ELOVL2 Upregulation Reverses Age-Related Decline in Vision Loss in Mice
In today's open access research materials, the authors report that upregulation of the gene expression of an identified marker of aging, ELOVL2, can improve visual function in aging mice. Normally, expression of ELOVL2 declines with age, and consequent effects on visual function may involve the role of ELOVL2 in production of long-chain omega-3 and omega-6 polyunsaturated acids. These metabolites are in high demand in retinal cells, and lowered levels may well cause a sizable fraction of age-related dysfunction.
Any discussion of this change in ELOVL2 expression and visual function is interesting in the context of why degenerative aging takes place. It is clearly the case that considerable dysregulation of cellular metabolism takes place with age. The proximate cause of this degeneration of function is changes in the epigenetic regulation of gene expression, the pace of production of various proteins essential to cell function. In near all cases it is quite obscure as to why exactly these epigenetic changes take place - researchers are far more interested in identifying changes than in the much more arduous work of understanding the full context of any given change. The underlying damage of aging is well catalogued, such as in the SENS view of aging, but linking this damage through a long chain of downstream consequences to specific age-related functional consequences is a sizable project, still in its very earliest stages.
Researchers Identify Gene with Functional Role in Aging of Eye
A lengthy-named gene called Elongation of Very Long Chain Fatty Acids Protein 2 or ELOVL2 is an established biomarker of age. Researchers found that an age-related decrease in ELOVL2 gene expression was associated with increased DNA methylation of its promoter. Methylation is a simple biochemical process in which groups of carbon and hydrogen atoms are transferred from one substance to another. In the case of DNA, methylation of regulatory regions negatively impacts expression of the gene. When researchers reversed hypermethylation in vivo, they boosted ELOVL2 expression and rescued age-related decline in visual function in mice.
ELOVL2 is involved in production of long-chain omega-3 and omega-6 polyunsaturated fatty acids, which are used in several crucial biological functions, such as energy production, inflammation response, and maintenance of cell membrane integrity. The gene is found in humans as well as mice. In particular, ELOVL2 regulates levels of docosahexaenoic acid or DHA, a polyunsaturated omega-3 fatty acid abundantly found in the brain and retina. DHA is associated with a number of beneficial effects. Notably, its presence in photoreceptors in eyes promotes healthy retinal function, protects against damage from bright light or oxidative stress and has been linked to improving a variety of vision conditions, from age-related macular (AMD) degeneration to diabetic eye disease and dry eyes.
The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina
Methylation of the regulatory region of the elongation of very-long-chain fatty acids-like 2 (ELOVL2) gene, an enzyme involved in elongation of long-chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age-associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age-related eye diseases.
We show that an age-related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5-Aza-2'-deoxycytidine (5-Aza-dc) leads to increased Elovl2 expression and rescue of age-related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2-specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well-established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration.
These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age-related eye diseases.
I think we need to be careful not to dismiss age-related functional decline that does not fit neatly into the SENS categories. There could theoretically be programmed kinds of cellular decline that are involved in aging. There is good evidence for programmed rapid senescence occurring in lower organisms, and I do not think we know enough to completely discount the possibility that this process could be at play in mammals as well.
If most early humans died at 40 years old, there would be nothing to select against if a run-away genetic circuit declined to sub-adequate levels of protein production by 80 years.
Thankfully, I think this decline is a) probably not very severe, as we don't see people dying in old age from processes of this nature and b) very easily treatable because we can either reprogram the cells to a younger state (as done in this study) or supplement the lacking proteins directly in some cases. However, we should continue to support research attempting to understand new types of damage even if they may appear at first glance to be downstream effects.
"There could theoretically be programmed kinds of cellular decline that are involved in aging."
The theoretical reasoning used to support programmed aging is very weak, requiring a very powerful (and unjustified) kind of group selection while the non-programmed aging theories are much more natural and straightorward.
"If most early humans died at 40 years old, there would be nothing to select against if a run-away genetic circuit declined to sub-adequate levels of protein production by 80 years."
That's a non-programmed view on aging! It's the classical reasoning of low selective pressure in old individuals -> not good repair/homeostasis of necessary mechanisms of life -> damage accumulation -> aging.
Programmed aging is very different. The failure of bodily systems is *selected for* , not simply non prevented by non perfect repair/homeostasis.
Well, I suppose it depends on your definition of "programmed aging." I take the term to mean "a genetic program which leads to damage in chronologically older individuals." I agree with you that such programs are unlikely to be selected for, but they could still arise through drift. Most likely, there is just no need for all genetic programs to be stable indefinitely.
Either way, the end result is the same: a genetic circuit becomes harmful over time. The harm is intrinsic to the program and will not be solved by correcting other kinds of damage. Therefore, such damaging circuits, if they exist, will eventually need therapies to correct them.
Now, I believe that there are bigger fish to fry when it comes to damages due to aging. Such damaging circuits will necessarily be unlikely to be exceedingly problematic because they are easy (evolutionarily) to fix and thus unlikely to be the sole limiting factors of our lifespans. However, we should be researching this and not dismiss all non-SENS forms of damage as second-order effects. Eventually, I am sure at least some of our genetic circuitry will go awry in the same sense that a robot programmed to go in a circle will eventually veer off course in a matter of centuries if the programmers only designed it to remain on course for a matter of years.
Nope. The programmed aging paradigm proposes there is a program in your normal genome that makes you aged when your time comes. The random degeneration of a program we all have is NOT A program. It fits instead in the damage-accumulation non-programmed aging paradigm. Please review any paper on programmed aging that defines it.
I think the classic definition of programmed aging is strictly a program that has evolved specifically for the purpose of destroying an older organism. I make no claim that we have programs that are intentionally (or naturally selected to) destroy us, but rather that we may have programs that inadvertently destroy us through non-selected mechanisms. My main point is that, whatever we want to call these circuits, they may cause damage in ways that are not covered by SENS strategies. As this article states with the ELOVL gene, we see decline in production in older organisms. The hypermethylation could be caused through non-genetic means (such as some stress response), but it could be the result of some run-away feedback loop that eventually declines with age.
Let's imagine some enzyme of which we need at least 100 copies per cell as a child and at least 50 copies per cell as an adult. A reasonable circuit to evolve would start off production high, and then decrease translation by a steady amount each year to avoid over-producing the enzyme. This works just fine for the first 80 years of life, but production drops too low in very late life. This doesn't matter historically, because most humans are dead by then anyway, so the circuit stays fixed in the population. However, this is going to be a problem for us in the modern era. You can call this programmed aging or not, but the point remains that we should stay vigilant for this kind of aging damage and not assume that it is a downstream effect of damage which we will deal with through other therapies.
Epigenetic drift has always been discussed in the framework of OncoSENS and dismissed as a problem for our current lifespans (like genetic drift too) save for its relation to cancer.
Decitabine looks interesting. Fortunately, I have recovered from retinal degeneration. There was a significant improvement in my vision both near and at night. To improve, it was enough to stop taking the aging accelerator citrulline (citrulline and arginine are in potency medications). I was also helped by the combination of two drugs:
Olive leaf extract contains hydroxytyrosol (enhances intestinal microbiota)
gymnema against fatigue
So far, my vision has not improved after any other medicine.