Introduction to Cellular Senescence (methylene blue)

[Bolt_Upright]

I was reading how "methylene blue is a strong anti-senescence agent" ncbi.nlm.nih.gov/pmc/articl... which made me wonder "is it a good thing that MB blue is a strong anti-senescence agent?", which led me to this: frontiersin.org/articles/10...

"Introduction to Cellular Senescence

Three fates ultimately await very aged or damaged cells: senescence, apoptosis, or autophagy (Vicencio et al., 2008). Autophagy (self-eating) is largely a homeostatic mechanism through lysosomal destruction of old or damaged cellular components, allowing for the recycling of cellular material. However, recent evidence also supports the view that autophagy plays an important role in mammalian cell death (Jung et al., 2020). Apoptosis (self-killing) is a morphologically unique, genetically programmed cell death. It has important roles in development, aging, and atrophy, to maintain an appropriate level of cells (Elmore, 2007). It also has many critical roles in immune system function (Nagata and Tanaka, 2017). Cells can also enter a state of senescence (stable cell cycle arrest) as a homeostatic response to various stressors in order to mitigate the proliferation of damaged cells and to prevent neoplastic transformation (Kritsilis et al., 2018). Senescent cells are metabolically active, stable, and viable, unlike cells destined for death and recycling. The classical understanding is that only mitotically active cells in the periphery can enter senescence by becoming arrested in the G1 phase, unlike quiescent cells that arrest in G0 (Di Leonardo et al., 1994; Vicencio et al., 2008). However, post-mitotic cells in the central nervous system are now recognized as being able to undergo senescence (Baker and Petersen, 2018). There is some evidence of crosstalk and shared regulated pathways between these three cell fate states, but there is much that is currently not understood about their relationships to one another (Abate et al., 2020). Also, there is some debate currently over the post-mitotic status of glia and CNS neurons.

Senescent cells accumulate during aging, both from an increased rate of production and a decreased clearance rate (Karin and Alon, 2021). Although the accumulation of senescent cells is associated with increasing age, it is not age-dependent. Senescence is a dynamic and context-specific state that involves many biochemical pathways, such as the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppression pathways (McConnell et al., 1998; Kumari and Jat, 2021). Senescent cells that form in response to stress during earlier life stages, such as from oncogene activation, inflammation, or DNA damage, contribute to protective functions such as tumor suppression, wound healing, preventing the propagation of tissue damage, and embryogenesis (Storer and Keyes, 2014; Ovadya and Krizhanovsky, 2018). In non-pathological states, senescent cells attract the immune system and are cleared (Langhi Prata et al., 2018).

There is a physiological threshold where senescent cells interfere with their own clearance, described by the recently proposed “immune threshold theory of senescent cell burden” (Tchkonia et al., 2021). According to this theory, once the saturation of senescent cells passes the senescent cell abundance threshold, the spread of cellular senescence outpaces the immune system’s ability to clear them and cellular senescence becomes “self-amplifying” and contributes to age-associated diseases (Tchkonia et al., 2021)."

My conclusion from reading this is: Senescence is not good. Anti-senescence should be a good thing.

[Bolt_Upright]

Combined activation of the energy and cellular-defense pathways may explain the potent anti-senescence activity of methylene blue 2015 frontiersin.org/articles/10...

"The significance of this study lies in the potent anti-senescence activity of MB as well as in that MB is an FDA-approved drug, which encourages repurposing its clinical use of low concentration to delay cell senescence in vivo if the scientific research supports this approach. MB is very effective in delaying cellular senescence in vitro, which makes it an attractive for studying the concept of anti-senescence therapy in vivo [1,17]. However, the optimal concentration of MB for in vivo testing needs to be defined [62]. Additional pathological conditions that could benefit from MB include diabetes and Alzheimer’s disease. Due to its modulatory effect on AMPK, MB could benefit diabetes patients. Enhancing mitochondrial activity and complex IV and lowering cellular oxidants production by MB might prevent or delay the onset of mitochondrial dysfunction and energy hypometabolism in Alzheimer’s disease.

Conflict of interest

HA has a patent on Diaminophenothiazines."

I searched on "diaminophenothiazines methylene blue" and found this: Methylene Blue: The Long and Winding Road From Stain to Brain: Part 2 2016 pubmed.ncbi.nlm.nih.gov/276...

"Methylene blue was the first synthetic drug ever used in medicine, having been used to treat clinical pain syndromes, malaria, and psychotic disorders more than one century ago. Methylene blue is a cationic thiazine dye with redox-cycling properties and a selective affinity for the nervous system. This drug also inhibits the activity of monoamine oxidase, nitric oxide synthase, and guanylyl cyclase, as well as tau protein aggregation; increases the release of neurotransmitters, such as serotonin and norepinephrine; reduces amyloid-beta levels; and increases cholinergic transmission. The action of methylene blue on multiple cellular and molecular targets justifies its investigation in various neuropsychiatric disorders. Investigations of methylene blue were instrumental in the serendipitous development of phenothiazine antipsychotic drugs. Although chlorpromazine is heralded as the first antipsychotic drug used in psychiatry, methylene blue is a phenothiazine drug that had been used to treat psychotic patients half a century earlier. It has also been studied in bipolar disorder and deserves further investigation for the treatment of unipolar and bipolar disorders. More recently, methylene blue has been the subject of preclinical and clinical investigations for cognitive dysfunction, dementia, and other neurodegenerative disorders. [Journal of Psychosocial Nursing and Mental Health Services, 54(10), 21-26.]. "

So... I am thinking HA, who had one of the first papers on using MB for PD in 2008, has created Diaminophenothiazines based on methylene blue (which is a phenothiazine). Just my guess.

