Today I had the pleasure of talking to Prof. Dorota Skowronska-Krawczyk (@DrDorotaSK) on the VitaDAO Aging Science Podcast (episode 8). We discussed the importance of basic aging mechanisms like senescence, repeated stress and inflammation as drivers of multiple eye diseases. We talked about the lack of good animal models for age-related eye diseases, prevention of age-related macular degeneration, unity therapeutics and recent trials of senolytics for eye diseases.
Short Bio
Dorota was born in Lodz, Poland and later studied biology in Warsaw, Poland where she finished her studies with distinction. She received a PhD in Biochemistry at the University of Geneva, Switzerland. Then she finished two postdoctoral trainings – in Lausanne, Switzerland and at UCSD San Diego before starting her independent career in May 2017.
Work in her lab focuses on deciphering the mechanism of age-related eye degeneration. Using retina as a model system, the lab employs modern technologies to address unresolved issues, such as the role of fatty acids in age-related neurodegeneration and the role of stress in accelerated aging. In her free time, she likes to travel alone or with family.
Prof. Dorota Skowronska-Krawczyk
Center for Translational Vision Research, UC Irvine, School of Medicine
https://faculty.sites.uci.edu/skowronska-krawczyk/
The eye is a privileged organ
The eye is sometimes referred to as an “immune privileged” organ because the blood-retinal barrier shields it from invading immune cells. While this may be beneficial, it could also mean reduced clearance of senescent cells via NK cells (or future adoptive cell based therapies). On the other hand, the eye is very accessible which makes it easy to administer drugs directly using intravitreal injections or topical application. Dorota and I agreed that this could mean early proto-gerotherapeutics would be first available to treat eye disease before they are used to treat other tissues, as the local nature of these treatments would prevent systemic side effects.
Aging promotes multiple eye diseases
We discussed just how exquisitely sensitive the eye is to aging. There are so many eye diseases that show a textbook exponential pattern of increasing incidence with age. This means if you live long enough you will likely develop one or all of these diseases. Dorota works on two of the more famous eye disease, age-related macular degeneration (AMD) and glaucoma. Other common age-related eye diseases include cataract, near-sightedness and diabetic and hypertensive retinopathy. The former two reaching a prevalence of 80% or more in the very old. Less know age-related eye disorders include dry eye disease and eyelid muscle weakness associated with drooping eyelids.
Nevertheless, there are species that can maintain their eye health far longer than humans including some turtles, whales and Greenland sharks. Dorota mentioned that she would really love to study the eyes of these sharks that are able to live up to 400 years. As we have discussed in the podcast with Vera Gorbunova, this kind of approach is called “comparative” and it often yields very interesting insights that are quite off the beaten path.
Age-related macular degeneration (AMD)
Age-related macular degeneration (AMD) is characterized by the progressive degeneration of the macula, the central part of the retina responsible for sharp, central vision. The incidence of AMD increases significantly with age, reaching >10% in people over the age of 80. AMD is categorized into two main forms, wet (neovascular) and dry (non-neovascular) AMD. As we discussed during the podcast, there are very few treatment options for dry AMD and mice do not have a macula, further hampering research into this pathology. Alternative models like dogs and non-human primates are very expensive.
Typical molecular hallmarks of AMD are extracellular deposits called drusen and intracellular deposits called lipofuscin. The retinal pigment epithelium is responsible for phagocytosing and removing outer segments of photoreceptors after they have become damaged during the vision process. The sheer volume of recycling is quite remarkable as every day 10% of these outer segments are lost and recycled. The sensitivity to AMD might be somehow rooted in this high metabolic activity, although we do not know for sure.
We mentioned during the podcast that AMD is one of the few diseases where the now unpopular “oxidative stress theory of aging” triumphed, since a cocktail of antioxidants was shown to slow progression of early AMD (AREDS study). Surprisingly, while omega 3 fatty acids from fish appear protective in observational studies, these benefits could not be replicated in controlled trials (AREDS2 study). Dorota believes that a better and more refined formulation might eventually work in another trial, perhaps AREDS3. Of course, it is also a real possibility that observational studies produced exaggerated or spurious results as they are wont to do.
Glaucoma
Glaucoma, is actually not just one disease but probably a whole group of eye conditions leading to optic nerve damage. Glaucoma is primarily associated with an increase in intraocular pressure (IOP), however – and this was quite a surprise to me – a subset of cases known as normal-tension glaucoma (NTG) occurs without elevated IOP. Importantly, IOP is unrelated to blood pressure.
The prevalence of so called open angle glaucoma is around 20% at the age of 90 with an exponential increase during aging.
Pathologically, glaucoma involves the progressive degeneration of retinal ganglion cells, causing irreversible vision loss. This is in contrast to AMD, where the retinal pigment epithelium and photoreceptors degenerate. Another difference between the two pathologies is that we have better treatments for glaucoma.
