Senolytic

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A senolytic (from the words senescence and -lytic, "destroying") is among a class of small molecules under basic research to determine if they can selectively induce death of senescent cells and improve health in humans. [1] A goal of this research is to discover or develop agents to delay, prevent, alleviate, or reverse age-related diseases. [2] [3] Removal of senescent cells with senolytics has been proposed as a method of enhancing immunity during aging. [4]

Contents

A related concept is "senostatic", which means to suppress senescence. [5]

Research

Possible senolytic agents are under preliminary research, including some which are in early-stage human trials. [6] [7] [ clarification needed ] The majority of candidate senolytic compounds are repurposed anti-cancer molecules, such as the chemotherapeutic drug dasatinib and the experimental small molecule navitoclax. [8] [9]

Soluble urokinase plasminogen activator surface receptor have been found to be highly expressed on senescent cells, leading researchers to use chimeric antigen receptor T cells to eliminate senescent cells in mice. [10] [11]

According to reviews, it is thought that senolytics can be administered intermittently while being as effective as continuous administration. This could be an advantage of senolytic drugs and decrease adverse effects, for instance circumventing potential off-target effects. [6] [12] [13] [14]

Recently, artificial intelligence has been used to discover new senolytics, resulting in the identification of structurally distinct senolytic compounds with more favorable medicinal chemistry properties than previous senolytic candidates. [15] [16]

Senolytic candidates

Hypothetical candidates for senolytics based on early-stage research
Medication/targetDescriptionTests as senolytic have been conducted in ...
human cell lines in vitro mice models xenograft model phase I trial phase II trialphase III trial
FOXO4-related peptides [13] [17] [12] [6] FOXO4 binding to p53 protein retains it in the nucleus, which prevents it from interacting with mitochondria in the cytosol where it would activate caspases, leading to apoptosis (programmed cell death). [18] Instead, retention of p53 in the nucleus by FOXO4 promotes cellular senescence. [18] A peptide that binds with FOXO4 disrupts the p53-FOXO4 interaction, releasing p53 into the cytosol and triggering cell death. [18] Yes [18] Yes [18]
BCL-2 inhibitorsInhibitors of different members of the bcl-2 family of anti-apoptotic proteins. [13] [19] [20] Studies of cell cultures of senescent human umbilical vein endothelial cells have shown that both fisetin and quercetin induce apoptosis by inhibition of the anti-apoptotic protein Bcl-xL (a bcl-2 family member). [6] Yes [6]
Src inhibitors Src tyrosine kinase inhibitors: dasatinib [21] – see "Combination of dasatinib and quercetin" below
USP7 inhibitorsInhibitors of USP7 (ubiquitin-specific processing protease 7) [17] Yes [22] Yes [22]
Dasatinib and Quercetin (D+Q)Combination of dasatinib and quercetin [20] [19] [14] [13] YesYesYes [23] [24]
Fisetin [13] [19] [12] [6] Yes [25] Yes [25]
Navitoclax [13] [6] xenograftYes [26]
SSK1Senescence-specific killing compound 1: A gemcitabine (a cytotoxic chemotherapeutic) prodrug that is activated by lysosomal β-galactosidase (a common senescence marker) [27] Yes [27]
BIRC5 knockoutCrispr/Cas9 BIRC5 Gene Knockout. Crispr/Cas9 is used to trigger apoptosis in relation to a specified gene sequence such as a cancer gene sequence or damage marker sequences. [28] Yes [28]
GLS1 inhibitorsTarget the enzyme kidney-type glutaminase 1 (GLS1). Senescent cells have a low pH due to their high lysosomal content and leaking lysosomal membranes. This low pH forms the basis of senescence-associated beta-galactosidase (SA-β-gal) staining of senescent cells. To help neutralize their low pH, senescent cells produce high levels of GLS1; inhibiting the activity of this enzyme exposes senescent cells to unsurvivably severe internal acidity, leading to cell death. [29] Yes [29]
Anti-GPNMB vaccineGlycoprotein nonmetastatic melanoma protein B (GPNMB). A protein that enrich senescent cells studied as molecular target for a senolytic vaccine in mice. [30] Yes [30]
Cardiac glycosides [13] [12] Yes [31] [32] [33] xenograftYes [32]
25-hydroxycholesterol (25HC) [34] 25-hydroxycholesterol targets CRYAB in multiple human and mouse cell typesYes [34] Yes [34]
Procyanidin C1 Yes [35] Yes [35]
EF-24 [19] [12] Yes
HSP90 inhibitors [36]
CUDC-907 [37]

Senomorphics

Senolytics eliminate senescent cells whereas senomorphics – with candidates such as Apigenin, Rapamycin and rapalog Everolimus – modulate properties of senescent cells without eliminating them, suppressing phenotypes of senescence, including the SASP. [13] [12]

See also

Related Research Articles

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Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled limit of 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

<span class="mw-page-title-main">Urokinase receptor</span> Mammalian protein found in Homo sapiens

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p16 Mammalian protein found in Homo sapiens

p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.

<span class="mw-page-title-main">Bcl-xL</span> Transmembrane molecule in the mitochondria

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Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

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<span class="mw-page-title-main">ID1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Cellular senescence</span> Phenomenon characterized by the cessation of cell division

Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things.

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<span class="mw-page-title-main">Human umbilical vein endothelial cell</span>

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<span class="mw-page-title-main">Navitoclax</span> Chemical compound

Navitoclax is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax.

Senotherapy is an early-stage basic research field for development of possible therapeutic agents and strategies to specifically target cellular senescence, an altered cell state associated with ageing and age-related diseases. The name derives from intent of the proposed anti-aging drug to halt "senescence". As of 2019, much of the research remains preliminary and there are no drugs approved for this purpose.

<span class="mw-page-title-main">ABT-737</span> Chemical compound

ABT-737 is a small molecule drug that inhibits Bcl-2 and Bcl-xL, two members of the Bcl-2 family of evolutionarily-conserved proteins that share Bcl-2 Homology (BH) domains. First developed as a potential cancer chemotherapy, it was subsequently identified as a senolytic.

Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases. SASP may also consist of exosomes and ectosomes containing enzymes, microRNA, DNA fragments, chemokines, and other bioactive factors. Soluble urokinase plasminogen activator surface receptor is part of SASP, and has been used to identify senescent cells for senolytic therapy. Initially, SASP is immunosuppressive and profibrotic, but progresses to become proinflammatory and fibrolytic. SASP is the primary cause of the detrimental effects of senescent cells.

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The hallmarks of aging are the types of biochemical changes that occur in all organisms that experience biological aging and lead to a progressive loss of physiological integrity, impaired function and, eventually, death. They were first listed in a landmark paper in 2013 to conceptualize the essence of biological aging and its underlying mechanisms.

This timeline lists notable events in the history of research into senescence or biological aging, including the research and development of life extension methods, brain aging delay methods and rejuvenation.

Laura J. Niedernhofer is an American professor of biochemistry, molecular biology, and biophysics, with expertise in the fields of DNA damage, repair, progeroid syndromes and cellular senescence

References

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