Cellular Senescence in Diseases of the Eye

Cellular senescence contributes to many age-related diseases. Senescent cells arise naturally as a result of the Hayflick limit on cellular replication, as well as injury, or due to molecular damage or a toxic environment that might give rise to cancer. A senescent cell ceases replication and secretes a potent mix of signals that produce inflammation and disrupt nearby tissue structure and function. In youth, senescent cells are near all quickly removed, via programmed cell death or the actions of the immune system, but these removal mechanisms falter with age. Senescent cells accumulate as a result, and the more of them there are, the worse the outcome. These errant cells are thought to be responsible for a sizable fraction of the chronic inflammation of aging, for example, and produce many other ill effects besides.

While good evidence has existed for decades to point to senescent cells as an important cause of aging, the research community at large has only gradually accepted this hypothesis over the last decade. Thus the contribution of senescence to age-related disease is only well studied in a handful of the hundreds of varied age-related diseases. This is very much the case for the eye. There is some recent evidence for senescence to be involved in cataracts and glaucoma, but for any number of other conditions the role of senescence remains to be investigated in depth.

This situation is repeated throughout the body. Since the first senolytic therapies capable of selectively destroying a meaningful fraction of senescent cells already exist, it seems likely that advances in knowledge will be driven by trying the treatments and watching the results, rather than by more passive investigation. This is probably for the best, and certainly much faster if the goal is rapid progress towards effective treatments that can turn back age-related conditions by addressing deeper causes.

The Emerging Role of Senescence in Ocular Disease

Cellular senescence is a state of irreversible cell cycle arrest in response to an array of cellular stresses. An important role for senescence has been shown for a number of pathophysiological conditions that include cardiovascular disease, pulmonary fibrosis, and diseases of the skin. As a central mechanism, senescent cells can impact the surrounding tissue microenvironment via the secretion of a pool of bioactive molecules, termed the senescence-associated secretory phenotype (SASP). However, whether senescence contributes to the progression of age-related macular degeneration (AMD) has not been studied in detail so far.

Acute senescence is mostly beneficial and presumably does not contribute to aging; it relies on the coordinated action of senescent cell production and subsequent elimination - the processes involved in wound healing, tissue remodeling, and embryogenesis. Paradoxically, while chronic senescence can initially have beneficial effects, its long-term existence could potentially aggravate age-related diseases. "Chronic" senescence develops gradually because of progressive damage over time as seen in aging and age-related diseases. During chronic senescence, the switch from temporal to persistent cell cycle arrest appears to be random, induced by the multiple inducing factors acting simultaneously on a cell. These results in arrest of proliferation and ultimately cells become dysfunctional and most importantly negatively affect local environment.

Aging is considered one of the most obvious predisposing factors for the development of AMD because prevalence of this disease rises in those over 60. With aging, the human retina undergoes various structural and physiologic changes. Several independent studies suggest senescence contributes to the development of many ocular diseases. Aging has been associated with fewer retinal neurons along with numerous age-related quantitative alterations such as decreased areas of dendritic and axonal arbors and decreased density of cells and synapses. One study found that retinal pigment epithelium (RPE) cells were lost in large numbers in the periphery of the human retina while a second study reported overall RPE to photoreceptor ratio dropped with age throughout the retina. Furthermore, protein levels of canonical senescence markers such as p16, p21, and p53 were shown to increase in the RPE isolated from aged human donors.

Retinal microaneurysms overexpress canonical senescence markers, suggesting that cellular senescence is associated with the pathogenesis. Apoptosis also cooccurs with cellular senescence in old-age retinal microaneurysms. The age-related decrease in the anterior segment outflow is largely responsible for the elevated intraocular pressure, one of the factors attributing to the development of glaucoma. Markers of cellular senescence are found in the trabecular meshwork of patients with primary open-angle glaucoma and aging of these cells leads to their decreased function and a consequent decreased outflow facility.

Beyond loss of retinal cells, aging is also associated with the accumulation of both intracellular and extracellular deposits. The finding that amyloid-β (Aβ) is also elevated in aging retina and is a component of drusen suggests that Aβ may be a key factor in AMD pathology. Aβ has been recently shown to induce RPE cells to enter senescence. A recent study shows the role of RPE senescence in the retinal degeneration induced by Aβ peptide as characterized by upregulation of senescence markers. Hence, cellular senescence of RPE or neuronal cells induce different age-related retinal diseases and targeting them could be a viable therapeutic strategy.

Comments

I'm wondering how dangerous trying dasatinib + quercetin is?

Posted by: jimofoz at April 13th, 2020 4:27 PM

The universal answer is ... It depends. Since dasatinib is taken by cancer patients it is not too dangerous. Like your will most probably not die, nor have long term measurable negative effects. However, you might be one of the unlucky few that hit the mine..

I was taking fisetin and quercetin and for 3 to 6 days had reduced booth clothing. In dinner cases that could mean the difference between like and death. Dasatinib is deemed nastier than fisetin (but fisetin didn't have to go through the same scrutiny) . From the did experimental crowd it seems If you are below 45, probably you will see almost no benefits. After 65 for sure they're will be benefits. But v how much and what will be the collateral damage? Who knows...

Anyway, if you are below 45 wait for better , more targeted Senolytics and better protocols.

Posted by: Cuberat at April 13th, 2020 8:33 PM

Hi Cuberat,
Please proof read your posts before hitting the Post button. You message above is almost unreadable and certainly not helpful.. You had "reduced booth clothing"? "In dinner cases"?? "From the did experimental"?

Posted by: Dean at April 27th, 2020 12:10 PM

I am wondering about the safety of such senolytics as fisetin and piperlongumine, sold as over-the-counter supplements, in cases of glaucoma, especially advanced glaucoma, as I was reading an article proposing development of drugs that would prevent apoptosis, seemingly the opposite of senolytic drugs, to preserve retinal ganglion cells in glaucoma.

Posted by: Dustin Ginsberg at March 21st, 2021 5:10 PM

@Dustin Ginsberg: the one doesn't preclude the other. Senolytics are anticancer drugs (or would be anticancer drugs that weren't strong enough and/or were too cheap and/or unpatentable to be proper 'anticancer drug' or have other contraindications like poor bioavailability and lack of repeatability of results due to it) that express many other properties. Flavonoids in principle are anti-inflammation and anti-apoptotic substances, fisetin is one of the stronger in this respect, just with exceptionally poor bioavailability. Beyond cancer, the Alzheimer prevention and other brain illness prevention and memory protection and enhancement was the main focus in it's medical development. If it can protect nerve cells it should also protect retinal ganglion cells. The case that it would kill them is only when they express cancer properties (as these are shared by some 'senescent' cells and some cancer cells), and it still must be checked if fisetin would kill them in this specific tissue at all at the doses used.

Posted by: SilverSeeker at March 22nd, 2021 7:24 AM
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