The "hard core" technology guide to slow aging

  Mu Luo knows the year and autumn, Ping Bing knows the weather. Aging, or age-related aging, is manifested as a series of irreversible declines in the health and function of tissues and organs, leading to a high incidence of aging-related diseases such as Alzheimer's disease, cardiovascular disease, and osteoarthritis. With the development of modern technology, people have gradually realized that interfering with the speed of aging and the length of life may prevent aging-related diseases and achieve healthy aging. Researchers combined new research techniques on aging with disease models, tracing back to the source, and found that during aging, stem cell depletion increased, senescent cell clearance decreased, intercellular communication changes, and nutritional sensation disorders, and senescent cells showed genomic instability and appearance. Features such as genetic modification and shortening of telomeres. However, "knowing the destiny" does not mean "receiving the destiny." At present, researchers are focusing on small molecule drug therapy, stem cell therapy, gene therapy, scientific dieting, exercise, etc., hoping to intervene in the aging level of specific tissues, organs or organisms, so as to promote the physiological maintenance of younger and healthier status.

① Small molecule drug intervention

  Finding a "magic bullet" that can interfere with the aging process and prolong healthy life is a key aspect of aging research. The most promising anti-aging drugs currently include rapamycin, metformin, spermidine, NAD+ (nicotinamide adenine dinucleotide) supplements, and Senolytics drugs. Such drugs usually show obvious anti-aging effects in model animals and even humans, with low side effects and good safety. They are the "hands" in the field of anti-aging drugs.

  Take the mTOR inhibitor rapamycin as an example. As early as 2009, it was proven to prolong the lifespan of elderly mice. Different studies have shown that it can not only delay aging, but also increase healthy lifespan, and improve cognition against aging-related diseases. Level, prevention of cancer has "miraculous effects." Rapamycin is currently approved by the FDA and used in clinical treatment.

  Metformin has been found to have life-prolonging effects in nematodes and mice, and in humans, a Cardiff University retrospective study reported that metformin-treated type II diabetes patients had a longer median survival time than non-patients. In 2015, the US FDA also approved the TAME (Targeting Aging With Metformin) project to carry out research on human aging intervention with metformin.

  Spermidine levels decrease with aging. Studies have reported that supplementing spermidine in the diet can prolong the lifespan of yeast, nematodes, fruit flies and mice. In 2011, scientists at Hadassah-Hebrew University discovered that spermidine can promote human hair growth and epithelial stem cell function. In 2019, Anna Simon of Oxford University and others found that spermidine slows down the aging speed of human B cells.

  In addition, the well-known NAD+ is not to be outdone. A number of mouse studies have shown that it can prolong healthy lifespan. For example, the teams of Shin-ichiro Imai and Rafael de Cabo found that nicotinamide mononucleotide or nicotinamide treatment in mice can improve The health status of mice.

  Senolytics, the latest "anti-aging drugs", are gradually becoming known to people. The most significant feature of these drugs is their ability to target and eliminate senescent cells. Senolytic drugs can delay or inhibit aging-related diseases such as atherosclerosis, diabetes, sarcopenia and osteoarthritis. For example, James L. Kirkland's team used drugs to remove senescent cells (a combination of dasatinib and quercetin) to treat mice, which significantly improved the physical functions of elderly mice and prolonged their lifespan. Deng Hongkui's team developed the SSK1 drug, which can target galactosidase to eliminate senescent cells, reduce the inflammatory response of aging mice, and improve body functions. There are also many drug companies, such as Senolytic Therapeutics, which have started the development of such drugs.

  Not only that, the "Longevity Package" also includes members such as optipra, vitamin C, and quercetin. The Liu Guanghui team of the Chinese Academy of Sciences found that these drugs can delay the aging of human stem cells. It is believed that in the future, more clinically applicable small molecule drugs for anti-aging will be discovered and researched to reduce the burden of patients with aging-related diseases and improve the quality of life.

