Mitochondrially Targeted Tamoxifen as a Senolytic Drug

Researchers here note that mitochondrially targeted tamoxifen, developed as a cancer therapeutic, is sufficiently senolytic to treat conditions in which senescent cells play a significant role. They have chosen to target type 2 diabetes, a case of following the money given the present epidemic of obesity. It is actually quite surprising that few of the groups developing novel senolytic drugs have set their sights on diabetes, given the solid evidence of the past few years for the pathology of both type 1 diabetes and type 2 diabetes to be mediated in large part by cellular senescence.

Senescent cells play an important role in the induction of type 2 diabetes mellitus (T2DM) pathogenesis. Considering that metabolic and signaling changes associated with T2DM can promote senescence, senescent cells are components of the "pathogenic loop" in diabetes. In obese and diabetic mice, visceral adipose tissue (VAT) is the most prominent compartment of senescent cells accumulation. VAT, therefore, presents the nexus of mechanisms involved in longevity and age-related metabolic dysfunctions. A close relationship between visceral fat content and the risk of T2DM and cardiovascular complications has also been demonstrated in humans. Components of the senescence-associated secretory phenotype (SASP) secreted by adipose-derived senescent cells confer insulin resistance to metabolic tissues and attract immune cells that can exacerbate the effects of insulin resistance. Moreover, there is a close relationship between senescence and fat accumulation in hepatocytes followed by the development of steatosis in diabetic mice.

Senolytic agents may improve glucose control and obesity- and diabetes-related pathologies, supporting the idea that targeting senescent cells may be a promising strategy for T2DM management. Mitochondrial function is an important determinant of the aging process, and we have recently reported that targeting mitochondria in senescent cells presents a plausible way to eliminate such cells in the context of pathological senescence as well as senescence-associated diseases. Using mitochondrially targeted tamoxifen (MitoTam), our proprietary agent with anticancer activity, we have achieved specific elimination of senescent cells.

Treatment with MitoTam effectively reduces oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential in senescent cells, and severely affects mitochondrial morphology based on a low level of the ADP/ATP translocation channel ANT2 (adenine nucleotide translocase 2). These cells cannot, therefore, pump ATP inside mitochondria in order to maintain mitochondrial potential by cleavage of ATP by ATPase, resulting in the collapse of mitochondrial integrity and function18. Based on these results, we reasoned that MitoTam may present a non-cannonical therapeutic modality to treat senescence-associated pathologies, such as T2DM.

Here we show that MitoTam considerably improves glucose control, decreases body weight, and reduces diabetic markers as well as diabetic comorbidities in mice with diet-induced obesity and prediabetes. These improvements are associated not only with a reduction of food intake and a drop in the number of senescent cells in the organism but also with rejuvenation of the adipose tissue, suggesting the role of MitoTam in T2DM treatment and prevention of chronic diabetic complications.


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