Fight Aging!

AMD, age-related macular degeneration, results in progressive retinal damage and consequent blindness in the central portion of the visual field. Like many age-related conditions at root it is caused by damage and failures in tissues that happen to everyone, but in some people this rises more rapidly to levels sufficient to cause noticeable pathology. Lifestyle choices with a negative impact on circulation and chronic inflammation, such as lack of exercise, obesity, and smoking, all raise the risk of suffering this form of degenerative blindness. But if everyone lived long enough, we'd all get it eventually: absent treatments for aging, missing out on any specific age-related disease at the present time is really just a matter of being nailed by something else first.

Of course we'd like to do better than rolling the dice and taking bets on what kills us first. We want the means to repair the slowly accumulating forms of cellular and molecular damage that cause aging - to miss out on all of the consequences of aging and continue living in good health and youthful vigor. This will be a new strategy in medicine, one that at present has only recently gained acceptance in the mainstream research community. Working to treat aging itself is a departure for the scientific community, which up until now in has focused on trying to patch over the consequences of aging, the many varied age-related diseases such as AMD, one by one. This end stage of aging is a complex forest of dysfunction and failing, flailing biological systems struggling to cope, and progress in any sort of meaningful treatment has been correspondingly expensive and the benefits marginal.

Aging has simple roots, however, just a few forms of cellular dysfunction and hardy waste products that result from the normal operation of our metabolism. Like rust in an intricate metal structure, the end result of simple damage accumulating in a system as complicated as human biology is by necessity very complex. Damage spirals out in chains of cause and effect, as systems that rely upon one another progressively fail in their function. There is a little of genetics and a lot of lifestyle choice in the risks of any particular age-related condition versus another, but mostly it is dumb luck: small random events in your biology snowball into large differences over time. Why focus on trying to manipulate and manage the complicated end results when you could focus on removing the simpler causes? It is well past time for this change in medical strategy.

AMD is a poster child for some attempts to repair the causes of aging because there is a fairly direct link between retinal cell death and one form of hardy, lingering metabolic waste product generated in the normal course of being alive:

Age-related macular degeneration is the leading cause of blindness in people over the age of 65. It is caused or exacerbated by the accumulation of A2E (a toxic byproduct of vitamin A metabolism) in the cells in the retina of the eye. A2E is resistant to breakdown in the lysosome, and therefore accumulates in the lysosomes of retinal pigment epithelial cells throughout life, until the cells become disabled and vision begins to fade. Enzymes that could break down A2E would thus lead to a regenerative cure for age-related macular degeneration.

Direct links are good because it makes for a more straightforward test case and proof of principle. The evidence to date strongly suggests that repair, in this case breaking down waste products, will cause benefits. So there is less likelihood of research efforts becoming bogged down in questions of interpretation or tracing cause and effect through several or more layers of poorly understood biological mechanisms. This is important when there is as little funding for rejuvenation research like this as is presently the case: work must be efficient and lead as directly as possible to solid proof for the repair approach as a research strategy.

Here is an interesting review of what is known of the mechanisms of AMD as well as the present mainstream approaches to treatment - a list that does not at this time include the approach of breaking down metabolic waste products like A2E known to contribute to the condition. It is a small illustration of the larger point that aiming at repair of root causes is a whole new paradigm for the research community, and one that is only just starting to gain greater acceptance. It is still the case that the overwhelming majority of research on age-related disease that you see today is not informed by that viewpoint on strategy and goals:

Present and Possible Therapies for Age-Related Macular Degeneration

AMD is an umbrella term that encompasses two pathologically overlapping, yet distinct, processes: geographic atrophy (GA) (dry) AMD and neovascular (wet) AMD. Clinically, the presentation of AMD differs depending upon the development of neovascular or GA AMD. Unfortunately, both GA and neovascular AMD orchestrate a progressive and unremitting sequential loss of central vision within the affected eye(s) cumulating to blindness.

Our current understanding behind the pathogenesis of AMD stipulates that there is no predominant aetiological factor dictating the development of AMD. Rather, there is a multifactorial element to AMD, whereby interactions between several facets intertwine and coordinate a cascade of sequential steps that provide the appropriate environment for AMD to flourish. However, implicated for both forms of AMD are the involvement and degeneration of four principle ocular regions: the outer retina, the retinal pigment epithelium (RPE), Bruch's membrane (BM), and the choriocapillaris. Although the intricate processes explaining their degeneration still remain elusive, four mechanisms have been postulated as being imperative to the formation of AMD: lipofuscinogenesis, drusogenesis, inflammation, and choroidal neovascularisation; the former three aspects are critical to formation of both types of AMD, whereas the last represents the final stage in the development of neovascular AMD.

Lipofuscinogenesis

Over the course of senescence, there is progressive dysfunction of the RPE, thereby inducing a state of metabolic insufficiency which results in the formation and accumulation of lipofuscin. Deemed highly potent, due to the major component of lipofuscin being N-retinylidene-N-retinyl ethanolamine (A2E), the A2E produced has the ability to interfere with the functional aspects of the RPE, thus triggering apoptosis of the RPE with subsequent development of GA. Furthermore, the accumulation of A2E within the RPE has been shown to increase the risk of choroidal neovascularisation and so neovascular AMD.

Drusogenesis and Inflammation

Defined as "discrete lesions consisting of lipids and proteins", these amorphous deposits accumulate within the region situated between the RPE and the BM. Their clinical significance differs as relatively few quantities of small, hard drusen have been identified in over 95% of the elderly population and are regarded as a benign occurrence. Nevertheless, presence of large, hard and/or large, soft drusen has been recognised as increasing the risk of AMD. One component of this affiliation orientates around the physical displacement, and resulting death, of clusters of photoreceptors within the RPE overlying the drusen, thus leading to GA AMD.

Another dimension to the relationship between drusogenesis and AMD occurs through the indirect influence of drusen on the immune system. Indeed, identification of several components of the immune system within drusen has raised the possibility that drusen mediated inflammation may lead to notable degeneration and disruption.

Choroidal Angiogenesis

There is a delicate balance within endothelial cells residing in the retinal vasculature between factors that promote and inhibit angiogenesis. However, in neovascular AMD, there is a pathological shift in favour of factors promoting angiogenesis. It is postulated that the inflammation and recruitment of several components of the immune system trigger the release of proangiogenic mediators such as VEGF, thereby forming a milieu that favours angiogenesis. Regardless of the exact mechanism, progression to neovascularisation leads to the formation and extension of permeable, weak, and leaky vessels from the vascular choriocapillaris to the avascular choroid which, in turn, induces local oedema but, more profoundly, acute central vision loss resulting from haemorrhage with successive development of a fibrous scar.