② Stem cell therapy

  The aging process is also related to the decrease in the number and activity of stem cells, which are the source of damaged tissue or cell regeneration potential. In recent years, induced pluripotent stem cells (iPSC) and mesenchymal stem cells (MSC) have attracted much attention in the field of regenerative medicine and aging-related disease intervention.

  In principle, induced pluripotent stem cells can differentiate into various types of cells, such as fibroblasts, nerve cells, and vascular endothelial cells; mesenchymal stem cells also have a certain differentiation ability and can differentiate into osteoblasts, adipocytes, and cartilage Cells, muscle cells, etc. Clinically, differentiated cells are transplanted to inflammation or different damaged sites to promote the repair of damaged tissues by producing chemical factors with biological activity.

  This type of stem cell therapy has been proven to treat many aging-related diseases. For example, Tom K Kuo and others used bone marrow-derived mouse mesenchymal stem cell transplantation to successfully rescue the symptoms of experimental liver failure, promote liver regeneration, and provide a possible alternative to organ transplantation for the treatment of liver diseases. Damian Garcia-Olmo and others used adipose-derived mesenchymal stem cell transplantation to treat Crohn’s disease. The study has entered a phase III clinical trial, and the follow-up recovery rate can reach 50% after one year.

  In 2018, the team of Zhou Qi and Hu Baoyang of the Chinese Academy of Sciences tried human embryonic stem cell-derived nerve cell transplantation in a monkey model of Parkinson's disease and achieved significant results. The first batch of clinical studies have been carried out. These reports indicate that stem cell therapy has broad application prospects in promoting regeneration and alleviating aging-related diseases in various tissues.

③ Gene therapy

  In addition to aging intervention at the stem cell level, gene therapy is also a key part of aging research. It is not the "black technology" in science fiction movies, but refers to the use of non-drug or surgical means to introduce gene fragments into cells for disease intervention. The traditional method is to use recombinant viral vectors for gene transfer. After the advent of CRISPR/Cas9 technology, it has become a powerful boost for gene therapy. The use of gene therapy can alleviate or even reverse the signs of aging in individuals, thereby making tissues or organs "younger".

  As early as 1998, scientists tried to use viral vectors to induce the expression of insulin-like growth factor IGF-1, thereby reversing the age-related changes in mouse skeletal muscle. The physical strength of the treated elderly mice was 30% stronger than that of the control group. There is also research to increase the expression of telomere protein complex TRF1 through gene therapy, which can effectively improve the cognitive function, muscle performance, chronic anemia and other pathological characteristics of aging in elderly mice. Researchers from the Salk Institute in the United States have intermittently induced the expression of Oct4, Sox2, c-Myc, and Klf4 recoding factors to induce cell reprogramming, and found that it can reverse the signs of aging in mice with progeria and make the mice lifespan. It was extended by 30%. Not only that, the institute also reported that gene therapy through CRISPR/Cas9 gene editing can reduce the toxic protein Progerin produced by LMNA gene defects, thereby inhibiting the premature aging phenotype in Hutchinson-Gilford Progeria Syndrome (HGPS) mice. In addition, Liu Guanghui’s team proved the feasibility of treating osteoarthritis through gene introduction of stem cell "rejuvenation" factors such as DGCR8, CBX4, YAP/FOXD1, CLOCK, etc., for the first time, providing a new solution for the intervention of aging-related diseases , Has broad application prospects in geriatrics and regenerative medicine.

  It is worth mentioning that gene editing technology combined with stem cell therapy is an aging intervention that has attracted much attention in recent years. The modified stem cells used for gene therapy are derived from the patient's own body, which has the advantages of avoiding autoimmunity and high safety. Stem cells and gene therapy have made significant progress in the fields of aging intervention and regenerative medicine. For example, Liu Guanghui and others used the genetic properties of the antioxidant transcription factor NRF2 gene to use the third-generation adenovirus vector HDAdV-mediated gene editing technology to directionally transform human embryonic stem cells, and obtain enhanced mesenchymal stem cells through targeted differentiation. The modified enhanced stem cells showed better effectiveness and safety in transplantation treatment of hindlimb ischemia in mice. In addition, the team also created the world's first genetically enhanced human vascular cells by targeted editing of a single longevity gene FOXO3. These works provide the possibility to explore the use of genetically enhanced (stem) cell transplantation to achieve tissue and organ regeneration and repair and delay the body's aging, and provide an important theoretical basis for exploring gene therapy to intervene in aging-related diseases.

