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All,

 

Here is an interesting new study [1] (popular press story) that I appreciated as much for its data as its conclusions. In it, researchers identified a group of ~1400 "Wellderly" individuals - which they defined as:

 

ndividuals who are >80 years old with no chronic diseases and who are not taking chronic medications.

 

As you might imagine, these folks are pretty rare, and so they wanted to compare their genomes with those of an average population of elderly people. But first, they did an interesting thing - they compared the longevity of the siblings of the Wellderly cohort (who share a lot of genetics, and probably some lifestyle factors too, with the Wellderly folks) to see how their lifespan compares with the average US population. Here are the "survival curves" for the Wellderly siblings (red) vs. average folks (blue):

 

ns3fzzM.png

 

As you can see, the Wellderly siblings had a more square mortality curve, but their survival curve wasn't shifted right - i.e. their "maximum lifespan" wasn't any longer than the average folks. Instead, both curves hit (near) zero around 100 years. Like the Wellderly themselves, their siblings appear to avoid / postpone the diseases of aging, and so do better in the "middle years" of elderliness (65-85), but beyond that have a mortality rate similar to the population as a whole.

 

They then looked at the Wellderly folks' genetics. Interestingly, they didn't find their genomes to be particularly enriched with so-called "longevity genes" - those that have been identified as more common in centenarians or other very long-lived people. In other words, these folks are healthy agers, but don't seem to be blessed with genes for extreme longevity, which I thought was interesting. It suggests that at least to some degree healthy aging and extreme longevity are distinct, based both on the (sibling) survival curve data and their own genetics. Here is how the authors summarized this part of their findings:

 

[O]ur results suggest that healthy aging is a genetically overlapping but divergent phenotype from exceptional longevity and that the healthy aging phenotype is potentially enriched for heritable components of both reduced risk of age-associated disease and resistance to age-associated disease.

 

I'm curious what Michael would say, but it seems like this apparent distinction between disease avoidance and extreme longevity might undermine to some degree the SENS hypothesis - that aging simple is the accumulation of damage from the diseases of aging. Note: that is my potentially inaccurate summary of the SENS hypothesis...

 

But what I found personally most interesting and helpful from this paper were two of their tables, listing the various genetic markers they tested for both longevity and Alzheimer's disease (AD). They quite explicitly listed the SNPs and which alleles of those SNPs are associated with longevity or AD.

 

I've reproduced the two tables below, and added my own data, a friend's 23andMe data I have access to, and links to 23andMe so that any other 23andMe customers can check their own status for the corresponding SNPs. I've even added a tally at the bottom of each table with a genetic "score" - basically the number of "good" alleles one carries minus (in the case of the AD table) the number of "bad" alleles one carries. Although in the case of AD, it was the evil APOE4 allele that dominated - i.e. the biggest difference between the genes of the "Wellderly" folks and the average population was that the Wellderly were a lot less likely to carry APOE4 alleles. Anyway, here are the tables.

 

First, the table with the SNPs and alleles previously identified (via other studies) to be associated with increased longevity. The "Longevity Allele" column shows that variant of the SNP that has been shown to be associated with increased longevity. The second column shows the gene the SNP is part of - as you can see many familiar names, including FOXO3, SIRT1, IL-6, IGF1, AKT (all of which I note have been associated with both CR and Cold Exposure in one way or another). The green letters show when I or "Person X" are carriers for the "good" longevity allele:

 

spKxxrF.png

 

Here are "live" links to the 23andMe page for each SNP so 23andMe customers can check their own results on these SNPs:

 

Here is the same sort of table, but this time for SNPs and Alleles associated with Alzheimer's disease and/or cognitive decline. Note, the last SNP in the table is the dreaded APOE4. As you can see from the p-value column, the APOE4 allele was far and away the most significant predictor of AD/cognitive decline, and the Wellderly had it less frequently that the general population (the column labelled "ITMI A2 Freq"). Also not that unlike the longevity SNPs, 23andMe didn't have data for many of the AD-related SNPs. Once again, the green letters show when I or "Person X" are carriers for the "good" allele (for avoiding AD) or and red letters show where one of us is a carrier for the "bad" allele (increasing risk of AD):

