Apologies to Hamlet

Apologies to Shakespeare and Hamlet.  Serotonin does “more things in heaven and Earth, Horatio, than are dreamt of in your philosophy.”  How about chemically modifying histones?We all know about serotonin and depression (or at least we think we know).  Block serotonin reuptake by the releasing neuron and bingo you’ve  cured depression (sometimes).  Do not ask the lecturer which of the 15 known serotonin receptors in the brain the increased serotonin actually binds to and what effects the increased levels produce after binding (and which are important for the alleviation of depression).The two body organs producing the most serotonin are the brain and the gut.  Chemical modification of proteins by serotonin has been known for 10 years.  The enzyme responsible is transglutaminase2, it takes the NH2 group of serotonin and replaces the NH2 of glutamine with it — forming an isopeptide bond.

Interestingly, the serotonylation of histones is quite specific.  Only glutamine #5 on histone H3 is modified this way.  For the reaction to occur lysine #4 on histone H3 must be trimethylated (H3K4Me3) — now you can begin to see the combinatorial possibilities of the various histone modifications known.  Over 130 post-ranslational modifications of histones were known by 2013 [ Cell vol. 155 p. 42 ’13 ].

The H3K4Me3Q5Ser is enriched in euchromatin and correlates with permissive gene expression.  Changing glutamine #5 to something else so it can’t be serotonylated changes the transcription pattern, and deficits in cellular differentiation.  You can read more about it in Nature vol. 567 pp. 464 – 465, 535 – 539 ’19 ]

You might as well watch the Kardashians

You might as well watch the Kardashians.  Reading Shakespeare will not protect you against cognitive decline.  Although you can spindle and mutilate the intellectual cards you were dealt, you can’t play them.  That’s the rather depressing result of from  large (over 1,000 subjects) just in [ Proc. Natl. Acad. Sci. vol. 116 pp. 1832 – 1833, 2021 – 2026 ‘ 19 ].  You have doubtless heard that people who have higher educational attainment, who have had intellectually demanding occupations, who stay mentally and physically active have a lower incidence of Alzheimer’s disease.  This is true, but it’s because they were smarter to begin with.

Before describing the paper please do note that high intellectual attainment (due to high intellectual ability) is not absolutely  protective against Alzheimer’s.  Claude Shannon died of it (https://en.wikipedia.org/wiki/Claude_Shannon), as did a Fields medalist who entered college when I did, as did a classmate who wrote 43 papers testing new drugs.   It does lower the odds though.

There were intimations of this years ago [ J. Am. Med. Assoc. vol. 275 pp. 538 – 532 ’96 ] Catholic nuns ages 75 – 95 were studied. All had written an autobiographical essay at age 22 explaining why they wanted to enter the order.  14 died and some had Alzheimer’s.  The essays were read blind and scored for idea density, grammatical complexity etc. etc. Those with the lowest idea density etc. had Alzheimer’s, while those with the most intellectual complexity were free of Alzheimer neuropathology.  Of the 79 living nuns, the smart ones at age 22 remained smart for the most part at 75+ while the less gifted stayed the same.  This was a select and far from average group — all were college educated and were parochial school teachers for most of their lives.  So the group was controlled for education and occupation.

The PNAS study concerned military recruits (average age 20) entering the service between 1965 and 1975.  The people going in at age 20 were not Ivy League types, who had concocted all sorts of reasons they couldn’t serve.  The Ivy league types going in were JAG officers or Docs like myself, but we were educated and long past 20.  89% were white, 80% did not have combat exposure.

The group was part of the Vietnam Era Twin Study of Aging.  Subjects took the Armed Forces Qualification Test (AFQT) which measures cognitive ability.  Then some 1,237 were  retested at ages 51 – 59 and 1,009 were retested at an average age of 62.

Subjects filled out questionnaires concerning education, job complexity, physical and mental activity etc. etc.

So what was the best predictor of General Cognitive Ability (GCA) at 62?  It was not subsequent education, job complexity, intellectual engagement.  Each of them predicted under 1% of the variance of GCA at age 62.  The best predictor (and not that great) was GCA at 20, which accounted for over 10% of the variance.

Pretty depressing.  You can’t even play the hand you were dealt.

Somehow Princeton undergraduates have found this out and p. 15 of the 6 Feb ’19 issue of the Princeton Alumni Weekly describes the” Kardashian Lifestyle Klub, a registered student organization with about 150 members, meetings and University support“.