Exploiting Senescence Associated β-Galactosidase to Selectively Destroy Senescent Cells

The accumulation of senescent cells with age is an important contributing cause of aging. Senescent cells are created constantly in the body, as somatic cells reach the Hayflick limit, or as a result of injury or toxins or potentially cancerous molecular damage. Near all either quickly self-destruct or are destroyed by the immune system, but a small fraction linger to cause harm over the long term. Senescent cells secrete a potent inflammatory mix of molecules that rouses the immune system to chronic inflammation, degrades nearby tissue structure, and changes the behavior of normal cells for the worse. The more senescent cells present in tissue, the worse the outcome.

Means to selectively remove 25% to 50% of senescent cells, and in only some tissues, reliably reverse aspects of aging and age-related disease in mice. Since the first compelling demonstration in 2011, many studies have been carried out using what have come to be called senolytic drugs. Researchers have demonstrated the ability to turn back Alzheimer's pathology, inflammatory conditions, fibrosis in hearts, lungs, and kidneys, the aging of skin, and many more pathologies characteristic of old age. A great deal of effort is now devoted towards finding new and better approaches to targeting senescent cells for destruction, to build upon the initial therapies.

The work here is an interesting example of the type. As the paper notes, to target senescent cells, one must find a way to interact with one or more mechanisms that are unique to senescent cells. The researchers choose the presence of senescence-associated β-galactosidase, which is still one of the most widely used markers of the senescent state. β-galactosidase is a part of the collection of enzymes that cells use when stressed in order to break down unwanted molecular waste, and senescent cells produce a lot of it. Thus giving cells carefully designed molecules that will be transformed into toxic compounds via the action of β-galactosidase is a potential approach to produce quite general senolytics, capable of destroying all varieties of senescent cells in all tissues.

Galactose-modified duocarmycin prodrugs as senolytics

Recent evidence drawn from genetic models has shown that eliminating senescent cells increases lifespan, improves healthspan, and benefits the outcomes of a wide range of diseases. These studies have led to a collective effort to identify 'senolytics', drugs that selectively kill senescent cells. Several senolytics have been identified including dasatinib and quercetin, piperlongumine, FOXO4 interfering peptides, HSP90 inhibitors, or the Bcl2 family inhibitors ABT-263 (navitoclax) and ABT-737. Currently, Bcl2 family inhibitors have become the gold-standard on senolysis. Bcl2 family inhibitors eliminate a range of senescent cells in vivo and reproduce the effects observed in transgenic mice modelling senescence ablation. However, ABT-263, causes severe thrombocytopenia and neutropenia, what might complicate its use on the clinic. Moreover, it is becoming evident than different senolytics might be necessary to eliminate different types of senescent cells. Therefore, there is a need to identify additional drugs with senolytic properties.

An alternative strategy for targeting senescence, is to exploit properties that differentiate senescent from normal cells. In this regard, the senescence-associated β-galactosidase activity (SA-β-gal) is one of the more conserved and defining characteristics of senescent cells. Senescent cells present an increased lysosomal mass. As a result, senescent cells display elevated levels of lysosomal enzymes such as β-galactosidase or α-fucosidases. Indeed, it has been shown that galacto-oligosacharide encapsulated nanoparticles (GalNP) preferentially release their content on senescent cells. Consequently, this GalNP can be used in combination with different cargos to either image or kill senescent cells.

Galactose-modification has been frequently used to improve the pharmacokinetic properties or the delivery of existing drugs. In addition, galactose modification can be used to generate prodrugs that rely on β-galactosidase for controlled activation. When combined with antibody-linked β-galactosidase, this approach is known as antibody-directed enzyme prodrug therapy (ADEPT). In ADEPT, a conjugate of a tumour-specific antibody and an enzyme, such as β-galactosidase, is combined with the application of a hardly cytotoxic prodrug. By means of the enzyme in the conjugate, the prodrug is selectively cleaved in cancer cells leading to the formation of a highly cytotoxic compound. Several of these galactose-modified cytotoxic prodrugs have been described. A class of such prodrugs are galactose-modified duocarmycin (GMD) derivatives.

Here, we investigated whether galactose-modified prodrugs can preferentially kill senescent cells. We have assessed the senolytic potential of several GMD derivatives and confirmed their senolytic potential in cell culture, ex vivo and in vivo. Given the increasing list of senescence-associated diseases and the positive effects associated with senolytic treatment, we propose GMD derivatives and more generally galactose-modified prodrugs are a new class of senolytic compounds with wide therapeutic promise.

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