Anti-aging strategies

Calorie Restriction (CR) refers to a dietary approach in which individuals intentionally reduce the caloric intake in their diet.

1.Calorie Restriction

Calorie Restriction (CR) refers to a dietary approach in which individuals intentionally reduce the caloric intake in their diet. This involves controlling caloric intake to levels below their usual daily consumption or below the daily caloric intake of similar individuals. However, calorie restriction should still provide the essential nutrients required by the body, as failing to do so can lead to various adverse consequences, including malnutrition.

Towards the end of the 20th century, research on CR extended to closely related primates, such as rhesus monkeys. A long-term calorie restriction study, spanning over two decades, involving 76 adult rhesus monkeys was conducted at the University of Wisconsin (UW). The results indicated that CR delayed the onset of various diseases (2.9 times) and mortality rates (3.0 times) in rhesus monkeys. In 2015, a randomized trial sponsored by the National Institute on Aging (NIA) and the National Institutes of Health (NIH), under the Diabetes Kidney Disease Program, revealed that a 2-year CR significantly reduced the risk of heart-related metabolic issues. Moreover, it led to adjustments in the body's daily energy allocation, changes in body weight, all without negatively impacting the quality of life of the subjects.

From a molecular biology perspective, calorie restriction has a regulatory effect on the mTOR and AMPK signaling pathways. Calorie restriction can enhance the activity of AMP-activated protein kinase (AMPK) and inhibit the mTOR signaling pathway. Both of these pathways are closely associated with aging, and many strategies for the development of anti-aging drugs involve either activating AMPK or inhibiting mTOR.

2.Activation of the AMPK 

Pathway Cells must adjust their energy supply and nutritional support to maintain metabolism. Eukaryotic cells have evolved a complex system, using AMP-activated protein kinase (AMPK), a serine/threonine kinase, to sense the cellular levels of ATP. Under conditions of low energy supply, AMPK phosphorylates specific enzymes and sites, increasing ATP generation while reducing ATP consumption.

In higher eukaryotes, AMPK senses the remaining available energy by directly binding to adenosine nucleotides. When there is a change in energy utilization, such as a change in the ratio of ATP/ADP or ATP/AMP, AMPK is activated through a conformational change in its activating kinase. Once activated, AMPK can phosphorylate key proteins in multiple signaling pathways, including mTORC1, lipid homeostasis, glycolysis, and mitochondrial homeostasis, to increase catabolic metabolism and reduce synthetic metabolism. In addition to directly regulating key enzymes in these pathways, AMPK maintains cellular metabolism by targeting transcriptional regulatory factors. During energy stress, AMPK directly phosphorylates key factors in multiple pathways to restore energy balance. The effects of AMPK on metabolism can be broadly categorized into two types: inhibiting synthetic metabolism to reduce ATP consumption and stimulating catabolic metabolism to enhance ATP production.

AMPK specifically regulates mitochondrial processes to maintain homeostasis. This includes controlling mitochondrial biogenesis to regulate mitochondrial quantity, regulating the shape of the intracellular mitochondrial network, and controlling autophagy and mitophagy to maintain mitochondrial quality.

AMPK is of particular interest due to its potential as a therapeutic target for metabolic disorders such as diabetes, obesity, fatty liver, and even cancer. Currently, metformin is a drug used in the treatment of type 2 diabetes and has been extensively employed in anti-aging research involving the AMPK pathway. The main evidence for the potential life-extending effects of metformin in humans is based on a retrospective trial published in 2014. The study involved approximately 180,000 individuals, with around 90,000 of them being diabetes patients, and had an average observation period of 2.8 years. The results showed that diabetes patients treated with metformin had significantly higher survival rates compared to the sulfonylurea group. Adjusted survival rates even exceeded those of matched non-diabetic groups.

3.Inhibition of the mTOR

Pathway mTOR, which stands for mammalian target of rapamycin, exists in two complex forms in the body, known as mTORC1 and mTORC2. It can sense the concentrations of amino acids, growth factors, insulin, oxygen, and ATP. When these components are abundant, the mTOR complexes become activated, leading to the synthesis of proteins, nucleic acids, and lipids. Simultaneously, mTOR inhibits autophagy and shifts glucose metabolism from aerobic (oxidative phosphorylation) to anaerobic (glycolysis).

Prolonged activation of mTOR leads to uncontrolled growth effects, promoting cellular and organismal aging, and may even shorten individual lifespans. mTORC1 can induce mitochondrial oxidative stress, enhance the expression of multiple inflammatory factors, and inhibit autophagy. Inhibiting the mTOR pathway has become a focal point in anti-aging research. What's more, an increasing number of mechanisms known to extend lifespan and delay aging have been found to be associated with mTOR inhibition, including autophagy, calorie restriction, and metformin.

4.Inhibition of the GH/IGF-I Axis (Growth Hormone-Insulin-Like Growth Factor Axis)

The GH/IGF-1 axis is an important endocrine pathway in the body, primarily consisting of growth hormone (GH) and its receptor (GHR), insulin-like growth factor-1 (IGF-1), and its receptor (IGF-1R). This axis promotes cell proliferation and skeletal growth, as well as regulates development and metabolic processes in the body. GH, through direct binding to target cells, and IGF-1, through both autocrine and paracrine mechanisms, can independently exert their effects. However, they also interact with each other; typically, GH does not act directly but stimulates the release of IGF-1 from liver cells in response to signaling. IGF-1 can, in turn, inhibit GH release through actions in the hypothalamus, creating a feedback loop between these two hormones.

Research has revealed that supplementing GH and IGF-1 does not delay aging and may pose metabolic abnormalities and an increased risk of cancer. Conversely, drugs that inhibit the GH/IGF-1 axis might become a novel approach to simultaneously extending healthy lifespan and overall longevity.

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