34 replies to this topic

[BrentS]

IMHO another serious question needs to be considered in senolytics, which is rarely mentioned,

namely that the neurons - which are post-mitotic cells - also develop a senescent-like state, and if these are removed too that can have catastrophic effects in humans.

 

1.  https://pubmed.ncbi....h.gov/26944285/

 

From the above "Fisetin treatment also markedly reversed Aβ_1-42-induced synaptic dysfunction by increasing the levels of both presynaptic (SYN and SNAP-25) and postsynaptic proteins (PSD-95, SNAP-23, p-GluR1 (Ser 845), p-CREB (Ser 133) and p-CAMKII (Thr 286) and ultimately improved mouse memory, as observed in the Morris water maze test. Fisetin significantly activated p-PI3K, p-Akt (Ser 473), and p-GSK3β (Ser 9) expression in Aβ_1-42-treated mice. Moreover, fisetin prevented neuroinflammation by suppressing various activated neuroinflammatory mediators and gliosis; it also suppressed the apoptotic neurodegeneration triggered by Aβ_1-42 injections in the mouse hippocampus. Fluorojade-B and immunohistochemical staining for caspase-3 revealed that fisetin prevented neurodegeneration in Aβ_1-42-treated mice. Our results suggest that fisetin has a potent neuroprotective effect against Aβ_1-42-induced neurotoxicity. These results demonstrate that polyphenolic flavonoids such as fisetin could be a beneficial, effective and safe neuroprotective agent for preventing neurological disorders such as AD."

 

2.  https://pubmed.ncbi....h.gov/19756810/

 

From the above "Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant. Fisetin can also maintain mitochondrial function in the presence of oxidative stress. In addition, it has anti-inflammatory activity against microglial cells and inhibits the activity of 5-lipoxygenase, thereby reducing the production of lipid peroxides and their pro-inflammatory by-products. This wide range of actions suggests that fisetin has the ability to reduce the age-related decline in brain function."

 

Fisetin seems to not have the effect you are describing.  Perhaps other less tested senolytic drugs do have that effect?
 

[Avatar of Horus]

IMHO another serious question needs to be considered in senolytics, which is rarely mentioned,
namely that the neurons - which are post-mitotic cells - also develop a senescent-like state, and if these are removed too that can have catastrophic effects in humans.

...
Fisetin seems to not have the effect you are describing.  Perhaps other less tested senolytic drugs do have that effect?

Some details:

"Due to their postmitotic status, the potential for neurons to undergo senescence has historically received little attention. This lack of attention has extended to some non-postmitotic cells as well." [1]

"Postmitotic neurons may constitute a dangerous target
Adult neurogenesis ... ability to restore overall brain function has been shown to be limited. As neurons do not proliferate, if killed by senolytics they are permanently lost. There is currently a slowly increasing consensus that neurons can indeed become senescent or 'senescent-like', although data that originally supported this concept was published nearly 10 years ago (Jurk et al., 2012). Regardless of whether neurons senesce or not, determining whether neurons are killed by senolytics may be important in terms of their potential use as a CNS intervention.
... it is important to consider the impact of removing these largely irreplaceable post-mitotic cells, including the stage at which they may be removed without having a major impact on overall brain function as well as possible drug side-effects." [2]

"The post-mitotic status of neurons has been traditionally considered to prohibit cellular senescence, however recent studies have provided compelling evidence that neurons may be capable of undergoing senescence in response to oxidative stress and other factors. Development of senolytics, small molecules that selectively induce senescent cell death, could represent a paradigm change for the treatment of neurodegenerative diseases including Alzheimer's and Parkinson's disease (AD, PD). However, their use depends on unequivocal validation that neurons can senesce and that they do not have detrimental off-target effects in other cell types in the brain and elsewhere.
... A critical matter to resolve is whether senescent neurons are being selectively killed by the senolytics. ...
If p16-positive pyramidal neurons in AD patients are indeed senescent but pathologically innocuous and, instead, senescent glial cells are the culprit, the off-target killing of senescent neurons by senolytics could prove devastating. It is equally vital to provide conclusive evidence that senolytics are not eliciting off-target effects on remaining healthy post-mitotic neurons or other cell types. ...
Neuronal senescence has to date not been extensively researched. ... much still remains to be determined including whether senolytics elicit their effects via targeting neurons, glial cells or both and whether they have detrimental off-target effects on healthy cell types in the brain and elsewhere. Without establishing whether neurons can or cannot senesce, we cannot truly understand the therapeutic effects of senolytics or how and when it is safe for their use. Unequivocally establishing whether neurons do or do not undergo senescence is therefore now a prime objective for the future use of senolytics in AD and other neurodegenerative diseases." [3]

Jurk et al., 2012 : Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response - 2012 Dec
https://pubmed.ncbi....h.gov/22882466/

1 - Senescence as an amyloid cascade: the amyloid senescence hypothesis - 2020 May
https://pubmed.ncbi....h.gov/32508595/
2 - A guide to senolytic intervention in neurodegenerative disease - 2021 Dec
https://pubmed.ncbi....h.gov/34627838/
3 - Unknown fates of (brain) oxidation or UFO: Close encounters with neuronal senescence - 2019 Apr
https://pubmed.ncbi....h.gov/30639615/

[Avatar of Horus]

...

Jurk et al., 2012 : Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response - 2012 Dec
https://pubmed.ncbi....h.gov/22882466/
...

