Senolytics: Targeting Senescent Cells for Age-Associated Diseases
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MOLECULAR BIOLOGY OF CELL DEATH AND AGING (N RAZDAN AND N MUHAMMAD, SECTION EDITORS)
Senolytics: Targeting Senescent Cells for Age-Associated Diseases Iman M. A. Al-Naggar 1
&
George A. Kuchel 1 & Ming Xu 1,2
Accepted: 16 October 2020 # Springer Nature Switzerland AG 2020
Abstract Purpose of Review Evidence suggests that senescent cells drive aging and age-related diseases, with interventions that clear them improving various conditions in preclinical models. Efforts to discover senolytics, drugs that can specifically kill senescent cells, are ongoing, guided by studies into their biology and several in vivo models. This review describes recently discovered senolytics and the pathways they target. Recent Findings Drugs targeting the BCL-2 family proteins, p53 activators, HSP90 inhibitors, cardiac glycosides, and fibrates along with several flavonoids are senolytic in vitro and in vivo. Methods for specifically delivering death to senescent cells to decrease non-specific off-target effects take advantage of their characteristic elevated level of p16 and increased β-galactosidase activity. Summary Effects of senolytics on age-related diseases in pre-clinical models have been so striking that several proof-of-concept and safety phase I human trials have begun. The search continues for additional senolytics that can target more types of senescent cells with the least side effects. Keywords Aging . Senolytics . Cellular senescence . Healthspan . Lifespan
Introduction Growing evidence indicates that most, if not all, chronic diseases and geriatric syndromes share common pathways with aging and that these mechanisms may be modified. This Geroscience Hypothesis arose from the observation that aging is the greatest risk factor for most chronic diseases, such as cardiovascular disease, type II diabetes, cancer, and many degenerative and neurodegenerative disorders [1]. The main advantage of looking at aging through the lens of the Geroscience Hypothesis is that, if true, then by targeting these shared aging mechanisms, it may be possible to prevent, delay
This article is part of the Topical Collection on Molecular Biology of Cell Death and Aging * Iman M. A. Al-Naggar [email protected] 1
UConn Center on Aging, UConn Health, 263 Farmington Avenue, EM013, Farmington, CT 06030-1835, USA
2
Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA
and perhaps even reverse multiple aging-related conditions and phenotypes simultaneously [2–4]. Such interventions would increase the human healthspan (quality, healthy, independent, productive years of life), while decreasing the burden of long disease-ridden years later in life on both caretakers and economy [5, 6]. Several molecular pathways contributing to aging have been identified collectively called “the Hallmarks of Aging” [7]. More recently, these have been grouped into 4 main categories, or fundamental aging mechanisms: (1) chronic, low-grade sterile inflammation and fibrosis; (2) macromolecular/organelle dysfunction; (3) stem and progenitor cell
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