Some of our most popular blogs on SAGE have been on calorie restriction (here, here, and here) and sarcopenia (here and here), better known as age-related muscle degeneration. Calorie restriction can extend lifespan in various animal models but has not been shown to extend lifespan in humans. Besides extending lifespan in animals, there are other beneficial effects resulting from calorie restriction and understanding the mechanisms behind these events is a priority in the field of aging. As for sarcopenia, muscle loss with age is inevitable and thus far, no cures or preventative therapies exist (however a number of potential therapies are being pursued). These are both very exciting aging topics, so I thought it was only fitting to follow up with a blog that combines the two.
This SAGE Review highlights a recently published article that probes the relationship between calorie restriction and sarcopenia, with respect to aging. Published in the American Journal of Physiology-Endocrinology and Metabolism, Chen et al. reported that calorie restriction in rats has an age-dependent protective effect on age-related muscle loss by improving skeletal muscle metabolism in rats.
The authors fed young (4 month) and middle-aged (16 month) rats one of two diets – either a normal diet, ad libitum (AL), or a restricted diet, 40% calorie restriction (CR), for a total of 14 weeks. They found that normalized muscle weight (muscle weight divided by body weight) was lower in normal, AL-fed, middle-aged rats compared to young rats. However, when the two age groups were fed the CR diet, skeletal muscle in middle-aged rats was protected from expected age-related degeneration and muscle mass was comparable to levels of young rats fed the AL diet. Interestingly, CR had a negative effect on normalized muscle weight in young mice and caused a decrease in muscle mass.
Next, the authors explored different aspects of skeletal muscle metabolism in young and middle-aged rats fed either AL or CR diets. It is well known that as animals and humans age, muscle loss occurs in part due to a disruption in cellular metabolism. This includes important processes that allow cells to produce the energy to function. Cells use sugar (glucose) to make a molecule called ATP. ATP is the fuel that powers nearly everything that a cell does. There are two ways to make ATP: glycolysis (breaking down sugar, or glucose, into pyruvate to make ATP) and mitochondrial oxidative phosphorylation (further oxidizing pyruvate to make ATP). While glycolysis makes 2 ATP molecules for every molecule of glucose, oxidative phosphorylation (OXPHOS) makes 30 molecules of ATP for every molecule of glucose. Glycolysis is the first step in OXPHOS, but not every sugar molecule that is broken down by glycolysis will be burned in the mitochondria via OXPHOS.
The balance between these two pathways changes as cells age. Older cells have a higher ratio of glycolysis to OXPHOS likely due to a decline in mitochondrial function (and therefore less usable ATP per sugar molecule), compared to younger cells, which have a higher ratio of OXPHOS to glycolysis and proper mitochondrial function. When middle-aged rats were fed the CR diet, the relative contribution of both pathways on skeletal muscle cells was similar to that of young mice fed a normal diet (ie. OXPHOS > glycolysis). Furthermore, middle-aged rats fed the CR diet had improved cellular metabolism, evidenced by an upregulation in mitochondrial pyruvate carrier (MPC) and in proteins involved in mitochondrial biogenesis, specifically SIRT1 and PGC-1α. Improvements in skeletal muscle metabolism in CR-fed middle-aged rats correlated with CR-induced increases in normalized muscle mass.
Thus, it seems that CR has an age-dependent beneficial effect on skeletal muscle mass in rats and can reprogram skeletal muscle metabolism to function at levels that resemble those of young rats fed a normal diet. While this study sheds new light onto the relationship between CR, sarcopenia, and aging, further studies looking into the long-term effects of CR on skeletal muscle metabolism, as well as lifespan extension, should be done. It will be important to know whether age-dependent CR has lasting beneficial effects on muscle metabolism, and whether it can reverse muscle degeneration in older-age rats.
A more applicable question arising from this study is whether CR can counteract muscle degeneration in middle-aged or elderly humans. This study suggests that middle-aged humans could potentially benefit from a CR diet with respect to preventing muscle loss, but that practicing CR as a young person could have detrimental effects. Conducting a similar experiment in humans will be a much larger endeavor, however, scientists can use what we learn from these rat studies and other model organisms to better understand metabolic pathways that go awry with aging. Ultimately, understanding the mechanisms behind the beneficial effects of CR and how they influence the process of sarcopenia during aging will open the doors for the development of therapies to prevent or treat aging-related diseases.
Calorie Restriction blogs:
- Skip the nachos: An interview with Brian M. Delaney on caloric restriction and longevity
- Caloric restriction and aging: why some people starve themselves to live longer
- SAGE Review: Hydrogen Sulfide Sheds Light on the Beneficial Effects of Dietary Restriction
- Interview with Dr. Alicia Kowaltowski: How Diet Affects Energy Metabolism