Quick Notes from Quebec

 (or “Short Takes from Sherbrooke”),
Center for Research on Aging, Symposium Nov 2-4

“Why does the cell appear to be shooting itself in the foot?” asked Andres Kriete of Drexel Bioengineering Dept.  All through the conference, I heard people puzzle that our bodies seem to miss opportunities to save themselves from aging, or worse, that they seem to be pouring gasoline on the fire.  Invariably, researchers sought to reconcile what they were seeing with their faith that the body really is evolved to protect itself as best it can.  Everything that looks on its face like a suicide mechanism is re-interpreted to have some hidden benefit.

I was invited to the conference as an advocate of programmed aging, the only one in the room.  I found everyone to be more than polite–listening with an open mind and eagerly engaging with me.  I spoke on a subject that I find exciting, and which has seen an explosion of results in recent months: the possibility that aging is controlled by a biological clock based on epigenetic programming.

 

Experts in diverse fields, hailing from La Jolla to Poland were represented, and I made several new friends, while renewing acquaintance with Siegfried Hekimi, whose lab I visited four years ago.  I woke up this morning visited by a muse, and penned this before I got out of bed.

Ballad of the Sherbrook Gerontologists

When joints and arteries become inflamed,
The body yields to nature’s conflagration
The standard culprit (as always) is blamed.
The problem must be some dysregulation

We scratch our heads, we wonder what went wrong.
To clearly programmed death we pay no heed…
And comfort find we in familiar song:
“Respect the body’s wisdom” is our creed.

The muscle’s satellites that proudly grew
Retire now and yield to cell senescence
Forsake their given mission, to renew…
But we question not their motives nor their essence.

We scratch our heads, we wonder what went wrong.
To clearly programmed death we pay no heed…
And find we comfort in familiar song:
“Respect the body’s wisdom” is our creed.

And even in the face of apoptosis,
The body’s good intent we must abide.
We tender our familiar diagnosis
And whisper not the phrase “cell suicide”.

For evolution is our benefactor
And we must never question her intent
We blame some tradeoff, or an unknown factor
Though on our own demise she is hell-bent.

We scratch our heads, we wonder what went wrong.
To clearly programmed death we pay no heed…
And comfort find we in familiar song:
“Respect the body’s wisdom” is our creed.

– JJM, 2014 Nov 4

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Here are some teasers for things I found most interesting in this brief symposium:

One study in Scotland found diabetics who take metformin live longer than non-diabetics who don’t!  (There’s no data on non-diabetics taking metformin, because there are so few of us.  But in studies with normal, non-diabetic mice, metformin extends life span.) (from presentation of Nir Barzilai)

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Centennarians don’t have healthy eating habits, don’t exercise more than others in their cohort or smoke or drink less.  They also don’t have genes that are associated with protection from cancer or heart disease or AD.  What they do have is genetic pre-disposition to long life, and it is specific genes that slow aging.  There are specific genes that are necessary to make to age 100, and without them your chances are slim.  (This is different from longevity between ages 70 and 90, which is affected much more by life choices, environment, etc.) (also from Nir Barzilai)

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During the last 2 years of life of a centennarian, health costs are ⅓ what they are for the last 2 years of someone who dies at 75. (also from Nir Barzilai)

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Burning ketone fuel instead of sugar helps protect the brain against Alzheimer’s Disease.  Fasting a few days, of course, shifts the body to ketosis.  A low-carb diet is ketogenic, but even better are medium-chain triglycerides, often refined from coconut oil for experimental diets. (presented by Alex Castellano)

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The Free Radical Theory of aging has it all backwards, says Siegfried Hekimi.  ROS are not a cause of the oxidative damage that accumulates with age, but rather a signal that turns on the body’s protection against that damage.  In his McGill laboratory, worm life span has been increased almost twofold by exposing them to a strong pro-oxidant chemical.  In biology experiments, it is called “paraquat”, but the Vietnamese knew it as Agent Orange.  Of course, large doses of paraquat poison the worms, and their lives are shortened.  But a range of low doses is beneficial.  This result comports with genetic experiments.  The all-time record for long-lived, genetically altered worms is a worm that lacks the ubiquinone gene, so that its energy metabolism is completely disrupted and it is unprotected from ROS.

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Children conceived to starving women in Netherlands 1944 had higher rates of metabolic syndrome 50 and 60 years later, due presumably to epigenetic patterns of methylation laid down at conception. (presentation of Irene Maeve Rea)

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Michael Kobor of UBritColumbia shared my enthusiasm for the epigenetic clock. He cited recent work of Steve Horvath, demonstrating a set of epigenetic changes that are characteristic of the aging human.  Some of his own work documents the influence of childhood deprivation on epigenetics that affect health, psychology and longevity much later.

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And in preparing my own presentation, I un-learned something that I been taught long ago.  DNA is supposed to be the same in every cell in our body (except for a small number of random mutations).  But a recent paper actually samples tissue from different organs and finds big differences.  Could it be that the body is re-configuring its own DNA, as well as epigenetics, when differentiating?  If this is real, it implies an ability we didn’t know cells possess.

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Rumors are the most fun

Alan Cohen (from the home team at University of Sherbrooke) told me that he was in touch with Vaupel, whose work I wrote about back in January.  Vaupel had just published a paper comparing the aging patterns of 48 different animals and plants, mostly animals.  Some age gradually, some hardly age at all until the end, and they all die suddenly.  Some age “backwards” in that they become less and less likely to die as time goes on.  Alan told me that Vaupel and his group at Max Planck Inst have been expanding this list, drawing a more representative sample of 10,000 species, and there is a great deal more “non-aging” than anyone expected.

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For at least 10 years, it has been known that senescent cells are “bad actors”, not just shirking their duty to the body but spewing out toxins that destroy neighboring cells and contribute to systemic inflammation, ultimately to cancer. In 2011, Jan van Deursen of Mayo Clinic in Minnesota published a paper that demonstrated this dramatically.  Mice were genetically modified to attach a self-destruct signal to the p16 gene, which is a marker of senescence.  The mice could then be dosed with a signal, and the senescent cells would eliminate themselves cleanly via apoptosis.  The mice with their senescent cells removed had a 20 to 30% greater mean life span and even better results for health span.  Even though these cells are less than 1 in 10,000, they do damage far out of proportion to their numbers.  (To my way of thinking, cell senescence is clearly part of the aging program.)

Van Deursen was there to explain and update his work.  The rumor is that there are at least five companies around the world working on drugs that will remove senescent cells without harming other cells, and that these drugs show promise for treating all the major diseases of old age.