Human Longevity, SRT1, and Alzheimers Disease: A Brief Review of A Recent Publication
Today we discuss, as we have many times in the past, some recent research pertaining to a condition that interests me. Alzheimers Disease, a disorder of the brain which results in an reduced ability to form new memories, access old ones, and over time, think in general. Its a disorder that touches the lives of many, and has certainly impacted my and my families lives, leaving its mark.
Our discussion today will revolve around a recent publication from Nature Scientific Reports titled "SIRT1, miR-132 and miR-212 link human longevity to Alzheimer’s Disease" (you will note the parallels between the articles title and this blog posts title). This work, done out of the university of Tel Aviv in Israel utilizes some quantitative PCR based techniques to characterize the relative expression levels of the protein SIRT1 (Sirtuin 1, a deacetylase, meaning a protein that is able to remove the protein acetyl modification) as well as two miRNA's (mirR-132 and miR-212), and compares the determined expression levels from extracted lymphoblastoid cells from healthy controls versus patients with Alzheimer's disease.
SIRT1
SIRT1 is a protein which is known to function as a deacetylase, with one major function being its involvement in removing acetyl groups from histones. Histones which I am sure many of you are aware are the proteins involved in the formation of nucleosome core particles and control the packing state of DNA, allowing genes to be accessable for transcription or unavailable depending on that packing state. Acetylation of histones is one such post translational modification with the ability to regulate this compaction, where acetylated histones have a less positive exterior charge and a weakened interaction with the negatively charged backbone of DNA, resulting in looser packing and the increased accessibility of genes.
One interesting finding that these authors previously reported relative to a homologous SIRT1 protein found in yeast (Sir2), was that increased expression of this protein resulted in a longer yeast lifespan. [2] Additionally, in an Alzheimer's mouse model, it was found that over expression of the mouse variant of SIRT1 helped to protect the mice against the neurodegeneration which is characteristic of the disease. [3]
miR's
miR stands for micro RNA. These are short RNA pieces, which do not code for anything. Rather they are complementary to sections of genes and can thus bind to their complementary regions on gene's mRNA. When miRNA bind to their complementary regions they block the protein translational machinery (the ribosome) from being able to properly assemble the respective encoded protein. This results in lower levels of gene expression in a cell. This means that miRNA's are a natural mechanism that cells use to regulate the expression levels of proteins. As such different cell types often have different miRNA expression levels, allowing them to control the amounts of specific proteins that are present, aiding that cell type in performing the functions that make it unique (note this is not the only regulatory mechanism, just one of many).
The two miR's studied in this article were found to target the SIRT1 mRNA. Above it was mentioned that over-expression of the SIRT1 was found to increase longevity in yeast, and protect against neurodegeneration in a mouse model. So one would hope that deleting these miR's would result in a similar effect as removing them would increase the expression levels of SIRT1. Researchers did find an Alzheimer's related phenotype from deleting the two miR's, however not one that is positive. Rather deleting miR-132 or miR-212 in a mouse model resulted in an increase in the expression of the Alzheimer's related Tau protein. [4]
Interesting Results From The Article
As was mentioned above, the authors cultured lymphoblast cells from both healthy and alzheimers patients and explored the relative expression levels of the components we outlined above (SIRT1 and the miR's)
The data relative to the expression levels of SIRT1 is depicted above. We can see that the expression level of the SIRT1 protein is always low in the alzheimers patients relative to healthy patients of any age. Interestingly you may note that those who are the oldest (100-105 group) all have very high expression levels of SIRT1.
The opposite was true for the miR's, where the data shows increased expression levels in the Alzheimer's patients and the lowest expression levels in the oldest healthy age group.
The authors also show a modest correlation (@lemouth, I said it was modest... try not to be too angry with my looseness in being excited by this data... yeah yeah I know P=0.02... Id rather it be 0.000005 but hey, these are cultured cells taken from real patients, not particle physics experiments!) between the expression level of the miR-132 and the age at which an Alzheimer's patient had an onset of symptoms.
Other Data
The authors illustrated strong correlations between the relative expression levels of SIRT1 and the two miR's and the cognitive function levels in the Alzheimer's patients. Where Alzheimer's patients with higher SIRT1 expression levels, and/or lower miR expression levels had significantly better cognitive functioning.
Some Take Aways
Mouse models indicated that SIRT1 had a protective effect against neurodegenerative effects in Alzheimer's mouse models, that would appear to be recapitulated by the experiments described by these authors here. Where Alzheimer's patients expressing more SIRT1 had better cognitive functioning. Additionally, the miR's which here would be down-regulating the expression of SIRT1 are shown to correlate to less cognitive functionality.
