Most of the work aimed at treating aging as a medical condition is focused on stress response upregulation, finding ways to trigger some of the regulatory pathways and mechanisms involved in beneficial cellular reactions to the mild stresses of exercise, reduced calorie intake, hypoxia, heat, cold, and so forth. Improved cell behavior leads to improved tissue function, which in turn slows the progression of degenerative aging. Many of these pathways converge on autophagy, and evidence from the study of calorie restriction suggests that improved autophagy is the largest contributing factor.
Autophagy is the name given to a collection of cellular maintenance processes that remove unwanted or damaged structures and proteins, ensuring that they are broken down in a lysosome and the raw materials returned to the cell for reuse. Autophagy becomes less effective with age, and researchers have in recent years identified a range of age-related defects in the various component parts of the autophagic process. Tracing these issues back to root causes is, as for most of the changes observed in cells in aged tissues, quite challenging and very much a work in progress.
Stress response upregulation is much more effective at extending life span in short-lived species than it is in long-lived species. Calorie restriction can increase life span by 40% in mice, but certainly doesn't do that in humans. Stress response upregulation as a strategy for the development of therapies does not seem likely to greatly improve the healthy human life span to a much greater degree than is already possible via lifestyle changes. So it is disappointing that so much of present efforts are directed towards this part of the field. Results in mice should not be taken as indicative of the benefits that these same treatments might achieve in longer-lived species such as our own.
Metabolic function, cardiac capacity, and vascular flexibility decline progressively with age, which in combination reduce work capacity, mobility, and quality of life. Type 2 diabetes (T2D) and cardiovascular diseases (CVDs) incidence increase with age and are current global epidemics representing major challenges to health care systems. Regular exercise not only increases work/exercise capacity but also counteracts the development of numerous age-related diseases, including several forms of metabolic and CVDs, thus promoting healthy aging. However, aged individuals are frequently unable to engage in regular exercise/physical activity. Thus, there is a large need to develop pharmacological treatments that can increase exercise/work capacity to counteract metabolic dysfunction and improve cardiac and vascular function and thereby promote healthy aging and increase quality of life in the aging population.
Insulin resistance and associated hyperinsulinemia are predictors of age-related diseases such as T2D and CVD. Increased activity of AMP-activated protein kinase (AMPK), a key energy sensor that is activated in response to low energy and glucose levels following exercise, enhances insulin-dependent and insulin-independent skeletal glucose uptake, thus improving glucose homeostasis and insulin resistance. AMPK activity declines however with age. Thus, AMPK has emerged as a potential important link between, and mediator of, numerous positive effects of exercise including protection against age-related diseases.
We previously showed that pan-AMPK activator O304 stimulates AMPK activity and glucose uptake in both skeletal muscle and heart of diet-induced obese (DIO) mice in vivo. In DIO mice, O304 mitigated hyperglycemia, hyperinsulinemia, insulin resistance, and obesity, and in a transgenic type 2 diabetic mouse model, O304 reversed established diabetes. O304 also significantly increased stroke volume, end-diastolic volume, and reduced heart rate in DIO mice, mimicking the cardiac effects of exercise. Thus, AMPK activator O304 efficiently ameliorated obesity-provoked insulin resistance, diabetes, and cardiovascular dysfunction in obese mice. O304 is currently in clinical development, and in a short proof-of-concept phase IIa clinical trial in T2D patients O304 reduced fasting plasma glucose levels and insulin resistance, i.e., HOMA-IR, and increased microvascular perfusion in the calf muscle and reduced blood pressure.
Here we show that the pan-AMPK activator O304, which is well tolerated in humans, prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice. These results provide preclinical evidence that O304 mimics the beneficial effects of exercise. Thus, as an exercise mimetic in clinical development, AMPK activator O304 holds great potential to mitigate metabolic dysfunction, and to improve cardiac function and exercise capacity, and hence quality of life in aged individuals.