 

By2RNgZ.png

 

Here are the direct links to 23andMe for the subset of SNPs from the table that were available (at least for me):

 

https://www.23andme.com/you/explorer/snp/?snp_name=rs190982

https://www.23andme.com/you/explorer/snp/?snp_name=rs2718058

https://www.23andme.com/you/explorer/snp/?snp_name=rs1476679

https://www.23andme.com/you/explorer/snp/?snp_name=rs11771145

https://www.23andme.com/you/explorer/snp/?snp_name=rs11218343

https://www.23andme.com/you/explorer/snp/?snp_name=rs17125944

https://www.23andme.com/you/explorer/snp/?snp_name=rs10498633

https://www.23andme.com/you/explorer/snp/?snp_name=rs2075650

 

As you can see, for both the longevity SNPs and the AD SNPs, my score is a bit better than the score for my friend, "Person X" - so I got that goin' for me. And they are an unfortunate carrier of one APOE4 allele. ☹

 

To wrap up, the researchers also also found that a few of the Wellderly folks were enriched with an ultra-rare variants of a gene that seems to be especially protective against AD, called COL25A1 but I couldn't figure out what SNPs or alleles they were talking about.

 

As always, these genetic marker studies need to be taken with a grain of salt. But it was fun to see where I and "Person X" stand regarding all these variants. I'd be curious if anyone else would be willing to share their data, or at least their "scores".

 

--Dean

 

-------

[1] Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.03.022

 

Whole-Genome Sequencing of a Healthy Aging Cohort

 

Galina A. Erikson5, Dale L. Bodian5, Manuel Rueda, Bhuvan Molparia, Erick R. Scott, Ashley A. Scott-Van Zeeland,

Sarah E. Topol, Nathan E. Wineinger, John E. Niederhuber, Eric J. Topol6, Ali Torkamani6

 

Free full text: http://www.cell.com/cell/pdf/S0092-8674(16)30278-1.pdf

 

Summary
 
Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype—healthy aging—to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors.
 
PMID: Unavailable

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It suggests that at least to some degree healthy aging and extreme longevity are distinct, based both on the (sibling) survival curve data and their own genetics. Here is how the authors summarized this part of their findings:

 

[O]ur results suggest that healthy aging is a genetically overlapping but divergent phenotype from exceptional longevity and that the healthy aging phenotype is potentially enriched for heritable components of both reduced risk of age-associated disease and resistance to age-associated disease.

 

I'm curious what Michael would say, but it seems like this apparent distinction between disease avoidance and extreme longevity might undermine to some degree the SENS hypothesis - that aging simple is the accumulation of damage from the diseases of aging. Note: that is my potentially inaccurate summary of the SENS hypothesis...

 

That is completely backward from what I've clearly (I think) said on the subject of intrinsic aging, the sources and accumulation of aging damage, and the diseases of aging, which you initially seemed to largely understand but have repeatedly mischaracterized (and not even in a consistent way!) ever since ...

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See - I'm glad I qualified my (apparently inaccurate) summary of the SENS hypothesis. Clearly I (still) don't quite grasp the distinction you're making Michael. Thanks for your patience.

 

I've now reread your posts (and mine) to the Intrinsic Aging vs. the Damage Model of Aging thread. Let me try again to summarize. Please correct me where I'm wrong, either in my summary and/or in my assessment of the implications of your perspective wrt the results from this threads' study.

 

You seemed to be saying in that thread that there are intrinsic and unavoidable processes going on that generate damage, which tends to accumulate as people age. When enough damage accumulates, it manifests as the "diseases of aging". Those diseases of aging progress and eventually kill us. Some people are fortunate enough to have genetic variants that can slow down the generation of this damage. They postpone the rate of damage accumulation, and so postpone the age at which enough damage accumulates to manifest as a "disease of aging". So they remain disease-free longer, and  ultimately live longer on average that people without these fortuitous genes. Other people slow down the damage accumulation through a healthy diet and/or lifestyle, and hence postpone the onset of disease of aging, and live longer too.

