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Rapamycin, caloric restriction, or both – choose the right weapon against muscle aging
A comparison of rapamycin and caloric restriction treatments confirmed different influences on the attenuation of muscle mass loss and glucose intake.
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Calorie restriction (CR), though being known as the most reproducible and efficient intervention to extend lifespan, is largely unachievable in humans. There are several reasons behind that, including potential side effects (extreme leanness and cold sensitivity), as well as the need for extreme willpower in order to maintain a low-calorie diet.
These limitations turn the researchers’ attention toward “CR mimetics” – a group of compounds able to reproduce CR effects. The most famous dietary mimetic is rapamycin (RM), which acts through inhibition of the mTORC1 protein (mammalian target of rapamycin complex 1). Rapamycin is known for prolonging the lifespan of multiple model organisms, including yeast, fruit flies, worms, and mice.
The CR effects result from downregulating the activity of nutrient-sensing pathways, which are also focused on mTORC1. Both CR and RM were found to promote autophagy, but their effects on insulin sensitivity strongly diverged, as CR was improving and RM was impairing glucose tolerance. This led Ham and colleagues to the question if “all roads lead to Rome” or, more precisely, if the mechanisms and effects behind CR and RM are indeed the same.
As the target, the researchers chose muscular aging since sarcopenia (age-related muscle loss) is one of the most pronounced aging effects, which significantly affects both life- and healthspan. They studied mice with introduced CR, RM, or CR+RM from 15-20 until 30 months of age (a period when sarcopenia usually develops). CR mice showed improved muscle function and improved markers of muscle quality. A comparison of RM and CR treatments confirmed different influences on the attenuation of muscle mass loss and glucose intake. Long-term RM treatment proved to be successful in stopping or reversing sarcopenia. Additional genetic analysis demonstrated that CR and RM have distinct expression signatures, pointing towards the hypothesis that the mechanism behind their action might differ though possible converging on the same target pathway. When combined, CR+RM showed an additive effect with mice successfully evading muscular aging but maintaining glucose tolerance.
These findings provide an important glimpse into the difference between CR and existing mimetics showing that their effects are distinct and mostly non-overlapping. In case ”true” CR mimetic appears, combined application of it together with RM might provide novel improved treatment to counteract aging. Further work is needed to discover more details of the targetable processes behind CR.
Source Nature Communications
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Calorie restriction (CR), though being known as the most reproducible and efficient intervention to extend lifespan, is largely unachievable in humans. There are several reasons behind that, including potential side effects (extreme leanness and cold sensitivity), as well as the need for extreme willpower in order to maintain a low-calorie diet.
These limitations turn the researchers’ attention toward “CR mimetics” – a group of compounds able to reproduce CR effects. The most famous dietary mimetic is rapamycin (RM), which acts through inhibition of the mTORC1 protein (mammalian target of rapamycin complex 1). Rapamycin is known for prolonging the lifespan of multiple model organisms, including yeast, fruit flies, worms, and mice.
The CR effects result from downregulating the activity of nutrient-sensing pathways, which are also focused on mTORC1. Both CR and RM were found to promote autophagy, but their effects on insulin sensitivity strongly diverged, as CR was improving and RM was impairing glucose tolerance. This led Ham and colleagues to the question if “all roads lead to Rome” or, more precisely, if the mechanisms and effects behind CR and RM are indeed the same.
As the target, the researchers chose muscular aging since sarcopenia (age-related muscle loss) is one of the most pronounced aging effects, which significantly affects both life- and healthspan. They studied mice with introduced CR, RM, or CR+RM from 15-20 until 30 months of age (a period when sarcopenia usually develops). CR mice showed improved muscle function and improved markers of muscle quality. A comparison of RM and CR treatments confirmed different influences on the attenuation of muscle mass loss and glucose intake. Long-term RM treatment proved to be successful in stopping or reversing sarcopenia. Additional genetic analysis demonstrated that CR and RM have distinct expression signatures, pointing towards the hypothesis that the mechanism behind their action might differ though possible converging on the same target pathway. When combined, CR+RM showed an additive effect with mice successfully evading muscular aging but maintaining glucose tolerance.
These findings provide an important glimpse into the difference between CR and existing mimetics showing that their effects are distinct and mostly non-overlapping. In case ”true” CR mimetic appears, combined application of it together with RM might provide novel improved treatment to counteract aging. Further work is needed to discover more details of the targetable processes behind CR.
Source Nature Communications
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Dr. Ana Baroni MD. Ph.D.
Scientific & Medical Advisor
Quality Garant
Ana has over 20 years of consultancy experience in longevity, regenerative and precision medicine. She has a multifaceted understanding of genomics, molecular biology, clinical biochemistry, nutrition, aging markers, hormones and physical training. This background allows her to bridge the gap between longevity basic sciences and evidence-based real interventions, putting them into the clinic, to enhance the healthy aging of people. She is co-founder of Origen.life, and Longevityzone. Board member at Breath of Health, BioOx and American Board of Clinical Nutrition. She is Director of International Medical Education of the American College of Integrative Medicine, Professor in IL3 Master of Longevity at Barcelona University and Professor of Nutrigenomics in Nutrition Grade in UNIR University.
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