Glaucoma is sometimes called the “silent thief of sight” because the vision loss only becomes obvious after a significant amount of irreparable cell loss. This is not unlike the situation with AMD, where the eye and brain are able to compensate for cell loss until a considerable amount of damage has been done.
Dorota in her research found that old mice are much more susceptible to increased IOP whereas in young mice it takes multiple cycles to cause the same amount of vision loss (Xu et al. 2022). This finding is consistent with the idea that aging can be broadly defined as the loss of resilience towards stressors. We also talked about inflammation during glaucoma and whether the inflammation is local or due to immune cell infiltration – a question that vexes almost every aging researcher studying any kind of tissue. Based on bulk RNAseq and RNAscope data she believes that inflammation in glaucoma is specific to ganglion cells.
Commonalities between eye aging and aging more broadly
Inflammation, repeated “stress” (e.g. elevated intraocular pressure), oxidative stress and senescence are hallmarks of both aging and eye aging. Dorota has had a lot of success using senolytics in mouse models of glaucoma, specifically dasatinib (Xu et al. 2022), underscoring the importance of senescence as a universal pathomechanism. She does believe there is some evidence for senescence in AMD as well, although this is not entirely clear due to a paucity of in vivo studies (Malek et al. 2022). Given this, we were both puzzled and disappointed by the failure of Unity’s senolytic – the Bcl-xL inhibitor UBX1325 – for wet AMD (1).
Obviously not everyone is in love with the senescence hypothesis and ultimately we have to wait for more data to settle the issue.
Targeting inflammation has been a glimmer of hope for those with dry AMD. The first ever approved drug for this condition, pegcetacoplan, inhibits the complement system, which is a cascade of proteins normally used to amplify immune responses against pathogens. Dorota believes that both AMD and glaucoma may have an inflammatory component. Thus it is tempting to speculate that chronic senolytic or other anti-inflammatory therapies could slow the development of both of these diseases. I mentioned to Dorota that perhaps starting treatment in late-stage disease was not such a good idea for this very reason.
Finally, we also speculated about general mechanisms of aging. Dorota asked how could it be that damage is repaired and completely removed, as far as we can tell, yet it still predisposes the organism to future disease and stressors? Could it be that the repair machinery was diverted from other places where it was needed? To me this whole idea is somewhat reminiscent of certain epigenetic aging theories where DNA damage, even when repaired, leads to local changes in epigenetic marks that predispose to aging. On the level of gene expression it seems very plausible that stressful events could introduce some kind of noise into the system that can be fully compensated while reducing the resilience of the system.
In her recent article titled "Hallmarks of Aging: Causes and Consequences." Dorota further elaborates on her views and tries to put the hallmarks into a temporal order. Her approach is certainly not bad considering how botched the naming of hallmarks is in the new paper. Who came up with the terms “primary, antagonistic, and integrative”? (2)
My opinion remains: all hallmarks are wrong, some of them are useful. We can achieve a lot without a full understanding of aging as the seminal discoveries of caloric restriction and rapamycin show. Now we just need to convince politicians that the only Manhattan project worth funding is the anti-aging project.
References
Stress induced aging in mouse eye.
Xu Q, Rydz C, Nguyen Huu VA, Rocha L, Palomino La Torre C, Lee I, Cho W, Jabari M, Donello J, Lyon DC, Brooke RT, Horvath S, Weinreb RN, Ju WK, Foik A, Skowronska-Krawczyk D. Aging Cell. 2022 Dec;21(12):e13737. doi: 10.1111/acel.13737. Epub 2022 Nov 17.
Does senescence play a role in age-related macular degeneration?
Malek G, Campisi J, Kitazawa K, Webster C, Lakkaraju A, Skowronska-Krawczyk D.
Exp Eye Res. 2022 Dec;225:109254. doi: 10.1016/j.exer.2022.109254. Epub 2022 Sep 21.
Skowronska-Krawczyk, Dorota. "Hallmarks of Aging: Causes and Consequences."
https://agingcelljournal.org/Archive/Volume2/hallmarks_of_aging/
(2) Obviously the failure of the hallmarks simply reflects the complexity of aging and lack of consensus rather than the shortcomings of the authors. There is no doubt that the hallmarks papers are useful.
Nevertheless, a few pet peeves of mine. Is the telomere not a part of the genome and central to genome stability? It has always been a very odd choice to put telomeres as their own hallmark. Another interesting choice is to put mitochondrial dysfunction as an antagonistic hallmark. Are other organelles not dysfunctional during aging?
I must say I fully agree with Dorota that the hallmarks were always somewhat confusing because they merrily mix together things like damage (genomic instability), pathways (nutrient sensing), cellular processes (autophagy or proteostasis), organelle dysfunction and systemic/tissue pathology (inflammation). I would much rather think and classify in these terms:
Damage -> cellular process -> cell level pathology -> tissue and organ level pathology
With another strict distinction between cellular processes of “damage prevention” (e.g. antioxidants), “damage repair” (e.g. DNA repair or autophagy) and “damage compensation”.