 

Which brings me to this study. What is the explanation for the fact that the Wellderly seem to postpone / avoid the "disease of aging", but nevertheless don't have a late-life mortality trajectory any different from the general population? Furthermore, how is it they avoid / postpone the disease of aging if they don't possess the identified extreme longevity alleles?

 

Would you chaulk it up to better diet / lifestyle, and being lucky enough not to have APOE4? From the table of demographics in the full text, the Wellderly do appear to be less overweight, exercise more frequently, and be better educated than the general population. Maybe their siblings are too, and so take better care of themselves, which might explain their squared mortality curve?

 

But either way (genes or good behavior), it seems that at least in the 65-85 range, they are generating less damage - otherwise it would seem to me that they (or their siblings) would be manifesting more diseases of aging. So why then, after 85, does the fact they've been accumulating less damage up to that point not result in a mortality advantage as they progress into their 90s? Do they play "catch up" on damage accumulation past age 85 for some reason?

 

Sorry for my (continued) confusion on this.

 

--Dean

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Michael,

 

I think I may have figured out what I'm missing. How about this for a hypothesis for what's going on with these Wellderly folks that accords with the SENS thesis.

 

These healthy old folks (the "Wellderly") are lucky enough to have genes and/or lifestyles that enable them to "dodge the bullet" wrt the common diseases of aging, like CVD, diabetes, Alzheimer's etc by staving off the accumulation of the types of damage associated with these afflictions. 

 

But unfortunately, all the while there are other processes creating other types of damage that are proceeding unabated as they age. By the time they reach 85-90, these other forms of damage have accumulated beyond the point at which the body can effectively cope with them. So they manifest as a disease, and eventually kill off the Wellderly.

 

In short, to extend lifespan beyond 85-90, it's not just enough to avoid the usual forms of damage that accumulate and eventually kill most people, like gunk in your arteries or plaques in your brain. Instead you need to avoid all forms of damage, including all seven of the forms SENS has identified. These Wellderly folks are lucky, but not lucky enough to avoid all the forms of damage. For that you need active interventions like SENS is trying to develop.

 

Is that it?

 

--Dean

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Dean, I am genuinely delighted to see that you not only continued to cogitate on this, but correctly deduced the substance of the matter. In addition to showing your own powers of analysis, it also reassures me that I am not so far burrowed into SENS Research Foundation and/or general biogerontological in-speak that I've lost the ability to clearly communicate with even the most highly intelligent of interlocutors.
 

These healthy old folks (the "Wellderly") are lucky enough to have genes and/or lifestyles that enable them to "dodge the bullet" wrt the common diseases of aging, like CVD, diabetes, Alzheimer's etc by staving off the accumulation of the types of damage associated with these afflictions.


(I think that, as your own (correct) analysis shows, "dodge the bullet" is the wrong metaphor: there isn't just a bullet, and they don't really dodge it. Rather, if we are all in front of a somewhat poorly-trained firing squad, each member of which represents one source of important aging damage, the particular squad that the Wellderly are face has some members that either take a bit longer than usual to initiate fire, or fire less frequently, or have unusually poor aim, so that it takes longer either for one bullet to hit squarely and kill them outright than usual, or they receive initially only a few non-fatal lacerations, and at the end of their lives you can't identify a single fatal shot, even tho' they are clearly quite dead).
 

But unfortunately, all the while there are other processes creating other types of damage that are proceeding unabated as they age. By the time they reach 85-90, these other forms of damage have accumulated beyond the point at which the body can effectively cope with them. So they manifest as a disease, and eventually kill off the Wellderly.


Correct — and they are also suffering from the accumulation of the form(s) of aging damage to which they are less susceptible — just less fulminantly than the general population.
 

In short, to extend lifespan beyond 85-90, it's not just enough to avoid the usual forms of damage that accumulate and eventually kill most people, like gunk in your arteries or plaques in your brain. Instead you need to avoid all forms of damage, including all seven of the forms SENS has identified. These Wellderly folks are lucky, but not lucky enough to avoid all the forms of damage. For that you need active interventions like SENS is trying to develop.


