Fight Aging!

The practice of calorie restriction is well documented to slow the progression of aging in mammals. In humans, there is comprehensive evidence for it to improve measures of health and reduce the risk of age-related disease. The mechanisms by which calorie restriction produces benefits are essentially the same across species, an upregulation of various stress response mechanisms that maintain and repair cell function. The short-term health benefits, the specific outcomes resulting from this favorable alteration in the operation of cellular metabolism, are also very similar. However, the extension of life span produced by calorie restriction diminishes as species life span increases. Calorie restriction can extend life in mice by up to 40%, but is thought to only add a few years to human life span.

Nonetheless, improved health is improved health, and calorie restriction does more for long-term health in humans than near any other available intervention. Perhaps only senolytic drugs that clear lingering senescent cells from old tissues will improve upon the benefits for older people, but a head to head comparison has yet to take place.

Today's open access paper offers a narrow focus on the interaction between calorie restriction and one specific age-related condition. It is a review of what is known of the mechanisms by which calorie restriction slows the onset of sarcopenia, the widespread loss of muscle mass and strength that takes place with advancing age. There are many contributing causes of sarcopenia, all of which interact with one another, though the most important are likely (a) a decline in muscle stem cell activity, leading to a reduced supply of new muscle cells to maintain this tissue, (b) damage and loss of function in neuromuscular junctions that link the nervous system to muscles.

Caloric restriction: implications for sarcopenia and potential mechanisms

Epidemiological investigations have indicated that the muscle mass of the human body decreases by approximately 1.5% yearly after the age of 50 and by 2.5-3.0% yearly after the age of 60. The incidence rate of sarcopenia among individuals over 80 years old is as high as 50%. Studies have shown that a 10% decrease in muscle mass leads to a decrease in immune function and an increase in the risk of infection. A 20% reduction in muscle mass results in muscle weakness, a decreased ability to participate in activities of daily living, and an increased risk of falling. A 30% reduction in muscle mass results in disability, loss of independent living ability, and failure of wound and pressure ulcer healing. A 40% reduction in muscle mass results in a markedly increased risk of death from pneumonia, respiratory dysfunction, etc.

The main manifestations of sarcopenia in elderly individuals are a decreased cross-sectional area of muscle fibers and reduced muscle strength and function. Clinical studies have shown that the reduction in muscle mass is much greater in the lower limbs than in the upper limbs. Gait speed or the short physical performance battery (SPPB) are commonly used to assess muscle function. Muscle strength tends to decrease with age, as manifested by reduced grip strength and knee joint extension, weakened hip joint bending activity, decreased pace, and increased time to maximal muscle contraction compared with those of young individuals. Additionally, the number and the proliferation and differentiation abilities of muscle stem cells (MuSCs), which play an important role in muscle cell regeneration, are reduced. The number of MuSCs in aged mice is 50% lower than that in young mice.

A recent study found that CR can improve the function of adult stem cells, including the regeneration ability of skeletal MuSCs. To study whether CR can affect the rhythmic activity of stem cells during aging, researchers conducted a 25-week comparative observation of aged mice that consumed a control diet or a diet with 30% fewer calories than the control diet. In this study, except for the reduction in body weight, the aging characteristics related to epidermal and muscle tissue in mice were significantly ameliorated in the CR group compared with the control group. Additional studies have indicated that not stem cells themselves but the stem cell microenvironment is the key factor mediating stem cell activation, proliferation and differentiation.

Mitochondrial dysfunction is an important factor leading to age-related muscular atrophy. Considering the dependence of skeletal muscle on ATP, loss of mitochondrial function, which can lead to a decrease in strength and endurance, is especially obvious in skeletal muscle. CR can preserve the integrity and function of mitochondrial structure via reducing oxidative damage. Previous studies have shown that CR reduces proton leakage and ROS generation in mitochondria in skeletal muscle while enhancing the expression of ROS scavenging-related genes. In addition, CR may alter the fatty acid composition of the mitochondrial membrane, reduce lipid oxidation, and reduce proton leakage.

Accumulating evidence suggests that apoptosis may constitute a fundamental mechanism driving the onset and progression of sarcopenia. There are two main pathways of apoptosis: activation of the apoptotic enzyme caspase through extracellular signaling and activation of caspases through the release of mitochondrial apoptosis activators. These activated caspases can degrade important proteins in cells and induce apoptosis. The gene expression and cleavage of pre-caspase-3 in the gastrocnemius muscle were significantly reduced in CR mice compared with control mice. In addition, CR increased the content of apoptosis inhibitors in the cytoplasm.

Experimental data strongly suggest that mTOR activity increases during aging, beginning in middle age and resulting in progressively altered mitochondria, in turn leading to mitochondrial oxidative stress and thus the induction of catabolic processes, including protein degradation, apoptosis, and necrosis. This elevated catabolic activity results in muscle fiber loss, atrophy, and damage. Recent evidence has shown that CR downregulates mTORC1 signaling in skeletal muscle independent of dietary protein intake. Moreover, a paper published in 2019 indicated that the effects of CR on mTOR signaling in skeletal muscles are age-dependent. CR altered mTOR signaling in the soleus muscles in middle-aged rats but not in young and adult rats.

Autophagy is essential for overall cellular health because in some residual tissues, the lack of an autophagic response gradually results in the accumulation of damage within the cells, eventually leading to cell death and loss of tissue function. In vivo studies have demonstrated that CR can increase autophagic responses in skeletal muscle. Additional studies have shown that CR regulates the transcription factor Forkhead box O3 (FOXO3), which is associated with human longevity, and recent studies have shown that muscle atrophy is associated with the expression of the transcription factor FOXO3 and other downstream target skeletal muscle atrophy-related proteins.

In summary, the protective effects of CR on sarcopenia are manifested as improved protein quality, maintenance of muscle strength, and enhanced muscle function, and these effects may be achieved via mitigation of cellular oxidative stress, promotion of mitochondrial function, alleviation of the inflammatory response, inhibition of apoptosis, activation of autophagy, and other mechanisms.