It is interesting to note that previous data indicated a link between longevity (in yeast) and the over expression of SIRT1, and all of the participants in this study who were of the oldest age all expressed the highest concentrations of SIRT1 in the study. The data presented here isn't strong enough (IMO) to conclude much of anything, but it is certainly an interesting coincidence, isn't it?
All in all, the authors of this article present some interesting data correlating the relative expression levels of these cellular components and illustrate clear (enough) relationships between those expression levels and Alzheimer's disease, implicating SIRT1 in a protective role, and illustrating that miR-132 and miR-212 may be able to serve as very effective biomarkers for cognitive decline in Alzheimer's patients.
...And potentially... even preliminary evidence for SIRT1's involvement in longevity in humans (though that truly remains to be seen!)
I await the next update from this field! How about you?
Article Citations
- https://www.nature.com/articles/s41598-018-26547-6
- https://www.nature.com/articles/35001622
- http://emboj.embopress.org/content/26/13/3169
- https://academic.oup.com/hmg/article/24/23/6721/2385776
Image Attribution
Image 2: By Kelvinsong [CC BY 3.0], from Wikimedia Commons
I am glad you said that this was a modest correlation because all I saw when I looked at this plot was a random scattering of data points.
Maybe they will be able to improve the data one day.
Its one of those situations where I would state that as there appears to be a trend in the data, but wouldn't go so far as to call it a correlation. Were it my data. But it isn't so hey... :D
I am modestly fine with this statement. Note that I only recommend people to add grains of salt where needed, nothing more nothing less :)
This being said, there is maybe a trend here and this is motivating enough to justify getting more data, no.
That's about as far as I could go with that last plot yeah.
Plus I was also just teasing you in the article :D
I missed this :)
How long has it been since I saw you blogging science?^^
SIRT and related miRs seem to look promising indeed. I am however quite surprised that you can publish something like figure 1F in fucking Nature. I see just scattered data points, sorry. Probably they should have increased the sample size by a lot. But hey, Nature, so who cares? ;-P
Being newish, I didn't even see him blogging science until now :)
Hmm, I've been here for a long time. I was also one of the main science bloggers early on.
I was talking about myself. I am the new guy, this was actually my first vote for you.
Keep writing if you have time, I really enjoyed it!
I will, don't worry.
It's nature scientific reports, not nature :)
Less scrutiny. You don't like figure 1F? It's seriously what I would expect given the nature of the samples.
The fact that they weren't completely random scatter is significant IMO.
Now, should someone look for whether that weak ass correlation holds in like 1000 samples? Hell yeah, then we will know it's real. For now it's just a "hmm" sort of plot.
Seems like 132 especially helps deal with tau formation. I think they should look at why some of those individuals in the two younger healthy groups had high levels of both... the graph seems a bit odd to me. Especially if 132/212 cause or are caused by an inflammatory state, then I'm not sure if on second inspection those individuals would really be considered "healthy".
This SiRT1 stuff is interesting.
Caloric restriction itself can make SiRT1 levels higher. To me this falls in line with research I've read about populations that have survived periods of famine and long-lived people who don't eat that much. It also really doesn't surprise me that only the 100+ healthy group has high levels, and a lot of the younger people don't.
I would like more information on what the diet of these people consisted of and how many calories they're taking in every day, as well as their bmi and body fat %. I know that many people with Alzheimer's basically can't control their sweet tooth in part due to their condition and are practically drowning themselves in sweets and meals much too large for their metabolisms to keep up with. And it's quite likely that the other groups aside from the 100+ group are also never experiencing caloric deficiencies or intermittent fasting scenarios.
It may, but I don't understand that relationship.
Anecdotal, I can add my own anecdotal evidence of the contrary for some Alzheimer's patients.
In all, I suspect that Alzheimer's has a plethora of contributory factors including general environmental factors, certainly their is a metabolic component but it may or may not be directly related to diet.
One of your links had this
Which led to this https://academic.oup.com/hmg/article/20/20/4016/697377
and
Yeah, I guess researchers don't know exactly why this all is, they just found the connections between the miRs and tau.
Well, there have been clear established links to, for example, dairy and red meat consumption and AD, and those things are also linked to inflammation and poor circulatory health, and about a quarter of AD is vascular and AD itself is contemplated by some to be an inflammation-related disease so...
