【Doctor commentary】History of Anti-Aging Treatments

Therapies targeting senescent cells have been gaining attention for decades. Since Hayflick reported human cell senescence, several mechanisms of cellular senescence have been elucidated. For example, the activation of the p53/p21 and p16/Rb signaling pathways and the role of p53 have been clarified. These signals are involved in aging, and the activation of these pathways halts cell division. Therefore, it was thought that by inhibiting these signals, cells could continue to divide without aging, enabling tissue repair.

Role of p53
It has been found that inhibiting p53 can suppress diabetes and cardiovascular diseases. However, on the other hand, proliferating cells that have accumulated damage due to halted cell cycles can lead to increased cancer, making p53-deficient mice short-lived due to malignant tumors. This demonstrates that aging and cancer are two sides of the same coin.

Regulation of SASP Factors
Next, attention turned to senescence-associated secretory phenotype (SASP) factors. Senescent cells not only complete their roles but also produce inflammatory cytokines and chemokines called SASP factors, affecting surrounding healthy cells. This can lead to dysfunction of nearby cells. Thus, it has been suggested that inhibiting SASP factors could extend healthy lifespan. Drugs that inhibit SASP factors secreted by senescent cells are called senomorphics, and it has been found that metformin, an anti-diabetic drug, and rapamycin, an immunosuppressant, exhibit this effect. However, since accumulated senescent cells remain, long-term medication is necessary, posing challenges.

Removal of Senescent Cells
Next, a new approach called senolysis, or the removal of senescent cells, has gained attention. Mice engineered to specifically induce apoptosis in senescent cells using p16 as a marker have been created. Removing senescent cells has been found to suppress muscle and fat tissue atrophy, cataracts, and cancer. Removing senescent cells has been shown to significantly improve tissue repair, drawing attention.

Drugs for Removing Senescent Cells
Drugs for removing senescent cells (senolytics) are being explored worldwide, with several dozen senolytics identified so far. Dasatinib, which inhibits tyrosine kinase, and quercetin, which inhibits PI3K, have been found to induce apoptosis in senescent human preadipocytes and senescent human endothelial cells, respectively. The combination therapy of these two drugs has been found to remove senescent cells and suppress declines in motor and cardiac functions. Senolytics have been reported to improve not only geriatric syndromes but also atherosclerosis, pulmonary fibrosis, diabetes, heart failure, liver fibrosis, arthritis, osteoporosis, and dementia.

In the latest research on anti-aging treatments, drugs such as GLS1 inhibitors and SGLT2 inhibitors are promising as senolytics. These drugs have been shown to remove senescent cells and contribute to the extension of healthy lifespan. Furthermore, immunotherapies such as CAR-T cell therapy have also been reported as senolytics, targeting specific antigens of senescent cells to enhance the treatment effects of aging-related diseases. New approaches such as identifying senolytics using machine learning are also gaining attention, and the field of anti-aging treatments is continually advancing.

Dr. Munenori Matsuzawa, Chief Medical Officer, Aoyama Medical Clinic.

References：
・Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established va- somotor dysfunction in aged or atherosclerotic mice. Aging Cel. 2016: 15: 9737.
・Xu M, Bradley EW, Weivoda MM, et al. Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. J
Gerontol ABiol Sci Med Sci. 2017 : 72 : 780-5.
・Wissler Gerdes EO, Misra A, Netto JME, et al.
Strategies for late phase preclinical and early clinical trials of senolytics. Mech Ageing Dev. 2021: 200: 111591.
・Anti-Aging medicine 2024vol20