Treating Senescence like Cancer: Novel Perspectives in Senotherapy of Chronic Diseases

Abstract

The WHO estimated around 41 million deaths worldwide each year for age-related non-communicable chronic diseases. Hence, developing strategies to control the accumulation of cell senescence in living organisms and the overall aging process is an urgently needed problem of social relevance. During aging, many biological processes are altered, which globally induce the dysfunction of the whole organism. Cell senescence is one of the causes of this modification. Nowadays, several drugs approved for anticancer therapy have been repurposed to treat senescence, and others are under scrutiny in vitro and in vivo to establish their senomorphic or senolytic properties. In some cases, this research led to a significant increase in cell survival or to a prolonged lifespan in animal models, at least. Senomorphics can act to interfere with a specific pathway in order to restore the appropriate cellular function, preserve viability, and to prolong the lifespan. On the other hand, senolytics induce apoptosis in senescent cells allowing the remaining non–senescent population to preserve or restore tissue function. A large number of research articles and reviews recently addressed this topic. Herein, we would like to focus attention on those chemical agents with senomorphic or senolytic properties that perspectively, according to literature, suggest a potential application as senotherapeutics for chronic diseases.

Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance

“…Increased ROCK2 expression may contribute to acquired olaparib resistance due to its impact on senescence. Targeting the protein with a ROCK inhibitor (ROCKi) as a senomorphic drug may limit the induction of the senescence phenotype [ 50 ]. Interestingly, the chemical structure of the ROCKi hydroxyfasudil contains the benzamide pharmacophore of PARPi and inhibits the activity of PARP1 and PARP2 by 27% and 50%, respectively [ 51 ].…”

New Trends in Aging Drug Discovery

“…Furthermore, prolonged oral administration of D + Q resulted in a reduction in plaque calcification in naturally aging mice and mice with chronic hypercholesterolemia as a model of atherosclerosis [ 105 ]. These studies suggest that senescence inhibition could improve cardiac function and support the emerging role of senolytics as a promising therapeutic option for atherosclerosis and cardiovascular disease management [ 49 , 53 , 54 , 106 , 107 , 108 ]; however, clinical trials of senolytic therapies in cardiovascular disease are scarce, mainly due to the limited tolerability of toxicity and side effects that limits current senolytic agents.…”

“…SnCs accumulate with age in different tissues [ 50 ], producing the characteristic SASP [ 31 ] that contributes to tissue deterioration and ultimately to a variety of diseases and disorders [ 51 ]. Beyond cancer, which is considered the aging disease par excellence, herein we discuss the numerous age-related diseases that have been associated with cellular senescence [ 49 , 52 , 53 , 54 , 55 , 56 ]. Preclinical and clinical studies performed with currently available senotherapeutic drugs are summarized below and in Table 1 , whereas the full description of compounds and their mechanisms of action are covered in the following section.…”

“…Cellular senescence has been hypothesized to play a pathogenic role in two chronic lung pathologies endowed with very limited therapeutic options: idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) [ 52 , 53 , 78 , 79 , 80 , 81 ]. Though their full etiology is unknown, some risk factors, such as smoking and aging [ 82 , 83 ], are well established and are suspected to be linked to cellular senescence [ 84 ].…”

Precise Diabetic Wound Therapy: PLS Nanospheres Eliminate Senescent Cells via DPP4 Targeting and PARP1 Activation

“…[ 28 ] Hence, strategies interfering with the antiapoptotic pathway might enable the selective clearance of senescent cells. [ 29 , 30 , 31 ] Highly selective targeted drug delivery systems might target the impaired tissue, achieve better therapeutic efficiency and reduce side effects. [ 32 , 33 ] Consequently, the design of a selective targeted drug delivery system loaded with an effective therapeutic factor for chronic wound healing is still a challenge for researchers.…”