A switch for aging

CRITICAL THINKING COURSE AVAILABLE STARTING TODAY!

I have an exciting announcement -- today, I'm launching a course called Introduction to Critical Thinking through Udemy!  It includes about forty short video lectures, problem sets, and other resources to challenge your brain, totaling about an hour and a half.  The link for purchasing the course is here, but we're offering it free to the first hundred to sign up!  (The free promotion is available only here.)  We'd love it if you'd review the course for us, and pass it on to anyone you know who might be interested!

Thanks!

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I, and many of my friends, are of That Certain Age where we have started getting such awesome physical symptoms as graying hair, wrinkles, arthritis, forgetfulness, and the necessity of either wearing reading glasses or getting arm extensions.  I'm not the sort that will let being 57 (or any other age) slow me down if I can help it, but there's no denying that I don't feel as young as I did twenty (or even five) years ago.

So any time I see an article on the biology of life span, my ears perk up.  I'm hopeful that there will eventually be medical ways to extend healthy life span (sure would be nice if it happened soon...), but to get there, we need to understand how aging actually works.  And a new piece of research out of the University of Minnesota has given us another clue.

Geneticists Adam McLain and Christopher Faulk were interested in a feature of the genetics of all eukaryotes (life forms that have nuclei -- therefore, every common organism with the exception of bacteria) called a promoter.  To see where this is going, a brief biology lesson.

You can think of genes as recipes.  They are a set of instructions that, speaking in the A/T/C/G language, spell out the directions for building proteins.  Many of those proteins then go on to influence other genes, creating a cascade of activity that we collectively call "development."

Promoters are, in a way, the director of the orchestra.  Or -- a more apt analogy -- they're like a set of switches.  The promoters are not part of the recipe itself; they have instead the critical job of pointing out where the recipe is, making sure that it's switched on (or off) at the right time, and regulating how fast the end product is produced.  Errors in a promoter region are usually devastating -- one of the milder examples is genetic lactose intolerance, where faulty promoter turns off the gene that produces lactase, the enzyme that digests lactose, leading to an inability to drink milk after the age of three or four (and some pretty nasty symptoms if you do).

[Image is in the Public Domain]

So promoters are critical to genes, not only turning them on or off in the right sequence, but making sure that the right amount of the protein is made in the right tissue type.  This importance means they're what geneticists call "highly conserved sequences" -- things go so badly awry when they malfunction that there are few mutational differences between promoters in different species.  What McLain and Faulk wondered is if promoter activity might have something to do with the rate of aging, so they set out to compare those small number of mutational differences between species that have generally short life spans (such as mice) and those that have generally long life spans (such as elephants).

What they looked at are called CpG sites -- areas high in the bases cytosine and guanine (and in which they occur right next to each other), which are found in promoters and are targets for methylation, a process that turns promoters off more or less permanently.  And what they found is that the density of CpG sites positively correlates with average age at death.

Which is pretty amazing.  The authors write:

As vertebrates age, the epigenomic pattern of DNA methylation degrades, with the highly methylated CpG sites gradually becoming demethylated, while CGIs increase in methylation.  Therefore, DNA methylation becomes dysregulated as a function of aging and high CpG density may delay or buffer specific regions from age-related changes.  Some gene exons have undergone accelerated evolution in long-lived species as their protein function is under selection.  However, unlike coding sequences, promoter regions alter gene expression, not protein function, so different species can regulate expression without altering the protein function.  Within promoter regions the rapid mutation of CpG sites and their function in epigenetic gene expression make them prime targets for natural selection.  We chose CpG site density because density alone is sufficient to predict methylation level.  Since methylation degrades over an individual's lifespan, we reasoned that selection for long lifespan may act not only on gene coding regions but on promoter regions.  This selection would change promoter CpG density for genes whose expression must be more tightly regulated to allow for longer lifespan.

So methylation, connected to the presence (and number) of CpG sites, is tightly connected to life span; as you age, the regulation of methylation starts to fall apart, deactivating genes that should be active and activating genes that should be turned off.  Species whose promoters have a higher density of CpG sites regulate methylation more tightly -- and age more slowly!

When I got to the punchline of their paper, I was a little stunned.  It's astonishing that life span could be controlled by something that simple (okay, the concept isn't simple, but the connection between CpGs and aging rate is pretty straightforward).  The next question, of course (especially those of us who are rapidly approaching geezerhood) is whether there's a way to affect the process of methylation -- preserving its ability to regulate gene expression, and (presumably) slowing down the aging process.

