Further Evidence for Cellular Senescence to Contribute Meaningfully to the Progression of Diabetic Retinopathy
Ever more of the research community is drawn to work on cellular senescence by the clear, robust, and expanding evidence for senescent cell accumulation to be a major contributing cause of aging. Clearance of senescent cells by senolytic treatments produces extension of healthy life span and rejuvenation in mice, the reversal of many different age-related conditions. Senolytics are presently in the early stages of human clinical trials, with promising results for some of the approaches taken, such as use of the dasatinib and quercetin combination.
The role of senescent cells in the progression of diabetic retinopathy was outlined in some detail five years ago or so. This form of retinopathy, and others such as macular degeneration, is characterized by the inappropriate growth of leaky blood vessels into the retina, disrupting structure and killing cells. This growth is driven in large part by the secreted signals of senescent cells.
Unity Biotechnology is focused on the development of first generation senolytic small molecule drugs derived from chemotherapeutics such as navitoclax. The company is targeting conditions of the eye for what looks to be much the same rationale as they targeted osteoarthritis of the knee: that they can use localized treatments that minimize any off-target side effects that might emerge with systemic delivery of a drug. Based on the failure of their last clinical trial for localized senolytic treatment of the knee joint, this strategy may prove to be a case of optimizing for regulatory approval at the cost of clinical efficacy. Sad to say, but a great deal of the medical landscape is defined not by what works most effectively, but instead by what the regulators are most likely to accept.
The likely problem with localized approaches to senolytic therapy is that the signals secreted by senescent cells enter the circulation and travel throughout the body. Removing the contribution of local senescent cells may well not be enough to produce reliable benefits in a patient exhibiting chronic systemic inflammation, with significant numbers of senescent cells in all tissues. The failed Unity Biotechnology trial is argued to have been a demonstration of this point. If the company also fails to produce benefits in patients for the eye via localized injection of senolytics, that would likely ensure that no group ever again tries a localized approach.
UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced new preclinical research that reveals a novel mechanism for treating age-related eye diseases - such as diabetic retinopathy and diabetic macular edema - by restoring vascular health in the retina. By selectively eliminating the senescent cells accumulating in diseased blood vessels of the eye, researchers identified a way to target diseased vasculature while leaving healthy blood vessels intact, thus enabling the retina to repair itself.
Researchers demonstrated that diseased blood vessels in the retina trigger molecular pathways associated with aging, collectively termed cellular senescence. The authors used a combination of animal models and human samples to identify a molecular target, called Bcl-xL, that is highly expressed in diseased retinal blood vessels. Targeting these senescent cells with a single dose of UNITY's Bcl-xL small molecule inhibitor led to selective elimination of diseased vasculature, while enabling functional, healthy blood vessels to reorganize and regenerate.
Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16 INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy.
Using either genetic approaches that clear p16 INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.
Although the focus of the research was Diabetic Retinopathy, the Discussion section of the publication specifically mentions possible therapeutic value in Age Related Macular Degeneration and Diabetic Macular Edema. And it mentions that there is mounting evidence for the role of endothelial cellular senescence in tumor metastasis, disruption of blood brain barrier function during aging, and in cardiovascular and metabolic disorders.
Anyone investing in UBX? It's definitely technology that seems to work, but they are using BCL-xl inhibitors which have already been developed by other companies. So what is to stop competitors from launching their own trials with their own BCL-xl inhibitors the moment UBX's trial shows positive results? Or is the pharmaceutical world not so cutthroat?
Hi there! Just a 2 cents.
''Ever more of the research community is drawn to work on cellular senescence by the clear, robust, and expanding evidence for senescent cell accumulation to be a major contributing cause of aging. Clearance of senescent cells by senolytic treatments produces extension of healthy life span and rejuvenation in mice, the reversal of many different age-related conditions.''
