Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways

Abstract

Methylene blue (MB) has been used clinically for about a century to treat numerous ailments. We show that MB and other diaminophenothiazines extend the life span of human IMR90 fibroblasts in tissue culture by >20 population doubling (PDLs). MB delays senescence at nM levels in IMR90 by enhancing mitochondrial function. MB increases mitochondrial complex IV by 30%, enhances cellular oxygen consumption by 37-70%, increases heme synthesis, and reverses premature senescence caused by H2O2 or cadmium. MB also induces phase-2 antioxidant enzymes in hepG2 cells. Flavin-dependent enzymes are known to use NAD(P)H to reduce MB to leucomethylene blue (MBH2), whereas cytochrome c reoxidizes MBH2 to MB. Experiments on lysates from rat liver mitochondria suggest the ratio MB/cytochrome c is important for the protective actions of MB. We propose that the cellular senescence delay caused by MB is due to cycling between MB and MBH2 in mitochondria, which may partly explain the increase in specific mitochondrial activities. Cycling of MB between oxidized and reduced forms may block oxidant production by mitochondria. Mitochondrial dysfunction and oxidative stress are thought to be key aberrations that lead to cellular senescence and aging. MB may be useful to delay mitochondrial dysfunction with aging and the decrease in complex IV in Alzheimer disease.

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

“…Similar to the results in a previous study (Atamna et al ., 2008), MB treatment improved normal cell proliferation (Fig. 4A).…”

“…MB is an effective agent to delay cellular senescence at nanomolar concentration and prevent age‐related decline in cognitive function and grip strength (Atamna et al ., 2008; Harrison et al ., 2014). It also exhibits potent antioxidant effects in mitochondria due to its redox property.…”

Methylene blue and dimebon inhibit aggregation of TDP‐43 in cellular models

“…It has recently been used in a phase II trial of AD [16]. Furthermore, MB has been reported to have activity as an enhancer of mitochondrial activity [24], and a recent study has reported that it delays cellular senescence in cultured human fibroblasts [25]. However, high doses of MB are known to be toxic and to cause the formation of Heinz bodies in erythrocytes in infants [39].…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…In a randomized, double-blind, multicenter study with 450 participants with mild-to-moderate AD, Idebenone showed minimal cognitive benefit [69][70][71], but was not approved for treatment of AD based on results not reaching statistical significance in larger trials [70][71][72]. Methylene blue can enhance cytochrome c oxidase activity through direct electron donation [80,81]. In a preclinical AD mouse model, methylene blue treatment reduced Tau-neurofibrillary tangle burden [82].…”