 

"to be or not to be that is the question":

"The DNA damage response in neurons: die by apoptosis or survive in a senescence-like state? - 2017
https://pubmed.ncbi....h.gov/28436392/

Abstract
Neurons are exposed to high levels of DNA damage from both physiological and pathological sources. Neurons are post-mitotic and their loss cannot be easily recovered from; to cope with DNA damage a complex pathway called the DNA damage response (DDR) has evolved. This recognizes the damage, and through kinases such as ataxia-telangiectasia mutated (ATM) recruits and activates downstream factors that mediate either apoptosis or survival. This choice between these opposing outcomes integrates many inputs primarily through a number of key cross-road proteins, including ATM, p53, and p21. Evidence of re-entry into the cell-cycle by neurons can be seen in aging and diseases such as Alzheimer's disease. This aberrant cell-cycle re-entry is lethal and can lead to the apoptotic death of the neuron. Many downstream factors of the DDR promote cell-cycle arrest in response to damage and appear to protect neurons from apoptotic death. However, neurons surviving with a persistently activated DDR show all the features known from cell senescence; including metabolic dysregulation, mitochondrial dysfunction, and the hyper-production of pro-oxidant, pro-inflammatory and matrix-remodeling factors. These cells, termed senescence-like neurons, can negatively influence the extracellular environment and may promote induction of the same phenotype in surrounding cells, as well as driving aging and age-related diseases. Recently developed interventions targeting the DDR and/or the senescent phenotype in a range of non-neuronal tissues are being reviewed as they might become of therapeutic interest in neurodegenerative diseases.

Keywords: Aging; DNA damage response; apoptosis; cell senescence; neurodegeneration.
...
Targeting senescence
...
The clearance of p16INK4a-positive senescent cells has been shown as a highly promising proof-of-principle therapy in mice ...
 This so-called senolytic approach delayed age-associated loss of function in multiple organs including eye, muscle, and kidney, and reduced tumor incidence. Initial research has not been focused on the brain, and so far no obvious cognitive effects of the treatment have been published. ...
Again, effects of the treatments on neuron function or cognition have not been published so far.
There are a number of unresolved issues when the extension of senolytic therapies, whether transgenic or drug-mediated, to neurons is contemplated. The first relates to the bioavailability of such drugs in the CNS and whether neurons in the brain can be targeted at all. ...
The second issue is, of course, whether ablation of senescence-like neurons, if it can be achieved, would have negative rather than positive consequences for the function of the neuronal network. Neurons with aneuploidy, for example ... appear to be at least somewhat functionally active and maintain distal axonal connections . If these neurons are actively contributing to the neuronal network, then avoiding the ablation of these cells and instead focusing on countering phenotypic changes, such as the SASP, may be the preferential option."

[Logic]

From the above link:

 

Dill extract in vitro increased the expression of the type 1 lysyl oxidase-like extracellular enzyme gene in skin fibroblasts, and also increased skin elasticity in women compared with placebo. This is important because a type 1 lysyl oxidase-like extracellular enzyme initiates covalent crosslinking of elastin precursor molecules (tropoelastin), which is a critical step in the normal maturation of elastin. In 2020, French researchers Vassim Feili and Quentin Bethe and colleagues published the result of an experiment with C57BL6 / J mice. The animals were treated for 3 months with an extract of dill seed powder, which was bred in the drinking water of the animals. Compared with control animals, treatment with dill seed powder extract yielded the following results:

• significant decrease in blood pressure by 11-12%
• reversing age-related heart hypertrophy
• additional newly synthesized elastic fibers in the aortic wall of old mice
• approximately twofold increase in the expression of genes tropoelastin and lysyl oxidase-like extracellular enzyme type 1
• increasing the extensibility of the tissues of the aorta
• decreased modulus of elasticity (Incremental elastic modulus) of the aorta
• Dill polyphenols dose-dependently reduce the activity of elastin-degrading enzymes belonging to the families of serine proteinases, cysteine ​​proteinases and metalloproteinases. Polyphenols reverse age-related elastic fiber calcification by inhibiting alkaline phosphatase activity.

pubmed.ncbi.nlm.nih.gov/31979322

 

Yes Dill, but don't forget the Blackberry:

"...The blackberry extract induced elastin gene expression, elastin promoter activity and inhibited elastic fibre degradation by matrix metalloproteinases (MMPs) 9 and 12. The dill extract induced elastin, collagen and LOXL1 gene expression, resulting in enhanced fibre cross-linking in human skin explants. Clinically, the blackberry and dill combination treatment displayed synergistic pro-elasticity activity as compared to each ingredient alone and placebo..."
https://pubmed.ncbi....h.gov/32583541/
 

Edited by Logic, 01 March 2024 - 11:14 AM.

[Logic]

A question everyone should ask here is:
Why don't senescent cells die when they're supposed to..???

IIRC (and it's been a while!): Viral and/or bacterial infection is a big reason.
ie:  The infected cell sends out fake signals to the immune sys etc, saying: "Everything's fine-n-dandy with this cell. Nothing to see/do here.."

That makes DRACO probably one of the most effective (and overlooked) senolytics ever..!
https://www.longecit...infected-cells/

Always ask "WHY". Then do a properly worded search and get to the root cause of things and hopefully a solution.

Edited by Logic, 01 March 2024 - 11:32 AM.