial function and proteostasis in male and female Hartley guinea pigs, which are a model for musculoskeletal ageing. PB125 improved mitochondrial respiration and attenuated disease- and age-related declines in skeletal muscle protein synthesis, a component of proteostasis, in both male and female Hartley guinea pigs.
Assuntos
Fator 2 Relacionado a NF-E2 , Proteostase , Masculino , Feminino , Animais , Cobaias , Fator 2 Relacionado a NF-E2/metabolismo , Músculo Esquelético/fisiologia , Mitocôndrias/metabolismo , Envelhecimento/fisiologiaRESUMO
Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.
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Acarbose , Sirolimo , Camundongos , Masculino , Feminino , Animais , Acarbose/farmacologia , Sirolimo/farmacologia , Captopril/farmacologia , Longevidade , EnvelhecimentoRESUMO
Dietary interventions such as sulfur amino acid restriction (SAAR) target multiple drivers of aging, and show promise for preventing or delaying the onset of chronic diseases. SAAR promotes metabolic health and longevity in laboratory animals. The effects of SAAR on proteostasis remain relatively unexplored. We previously reported that SAAR promotes mitochondrial proteostatic maintenance, despite suppression of global protein synthesis, in two peripheral tissues, the liver and skeletal muscle. However, the brain, a tissue vulnerable to age-related neurodegenerative diseases due to the loss of proteostasis, has not been thoroughly studied. Therefore, we sought to reveal proteostatic responses in the brains of mice fed SAAR for 35 days. Here, we demonstrate that male C57Bl/6J mice fed two levels of SAAR maintained rates of protein synthesis in all sub-cellular fractions of the pre-frontal cortex. In comparison, rates of skeletal muscle protein synthesis in SAAR fed mice were slower than control-fed mice. To gain mechanistic insight, we examined several key nutrient/energy sensitive signaling proteins: AMP-activated protein kinase (AMPK), eukaryotic initiation factor 2 (eIF2), and ribosomal protein S6 (rpS6). SAAR had minimal to modest effects on the total abundance and phosphorylation of these proteins in both tissues. Our results indicate that the pre-frontal cortex in brain is resistant to perturbations in protein synthesis in mice fed SAAR, unlike skeletal muscle, which had a reduction in global protein synthesis. The results from this study demonstrate that proteostatic control in brain is of higher priority than skeletal muscle during dietary SAAR.
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Older age is the primary risk factor for most chronic diseases, including Alzheimer's disease (AD). Current preclinical models to study brain aging and AD are mainly transgenic and harbor mutations intended to mirror brain pathologies associated with human brain aging/AD (eg, by increasing production of the amyloid precursor protein, amyloid beta [Aß], and/or phosphorylated tau, all of which are key pathological mediators of AD). Although these models may provide insight on pathophysiological processes in AD, none completely recapitulate the disease and its strong age-dependence, and there has been limited success in translating preclinical results and treatments to humans. Here, we describe 2 nontransgenic guinea pig (GP) models, a standard PigmEnTed (PET) strain, and lesser-studied Dunkin-Hartley (DH) strain, that may naturally mimic key features of brain aging and AD in humans. We show that brain aging in PET GP is transcriptomically similar to human brain aging, whereas older DH brains are transcriptomically more similar to human AD. Both strains/models also exhibit increased neurofilament light chain (NFL, a marker of neuronal damage) with aging, and DH animals display greater S100 calcium-binding protein B (S100ß), ionized calcium-binding adapter molecule 1 (Iba1), and Aß and phosphorylated tau-which are all important markers of neuroinflammation-associated AD. Collectively, our results suggest that both the PET and DH GP may be useful, nontransgenic models to study brain aging and AD, respectively.
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Doença de Alzheimer , Envelhecimento/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Cobaias , Humanos , Proteínas tau/metabolismoRESUMO
The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve-month-old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long-term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age.
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Envelhecimento/fisiologia , Dieta Cetogênica/métodos , Músculo Esquelético/metabolismo , Transdução de Sinais/fisiologia , Animais , Antioxidantes/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Junção Neuromuscular/metabolismo , Biogênese de Organelas , Oxirredução , Estresse Oxidativo/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Biossíntese de Proteínas/fisiologia , Sarcopenia/dietoterapia , Sarcopenia/metabolismoRESUMO
BACKGROUND: Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR). OBJECTIVE: We investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR. METHODS: Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR. RESULTS: We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR. CONCLUSIONS: Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice.
Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Aminoácidos Sulfúricos/deficiência , Fator 4 Ativador da Transcrição/deficiência , Fator 4 Ativador da Transcrição/genética , Aminoácidos Sulfúricos/sangue , Aminoácidos Sulfúricos/metabolismo , Animais , Antioxidantes/metabolismo , Composição Corporal , DNA/biossíntese , Dietoterapia , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Sulfeto de Hidrogênio/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Biossíntese de Proteínas , Fatores Sexuais , Estresse FisiológicoRESUMO
Loss of protein homeostasis is a hallmark of the aging process. We and others have previously shown that maintenance of proteostasis is a shared characteristic of slowed-aging models. Rapamycin (Rap) exerts sex-specific effects on murine lifespan, but the combination of Rap with the anti-hyperglycemic drug metformin (Rap + Met) equally increases male and female mouse median lifespan. In the current investigation, we compare the effects of short-term (8 weeks) Rap and Rap + Met treatments on bulk and individual protein synthesis in two key metabolic organs (the liver and skeletal muscle) of young genetically heterogeneous mice using deuterium oxide. We report for the first time distinct effects of Rap and Rap + Met treatments on bulk and individual protein synthesis in young mice. Although there were decreases in protein synthesis as assessed by bulk measurements, individual protein synthesis analyses demonstrate there were nearly as many proteins that increased synthesis as decreased synthesis rates. While we observed the established sex- and tissue-specific effects of Rap on protein synthesis, adding Met yielded more uniform effects between tissue and sex. These data offer mechanistic insight as to how Rap + Met may extend lifespan in both sexes while Rap does not.
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Metformina , Sirolimo , Animais , Feminino , Longevidade , Masculino , Metformina/farmacologia , Camundongos , Biossíntese de Proteínas , Caracteres Sexuais , Sirolimo/farmacologiaRESUMO
Skeletal muscle dysfunction, articular cartilage degeneration, and bone loss occur essentially in parallel during aging. Mechanisms contributing to this systemic musculoskeletal decline remain incompletely understood, limiting progress toward developing effective therapeutics. Because the progression of human musculoskeletal aging is slow, researchers rely on rodent models to identify mechanisms and test interventions. The Dunkin Hartley guinea pig is an outbred strain that begins developing primary osteoarthritis by 4 months of age with a progression and pathology similar to aging humans. The purpose of this study was to determine if skeletal muscle remodeling during the progression of osteoarthritis in these guinea pigs resembles musculoskeletal aging in humans. We compared Dunkin Hartley guinea pigs to Strain 13 guinea pigs, which develop osteoarthritis much later in the lifespan. We measured myofiber type and size, muscle density, and long-term fractional protein synthesis rates of the gastrocnemius and soleus muscles in 5, 9, and 15-month-old guinea pigs. There was an age-related decline in skeletal muscle density, a greater proportion of smaller myofibers, and a decline in type II concomitant with a rise in type I myofibers in the gastrocnemius muscles from Dunkin Hartley guinea pigs only. These changes were accompanied by age-related declines in myofibrillar and mitochondrial protein synthesis in the gastrocnemius and soleus. Collectively, these findings suggest Dunkin Hartley guinea pigs experience myofiber remodeling alongside the progression of osteoarthritis, consistent with human musculoskeletal aging. Thus, Dunkin Hartley guinea pigs may be a model to advance discovery and therapeutic development for human musculoskeletal aging.
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This study examined the feasibility and effects of a 1-hr physical activity (PA) behavior change (PABC) discussion session on PA, 12 weeks after completing an exercise trial. Adults at high risk of Type II diabetes were randomized to the PABC or a control group. PA was self-reported using the International Physical Activity Questionnaire. Chi-square tests compared the proportion of participants classified as moderately active or greater at the 12-week follow-up. Participants (N = 50) were M = 61.8 ± 5.5 years old and mostly female (80%). All participants completed the PABC discussion session, and compliance with the International Physical Activity Questionnaire at 12-week follow-up was 78%. Barrier self-efficacy increased immediately following the PABC (MΔ0.5 ± 0.9; t(22) = -2.45, p = .023). At 12-week follow-up, 88% in the PABC were moderately active or greater, compared with 50% in the control (p = .015). Incorporating a PABC discussion session as part of an exercise efficacy trial was feasible and may help improve PA maintenance.
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Treatment with the mechanistic target of rapamycin (mTOR) inhibitor, rapamycin (RAP), alone and in combination with the antidiabetic drug, metformin (RAP+MET), extends lifespan in mice. The mechanisms underlying lifespan extension are unclear. One possibility is improved capacity for proteostatic maintenance. We have previously characterized peripheral protein synthesis rates following treatment with RAP. However, it is unknown if RAP+MET elicits similar changes, or if either treatment affects protein synthesis in the brain. We hypothesized that 8 weeks of treatment with RAP and RAP+MET would alter brain protein synthesis rates to reflect proteostatic processes. Using the stable isotopic tracer, deuterium oxide (D2O), we demonstrate in UM-HET3 mice that protein synthesis rates measured in whole brain were unaffected by treatment in young male mice, whereas RAP+MET decreased mitochondrial protein synthesis in young females. Conversely, RAP increased mitochondrial protein synthesis rates in older females. Activity through the AMPK/mTOR pathway was affected in a sex-specific manner in young mice, and minimal changes were observed in the older cohort. Thus, we establish D2O for measurements of biogenesis in the brain. These results provide initial insights into the effects of RAP and RAP+MET on brain protein synthesis. Additionally, these data emphasize that responses to slowed aging treatments vary with sex and age.
