A senolytic (from the words "senescence" and "lytic" - destroying) is among the class of senotherapeutics, and refers to small molecules that can selectively induce death of senescent cells.
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Senescence is a potent tumor suppressive mechanism. It however drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Senescent cells accumulate in aging bodies and accelerate the aging process. Eliminating senescent cells increases the amount of time that mice are free of disease.
The goal of those working to develop senolytic agents is to delay, prevent, alleviate, or reverse age-related diseases. Targeting premalignant senescent cells could also be a preventive and therapeutic strategy against late-life cancer given the deteriorated efficacy of the senescence response in stopping cancer.
Agents
Multiple senolytic agents are under investigation.
Certain anti-cancer agents may in low doses decelerate aging and age-related diseases. Targeting cancer prevention pathways with anti-cancer agents may confer longevity effects by offering protection from metabolic pathologies during aging, independently of effects on cancer.
Quercetin is a natural compound that acts as an antihistamine, anti-inflammatory and anti-cancer drug. Quercetin eliminates senescent human endothelial cells and mouse bone marrow mesenchymal stem cells.
Dasatinib is a cancer drug. It eliminated senescent human fat cell progenitors.
Navitoclax, also known as ABT-263, was originally studied as an anti-cancer drug. It is an inhibitor of the anti-apoptotic proteins BCL-2, BCL-w, and BCL-xL. Navitoclax is senolytic against some cell types (e.g., human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts and murine embryonic fibroblasts (MEFs), but not all (e.g., human primary preadipocytes). Oral administration of ABT263 to either sublethally irradiated or normally aged mice reduced senescent cells, including bone marrow hematopoietic stem cells and muscle stem cells. This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated aged hematopoietic stem cells and muscle stem cells in normally aged mice. It has toxic side effects including thrombocytopenia and lymphopenia.
Studies in animals and cells
The senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging. As such, chronic accumulation of senescent cells can lead to cancer in addition to aging.
Senescent cells are similar to cancer cells in that they have increased expression of so-called pro-survival networks that help them resist apoptosis (programmed cell death).
The elimination of p16-expressing senescent cells can impair wound healing. This is due to a positive role of senescent cells during tissue repair. The presence of senescent cells also restrains fibrosis. Their absence significantly retards the kinetics of wound closure.
Senolytics induce apoptosis preferentially in senescent cells. Although apoptosis is a mechanism of anti-cancer defense, it can also drive tumor formation. It can promote proliferation critically needed to compensate for cell loss and to restore tissue homeostasis. Apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage. Tumorigenesis is initiated by repeated cell attrition and repopulation, as demonstrated in therapy-induced secondary malignancies and myelodysplastic syndromes.
The combination of dasatinib and quercetin, the first senolytic drugs discovered, reduced senescent cell burden in multiple tissues of old mice and in the legs of young mice after senescence had been induced by radiation. The senolytic drugs improved cardiovascular function in old mice as well as mice with atherosclerosis, restored leg function in the younger mice that had received leg irradiation sufficient to impair walking, and enhanced healthspan in mice with an "accelerated aging" condition. In these mice, the combination of dasatinib and quercetin delayed neurological dysfunction, bone loss, and dysfunction of intervertebral discs of the backbone.
An engineered suicide gene was used in transgenic mice to delete senescent cells. This approach demonstrates that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan. It provided the first direct evidence that senescent cells can, at least in a premature aging mouse model, drive degenerative age-related pathology, and that clearance of such cells can delay or arrest senescence.
AP20187 was used to activate an engineered suicide gene under the promoter for p16 in transgenic mice. Cells expressing p16 are predominantly senescent, and administration of AP20187 led to selective apoptosis of these cells. AP20187 was used to restore fat tissue and stem cell function in older naturally-aged mice. AP20187 was used similarly in a later study to extend the median lifespan of mice. In these mice, the clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects. Furthermore, late-life clearance of these cells attenuated progression of cancers and of established age-related disorders.