动物造模,非人类灵长类动物衰老模型 z-bio 2021-09-16 1026

　　Simulating human aging: Ideally, all biomedical research related to humans should be conducted on humans, but due to many ethical and technical considerations, this is obviously impractical. Therefore, it is necessary to model the human aging process in non-human systems. Many operations can be performed without animals, such as using computer models or in vitro systems. Although these systems are generally useful, they cannot reproduce the complex and multifaceted physiological functions of aging in the body. Many different non-human models (yeast, roundworms, fruit flies, rats, etc.) are used to study the aging process, but mice are usually the best model.

　　Non-human primate aging research model: Although rodent models have some obvious advantages, the fundamental difference between rodent and human aging process makes rodents find directly humans. Will not be converted to. On the other hand, non-human primates are an important link between basic research and clinical applications, because the discoveries of non-human primates can be highly translated into human health problems. Non-human primates are ideal translation models because they have genetic, physiological and behavioral characteristics that are surprisingly similar to humans. Non-human primate research provides a good trade-off between the limitations of rodent and human research. However, few studies have used non-human primate models for aging. This may be due to the challenges faced by the model, such as the limited supply of elderly animals, the need for professional care, and the associated high cost of use. Potential ethical issues. There are several different types of primates used to simulate human aging, but the old world monkeys, especially the rhesus monkeys, have historically been the most studied. Recently, there has been increasing interest in using new small primates (common marmosets) in aging research. The following focuses on rhesus monkeys and marmosets.

　　Rhesus musculoskeletal aging: Weakness is a condition of increased vulnerability, which has an adverse effect on health. There is an increased risk of disability, falls, hospitalization, and death. The prevalence of frailty increases with age. As we age, the deterioration of the musculoskeletal system can lead to physical weakness. Rhesus monkeys cause muscle and bone loss during the aging process, and are very general human conditions, which are very useful for simulating age-related changes in the human musculoskeletal system.

　　Muscle atrophy: Muscle atrophy is the loss of skeletal muscle mass and function during aging. As we age, muscle atrophy becomes more common and is associated with weakness, disability, falls, fractures, and increased morbidity and mortality. The rhesus monkey is the best model of human muscle atrophy. Unlike rodents, rodents will experience significant muscle atrophy later in their lives. The dynamics of muscle atrophy in rhesus monkeys is consistent with that of humans. It develops in middle age and then gradually disappears. It was observed that due to age-related mitochondrial DNA deletion mutations, the decrease in the cross-sectional area of muscle fibers led to muscle atrophy and a significant increase in muscle fibers with abnormal mitochondrial enzymes. In addition, compared with rodents, skeletal muscle accounts for a higher proportion of the body weight of primates and is a huge energy consumer.

　　Osteoporosis: Osteoporosis is a major health and economic problem worldwide. Osteoporosis is characterized by bone loss, bone tissue degradation, bone structure destruction, and bone strength damage, all of which increase the risk of fractures. Although commonly used, mice are not an ideal model for human osteoporosis. Human cortical bone reflects constant remodeling throughout life. Mouse cortical bone rarely undergoes Havers remodeling. The cortex is mainly composed of an annular layer that forms on the outer surface as the bones grow. Unlike humans, the bone acquisition and longitudinal bone growth in mice will continue after sexual maturity. In many strains, bone growth continues into old age. In addition, mice will not go through true menopause. They may experience irregular cycles during the first 10 months of life, but their estrogen levels remain the same, and the uterine weight (an indicator of functional estrogen exposure) remains normal until old age. Similarly, male mice maintain their testosterone levels as they age. On the other hand, rhesus monkeys and other old world monkeys are excellent models of human osteoporosis because they have similar reproductive endocrine systems that affect bone remodeling and bone metabolism in cortical bone. After bone mass reaches its peak at about 10 years of age, rhesus monkeys steadily increase bone regeneration and bone loss with age, leading to natural or surgically induced estrogen depletion. This is not surprising. This is because it is surprisingly similar to humans in the menstrual cycle, the occurrence of natural menopause, and the bone remodeling process of cancellous and cortical bone.

　　Osteoarthritis: Osteoarthritis has the highest incidence of all types of arthritis in the world and is the main cause of chronic pain diseases. Non-human primates (such as rhesus monkeys) provide a special case for studying naturally occurring osteoarthritis.