All of which is far beyond the scope of this study.  But still, it's an intriguing prospect, whether or not it ever becomes feasible in practice.  Me, I hope it does, and I hope it's soon.  Because I've about had it with gray hair, creaky joints, and entering a room only to immediately forget why I'm there.

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This week's featured book is a wonderful analysis of all that's wrong with media -- Jamie Whyte's Crimes Against Logic: Exposing the Bogus Arguments of Politicians, Priests, Journalists, and Other Serial Offenders.  A quick and easy read, it'll get you looking at the nightly news through a different lens!

Worrywarts

It will come as no particular surprise to people who know me that I can be a little neurotic at times.  I'm nervous to the point of not being able to sit still, and get seriously worked up before (for example) races, because I can so vividly envision everything going wildly wrong.  Mental images of me running out in front of a truck or collapsing with heat stroke or simply being the last person to limp across the finish line gain a life of their own, despite the fact that none of those things have ever happened to me.

Traveling is worse.  I say I love to travel, but what I actually mean is that I love being at my destination.  Traveling with me is kind of a nightmare, because I experience gut-clenching anxiety about missing a connection or losing my luggage or worse.  I still vividly recall watching with increasing horror as my wife tried to get through the immigration checkpoint on our way back into the U.S. from our first trip to Ecuador fifteen years ago.  I watched her searching her pockets and backpack for her passport, her expression gradually moving from perplexity to worry to outright panic -- and there was nothing I could do.  I couldn't go back in the line from the other side of the checkpoint and help her; even if I could, it's not like I knew where her passport was.  Images of Carol being hauled off to a windowless room with a bare light bulb to be interrogated as to why she was trying to enter the country illegally flitted through my head.

Of course, in short order she did find her passport, and disaster was averted, but it took me about three weeks to calm back down.

We also ended with nothing more than a serious adrenaline rush the time the drug-sniffing dogs flagged my backpack in Belize, although I did have to find a place to change my pants afterwards.

It's not like I have a history of terrible things happen to me.  I've never had anything worse than getting ill for a day or two, on any trip I've ever taken, and even that has been mild.

So none of this is connected to reality, not that this matters.  If no real crisis presents itself, my brain is perfectly capable of inventing various scenarios on its own.  The fact that these are highly improbable, and many of them are mutually exclusive, doesn't seem to matter.

[image courtesy of the Wikimedia Commons]

Which is why I have now been sent a link three times by various friends and family members about a recent study showing that people who are neurotic live longer.  The study, conducted by Catharine Gale of the University of Edinburgh et al., was huge -- Gale and her team tracked 500,000 people aged 37 to 73 in the United Kingdom for six years, after giving them a personality assessment designed to determine their degree of anxiety and neuroticism.

The results were fascinating.  Even when controlled for typical risk factors -- smoking, heavy alcohol use, genetic predispositions to heart disease, cancer, or stroke -- neurotic people were less likely to die young.  Gale says:

There are disadvantages to being high in neuroticism, in that it makes people more prone to experiencing negative emotions.  But our findings suggest it may have some advantages too...  For some individuals, it seems to offer some protection against dying prematurely. 

At this point, Gale has no idea why this trend exists, so the next step is to figure out whether there's a causative link to something else, either genetic or behavioral.  Their first conjecture was that neurotic people, being worriers, might be less prone to engaging in unhealthy habits, but that turned out to be incorrect.  The percentage of smoking, drinking, and obesity among the neurotic group was not appreciably different from that of the control group.  Gale says:

We had thought that greater worry or vulnerability might lead people to behave in a healthier way and hence lower the risk of death, but that was not the case...  We now have to figure out why [this correlation] exists.

My own supposition is that neurotic people don't actually live longer, it just seems longer to their family and friends.  Heaven knows my wife, who has the patience of a saint, puts up with a great deal from my tendency toward getting anxious about damn near everything.  Amazingly enough, she still likes to travel with me, which I find a little baffling.  Sometimes I even drive myself crazy; I can't imagine what it'd be like for a normal person to put up with my continual twitching.

In any case, the whole thing is pretty fascinating, and I'm looking forward to seeing what more comes out of the study by Gale et al.  But now I need to wrap this up, because I have a race in three weeks and I need to start worrying about it.  What shall I fret about this time?  Maybe being chased and mangled by a Rottweiler.  I don't think I've used that one yet.