Senolytic Treatments Clear Harmful Senescent Microglia from the Aging Brain
Researchers here show that a few different senolytic approaches improve the state of the population of microglia in the white matter of the brain in aged mice. This is much as one might expect, given past work into the effects of clearing senescent cells on cognitive function and neurodegeneration in various mouse models. Microglia are innate immune cells of the brain. The presence of senescent and inflammatory microglia is important in the age-related disruption of normal function in the brain, and removing them is beneficial. Sadly, little progress has been made to date in assessing established low-cost senolytic drugs in patients with neurodegenerative conditions; one small clinical trial was conducted for Alzheimer's disease, and that is about it.
Brain white matter undergoes structural and functional alterations linked to late-life cognitive decline, but the cellular and molecular basis of its selective vulnerability remains incompletely defined. Here, in naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampal-adjacent white matter, particularly in the fimbria. Using regional gene expression profiling, GeoMx immunolabeling, digital spatial profiling and CosMx spatial molecular imaging, we identify an aged brain-exclusive microglial population concentrated in white matter that expresses DAM genes together with a 'SenBrain' senescence gene signature, including galectin-3 (GAL3/Lgals3).
Single-cell spatial trajectory analyses suggest that multiple cell fate transitions may give rise to this aged, proinflammatory, senescent- and DAM-linked state. Pharmacogenetic or pharmacological senotherapeutic interventions reduced white matter GAL3+ DAM abundance and restored a more youthful microglial organization in aged fimbria. These findings identify a senescence- and DAM-enriched microglial state as a prominent and partially reversible feature of aged brain white matter.
The more research that comes out I am starting to think the biggest issue with senescent cells as we age is resident senescent immune cells like microglia and macrophages. I think in the liver they showed senescent macrophages increased from about 4 % in young ages all the way to around 70% were senescent in old age. That must really mess up the environment for repairs of tissue. In mice at least removing a bunch allowed the liver to start fixing itself.
Liposomal fisetin at very high doses at one time for 2 days in a hit and run fashion every few months seems to be working for me.
What brand Fisetin and what dose?
I use Sharoaid 1500 MG liposomal fisetin 60 count bottle from Amazon. I did it half bottle (30) at once one day then the rest of bottle the next day at once to make sure blood levels got very very high. Then did it again 2 months later and plan every 3 months now for maintenance. It was after 2nd hit and run that I really noticed a big effect. Needed time for body to respond I guess. If you have any medical issue you might want to see if that could affect things or not though. No problems on my end though. Studies show higher dose in blood the more senescent cells it takes out.
M Best: Do you monitor your systemic senescence burden before and after treatment? If so, how (e.g, what markers, what vendor/lab)?
No I haven't done that but I would say about a week after the 2nd very high dose hit and run is when I started noticing big changes.Bad inflammation in knees and shoulder 100% went away after having the stuff for probably a decade. Feel better and now am actually making some gains in pull ups and push ups after just slowing down decline previously. Facial skin has a slight glow now it didn't have before (I assume I added a little collagen there). I am just short of 58. That mess some researchers said about some 60 year olds not having much senescent cells is BS as certain T cells and macrophages get ate up with cells becoming senescent as you age which affects your organs etc.
M Best: Great to hear it's been helpful! Agreed that senescent cell burden can be variable: chronological age isn't the whole story and cell type/tissue type matters.