A Discussion of Present Drug Development to Target Senescent Cells
The paper noted here is titled "New Trends in Aging Drug Discovery", but the authors really only discuss the development of senolytics and other classes of treatment that target the burden of senescent cells in aged tissues. Senescent cells are created throughout life, but in youth are cleared quickly by the immune system; with age, the balance between creation and destruction shifts, and the numbers of such cells increase. Lingering senescent cells produce disruptive signaling that changes the behavior of normal cells for the worse and provokes the immune system into chronic inflammation, contributing to age-related disease and mortality.
Research over the past decade has demonstrated that selective elimination of senescent cells (SnCs) extends health and lifespan in animal models and can significantly ameliorate aging-associated diseases; therefore, numerous efforts are invested in the development of senolytics that target molecular pathways underlying senescence to selectively kill SnCs. In this sense, resistance to apoptosis is a key characteristic feature of SnCs and inhibition of pro-survival and anti-apoptotic regulators is the most common strategy for the development of means to remove senescent cells.
The removal or modulation of SnCs by senotherapeutic drugs has become an attractive approach to prevent, delay, and even revert many of the chronic age-associated disorders and to extend healthspan. Senotherapeutic compounds can be divided into senolytics, which selectively promote the death of SnCs or induce senolysis, and senomorphics that suppress markers of senescence, in particular the senescence-associated secretory phenotype (SASP), to cause senostasis and prevent the detrimental cell-extrinsic effects of SnCs. Here we detail the most profoundly characterized small molecules and their mechanism of action in the context of the diseases in which they have been studied.
Aging is commonly regarded as an inevitable part of the life cycle; however, current research suggests that it may not be the inexorable process we consider it at the present moment. Actually, obtained results with different models indicate that (i) cells become senescent as time passes; (ii) SnCs have altered functions, which eventually lead to aging-related diseases; (iii) aged cells are different from young cells and these differences can be exploited for specific targeting; (iv) senescent cell removal or rejuvenation strategies involve improvements in aging-related pathological states; (v) there exist compounds (that may become drugs in the near future) that, by correcting and modulating cellular senescence can slow down, halt or even reverse aging-related diseases. Globally, these results suggest that aging is a druggable process that can be targeted with the appropriate drugs, similar to other chronic disorders.