Monday, January 11, 2016

Uncertain Health in an Insecure World – 71

“Before I Get Old”

In My Generation (1965), The Who protested that their parents were holding them back. “Hope I Die Before I Get Old” was the youthful Pete Townshend’s lament against the ravages of time. 

Pete is now 70 years old.

In their parents’ era, BBC Radio listeners heard poet Dylan Thomas’ read Do Not Go Gentle Into That Good Night. Thomas chided his father to fight on, despite the old man’s life being filled with disease and pain. “Old age should burn and rave at the close of day…Rage, Rage against the dying of the light”, even if the next day brings suffering. In the sci-fi movie Interstellar (2014), Professor John Brand (played by Michael Caine, age 82) repeated this line as the world urged NASA astronauts into the abyss of space on a vain mission to save struggling humankind.

Life expectancy at birth (LEB) is a statistic applicable to all living organisms – man, animals and plants.

LEB is an actuarial measure of an organism’s expected survival in the face of evolution, innate host defenses and lifestyle. Whether humans, opossums or guppies are involved, greater predation and accidental death lessens the impact of natural selection on increased life span.  Externally imposed caloric restriction and intrinsically lower basal metabolic rates are also known to lengthen lifespans – just ask any 190 year old Galapagos giant tortoise, or 405 year old Arctic Ocean quahog clam!

In the Bronze Age (3,000 – 1,200 B.C., left) and Iron Age (1,200 – 550 B.C., right), human LEB was just 26 years. Over thousands of intervening years, world-wide LEB doubled to 52 years for those born in 1960-65.  For the 2010-2015 birth cohort, LEB increased to 71 years. Ceteris paribus, current projections are that LEB will rise to 75 years by 2040-45. 

Doing the math, LEB gained +0.38 years per year over the prior 50 years, but will grow by only +0.13 years per year over the next 30 years. If the human genome remains largely stable, then this apparent blunting of the LEB curve (below) must be due to putative externalities – accidental deaths, predation (i.e., wars, genocides), excessive caloric intake (i.e., diabetes), and/or global environmental decline.

For rockers, life has an especially poor prognosis.

The Who drummer, Keith Moon (above), died at age 32; it was not a natural death. A 2012 British Medical Journal study sampled 1,489 rock and pop stars from 1956 and 2006, and showed that 9% died prematurely, largely as a result of substance abuse tied to psychic trauma from adverse childhood experiences (ACE).

Evolution tinkers very slowly with the human genome.

The best kept Human Genome Project (2000) secret is that differences in our genes’ DNA explain very little of why most of the lethal chronic mental and physical diseases occur – 5-10% at most!! In his January 5, 2016 blog, National Institutes of Health chief Francis Collins (age 65) reflected back on 2015’s scientific breakthroughs, highlighting the CRISPR/Cas9 gene-editing technique – Science magazine’s breakthrough of the year. “Like a scalpel”, CRISPR (below) uses an RNA segment attached to an enzyme to seek out and cut a short DNA sequence from the genome. This so-called ‘gene drive’ can re-engineer an organism’s genome, intentionally spreading a trait through a population much faster than Mendelian inheritance. Recently, Chinese scientists have used CRISPR to edit germ line cells in human embryos, edging up to the ethical red-line of engineering human life.

There are good natural selection reasons, seemingly perverse, for the preservation of mixed bag genes.

For example, the APO E4 gene located on the long arm of chromosome 19 at position 13.2 (i.e., locus 19q13.2, above) has three apolipoprotein E alleles – e2, e3 and e4 – which produce three different proteins that combine with lipids like cholesterol. More than 50% of the world’s population owns the benign ‘e3’ haplotype. But the ‘e2’version carries the risk of hyperlipoproteinemia type III, which increases the risk of atherosclerotic heart disease and stroke.  The ‘e4’ version increases the risk of late-onset Alzheimer’s disease and age-related macular degeneration.

Teleologically speaking, it could be argued that these diseases of aging are emerging now as the elderly population expands, while they were relatively rare occurrences earlier in human evolution.
Like evolution, genome-modifying research successes come slowly.

It is becoming abundantly clear that our capacity to sequence and snip genes remains a pale imitation of the natural evolution of the genome. The massive quantity of big data from genetic research initiatives continues to challenge scientists. Memorial Sloan Kettering Cancer Center’s global Project GENIE database has accrued 17,000 patient records awaiting decryption. We know that characterizing genomic mutations in tumors leads to precision medicine insights that inform clinical decision-making regarding existing drug treatment and new drug development (see Post #65). But computational challenges implicit to Project GENIE’s big datasets require big bioinformatics partners like Sage Bionetworks.

Of course, Facebook isn’t standing idly by watching the others.

At the University of Michigan, researchers have developed a Facebook app called Genes for Good, to support a genetic testing initiative that links ancestral genetic data to the daily health habits of study participants. In 2015, of the 8,310 would-be participants (below) who used the app, only 3,702 were eligible for submitting a study spit kit. Once privacy issues are managed, in 2016, the participants will receive their raw genetic data in a manageable format. Who knows what, if any, insights this information will provide to those enrolled?

In a 1989 ABC Good Morning America interview, Pete Townshend confessed that when writing the lyrics to My Generation, while riding on a train, his meaning for “old” was actually “very rich.”

There are some who believe that many nouveau riche high-tech billionaires are investing in genome manipulating precision medicine technologies to forestall their own mortality. Mark Zucherberg is 31, Travis Kalanick is 39, Sergey Brin is 42, Jeff Bezos is 51 and Bill Gates is 60.

Perhaps The Who was being prescient when Pete conflated the “old” and the “very rich”, in an era before the rise of potential LEB-adding gene-modifying technologies.

Facing it squarely, it's 2016, and we in the Square are all aging.

But before we get old, let's explore this uncharted space quadrant, and “Rage, rage against the dying of the light…”  

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