1. Sledge, George W. Jr. MD

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Over time I have accumulated numerous defects. When I was four years old I hypothesized that I could balance on top of a large beach ball. I was wrong, and in proof of the null hypothesis received several stitches over my left eyebrow. When I was in fifth grade I broke a finger playing football. Six weeks later the splint came off. I went outside that same afternoon, played football, and broke another finger on the same hand. My GP looked at me with mild disgust and said, "You clown," having used up all his compassion with the first fracture. The following year I assaulted a plate glass window with my left knee, leaving another scar.


In high school I spent a day helping my dad put shrubs and trees-a veritable forest of shrubs and trees-into our back yard, after which my back went into spasm. I have never had it imaged, but I am pretty sure I herniated a disc. Every two or three years it reminds me of that day in my teens. Joyce Kilmer obviously never spent an afternoon planting trees, or he would have found them less charming.

GEORGE W. SLEDGE JR.... - Click to enlarge in new windowGEORGE W. SLEDGE JR., MD. GEORGE W. SLEDGE JR., MD, is Professor of Medicine and Chief of the Division of Oncology at Stanford University. His

I was blessedly free of further physical insults for nearly a decade. In my fellowship I had a varicocoele ligation: more scars. Early on as an Assistant Professor I found that I had lattice degeneration, a precursor lesion for retinal detachment. I was told not to worry about it unless I found myself going blind suddenly, and not to play football without a helmet. I haven't gone blind yet, but my football days are over. On a recent exam I was told that I had early cataracts. And, by the way, I do not appreciate being labeled a degenerate by an ophthalmologist.


And don't even get me started on my teeth. A bunch of my adult teeth never came in, a condition known as hypodontia. I kept several of my baby teeth well into my 40s before they all eventually fell out, to be replaced over time with dental implants. According to Wikipedia, hypodontia is statistically linked to epithelial ovarian cancer, which I guess is interesting. As to etiology, Wikipedia says "the condition is believed to be associated with genetic or environmental factors during dental development." Duh. Anyways, some defects you accumulate, some you are born with.


I've accumulated a number of benign neoplasms and the like: nevi, warts, a few small colon polyps (resected times 2 per colonoscopy). I think I have an early actinic keratosis, some lichen planus, and a few other nonthreatening-looking skin nodules that I am sure are named after someone or have some Latin name known only to dermatologists, their verbal equivalent of a secret handshake.


A couple of winters ago, on Christmas Eve, I ran into a pillar in the foyer of my house: more stitches, this time above my right eyebrow, more scar tissue. Shortly after that I caught my heel on a splinter while climbing up the basement stairs. I hobbled around for a week or two, self-medicating, until I had sufficient scar tissue to regain unhampered mobility.


Of course it's the defects you accumulate internally that you worry about. Once you get past the skin or gastrointestinal mucosa it's hard to detect them with ease. My cholesterol is up there without a statin, and my glucose level has suggested from time to time that I may be prediabetic. Coronary arteries, carotid arteries, pancreas? Which one is lying in wait to do me in? The problem with getting older is that you take increasingly frequent journeys to Comorbidity Island, accumulating defects like some crazy recluse collect cats.


Below the tissue level, the medical oncologist in me always worries about the accumulation of genetic defects. Our DNA is under constant assault: one paper I read, looking at a mouse model, estimated somewhere in the range of 1500 to 7000 DNA lesions per hour per cell. Most of them don't take: we're fitted out by nature with excellent DNA damage repair mechanisms.


Still, it gives you pause. Some of those mutations slip through. Over time they add up. Some combination of mutations in some cells eventually results in cancer, as we all know. But there is also a theory of aging (there are lots of theories of aging) implicating the progressive accumulation of genetic defects for the loss of organ function as we grow older. Take your muscles, for instance. The older you get, the more mitochondrial DNA mutations you accumulate. At some point, muscle fibers lose cytochrome C oxidase activity due to these mutational defects. Your muscles rot.


This accumulation of mutational defects is quite organ-specific, at least in mice: Dolle and colleagues, writing in the PNAS over a decade ago, showed that the small intestine accumulated only point mutations, whereas the heart appears to specialize in large genome rearrangements. They spoke of "organ-specific genome deterioration," a term that does not give me warm and fuzzy feelings.


And these mutations start accumulating at a very early point in life. Li and colleagues at McGill studied identical twins in a recent Journal of Medical Genetics paper. Identical twins are that great natural experiment that allows us to ask "just how identical is identical?" Looking at genome-wide SNP variants in 33 pairs of identical twins, they estimated a mutation frequency of 1.2 X10-7 mutations per nucleotide. This may not seem like much, but given three billion base pairs in the human genome, they concluded "it is likely that each individual carries approximately over 300 postzygotic mutations in the nuclear genome of white blood cells that occurred in the early development."


Our cells are all potentially mutinous traitors, held in check only by the determined efforts of the molecular police force. We carry the seeds of our ultimate demise from birth.


Well, that's all very cheery, you say. We all know that we grow old, and then we die, and the growing old part is only if we are lucky. This isn't exactly late-breaking news. Applying a molecular mechanism to mortality is interesting, but my hair is still getting grayer by the day. Do something!


And something cool they are doing. Villeda and colleagues just published a paper in Nature Medicine looking at cognitive function in old mice. Mice, like humans, get duller as they get older. But give the old mice a transfusion of plasma from young mice, and you reverse age-related cognitive function. This has a somewhat vampirish sound to it: the old guy rejuvenating after sucking the life force out of some sweet young thing. But apparently Hollywood got it right.


Before I start lining up medical student "volunteers" for blood transfusions, can we drill down a bit on what is actually happening? Two new papers in Science suggest that the "young blood" factor responsible for the cognitive improvement is GDF11, a circulating member of the TGF-b family. GDF11 increases neurogenesis and vascular remodeling in the brain. It also reverses cardiac hypertrophy in old mice. Unsurprisingly, the lead investigators are already speaking to venture capitalists to commercialize the findings.

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It's always a leap from mouse to man, and certainly a danger to assume that a single molecule will be a sovereign cure for all our ills. But I'll sign up for the Phase II trial. I could use some neurogenesis right now.


Nothing in life is free, of course. The dentate gyrus, part of the hippocampus, generates neurons throughout adult life, and these adult neurons are incorporated into pre-existing neural networks. That's a good thing. But it comes at a price: a paper just published in Science also shows that adult hippocampal neurogenesis promotes forgetting.


So, the dilemma we may face a few years from now: you are starting to lose your memory. You take GDF11 or whatever the very expensive synthetic equivalent is called in 2024. It promotes neurogenesis and you get a new lease on life. But you forget your spouse's birthday in the process, and maybe some of what makes you "you." Is the new "you" really you any more?


One is reminded of the Ise Grand Shrine in Japan. This beautiful Shinto wooden temple is rebuilt to the same design every 20 years, using trees from the same forest. Is the 2014 temple the same temple as the 1014 temple? Last year represented the 62nd time the temple was rebuilt. Ise is forever new, forever ancient. Maybe we will be too.


But I doubt it. We'll still keep accumulating defects. And, being a drug, GDF11 will do something bad and unexpected. But it should be fun to find out.

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