Yep, lots of interesting findings, but not a clear picture of how it all pieces together. For that, we will need... more data.
Yes and? Correlation is not causation. I just don't believe the data yet. I need more information and stronger relationships! I find a lot of things interesting, I just don't ascribe to any of it being the answer. If that makes any sense...
Yeah, more data is always nice. I do think the next few decades will be interesting as we've already seen increased incidents in countries that previously didn't have many, and more countries seem to be adopting a western lifestyle.
I don't think any single factor will ever be discovered to be the cause, I just think that a slew of factors increase the chance the brain reaches the tipping point where things start to go wonky and the brain is creating more tangles, failing to successfully create new neurons, and isn't properly flushing out the tangles during sleep.
Like, for example, statins, they say they aren't sure if they help or not, but on the one hand you have people who are perhaps suffering more from the vascular aspects and it might help them a bit more than others, but on the other hand it might make things worse for some if there is some interaction where it's interfering with myelin health.
Well that's sort of the deal with medicine, everything has a trade off. Incorporate drugs to modify aspects of your bodies function when the net effect will extend your life. Their ain't no such thing as a free lunch. I take hypertension medication, knowing full well that it's damaging my circulation. I must work to mitigate that damage, but irregardless, I would die much sooner from my blood pressure damaging my arteries and organs the opposite way, then I will from the BP meds.
Same goes for everything, statins are no excepton. They don't come with out a cost, but for some, that cost is less then not using.
I wish people thought more about what medications are, and didn't just think they were cost free.
Tiny bits of advances, but they seem hardly relevant for this generation. Charming for the future generations, but we still have to live in the doom of the uncurable degeneration of our minds. Still gotta love the doctors and researchers who put all of their time in this field. I hope that just as technology accelerates on other things, our genetic analysis tools get better with time as well in a super fast way.
Maybe in 20 years they'll have a decisive delayer of brain degeneration.
Science is built upon tiny advances ;)
I know :D It's just despairing. I want to be immortal now, not in my next life. :D
Eh, enjoy your days. I don't think immortality would be all it's cracked up to be. That said living for a few hundred years wouldn't be too sad!
I agree, but I believe that nature and organic foods play a role in this, as this disease was not viral as it is today.
I think the ability to share information that we have today can make these advances happen faster and faster. Lots of little advances all adding up
Welcome BACK!!!!!!!!
Thanks man. Yeah, trying to write again. :)
One man step for man and a giant leap for humankind. I'm always horrified of ever losing my memories, I have watched a close relative lose him, it is almost like you are no longer you. Afterall what makes us who we are our experiences and memories, if that is taken away from us we will be nothing. I'm always happy to see advances in the study towards a cure or better understanding of Alheizeimers diseases and cancer.
I know exactly how you feel. Trust me.
We have a lot of ways to improve people's lives. And scientists are working on a study to replicate tissue damage as an endless recovery like DealPool.
Sounds interesting
You can look at it lightning in my article, and give me your own opinion
https://busy.org/@lienminh247/can-humans-replicate-the-body-like-deadpool
Interesting article I must say but the level of significance in the last diagram suggests that this work cannot fully be relied on. More data are needed. It is also interesting to see the correlation between SRT1 levels and life longevity as well as the correlation between miR’s and Alzheimer’s Disease. But sadly, correlation doesn’t necessarily mean causation. Interesting piece of work nonetheless.
The last diagram is not remotely the focus of the work. The first three are. It doesn't suggest anything and statements like that are not how science articles should be reviewed.
This article also wasn't exploring treatments for Alzheimer's. In this case I think they did a good job of identifying potential biomarkers for the disease.
Oh okay. I think I was too radical on my reply there. I think they did a great job too.
Too radical the other way! :P
They published some interesting work. Some worthy of further exploration. Some adding to their previous publications.
I will check out their works in depth. Glad to see you blogging again.
AD is a very hard desease to deal with, even if you are not affected directly because knowing somebody that has AD is kinda depressive. But this study has great news even if it is just a little step but is something we need to make more research.
Slowly, progress is being made. The media hypes up everything too much and creates impossible expectations. That said, understanding is being built and upon that future treatments WILL come. It's a matter of when not if :)
the studies in the last decade related to degenerative deasesses is strongly involved with the presence of many types of proteins. the expectation for the millions peoples that has affected is the posibility of controling the amount of the particular protein related in the particular case, and so limits the effects of the advance of the degeneration of the cognitive functions. we hope that that control can be found in the near future