A study in Cell Reports shows senolytic treatments with ABT-263 (Navitoclax) and Dasatinib plus Quercetin promote functional recovery of the spinal cord in mice.
· Upon injury, senescent cells accumulate next to the lesion in the spinal cord.
· Targeting senescent cells favors a pro-repair microenvironment in the spinal cord after injury.
· Administration of senolytic drugs promotes recovery of spinal cord mediated functions, such as locomotion and sensation.
Underlying many aging-related chronic disorders are cells that stop growing and replicating — a process called senescence. But senescent cells are now being recognized for their role in tissue remodeling events, especially as organs and tissues try to react and repair themselves in response to damage.
In a study published in Cell Reports, Paramos-de-Carvalho and colleagues from Nova Medical School (NOVA Medical School – Faculdade de Ciências Médicas) show, that following spinal cord injury, senescent cells accumulate over the ensuing weeks and months in mice. This build-up of non-proliferating cells appears to lead to the functional deterioration of the spinal cord. But when the Portuguese researchers depleted these post-injury senescent cells with different senolytic drugs, such as ABT-263 or the combination of dasatinib and quercetin, the locomotor, sensory, and bladder functions of these mice improved.
“Our data support the potential use of therapeutics targeting senescent cells to promote neuroprotection in the context of spinal cord injuries,” propose Paramos-de-Carvalho and colleagues. “Targeting senescent cells is a promising therapeutic strategy not only for spinal cord injuries but potentially for other organs that lack regenerative competence.”
Though we’ve learned quite a bit of what happens after spinal cord injury, little progress has been made on therapeutic options, suggesting that something might be missing. That’s why Paramos-de-Carvalho and colleagues took a look to see if the induction of senescent cells is a cellular response triggered by an injury in the spinal cord. The Portuguese research team found that the number of senescent cells increased in the spinal cord in the ensuing few weeks after spinal cord injury. These induced senescent cells were primarily seen in the gray matter — where nerve cell bodies lie.
So, if senescent cells are induced after spinal cord injury, what happens if you administer drugs called senolytics that target these cells? After treating mice that had spinal cord injuries with the senolytic ABT-263, Paramos-de-Carvalho and colleagues saw significantly improved locomotor performance, an effect maintained until the end of the study. These mice treated with ABT-263 also had improvements in their ability to sense cold stimuli through touch.
Notably, the effects of ABT-263 on locomotor and sensory recovery were corroborated by a second independent assay using the Dasatinib plus Quercetin senolytic cocktail. In addition, the Portuguese researchers could show that similarly to ABT-263, the Dasatinib plus Quercetin cocktail resulted in efficient depletion of senescent cells at the spinal cord lesion periphery. Taken together, these results highlight the detrimental impact of the persistent accumulation of senescent cells on motor and sensory functions after a spinal cord injury.
Paramos-de-Carvalho and colleagues show that at the root of this functional recovery is an improved and attenuated inflammation, scarring, and demyelination — the loss of the conductive material wrapping nerve cells critical for the transmission of electrical signals in the nervous system. What’s more, the Portuguese researchers were able to pin down key senescence-inducing compounds called SASP (senescence-associated secretory phenotype) factors that contribute to the inhibitory microenvironment for repair in mammalian spinal cord injury settings.
Senolytic drugs like ABT-263 selectively eliminate senescent cells by transiently disabling the pro-survival networks and inducing their death, but it does not prevent new senescent cells. The generation of new senescent cells becomes relevant when thinking in a translational approach to optimize the time window for treatment to achieve high efficacy with low toxicity. However, senolytics themselves may not be enough.
NMN supplementation is an effective therapy protecting against multiple related conditions, such as nerve damage to the eye. Also, deletion of the NMN-producing enzyme NAMPT in neurons projecting from the brain to the spinal cord in adult mice leads to motor dysfunction, neurodegeneration, and death; however, NMN treatment reduced motor deficits and increased the lifespan of these mice. A similar paradigm was shown in neurons that project from the spinal cord to muscles. Together, these findings point to using senolytics combined with NMN to prevent degeneration of the nervous system.