I guess we have to agree to disagree here, but I'm the visitor annoying you/your blog so I'll take the blame first. It is sad that ever more research is done on senolytics, such a dead end. Senescence that They speak of is the 'spontaenous senescence (exit of cell cycling) by oxidation/ROS overload' causing p53->-p16 senescence (not p21 senescence which this one gene is replicative senescence causing); not replicative senescence (which is independent) from oxidative damages and replicative senescence - is telomere dependent; if telomeres are too short then replicative senescence will happen; it's what happens in late life when telomere shrink too low (as like that 115 year old woman with 3kbp tall telomeres in immune leukocytes (activation of p21 gene in low telomere size); it means replicative immunosenescence has been reached in immune cells or immune-system related stem cells). Which means immunity loss/no more bactericide killing capacity and later death (by no immunity/bacterial/pathogen invasion/cancer..). It is why people can catch immunity diseases in old age (like pneumonia, tuberculosis, staphiloccoccus, virus (covid), cancer, etc).
''Ever more of the research community is drawn to work on cellular senescence by the clear, robust, and expanding evidence for senescent cell accumulation to be a major contributing cause of aging. Clearance of senescent cells by senolytic treatments produces extension of healthy life span and rejuvenation in mice, the reversal of many different age-related conditions.''
cellular senescence is a clear health degrader 100% agree, this cellular senescence spoken of, is classified and differentiated/nuanced as 'spontaneous/cell cycling exit' due to damages/oxidation causing sudden exit of cycling/ 'normal aging' cell cycling. It is Not the Replicative senescence when they talk of cellular senescence; or, let's say, it is not the brunt of the senescence; their might be some accelerated replicative senescence; but the brunt of it is Spontaneous Senescence/Damage-caused Senescence; Unrelated to cell cycling - causing replicative senescence - by time passing and 'the limit' being reached - Hayflick Limit/when telomeres are Too Short - Replicative Senescence (activation of p21 signal at low telomere bp size).
p53 -> p16 -> spontaneous senescence/cell cycle premature exit (p21 is not there at all).
p21 -> replicative senescence/cell cycling hayflick reached (p21 is Required to make replicative senescence).
''Ever more of the research community is drawn to work on cellular senescence by the clear, robust, and expanding evidence for senescent cell accumulation to be a major contributing cause of aging. Clearance of senescent cells by senolytic treatments produces extension of healthy life span and rejuvenation in mice, the reversal of many different age-related conditions.''
It is not a cause of aging the real one), it is (just my p.o.v) instead, a degrader of health/premature 'end' when you die of disease too fast/before your time; senescent cell accumulation only Hastens the loss of health - with age 'hence die younger -Unrelated to aging'; by not preserving it. It is why studies is mice produce health lifespan extension after senolytics but little maximal lifespan extension; in essence, it is a Health promoter/preserver; to live your full life 'to its maximum'; notthing more. It reduces inflammation - inflammation = health related. Not even damages are related to aging because they can be Uncoupled from aging. That is why it so ambiguous. Thus, is Not of aging. Is of healthspan control/preservation. That is my point of view only. We have a life, and we may die prematurely of 'inflammation or 'spontaenous senescence' causing some disease...that one..they talk of continuously not mentioning that is it different than 'passaged replicative senescence' (telomere/cell cycling hayflick limite dependent); not making that difference is commiting an error and being fool(ish) of the whole thing. Anyway that' just what I believe (and I have been wrong many times, I admit it, I often backtrack on things when I found out 'oh no....sht...I thought it was that all along...I was wrong, totally wrong 'out there in the field''). Aging is complicated, it is sadly not simply damages equal aging. It's more nuanced than that and very paradoxal/catch22/2-faced because body is continious 'yin-yan' balance that autobalances itself; evolution evolved this 'perfect' paradoxal balance (I say perfect, it's not perfect but it is 'in balance' enough to function in the first place, a pretty incredible feat biologically speaking). When we see white, it's actually black; when we say yes, it's actually no. Etc.
Just a 2 cents.
PS: Epigenetic aging completely changed my thinking of it all, it used to be simpler, it got (more) complicated (sadly). I wish us all to have biorejuvenation that Works and Truly ends aging in the truest of the truest of the...sense; and senescence is not whole sense of it (well, spontaneous 1 that is). We have a finite life due to these limits (imposed by epigenetic clock ticking down), we die prematurely of diseases, which are related to spontaneous senescence; or, we can live longer without them; healthy and inflammation-free; We Still Die, one day, 122 or so. the max; imposed by clocks and hayflick happening at one time or another as our telomers dwindle down.