Yes — exactly:
 

By definition, then, to extend maximum lifespan, you have to get at those intrinsic drivers of aging — and you have to reduce all of them to some degree, because even if you were somehow able to dramatically reduce the intrinsic rate of nuclear DNA mutation accumulation, you would still develop atherosclerosis and die of a heart attack or stroke at exactly the same time you were already "scheduled" to do unless you also affected the rate of accumulation of toxic cholesterol byproducts in arterial macrophages — and so on down the line. This is why measuring maximum lifespan is the gold standard for empircally evaluating whether an intervention affects aging or not: the fact that things like Calorie restriction, mutations in the IGF-1 signaling pathway, true methionine restriction, and rapamycin increase maximum lifespan tells you that they are getting at all of the drivers of degenerative aging at once, and doing so to the proportion that they extend maximum lifespan.


So the difference between genetic centenarians and the genetic Wellderly is that the former either have some extremely lucky combination of multiple genetic variants that each in different ways attenuates the accumulation of one or a few forms of aging damage, and between all of them they collectively manage to attenuate all of them (for cases of which there is some evidence); or (as I expect is more common) they have just one or a few mutations that are sufficiently high in the causal chain regulating multiple such pathways as to slow the accumulation of all of the various cellular and molecular aging lesions through efferent pathways that they regulate (or perhaps all but the most slowly-acting) — the human equivalent of Ames dwarf or GHRKO mice (which also seem to exist).

The lifestyle Wellderly, such as the Seventh Day Adventists and to at least some extent the longer-lived low-risk people in this cohort study, get there largely or exclusively because their lifestyle is free or very low in many of the lifestyle and environmental factors that lead to supernumerary aging lesions over and above the intrinsic ones, which of course are highly prevalent in the general population and thus "corrupt" the survival curve of the population as a whole.

A couple of additional clarifications and caveats:
 

You seemed to be saying in that thread that there are intrinsic and unavoidable processes going on that generate damage, which tends to accumulate as people age. When enough damage accumulates, it manifests as the "diseases of aging".


Correct. A bit more specifically, as I mentioned in a previous post,
 

particular diseases of aging are the late, pathological stage of the previously-silent accumulation of particular kinds of damage characteristic to an organ or tissue, so that that organ or tissue can no longer carry out its function, manifesting in a characteristic "disease of aging." I discuss all of this in a blog post on aging and diseases of aging.



Would you chaulk it up to better diet / lifestyle, and being lucky enough not to have APOE4? From the table of demographics in the full text, the Wellderly do appear to be less overweight, exercise more frequently, and be better educated than the general population. Maybe their siblings are too, and so take better care of themselves, which might explain their squared mortality curve?


It could certainly be a combination of some true "slow-aging" (in particular forms of aging damage) genes, a lack of "supernumerary damage" variants (ApoEε4), and good lifestyle. To really tease lifestyle factors out of the analysis, you'd want to use siblings raised apart, since obviously siblings raised in the same household will have substantial early-life exposures in common and also will be more likely than siblings raised apart to share some lifestyle factors in common because of that background. And, of course, some genetic variants linked to longevity may yet run causally through what are or appear to be behavioral factors: the presence or lack of variants that dysregulate appetite and lead to obesity is a particularly hard nut to crack on this front, as may be vegetable consumption (people with more or less genetic aversion to bitter compounds could be one such example, by causing them to avoid or embrace Brassica vegetables; people with greater or lesser genetic susceptibility to alcoholism might be another).

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Here are "live" links to the 23andMe page for each SNP so 23andMe customers can check their own results on these SNPs:

 

 

 