Assuntos
Encéfalo/metabolismo , Longevidade/fisiologia , Metformina/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Sirolimo/farmacologia , Animais , Western Blotting , Feminino , Hipoglicemiantes/farmacologia , Imunossupressores/farmacologia , Longevidade/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , Transdução de SinaisRESUMO
mTOR inhibition extends life span in multiple organisms. In mice, when metformin treatment (Met) is added to the mTOR inhibitor rapamycin (Rap), median and maximal life span is extended to a greater degree than with Rap or Met alone. Treatments that extend life span often maintain proteostasis. However, it is less clear how individual tissues, such as skeletal muscle, maintain proteostasis with life span-extending treatments. In C2C12 myotubes, we used deuterium oxide (D2O) to directly measure two primary determinants of proteostasis, protein synthesis, and degradation rates, with Rap or Met+Rap treatments. We accounted for the independent effects of cell growth and loss, and isolated the contribution of autophagy and mitochondrial fission to obtain a comprehensive assessment of protein turnover. Compared with control, both Rap and Met+Rap treatments lowered mitochondrial protein synthesis rates (p < .001) and slowed cellular proliferation (p < .01). These changes resulted in greater activation of mechanisms promoting proteostasis for Rap, but not Met+Rap. Compared with control, both Rap and Met+Rap slowed protein breakdown. Autophagy and mitochondrial fission differentially influenced the proteostatic effects of Rap and Met+Rap in C2C12 myotubes. In conclusion, we demonstrate that Met+Rap did not increase protein turnover and that these treatments do not seem to promote proteostasis through increased autophagy.
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Longevidade/efeitos dos fármacos , Metformina/farmacologia , Mioblastos/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Proteostase/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Western Blotting , Células Cultivadas , Humanos , Hipoglicemiantes/farmacologia , Imunossupressores/farmacologia , Lisossomos/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Mioblastos/efeitos dos fármacos , Transdução de Sinais , Serina-Treonina Quinases TOR/efeitos dos fármacosRESUMO
17α-Estradiol (17α-E2) is a "non-feminizing" estrogen that extends life span in male, but not female, mice. We recently reported that 17α-E2 had robust beneficial effects on metabolic and inflammatory parameters in aged male mice. However, it remains unclear if 17α-E2 also delays other "hallmarks" of aging, particularly maintaining proteostasis. Here, we used isotope labeling methods in older mice to examine proteostatic mechanisms. We compared weight-matched mild calorie restricted (CR) and 17α-E2 treated male mice with the hypothesis that 17α-E2 would increase protein synthesis for somatic maintenance. 17α-E2 had no effect on protein synthesis or DNA synthesis in multiple tissues, including white adipose tissue. Conversely, mild short-term CR decreased DNA synthesis and increased the protein to DNA synthesis ratio in multiple tissues. Examination of individual protein synthesis and content did not differentiate treatments, although it provided insight into the regulation of protein content between tissues. Contrary to our hypothesis, we did not see the predicted differences in protein to DNA synthesis following 17α-E2 treatment. However, mild short-term CR elicited differences consistent with both lifelong CR and other treatments that curtail aging processes. These data indicated that despite similar maintenance of body mass, 17α-E2 and CR treatments elicit distinctly different proteostatic outcomes.
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Envelhecimento/metabolismo , Restrição Calórica , Estradiol/farmacologia , Proteínas/análise , Proteostase/efeitos dos fármacos , Animais , DNA/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Biossíntese de Proteínas/efeitos dos fármacosRESUMO
Oxidative damage is one mechanism linking aging with chronic diseases including the progressive loss of skeletal muscle mass and function called sarcopenia. Thus, mitigating oxidative damage is a potential avenue to prevent or delay the onset of chronic disease and/or extend healthspan. Mitochondrial hormesis (mitohormesis) occurs when acute exposure to stress stimulates adaptive mitochondrial responses that improve mitochondrial function and resistance to stress. For example, an acute oxidative stress via mitochondrial superoxide production stimulates the activation of endogenous antioxidant gene transcription regulated by the redox sensitive transcription factor Nrf2, resulting in an adaptive hormetic response. In addition, acute stresses such as aerobic exercise stimulate the expansion of skeletal muscle mitochondria (i.e., mitochondrial biogenesis), constituting a mitohormetic response that protects from sarcopenia through a variety of mechanisms. This review summarized the effects of age-related declines in mitochondrial and redox homeostasis on skeletal muscle protein homeostasis and highlights the mitohormetic mechanisms by which aerobic exercise mitigates these age-related declines and maintains function. We discussed the potential efficacy of targeting the Nrf2 signaling pathway, which partially mediates adaptation to aerobic exercise, to restore mitochondrial and skeletal muscle function. Finally, we highlight knowledge gaps related to improving redox signaling and make recommendations for future research.