Fight Aging!

Almost a decade has passed since the first compelling demonstration that clearance of senescent cells in mice could produce rejuvenation. This validated decades of prior evidence, largely ignored in the research community, indicating that accumulation of senescent cells is a significant cause of degenerative aging. It was a wake-up call. Since then, numerous research groups have shown that targeted clearance of senescent cells reverses many age-related conditions and extends healthy life span in mice. It is easy to accomplish in the lab. Near any approach works, to the degree that it can destroy senescent cells without harming normal cells. As a consequence, a new biotech industry has come into being, a range of startups and programs working on clinical development of the first generation of senolytic drugs capable of safely removing senescent cells from aged tissues.

As a result of this field of research, it has been shown that accumulation of senescent cells is an important part of the development of cardiovascular disease. Senescent foam cells accelerate the progression of atherosclerosis, driving the growth of fatty lesions that narrow and weaken blood vessels, leading to stroke and heart attack. Senescent cells drive the calcification of blood vessels, and degrade the function of smooth muscle tissue in blood vessel walls. Senescent cells are a part of the dysfunction that leads to cardiac hypertrophy, the enlargement and weakening of heart muscle that causes heart failure, as well as fibrosis, a disruption of tissue structure by inappropriate collagen deposits. We now know all of this because it is possible to run animal studies in which senolytic treatments remove senescent cells, and then observe the result - a reversal of age-related cardiovascular disease.

Therapeutic Potential of Senolytics in Cardiovascular Disease

The most significant determining factor of cardiovascular health is a person's age, with cardiovascular disease (CVD) being the leading cause of death in 40% of individuals over 65 years. The ageing heart undergoes a process of myocardial remodelling, which is characterised by physiological and molecular alterations that result in endothelial stenosis, vasomotor dysfunction and stiffening, cardiomyocyte hypertrophy, myocardial fibrosis, and inflammation which result in increased ventricular stiffness, impaired cardiac function and can ultimately lead to HF. In particular, HF with preserved ejection fraction (HFpEF), characterised by diastolic ventricular dysfunction with maintained systolic function, is clinically associated with ageing.

The association between senescence and myocardial ageing in humans has been reported for nearly 20 years. More recently it has been demonstrated that senescence contributes directly to age-related myocardial remodelling in mice, as pharmacogenetic elimination of senescent cells, using the p16-INKATTAC model, reduced myocardial fibrosis, and attenuated cardiomyocyte hypertrophy. Elimination of senescent cells from aged p16-INKATTAC mice also increased their survival and reduced the development of cardiac dysfunction following isoproterenol-induced myocardial stress. Following on from this data, we and others have hypothesised that an accumulation of senescence and the expression of a senescence-associated secretory phenotype (SASP) drive age-related myocardial remodelling and have begun to independently investigate if senolytics can eliminate senescent cell populations resident in the aged heart in order to improve myocardial function.

Pharmacological elimination of senescent cells from aged mice could improve myocardial function. Treatment of 24-month-old mice with a single dose of dasatinib and quercetin significantly improved left ventricular (LV) ejection fraction and fractional shortening. This observed change in function was suggested to be a result of a restoration in vascular endothelial function. We have shown in aged mice that senescence occurred primarily within the cardiomyocyte population and led to the expression of a cardiomyocyte-specific SASP with the potential to promote myofibroblast differentiation of fibroblasts and induce cardiomyocytes to hypertrophy in vitro. In vivo, cyclical oral administration of navitoclax reduced the number of senescent cardiomyocytes, attenuated components of the cardiomyocyte SASP and reduced myocardial remodelling as indicated by a reduction in both cardiomyocyte hypertrophy and interstitial fibrosis.

Given the limited regenerative capacity of the heart, there is considerable interest in the potential of regenerative cellular therapies for the treatment of CVD such as myocardial infarction (MI) and age-related HF. For cellular therapies to be effective, the grafted cells must survive, integrate, and function within the surviving myocardium. The data discussed above suggest that older age not only increases the potential for dysfunction in the very populations that are being used for cellular therapies but also increases the hostility of the recipient myocardial environment as a result of SASP mediated inflammation and the bystander effect. This may in part explain the failure of pre-clinical trials to translate clinically into regenerative therapies. Preclinical studies showing successful cell regenerative therapies use young healthy animals, whereas the prevalence of CVD increases linearly with age, and therefore, most patients undergoing cellular therapy are likely to display high levels of myocardial senescence which could create an unfavourable environment impeding incorporation and differentiation of the transplanted cell populations. Senolytic-mediated elimination of senescent cells from aged patients may, therefore, have the potential to improve the outcomes of such regenerative cellular therapies.