Elevated peripheral levels of receptor-interacting protein kinase 1(RIPK1)and IL-8 as biomarkers of human amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a devastating fatal neurodegenerative disease with no cure.Receptor-interacting protein kinase 1(RIPK1)has been proposed to mediate pathogenesis of ALS.Primidone has been identified as an old drug that can also inhibit RIPK1 kinase.We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1G93A mice and ALS patients.SOD1G93A mice treated with primidone showed significant delay of symptomatic onset and improved motor performance.One-hundred-sixty-two ALS participants dosed daily with primidone(62.5 mg)completed 24-week follow-up.A significant reduction was showed in serum levels of RIPK1 and IL-8,which were significantly higher in ALS patients than that of healthy controls(P<0.0001).Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms(P<0.05).Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients.Repurposing primidone may provide a promising therapeutic strategy for ALS.The effect of primidone for the treatment of other inflammatory diseases may also be considered,since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome(CRS).(ChiCTR2200060149).

Biomarkers of aging

Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.