A Role for Cellular Senescence in Brain Aging, and for Senolytics in the Reversal of Brain Aging

Senescent cells accumulate throughout the body with age, the result of an increased pace of creation and slowed pace of clearance. Senescent cells secrete a mix of inflammatory signals that disrupt tissue maintenance and function, and this contributes to the progression of degenerative aging. Clearing senescent cells with senolytic therapies has been shown to produce rejuvenation in mice, robust reversal of many different age-related conditions. That includes demonstrations of efficacy in animal models of neurodegenerative conditions such as Parkinson's disease and Alzheimer's disease. Senescent cells are not the whole of aging, but they are a large enough fraction of it to be most promising as a point of intervention.

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs.

Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression.

Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly it has emerged recently that non-proliferating neuronal cells present in the brain or cultivated in vitro can also exhibit some hallmarks, including SASP, typical for senescent cells that ceased to divide.

It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

Link: https://doi.org/10.3389/fnagi.2021.646924

Comments

I came across this recent paper yesterday which looked at the many individual statins and their effect on neurodegenerative diseases.

Pitavastatin use was associated with a 96% reduced Alzheimer's rate and ezetimibe/simvastatin reduced Parkinson's by 98%.

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12108

Posted by: Lee at March 29th, 2021 6:26 AM

"to be most promising as a point of intervention" - senolytics are not the most promising, there are many much more promising interventions, by my subjective judgement the most promising is telomerase activators to make telomere elongation (the second being epigenetic clock resetters). Just if you are old age and have weak telomerase activators only (as for now is the case) you need senolytics and other anti-SAPS agents to remove SASP (ASAP!) that is blocking telomerase highly efficiently.

Senolytics are just the first anti-aging treatment that is already WORKING and as a common supplements that can be bought without presciption at the nearest supplement store they are AVAILABLE NOW NOW NOW.

Posted by: SilverSeeker at March 29th, 2021 7:18 AM

@SilverSeeker
Senolytics are most promising in the sense that they are just around the corner and with very good chance to work. For the moment, however , we don't have conclusive human studies and even less a good application protocol.

As for promising most results. Nanotechnology could in theory repair every single cell in our bodies. It remains quite remote and elusive, though...

What is very probable are:
Senolytics (5-10) to have widespread use
Compounds to break and clean up extracellular waste like cholesterols plaques, amyloid buildups and such. Hehe I would shift the expected arrival date by 3-4 extra years so I 8 to 14 years from now. This gives higher uncertainty too.
Extracellular vesicle therapies to replace mitochondria, and other organelles. 3-5 exists years again, so the earliest that can arrive is in 6 years but probably in 15...
And then we have the more exotic stuff which will take even longer

Posted by: Cuberat at March 29th, 2021 1:03 PM

It would be useful if someone could develop a means of detecting senescent cells in the body via a scan, rather than the current method of a tissue biopsy which is unpleasant in the skin and impossible in the brain except in cases of brain surgery for cancer.

Maybe something that looks at changes in senescence in the eye as giving senolytics to humans then trying to detect changes in brain function via oservational studies sounds slow and expensive.

Posted by: jimofoz at March 30th, 2021 5:10 AM

"Extracellular vesicle therapies to replace mitochondria" how much it will be better in repairing mitochondria than PQQ (40 mg daily per 100kg, yes it has a deadband that lies above 20mg daily recommended dose) and astaxanthin (4 mg daily per 100kg) is today? And what will be the cost? And yes it's another intervention that is already available NOW, not after we will die...

Posted by: SilverSeeker at March 30th, 2021 9:05 AM

@SilverSeeker
Calorie restriction and fasting probably give the best mito repair results for now. However, at some point they can go so far. It is good that there's a potential breakthrough . The same therapy can be used to deliver genetically modified mitochondria to reduce the ROS damage. It seems easier to implement than stem cells. Much safer too.

Posted by: Cuberat at March 30th, 2021 6:04 PM

@Cuberat The strongest mitochondria rejuvenator I found so far is PQQ. After the collapse of the body's efficiency in my early 40s, PQQ restored at least short-term efficiency in running and exercising to the peak I had in my life before my 30. It is a vitamin that is denied the name of a vitamin because mammals produce it into the milk during feeding the young.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804159/ "Pyrroloquinoline Quinone Stimulates Mitochondrial Biogenesis through cAMP Response Element-binding Protein Phosphorylation and Increased PGC-1α Expression"

Posted by: SilverSeeker at March 31st, 2021 6:57 AM

@SilverSeeke what was your protocol and supportive results?

Posted by: Cuberat at March 31st, 2021 7:51 PM

testing various anti-inflammatory drugs (I am still looking for a psoriasis medicine that will work...) I came to astaxanthin (it lowers my blood pressure too much so I use the minimum dose of 4 mg once a day in the evening but I stick to it as it considerably improves skin look...), and then I added PQQ - once a day 20 mg taken in the morning. After a few months of taking I got a flu, but the first days were very strange - in the morning I wake up broken and after 2-3 hours you can go to work without any symptoms, and in the evening I was broken again and I fell asleep earlier. In addition, a runny nose, as in the case of an allergy, joined it. After a few days I fell asleep early enough that I forgot to take my astaxanthin, and the next afternoon I started suffering from severe sinus pains and all the flu symptoms ... after returning home I took 8 mg of astaxanthin and PQQ right away, and the painful rhinitis symptoms passed off before next morning... I immediatelaly also tested the combination that I took the second 20mg of PQQ the next day also in the afternoon (about 10-11 hours after the first dose), it also eliminated these evening symptoms. After the runny nose stopped, I continued this dose (2 x 20 mg PQQ + 4 mg astaxanthin) for a few weeks - only the time between doses of PQQ was changing (40 mg taken at a time gives a bit of a migraine response), sometimes changing from 10-13 hours shortening to 5-6. And after less than 4 weeks, I already noticed strong effects of improving my performance. Good question, is it just a combination of PQQ + astaxanthin, or something else I took from it (rosary, eleutherococcus) added to it...? I tried this antimflammatory effect several times after and it seems that only PQQ + astaxanthin are required. But if it apply to improving performance too...?

Posted by: SilverSeeker at April 1st, 2021 11:39 AM

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