Researchers here discuss the distinguishing features of senescent cells and known ways to target those features in order to selectively destroy these cells. Senescent cells accumulate with age throughout the body, likely the consequence of an accelerated pace of creation and a slower pace of destruction by the immune system. These errant cells cease replication and secrete a potent mix of signals that provoke chronic inflammation and disrupt normal tissue structure and function. Removal of as little as a third of the senescent cells present in old mice produces quite impressive reversals of aging and age-related disease.
As senescent cells are highly heterogeneous in both their molecular biology and their physiological function, targeted strategies are needed that ideally preserve senescent cells in beneficial contexts while eliminating effects that are detrimental. Broadly, these therapies can be broken down into the major categories of senomorphic and senolytic drugs, although this classification might be arbitrary as agents with senomorphic effects in one cell type or context may be senolytic in another and vice versa. Senomorphic compounds target pathologic SASP signaling, while senolytics eliminate the underlying senescent cells that release damaging SASP factors. Senomorphics are discussed elsewhere, but in brief senomorphics prevent the production of, antagonize or neutralize SASP components, and usually require continuous administration. We will instead focus on emerging senolytic strategies that address a root cause of senescence pathology, senescent cells, yielding pleiotropic benefits with intermittent administration.
While the first senolytics were developed using a bioinformatically informed approach aimed at disrupting senescent cell anti-apoptotic pathways (SCAPs) and other pro-survival networks, the class has expanded to take advantage of additional senescence features and enhance immune-mediated clearance. Broadly, first-generation agents act by transiently disabling SCAPs, causing those senescent cells with a tissue-damaging SASP to kill themselves. Importantly, while all senolytic strategies may elicit off-target effects or interfere with beneficial populations, these can often be limited as most therapeutics are amenable to intermittent 'hit-and-run' dosing strategies that do not require daily, or even weekly, administration.
Characterization of senescent cells has revealed unique markers that serve as senescence-associated self-antigens. These can be co-opted for immune system-mediated senolytic activity and clearance. A recent study took advantage of this using chimeric antigen receptor (CAR) T cells targeted against the urokinase-type plasminogen activator receptor (uPAR) in a mouse model. uPAR is associated with extracellular matrix remodeling that is upregulated at the cell surface of senescent cells during replicative, oncogene-induced and toxicity-induced senescence. Cytotoxic CAR T cells were able to selectively clear uPAR-expressing senescent cells in vitro and in vivo.
Prototypic senolytic drugs were developed to target SCAP networks. In contrast to a one-drug, one-target approach, SCAP inhibition may interface with several pro-survival signals at once. As a result, these early senolytics typically possess several pharmacologic mechanisms of action that interact synergistically. Prime examples of this are the flavonoid fisetin as well as dasatinib and quecertin (D + Q), which have been utilized and reviewed thoroughly. In brief, although the precise mechanism of action is unknown (as is the case for most agents), the D + Q combination exerts broad spectrum senolytic activity through interference with several pro-survival networks.
Additional aspects of senescent cells are advantageous for directed senolysis. One such feature is their increased lysosomal enzyme activity. This can be leveraged with the use of prodrugs that are cleaved and activated by the lysosomal enzyme SA-β-gal or by loading cytotoxic chemicals into galacto-polymer-coated nanoparticles that can be preferentially released into senescent cells. Further, outside its role as a cellular recycling system, autophagy can lead to activation of cell death pathways when highly activated under persistent stress. Autophagy is inhibited within senescent cells, but senescent cells are primed for cell death following an autophagic push. This is demonstrated by autophagy induction and subsequent senolysis.