[Despe in reply to Bolt_Upright]

Bolt,

Do you read the whole study? I usually go down to the "Results" or "Conclusion."

I will have my husband try it, nothing to lose.

[Hidden in reply to Despe]

Despe, is it okay with Ambroxol and Montelukast? I wonder if it is okay with Exenatide. Maybe other senolytics should not be used at the same time (Fisetin, Quercitin for example) I need a new functional doc in my new state.

[Despe in reply to Hidden]

I know it's OK for Ambroxol and Montelukast. My sister asked our pharmacist at home. I am not sure about Exenatide, Fisetin and Quercetin.

Searching the net I found this amazon.com/Limitless-Reinve...

Nootropics all in one supplement.

[Bolt_Upright in reply to Despe]

I kind of skim over the whole paper. A lot of it goes right over my head. Be careful. I am sure we do have something to lose.

[Bolt_Upright in reply to Despe]

FB has a Methylene Blue group: facebook.com/groups/5824402...

[Despe in reply to Bolt_Upright]

No FB account,

[JayPwP]

Any recommendations on MB dosage?

[Bolt_Upright in reply to JayPwP]

Please read through this thread: healthunlocked.com/cure-par...

Per Dr Mercola, seems to be .5 to 1 mg per kg. I am going to start lower than that.

[Hikoi in reply to Bolt_Upright]

Do you trust Mercola for information?

[Bolt_Upright in reply to Hikoi]

I would not trust any single source for this treatment. I have not started it yet. I think I need to at least start weening off of my SSRI first.

[Bolt_Upright]

Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer's Disease 2019 pubmed.ncbi.nlm.nih.gov/309...

"Alzheimer's disease pathology is characterized by extracellular deposits of amyloid-β (Aβ) and intracellular inclusions of hyperphosphorylated tau. Although genetic studies of familial Alzheimer's disease suggest a causal link between Aβ and disease symptoms, the failure of various Aβ-targeted strategies to slow or halt disease progression has led to consideration of the idea that inhibition of tau aggregation might be a more promising therapeutic approach. Methylene blue (MB), which inhibits tau aggregation and rescue memory deficits in a mouse model of tauopathy, however, lacked efficacy in a recent Phase III clinical trial. In order to gain insight into this failure, the present study was designed to examine the mechanism through which MB inhibits tau aggregation. We found that MB inhibits heparin-induced tau aggregation in vitro, as measured by thioflavin T fluorescence. Further, MB reduced the amount of tau in precipitants recovered after ultracentrifugation of the aggregation mixture. Atomic force microscopy revealed that MB reduces the number of tau fibrils but increases the number of granular tau oligomers. The latter result was confirmed by sucrose gradient centrifugation: MB treatment was associated with higher levels of granular tau oligomers (fraction 3) and lower levels of tau fibrils (fractions 5 and 6). We previously demonstrated that the formation of granular tau oligomers, rather than tau fibrils, is essential for neuronal death. Thus, the fact that MB actions are limited to inhibition of tau fibril formation provides a mechanistic explanation for the poor performance of MB in the recent Phase III clinical trial."

[Bolt_Upright in reply to Bolt_Upright]

But then MB WORKED in this study: Visualization of soluble tau oligomers in TauP301L-BiFC transgenic mice demonstrates the progression of tauopathy 2020 pubmed.ncbi.nlm.nih.gov/321...

"Accumulation of abnormal tau aggregates in the brain is a pathological hallmark of multiple neurodegenerative disorders including Alzheimer's disease. Increasing evidence suggests that soluble tau aggregates play a key role in tau pathology as neurotoxic species causing neuronal cell death and act as prion-like seeds mediating tau propagation. Despite the pathological relevance, there is a paucity of methods to monitor tau oligomerization in the brain. As a tool to monitor tau self-assembly in the brain, we generated a novel tau transgenic mouse, named TauP301L-BiFC. By introducing bimolecular fluorescence complementation technique to human tau containing a P301L mutation, we were able to monitor and quantify tau self-assembly, represented by BiFC fluorescence in the brains of transgenic TauP301L-BiFC mice. TauP301L-BiFC mice showed soluble tau oligomerization from 3 months, showing significantly enriched BiFC fluorescence in the brain. Then, massive tau fragmentation occured at 6 months showing dramatically decreased TauP301L-BiFC fluorescence. The fragmented tau species served as a seed for insoluble tau aggregation. In a result, insoluble TauP301L-BiFC aggregates coaggregated with endogenous mouse tau accumulated in the brain, showing subsequently increased BiFC fluorescence from 9 months. Neuronal degeneration and cognitive deficits were observed from 12 months of age. TauP301L-BiFC mouse model demonstrated that methylene blue reduced the amount of soluble tau oligomers in the brain, resulting in the prevention of cognitive impairments. We assure that TauP301L-BiFC mice are a bona-fide animal tool to monitor pathological tau oligomerization in AD and other tauopathies."

[Bolt_Upright]

Yikes! According to RXlist.com you should NOT take Methylene Blue and Levadopa: rxlist.com/drug-interaction...

"methylene blue oral and levodopa oral

methylene blue oral and levodopa oral both increase affecting serotonin levels in the blood. Too much serotonin is a potentially life-threatening situation. Severe signs and symptoms include high blood pressure and increased heart rate that lead to shock. Combination may cause severe harmful effects. If methylene blue must be taken, stop taking the serotonergic drug until 24 hours after finishing methylene blue or after 2 weeks of observation for side effects."