Evidence for Cellular Senescence to Contribute to Retinal Degeneration

Forms of retinal degeneration are commonplace in later life, leading to progressive and presently irreversible blindness - though there are promising human trial results emerging from the tissue engineering community of late. The accumulation of senescent cells is a feature of aging found in all tissues. These errant cells should self-destruct or be destroyed by the immune system, but enough survive to linger and cause problems. They secrete an inflammatory mix of signals that disrupts normal tissue structure and function, and their presence is one of the root causes of aging. Thus it is not surprising to find evidence for senescent cells to contribute to retinal degeneration, such as that presented here.

It is good news for patients, and everyone else, whenever cellular senescence is associated with the progression of yet another age-related condition. Low-cost senolytic drugs capable of removing a significant fraction of senescent cells already exist, and numerous companies are working on the commercial development of further and better options. To the degree that we can all access senolytic treatments, and to the degree that those treatments are efficient in removing unwanted senescent cells, then we will age more slowly and the onset of age-related diseases will be postponed.

Regenerative medicine approaches based on mesenchymal stem cells (MSCs) are being investigated to treat several aging-associated diseases, including age-related macular degeneration (AMD). Loss of retinal pigment epithelium (RPE) cells occurs early in AMD, and their transplant has the potential to slow disease progression. The human RPE contains a subpopulation of cells - adult RPE stem cells (RPESCs) - that are capable of self-renewal and of differentiating into RPE cells in vitro. However, age-related MSC changes involve loss of function and acquisition of a senescence-associated secretory phenotype (SASP), which can contribute to the maintenance of a chronic state of low-grade inflammation in tissues and organs.

In a previous study we isolated, characterized, and differentiated RPESCs. Here, we induced replicative senescence in RPESCs and tested their acquisition of the senescence phenotype and the SASP as well as the differentiation ability of young and senescent RPESCs. Senescent RPESCs showed a significantly reduced proliferation ability, high senescence-associated β-galactosidase activity, and SASP acquisition. RPE-specific genes were downregulated and p21 and p53 protein expression was upregulated. Altogether, the present findings indicate that RPESCs can undergo replicative senescence, which affects their proliferation and differentiation ability. In addition, senescent RPESCs acquired the SASP, which probably compounds the inflammatory RPE microenvironment during AMD development and progression.

Link: https://doi.org/10.18632/aging.101624


Good. It seems that the senolitics can bring a quick win for a host of conditions. And since the damage leads to a Vicious circle, removing even a single major cause could potentially lead to much of improvement. I suspect that event people in their 30s have some SASP burden , so the moment we have highly targeted and safe senolitics the 50s might become the new 30s, at least from health point of view. Of course, even 90 bring the new 60 would be huge...

Posted by: Cuberat at November 26th, 2018 12:15 PM

I'm only 28 and I'm already seeing signs of aging and I'm guessing this is the case for most people around 30. I look and feel more tired and my hangovers are terrible. I was considering doing a round of fisetin but decided against it after seeing the underwhelming accounts on the fisetin Longecity thread.

I'm guessing 30+ year olds have some SASP burden but perhaps the senolytics we have available aren't effective enough to have a significant effect. There's also the possibility that fisetin isn't very bioavailable in humans.

Posted by: Nina at November 26th, 2018 2:49 PM

@Cuberat We had discussed last month d&q treatment reg. eye sight and hair colour.
Saw an optician last week, the vision of 1 eye had slightly improved, the other not. But he mentioned and made a point the lens in both eyes were perfectly clear. Side effect of the senolytic?
Hair colour: I had taken my first senolytic August 10th. Had my hair tinted August 23rd.
Had now 3 months new hair growth when I saw my hairdresser on the 24th of November.
She really looked hard, still found some grey hairs on the crown of my head, but the back of my head and the nape were completely my old hair colour, not a single grey hair in sight.
My verdict is: yes, senolytics will have an effect on one's hair colour.
remember, I am 80 years of age and only took a low dose - 40mg of D and 500mg of Q - in total 3 doses roughly 1 month apart. This does not mean that I recommend to take senolytics in order to revert to one's old natural hair colour. But still interesting.

Posted by: Helga at November 26th, 2018 2:59 PM

Thanks for the update. It is very interesting, especially when you take in account the low dose. What about the skin. Did it get more elastic ? Your husband took D+Q too. What did he experience ?

The hair color is simply an easy indicator, that is easy to see. The last few years my hairs started getting grey and sparser. For a guy, that's a minor concern, except that it indicates a general deterioration. The eyes, on the other hand, are very important. Could mean the difference between disability and a normal lifestyle.

You are at the age where you barely start getting concerned with the abuse your body can take :), but still don't have that much of a SASP burden. Probably a little, but still probably not worth the risk of taking dasatinib...
As for the bio-availability or efficacy of fisetin it is too early to tell, especially when you follow anecdotal results without a rigorous test protocol. I do hope that if it gets combined with D+Q it would have a compounding synergy, however. And surprisingly fisetin might be more expensive per dose than generic dasatinib.

Posted by: cuberat at November 26th, 2018 5:54 PM
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