　　Rhesus monkey menopause: Menopause can be defined as the natural result of the aging process in which human females gradually lose their fertility. This failure in childbirth includes complete cessation of ovulation and menstruation, accompanied by changes in the function and structure of the hypothalamic-pituitary-ovarian axis. The importance of studying menopausal model species cannot be underestimated. Not only are there adverse effects directly related to menopause, but the changes in the hormonal environment associated with menopause also mean an increased risk of age-related diseases and conditions, including musculoskeletal and cardiovascular diseases. .. Globally, a positive correlation has recently been established between menopause and blood epigenetic aging. Rhesus monkeys have undergone true menopause, mimicking the physiological changes in human conditions. In view of the wide application of rhesus monkeys in biomedical research, compared with other non-human primates, this reproductive aging has more comprehensive characteristics.

　　Rhesus monkey calorie restriction (CR): A major challenge in aging research comes from the biological complexity of the aging process itself. More than 80 years ago, a seemingly simple method of reducing calorie intake was proven to delay rodent aging and the development of age-related diseases. Since then, continuous reduction of caloric intake without malnutrition proved to be the most effective and long-term intervention, which can delay the aging of various species and make experimental mice effective. It is the only environmental intervention that can be extended and extended. . Delay the longest life span and biological aging. Rhesus monkeys are a good model of musculoskeletal aging. Bone and muscle health has long been an area of concern for calorie restriction (CR). In human and non-human primate models, short-term (u003c1 years) CR has been reported to reduce physical activity and metabolic rate. Long-term CR reduces the basal metabolic rate, but maintains a higher physical activity and a lower exercise metabolic rate. Animals related to CR appear to be biologically younger than normally bred animals.

　　New World Monkey Aging Model: Among the New World monkeys, common marmosets are the most promising for aging research. Common marmosets, such as rhesus monkeys, share approximately 93 sequence homology with the human genome, leading to age-related diseases and conditions similar to humans, such as diabetes, cardiovascular disease, and cancer. The marmoset is a mature model of neuroscience, infectious diseases, behavioral research, obesity, and reproductive biology. Researchers are actively looking for new technologies (such as CRISPR) to create disease-targeted genetically modified marmosets. This makes marmosets a particularly attractive model for neurodegenerative diseases such as Parkinson's disease. Compared with rhesus monkeys, one of the main advantages of marmosets is their short life span. By reducing the passage of time, you can reduce the risk of losing control of research variables (including equipment and personnel availability) during an aging research process. The second major advantage of the marmoset model is its high fertility rate and littermal hematopoietic chimerism. This chimera offers several potential benefits, including the ability to limit the differences between the control and experimental groups, and the opportunity to study the impact of the early environment on later life outcomes. Another advantage is its small size. It is generally easier to handle and maintain than macaques, and requires less moving space. Unlike rhesus monkeys, marmosets do not have zoonotic diseases.

　　Common neurodegenerative disease models of Marmoset Sal: Marmoset combines proven behavior, surgery, and imaging techniques, including small epidemiological models of neurodegenerative diseases in Alzheimer's disease (including Parkinson's disease and Hirsch's disease) , Similar to the human brain. Huntington's disease and multiple sclerosis. These similarities include evidence of decreased age-related neurogenesis that occurs before aging. Marmosets are particularly useful as a neurotoxin induction model for Parkinson's disease, and a genetic model for Parkinson's disease has recently been developed.

　　Marmoset Aging Interventions: There is a lot of evidence supporting that maintaining cell protein balance is one of the key processes to ensure longevity. People are increasingly aware of the role of rapamycin (mTOR) mechanism targets in regulating this process. Rapamycin (rapamycin) is an mTOR inhibitor used in human immunosuppressive therapy after transplantation. Rapamycin was first shown to extend the lifespan of yeast cells, and later proved to have a beneficial effect on the lifespan of nematodes, fruit flies, mice, and human cells. It has been found to extend lifespan, even in elderly mice treated with rapamycin. Research is currently being conducted on marmosets to investigate the effect of rapamycin on the lifespan of non-human primates. Further studies have shown that rapamycin induces marmoset tissue to specifically up-regulate certain components that regulate protein homeostasis. These studies prove that the marmoset is an excellent model for studying long-term aging interventions.

　　Conclusion: Most aging research focuses on non-primates. Although this work is very valuable, non-human primates provide a combination of manageable models that are very close to human anatomy, physiology, and behavior, and their development and age are similar to humans. Ideally, age-related diseases and conditions should be studied in the aging model to reconstruct the aging environment that exists in the human condition. The further development of research methods and resources will improve the practicability of marmoset aging models and fully realize the value of genetically modified marmosets.