Cellular senescence and senolytics: the path to the clinic

Abstract

he aging population is steadily increasing. The World Health Organization (WHO) estimates that 1 in 6 people, or 2.1 billion, are expected to be over age 60 by 2030 (ref. 1 ). Chronological age is the major predictor for most of the diseases that account for the bulk of morbidity, mortality and health costs across low-, middle-and high-income countries [2][3][4][5][6][7] .Aging progresses throughout the lifespan can be accentuated at etiologic sites of multiple acute and chronic diseases, including in children 6,[8][9][10][11][12] . Indeed, fundamental aging processes can operate even before conception, for example, in the context of aged oocytes linked to Down syndrome 12,13 . A fundamental aging mechanism that has gained increasing attention is cellular senescence. Senescent cells accumulate during aging and at pathogenic sites of multiple disorders and diseases. After the first reports of senolytic drugs (agents that selectively eliminate senescent cells) in 2015 (ref. 14 ), promising results from preclinical studies have facilitated progression to early-phase clinical trials evaluating the safety and efficacy of senolytics, some of which have now been published (Table 1).Fundamental aging mechanisms can be grouped into so-called hallmarks or 'pillars' of aging; these include genomic instability, progenitor cell exhaustion/dysfunction, telomeric and epigenetic changes, dysregulated protein homeostasis, altered nutrient sensing, mitochondrial dysfunction, altered intercellular communication, chronic low-grade inflammation, fibrosis, microbiome dysregulation and cellular senescence 3,15 . The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases, age-related dysfunction (including the geriatric syndromes such as frailty, immobility, sarcopenia/ muscle wasting, mild cognitive impairment and incontinence) and loss of resilience (for example, decreased ability to recover from stresses such as injury, surgery, chemotherapy or infections or to mount an antibody response to immunizations) 3,[15][16][17][18] . The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others 6 . For example, interventions that target cellular senescence tend to attenuate other

Therapy-induced senescence upregulates antigen presentation machinery and triggers anti-tumor immunity in Acute Myeloid Leukemia

“…While our data show that senescence induction shortly after chemotherapy renders AML cells highly immunogenic, there is also evidence that senescence may be detrimental in the long-term promoting leukemia stemness and chemoresistance 8 . Attempts to mitigate the long-term detrimental aspects of senescence in cancer have been the focus of intense scientific investigation 39 . Although their effects may be transient, selective SASP inhibitors may reduce senescence-related chronic inflammation that contributes to tumor growth and immune evasion.…”

Targeting cellular senescence in metabolic disease

“…Standard biomarkers for aging have not been established, although expert panels have convened to tackle a framework for clinical trials going forward [ 80 , 81 ]. In particular, detection of senescent cells is challenging due to lack of universal markers of cellular senescence, owing to lack of adequate sensitivity and specificity of individual markers, such as p16 INK4a expression or senescence-associated beta galactosidase (SA-βgal) activity.…”

“…Cellular senescence is an essentially irreversible cell fate that occurs in response to various cellular stressors and involves cell cycle arrest, chromatin rearrangement, morphologic changes, metabolic shift toward glycolysis, and release of factors comprising the senescence-associated secretory phenotype (SASP), which can include pro-inflammatory and matrix remodeling proteins [ 1 , 2 ]. Cellular senescence is a fundamental mechanism of aging [ 3 ].…”

Cellular senescence and lung cancer prognosis

“…Therefore, the timely elimination of senescent cancer cells by using senolytic drugs (drugs targeting senescent cells specifically) or “senomorphics” (drugs targeting the SASP secretome) could potentially benefit cancer control ( Figure 1 ). Senolytic compounds that target either several or single SCAP pathways are in different phases of clinical trials ( 24 ). Of significant importance, none of the current trials are directed as cancer therapeutic trials.…”