④ Active health

  Active health is the guide of "healthy aging", and scientific dieting and appropriate exercise are the "general trends" in actively responding to an aging society. Scientific dieting (calorie restriction) is an intervention by reducing the amount of normal diet or reducing calorie intake in food. This method has been proven to prolong life, prevent aging-related diseases, and thereby extend healthy life. The legendary "satisfaction with food and drink" does not actually achieve a high-quality state of life, and it is precisely the redundancy of a large amount of food that will increase the burden of the stomach, and the high blood pressure and diabetes caused by obesity make people miserable. Research for nearly a hundred years has found that scientific dieting has a certain anti-aging effect on yeast, fruit flies, nematodes and mammals. Scientific dieting can regulate the mitochondrial network, reconstruct peroxisomes and extend the life of nematodes. Diet-mediated epigenetic regulation affects aging and prevents aging-related changes in DNA methylation, histone modification and chromatin remodeling to a certain extent. Scientific dieting can promote the expression of the Sirtuins family of apparent regulatory factors or its enzyme activity to extend life. Recently, the Liu Guanghui team of the Chinese Academy of Sciences has drawn a high-throughput single cell and mononuclear transcriptome map of rats under dieting conditions in view of the heterogeneity and complexity of tissues and organs in the aging process, revealing that scientific dieting regulates multi-tissue immune inflammation. New molecular mechanism.

  Life is endless, movement is endless. Appropriate exercise is also one of the effective ways to improve the quality of life and delay aging. The decline in muscle mass and bone density brought about by aging will make the movement of the elderly less convenient than before, and different exercises or exercises will prevent this regression. The beneficial effects of exercise are not limited to muscles. Relevant studies have also found that people who ride on a regular basis not only have no loss of strength, but also have limited body fat or cholesterol levels. And exercise can benign to stimulate the brain hippocampus activity, resist depression, improve memory, inhibit brain atrophy, and bring hope for the prevention of neurodegenerative system diseases. Researchers agree that moderate exercise can increase blood circulation and the formation of new blood vessels, keeping away from venous thromboembolism. Appropriate exercise can also increase body fat burning to improve endurance in extreme environments, and protect human health through a series of signal transmission to promote healthy mitochondrial production, glycolipid energy metabolism and oxygen free radical scavenging. Peking University's Han Jingdong team found that diet or exercise intervention can also inhibit the expression of non-coding RNA and transposon through the chromatin remodeling protein Chd1, thereby prolonging life.

  The research on aging has now entered a golden age. The 150th Anniversary Special Issue of "Nature" has launched the research topic "Aging and Lifespan Intervention", and "Nature" and "Lancet" have also recently released new publications in the field of aging, "Nature". "Aging" and "The Lancet-Health and Longevity" aim to develop the research on key factors, molecular mechanisms and age-related diseases that affect aging into a new field, and promote the clinical development of aging intervention, which means that "healthy aging" has become Research focus in the field of life medicine. The target of drug therapy is clear, stem cell therapy promotes regeneration, gene therapy editing is possible, dieting exercise is safe and effective. However, taking into account the biological differences of species and the genetic heterogeneity of humans, the extensive establishment of clinical trials and systems for aging interventions is still facing huge challenges, and it is also crucial for the development of aging biological markers and the quantitative assessment of aging levels. In the future, we look forward to more disruptive and innovative interventions that can effectively delay aging and realize the vision of "healthy aging".

(Author: Wong Sze, Associate Professor Department of Institute of Zoology; Bi Shi-kai, Dr Department of Institute of Zoology; Ran Wang Qiao, Department of the Beijing Genomics Institute, Chinese Academy of Master)