https://www.23andme.com/you/explorer/snp/?snp_name=rs2802292

https://www.23andme.com/you/explorer/snp/?snp_name=rs1935949

https://www.23andme.com/you/explorer/snp/?snp_name=rs3758391

https://www.23andme.com/you/explorer/snp/?snp_name=rs5882

https://www.23andme.com/you/explorer/snp/?snp_name=rs1042522

https://www.23andme.com/you/explorer/snp/?snp_name=rs1800795

https://www.23andme.com/you/explorer/snp/?snp_name=rs2811712

https://www.23andme.com/you/explorer/snp/?snp_name=rs34516635

https://www.23andme.com/you/explorer/snp/?snp_name=rs2542052

https://www.23andme.com/you/explorer/snp/?snp_name=rs3803304

Here is the same sort of table, but this time for SNPs and Alleles associated with Alzheimer's disease and/or cognitive decline. Note, the last SNP in the table is the dreaded APOE4. As you can see from the p-value column, the APOE4 allele was far and away the most significant predictor of AD/cognitive decline, and the Wellderly had it less frequently that the general population (the column labelled "ITMI A2 Freq"). Also not that unlike the longevity SNPs, 23andMe didn't have data for many of the AD-related SNPs. Once again, the green letters show when I or "Person X" are carriers for the "good" allele (for avoiding AD) or and red letters show where one of us is a carrier for the "bad" allele (increasing risk of AD):

 

By2RNgZ.png

Here are the direct links to 23andMe for the subset of SNPs from the table that were available (at least for me):

 

https://www.23andme.com/you/explorer/snp/?snp_name=rs190982

https://www.23andme.com/you/explorer/snp/?snp_name=rs2718058

https://www.23andme.com/you/explorer/snp/?snp_name=rs1476679

https://www.23andme.com/you/explorer/snp/?snp_name=rs11771145

https://www.23andme.com/you/explorer/snp/?snp_name=rs11218343

https://www.23andme.com/you/explorer/snp/?snp_name=rs17125944

https://www.23andme.com/you/explorer/snp/?snp_name=rs10498633

https://www.23andme.com/you/explorer/snp/?snp_name=rs2075650

As you can see, for both the longevity SNPs and the AD SNPs, my score is a bit better than the score for my friend, "Person X" - so I got that goin' for me. And they are an unfortunate carrier of one APOE4 allele. ☹

Ok so if (hmmm hypothetically one day) you are able to set up our own CRISPR editing dream station in your living room (next to the dusty bookshelves; under that poster of Darwin peering down), will you choose to go in and edit the individual letters you believe are conducive to increasing longevity and decreasing disease?

 

http://futurism.com/new-crispr-gene-editing-method-can-edit-single-letters-dna/

 

New CRISPR Gene Editing Method Can Edit Single Letters of DNA

 

In Brief

 

Harvard University researchers have developed a new method of using CRISPR to alter single letters in the DNA code. This opens up the possibility of reversing mutations caused by the changing of only one letter, which represents nearly two thirds of all genetic mutations.

 

Refined techniques

 

CRISPR has revolutionized the world of gene editing. It has allowed scientists to conduct advanced research into diseases, research live cells, and it’s not expensive or overly complicated. But one thing it has always lacked is specificity. In some respects, it is the sledgehammer, not the sword; the cleaver, not the scalpel.

 

That is, until now.

 

Harvard University researchers have developed a new method of using CRISPR to alter single letters in the DNA code. This opens up the possibility of reversing mutations (and the diseases that stem from them) caused by the changing of only one letter, which represents nearly two thirds of all genetic mutations.

 

In an article in the journal Nature, the researchers described the new method, which doesn’t need to cut both strands of the DNA double-helix to alter the genetic code. It can directly convert a single letter of DNA to another, without deleting and inserting a bunch of random letters.

 

A new tool

 

Specifically, the researchers decided to glue two proteins to a type of Cas9 enzyme that doesn’t cause double-stranded breaks in DNA. The two proteins allowed the Cas9 to directly convert one specific letter in the four-letter genetic code, while preventing the cell from undoing the change.

 

The actual tests involved mouse and human cells, and a mutation that causes late onset Alzheimer’s disease and breast cancer. In one attempt, they were able to effectively change 58% of the cells without much unintended side effects, while other tests registered as much as 75%.

 

This level of specificity allows high precision gene editing. Though still in its infancy, and still displaying a number of limitations (animal tests are still years away from occurring, and human tests may take decades), the new method could one day allow the treatment of diseases without permanently altering the human gene pool.

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Sthira,

Ok so if (hmmm hypothetically one day) you are able to set up our own CRISPR editing dream station in your living room (next to the dusty bookshelves; under that poster of Darwin peering down), will you choose to go in and edit the individual letters you believe are conducive to increasing longevity and decreasing disease?

