If you want to live longer and slow down aging, remember not to peel off the skins of citrus fruits when you eat them. According to an animal experiment led by National Yang Ming Chiao Tung University (hereinafter referred to as NYCU), hesperetin turned out to be effective in terms of anti-aging. The team fed hesperetin to old mice, and it eventually promoted the performance of the CISD2 longevity gene in the old mice’s bodies; hesperetin restored the functions of aged heart and muscles, elevated the metabolism of the whole body, and even regained the pattern of gene transcription associated with younger ages. The results of the study have been published in the leading biomedical journal (Journal of Biomedical Science).
In 2009, Ting-Fen Tsai, the distinguished professor in the Department of Life Sciences and Institute of Genomic Sciences at NYCU, was originally looking for a gene that causes liver cancer when she accidentally discovered that the CISD2 gene regulates the longevity in mammals. This discovery cracked the genetic code of aging and heredity, further disclosing the target for clinical drugs that aim to slow down aging.
A team of researchers from NYCU, Chang Gung Memorial Hospital in Linkou, National Health Research Institutes, National Research Institute of Chinese Medicine from Ministry of Health and Welfare recently searched for a promoter of longevity genes by extracting compounds from the finest medicinal plants recorded in the classical Chinese medical manuscript The Divine Husbandman’s Herbal Foundation Canon. The team fed the mice hesperetin at the age of 21.5 months old (equivalent to the age of 70 in humans), and their CISD2 performance were increased by about 3 times at the age of 26.5 months old (equivalent to the age of 80 in humans), confirming that hesperetin is the promoter for the CISD2 longevity gene.
The CISD2 longevity gene exists in vertebrates such as fish and mammals (including humans), and the expression of CISD2 gene in mammals may decrease as they age. The CISD2 protein is able to maintain calcium balance in the cells while enhancing the function of mitochondria as an energy plant, thus it may help regulate the lifespan and maintain the body in a healthy state. In 2012, the research team found that mice with increased expression of the CISD2 longevity gene in old age through gene transfer had an average life expectancy of 20% longer than regular wild mice and could live up to 39 months (which is equivalent to about 120 years old in humans). The discovery brings hope to the scientists, who have long been searching for medication that can slow down aging or even create rejuvenation.
According to Ting-Fen Tsai, the leader of the project, hesperetin discovered by the team can help improve a variety of structural and functional impairments caused by aging, including decreased metabolism, changes in body composition due to the increase of fat and loss of muscles, low glucose tolerance and aging in multiple organs. Furthermore, hesperetin also enables cells to regain their youthful transcripts (sum of transcribed RNA expression) after aging, showing the potential of oral hesperidin as a CISD2 booster.
Professor Chi-Hsiao Yeh, Associate Director of the Department of Surgery at Chang Gung Memorial Hospital, Linkou, who participated in the study, implied that there are nine agreed-upon markers of cellular aging: DNA damage, loss of chromosomal telomere, epigenetic changes, loss of proteostasis, nutrient-sensitive dysregulation, mitochondria dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These aging markers are all related to each other, which means improvement in any one of them may affect the others. For example, hesperetin may not only enhance mitochondria function but also reduce cellular senescence, leading to breakthroughs in the field of longevity research. The animal studies of the team also show that these long-lived mice not only live longer but also maintain better function of their vital organs, expanding the translational study of healthy aging.
The precursor of hesperetin is hesperidin, which is mainly found in the peel of citrus fruits, such as tangerines, oranges, lemons or oval kumquats. After hesperidin is consumed into human bodies, it is mainly transformed into hesperetin by bacteria in the small intestine and then sent to the whole body through blood circulation. However, the amount of hesperetin that can be produced and absorbed by the body is very limited when taken through natural fruit peels. Therefore, hesperidin is developed as nutrient supplements, making it a direct hesperidin intake that can quickly enhance the performance of the CISD2 longevity gene and achieve the effect of promoting healthy longevity.
Prof. Ting-Fen Tsai added that the study of the CISD2 longevity gene will contribute to a deeper understanding of the aging process and provide new solutions for the prevention of aging and healthy longevity. The development of CISD2 promoters, including healthy food and small molecule drugs, will contribute to the future development of anti-aging therapies and treatments of aging-related diseases.
This study has been published in the Journal of Biomedical Science and has also been transferred to Orient EuroPharma, a major domestic biotech company.