Minamino, Tohru

Abstract Multiple changes occur in hormonal regulation with aging and across various endocrine organs. These changes are associated with multiple age-related disorders and diseases. A better understanding of responsible underling biological mechanisms could help in the management of multiple endocrine disorders over and above hormone replacement therapy (HRT). Cellular senescence is involved in multiple biological aging processes and pathologies common in elderly individuals. Cellular senescence, which occurs in many older individuals but also across the lifespan in association with tissue damage, acute and chronic diseases, certain drugs, and genetic syndromes, may contribute to such endocrine disorders as osteoporosis, metabolic syndrome, and type 2 diabetes mellitus. Drugs that selectively induce senescent cell removal, “senolytics,”, and drugs that attenuate the tissue-destructive secretory state of certain senescent cells, “senomorphics,” appear to delay the onset of or alleviate multiple diseases, including but not limited to endocrine disorders such as diabetes, complications of obesity, age-related osteoporosis, and cancers as well as atherosclerosis, chronic kidney disease, neurodegenerative disorders, and many others. More than 30 clinical trials of senolytic and senomorphic agents have already been completed, are underway, or are planned for a variety of indications. Targeting senescent cells is a novel strategy that is distinct from conventional therapies such as HRT, and thus might address unmet medical needs and can potentially amplify effects of established endocrine drug regimens, perhaps allowing for dose decreases and reducing side effects.

Introduction: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been developed as a new class of anti-diabetic drug, and shown cardio- and renal-protective effects in patients with diabetes, heart failure, and chronic kidney diseases. SGLT2 inhibitor also has effect to expand lifespan in aged mice, suggesting anti-aging effect. But the detailed machinery of these protective effects is still to be clarified. Here we demonstrate that canagliflozin has a effect to eliminate senescent cells from pathological tissues, so-called "senolysis" in murine aging or age-related disease models. Methods: Canagliflozin mixed in food at 0.03% (w/w) was administered for up to 4 weeks to high-fat-fed diabetic mice, for 2 weeks to ApoE-knockout atherosclerotic mice model, for 20 weeks for chronological aged mice, and for lifetime to Zmpste-knockout progeroid mice. Burden of senescent cell accumilation as well as pathological or aged phenotype were measured in each mice model. Results: Canagliflozin reduced senescent cells in visceral adipose tissue within 1 week. Also, we found that senolytic effect of canagliflozin was provided through enhancing endogenous senolytic function by immune cells such as CD8+T cells. This machinery was mediated by enhanced AMPK signaling through incrase of endogenous AICAR production, which leads to the downregulation of PD-L1 expression on senescent cells. Oppositely, inhibition of AMPK signaling with Compound C administration (10mg/kg ip daily) resulted in abolishing senolytic effect of canagliflozin. Furthermore, canagliflozin reduced their senescent cell burden and alleviated atherosclerosis in ApoE-knockout mice, extended lifespan in progeroid mice, and altered physical function in aged mice. Conclusions: Our results showed new aspect of protective efficacy of SGLT2 inhibitors and would be promising evidence that SGLT2 inhibitors can be used as not only cardio- or renal-protective drugs but also anti-aging drugs.

Senescent cell accumulation has been observed in age-associated diseases including cardiovascular diseases. Senescent cells lack proliferative capacity and secrete senescence-associated secretory phenotype (SASP) factors that may cause or worsen many cardiovascular diseases. Therapies targeting senescent cells, especially senolytic drugs that selectively induce senescent cell removal, have been shown to delay, prevent, alleviate, or treat multiple age-associated diseases in preclinical models. Some senolytic clinical trials have already been completed or are underway for a number of diseases and geriatric syndromes. Understanding how cellular senescence affects the various cell types in the cardiovascular system, such as endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells, progenitor cells, and cardiomyocytes, is important to facilitate translation of senotherapeutics into clinical interventions. This review highlights: (1) the characteristics of senescent cells and their involvement in cardiovascular diseases, focusing on the aforementioned cardiovascular cell types, (2) evidence about senolytic drugs and other senotherapeutics, and (3) the future path and clinical potential of senotherapeutics for cardiovascular diseases.