I wouldn't be inclined to start hacking away at my genome willy-nilly. But if the procedure itself was safe and effective, and could change a single nucleotide in every cell (or most cells) in the body, the one tweak I'd be inclined to make if I was like my APOE4 friend would be to flip that 'G' to an 'A' in that particular APO gene SNP, to go from APOE4 to APOE3 (or maybe while I'm in there tinkering go for APOE2!). The evidence is pretty overwhelming that having the e4 variant of the APO gene is bad news.

 

As for all the rest, there seems to be much less definitive evidence of either benefit or harm, although FOXO3 might be a good candidate for tweaking for its potential longevity benefits, as opposed to tweaking APO to avoid harm.

 

--Dean

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[...]

As always, these genetic marker studies need to be taken with a grain of salt. But it was fun to see where I and "Person X" stand regarding all these variants. I'd be curious if anyone else would be willing to share their data, or at least their "scores".

 

--Dean

[...]

 

My 23andme chip is as rotten as yours apparently, Dean, so my data is just as spotty. That's why I keep asking whether the new kits offered by 23andme are going to result in more complete sequencing data - and failing that, what other services are available at reasonable cost/hassle (the answer to the latter appears: not at the moment).  Anyhow, here's my data FWIW:

 

Longevity:

 

rs2802292 - GG          2

rs1935949 - AG     1

rs3758391 - CC     0

rs5882 - AA            0

rs1042522 - CC     2

rs1800795 - CG     1

rs2811712 - AA        0

rs34516635 - GG    0

rs2542052 - AA        0

rs3803304 - CC      2

 

final score: 8

 

And dementia:

 

rs190982 - AG       1

rs2718058 - AG     1

rs1476679 - CT      1

rs11771145 - AG     1

rs11218343 - TT      0

rs17125944 - TT      0

rs10498633 - GT      1

rs2075650 - AA       0

 

final score 5

 

No "increased risk" alleles, but the data is very gappy with tons of missing info thanks to the underpowered and obsolete (read: weak and geriatric) 23andme chip.

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Guest TomBAvoider

Since genes associated with Alzheimer's and cognitive decline appear to be so strongly correlated with longevity, it may be of interest to attempt to calculate one's odds of developing Alzheimer's. Here someone has taken a mathematical approach to risk factors and come up with a score:

 

http://genomesunzipped.org/2011/05/calculating-your-alzheimers-risk.php

 

Those who have 23andme are in luck insofar as all the SNPs used in the calc are available. FWIW, for me it's:

 

rs3818361 GG 0.89 (0)

rs11136000 CT 0.97 (1)

rs541458 TT 1.13 (2)

rs1800764 CT 0.98 (1)

rs1064039 CT  0.9 (1) 

 

I put my number of risk alleles in parenthesis for any given SNP. I'm also E3/E3 (rs429358 TT; rs7412 CC)- the APOE for E3/E3 is 0.56. So the first multiplications are: 0.89x0.97x1.13x0.98x0.9=0.86, now times APOE 0.56x0.86=0.48 and so on, you can do the rest depending on whether you're a man, woman etc. 

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Sorry about the "guest" login, I was not at my regular computer. 

 

Meanwhile, if you feel like it, you can test yourself for the prevalence of the Y chromosome in your blood cells. Any appreciable loss is strongly correlated with likelihood of contracting Alzheimer's. Oh, and by the way, now you know why men live shorter lives than women. See (warning: pdf):

 

Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease

 

"Jan P. Dumanski,1,2, * Jean-Charles Lambert,3 Chiara Rasi,1,2 Vilmantas Giedraitis,4 Hanna Davies,1,2 Benjamin Grenier-Boley,3 Cecilia M. Lindgren,5,6 Dominique Campion,7 Carole Dufouil,8 The European Alzheimer’s Disease Initiative Investigators, Florence Pasquier,9,10 Philippe Amouyel,3 Lars Lannfelt,4 Martin Ingelsson,4 Lena Kilander,4 Lars Lind,11 and Lars A. Forsberg1,2, *

 

Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio ¼ 2.80, p ¼ 0.0184, AD events ¼ 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio


¼ 6.80, 95% confidence interval [95% CI] ¼ 2.16–21.43, AD events ¼ 140, p ¼ 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females."

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