Is Cellular Senescence Involved in ALS?
Amyotrophic lateral sclerosis (ALS) is not an age-related condition per se, but most cases do occur in later life. Is this because one or more mechanisms of aging are relevant to the onset of ALS? Researchers here argue for cellular senescence to be involved. It is already the case that cellular senescence has been implicated in a broad range of conditions, not all of which are age-related, such as type 1 diabetes. The advent of effective senolytic therapies to clear senescent cells from tissues will benefit more than just aged people.
Our unbiased proteomic analysis of plasma and peripheral blood mononuclear cells (PBMCs) in blood samples from patients with ALS has shown the activation of molecular pathways involved in immunoregulation and cell senescence in faster progressing ALS and at a later stage of disease. We and others have also reported an increased blood and cerebrospinal fluid concentration of proinflammatory cytokines in individuals with ALS. These inflammatory mediators are enumerated within the senescence-associated secretory phenotype (SASP) and have been described in age-related immune dysregulation.
The SASP inflammatory microenvironment spreads the tissue-disrupting effect of senescence regionally and systemically, impairing the function of other immune cells. Critically, other alterations observed in aging and senescence are aligned with brain-specific changes seen in ALS, including a disturbed autophagy/lysosomal protein degradation, altered RNA splicing, and errors in nuclear-cytoplasmic transport. We can therefore hypothesize a potential role for cell senescence in the immunologic dysregulation identified in ALS.
In this study, we used a two-stage approach to first investigate the immunophenotype of PBMCs from individuals living with ALS and then focused on lymphocytes expressing known features of immunosenescence. We showed that lymphocytes from patients with ALS are skewed toward a senescent and late memory state when compared with those from age-matched healthy controls.
The first paper implicating senescent glial cells in ALS came out back in 2019, and as someone who's pretty much guaranteed to get ALS in the next 10-30 years without a medical breakthrough, I'm infuriated at the way the research community seems to have been sitting around twiddling their thumbs instead of following this lead. In these three years, I don't think there has even been an animal study of senolytics in ALS.