Before the advent of the first senolytic drugs capable of selectively destroying senescent cells, it was thought by many that progress towards producing rejuvenation in the old via the safe elimination of senescent cells from the body would require the identification of surface markers that are distinctive to the state of senescence. Given a surface marker that clearly and distinctively identifies a cell population, a broad range of strategies become available for the development of targeted therapies. As it turned out,, however, the first senolytics took advantage of the peculiarities of the internal state of senescent cells. These cells are primed to undergo the self-destruction of apoptosis, and as a consequence it was discovered that interference in anti-apoptosis mechanisms will kill senescent cells without harming normal cells. The question of surface markers was largely put aside, with only a few groups, such as SIWA Therapeutics, pursuing approaches of that nature.
Given that, it is interesting to take a look at today's open access paper, in which researchers report a distinctive surface marker for senescent cells. It remains the case that any such marker can enable many novel approaches to senolytic therapy, not just the one used as a proof of concept by the authors of this paper. It has to be said that the senolytics field is already well stocked with a diversity of innovative approaches at various stages of development - but more can't hurt! Ultimately, multiple senolytic therapies that are based on very different strategies may be needed in order to obtain an optimal coverage of tissues and high level of senescent cell destruction in older people. Even without considering that point, a marketplace that will ultimately consider everyone much over the age of 40 an occasional customer has plenty of room for products and providers.
Senescence is an irreversible proliferation arrest and a key restriction mechanism to prevent the propagation of damaged cells. However, the progressive accumulation of senescent cells with time has been associated with loss of tissue homeostasis, and is known to contribute to the functional impairment of different organs typically seen in ageing. Recently, it has been shown that it also plays an important role in fibrosis and tumour progression, and that it may be involved in cataracts, obesity, diabetes, Alzheimer's and Parkinson's diseases, arthritis, atherosclerosis and many other age-related conditions. This supports the hypothesis that senescence is an antagonistically pleiotropic process, with beneficial effects in the early decades of life of the organism (in development, tissue repair, and as a tumour suppressor mechanism) but detrimental to fitness and survival at later stages, after the percentage of senescent cells in tissues reaches a critical threshold.
Consistent with this view, it has been reported that clearing senescent cells from tissues has a protective effect against cancer and the onset of age-related pathologies. Because of this, great interest has been placed in a recently discovered group of drugs that can preferentially kill senescent cells, collectively known as senolytics, which have been shown to increase healthspan and lifespan of mice with attenuation of age-related dysfunctions like emphysema, hepatic steatosis, lung fibrosis, osteoporosis, osteoarthritis, cardiac regeneration dysfunctions, cognitive memory impairments or Alzheimer disease in different in vivo models. Recently, senolytics, were shown to also decrease the number of senescent cells in humans and alleviate the symptoms of idiopathic pulmonary fibrosis.
In this context, targeted senolytics are emerging as a promising alternative. For instance, it has recently been shown that toxic nanoparticles activated by the presence of β-galactosidase can eliminate senescent cells in vitro and in vivo, confirming the feasibility of the approach. We propose that the senescent surfaceome, the specific profile of membrane proteins differentially upregulated in senescent cells, could be used to this end even more effectively. Using mass spectrometry, we identified a number of markers highly expressed in the plasma membranes of senescent cells in response to the activation of one of the two main pathways of induction of the phenotype (p53/p21 or p16).
We show that an antibody-drug conjugate (ADC) against the marker B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.
View the full article at FightAging
