1. Sledge, George W. JR. MD

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I was, I suspect, almost the last person to hear Kelly Clarkson's number one hit song "Stronger," which topped the charts a couple of years ago. In case you haven't listened to it yet, it has as the catchy refrain "What doesn't kill you makes you stronger, stronger."

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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

If that sounds familiar, that's because it is a line from the 19th century German Philosopher Friedrich Nietzsche's 1888 great hit, Twilight of the Idols. Clarkson, of course, first came to attention through her victory on TV's American Idol. And American Idol, of course, is now in its final year: Twilight of the Idols, indeed. Sometimes irony is piled on irony.


John Maynard Keynes famously wrote: "Practical men, who believe themselves to be quite exempt from any intellectual influences, are usually the slaves of some defunct economist." To which, apparently, we can now add: songwriters are slaves of some defunct philosopher.


Nietzsche loved catchy aphorisms. His works are full of them. But this is one that never made much sense to me, in either a physical or emotional sense. Imagine being in a horrible automobile accident, with a plethora of broken bones, a pneumothorax requiring a chest tube, a ruptured spleen, and a concussion. "That which doesn't kill me, makes me stronger?" Yeah, right.


Does anyone really believe such nonsense? Certainly not Nietzsche himself, succumbing to the dementia that condemned him to an asylum, leading to his premature death at the age of 44.


Well, perhaps Nietzsche and Clarkson mean it in the emotional or metaphorical sense of "Sure, I've been through hard times, but it has made me a stronger, better person." The world is full of people with post-traumatic stress disorder who might beg to differ. Emotional wounds frequently hurt as much or more as the physical ones, and can take a lifetime to heal. So Nietzsche and Clarkson are two remarkably silly people to spout such balderdash.


Or so I had thought, until recently, when I discovered the emerging literature on senescence.


Senescence (from Latin: senescere, meaning "to grow old") has two meanings-one at the general level and one at the cellular level. In the popular mind, senescence refers to age-related deterioration: the grey hair, wrinkles, and loss of memory that I am so familiar with.


But at the cellular level senescence refers to age-related loss of division. In 1961 the Wistar Institute's Leonard Hayflick noted that normal fetal cells would divide a certain number of times (up to about 60) and then hit a wall. That wall is now called the Hayflick limit, and represents the point at which cells senesce. They don't die, at least not right away. They just stop dividing.


In humans (though not in all organisms) the Hayflick limit is linked to telomere shortening. Although senescent cells no longer divide, they remain metabolically quite active. They have a specific secretome, pumping out pro-inflammatory molecules as well as potent pro-survival signals. They grow older and older, but cling tenaciously to life. Their secretome affects surrounding normal cells, poisoning them with their decrepitude.


The Greeks had a myth that encapsulates this view of cellular senescence. In it, Eos, the goddess of the dawn, falls in love with a handsome youth named Tithonus. Knowing that Tithonus will inevitably die, Eos asks Zeus to make her lover immortal. Zeus, who as Greek gods go had a pretty sinister sense of humor, rendered Titonus immortal but not eternally young.


Tithonus lives forever, but in a progressively shriveled, ever-more miserable state. Tennyson's poem on Tithonus includes these lovely lines:


The woods decay, the woods decay and fall,


The vapours weep their burthen to the ground,


Man comes and tills the field and lies beneath,


And after many a summer dies the swan.


Me only cruel immortality


Consumes: I wither slowly in thine arms.


Is all this inevitable? Are we condemned to "wither slowly"? Maybe, maybe not. Yi Zhu and colleagues at Scripps recently published a paper in Aging Cell describing a new approach to identifying drugs that would specifically eliminate senescent cells. The first two drugs they came up in their screen were dasatinib (a Src kinase inhibitor already in the clinic) and quercetin, a natural compound found at most nutrition stores. Dasatinib eliminates senescent human fat cell progenitors, while quercetin takes down senescent endothelial cells and bone marrow stem cells. I'm partial to quercetin because I am coauthor of a very old quercetin paper.


The authors call these compounds "senolytics," and senolytics in aging mice work wonders-improving heart function, exercise endurance, bone function, and overall survival. Sometimes a single course is enough. Take that, Zeus!


But what about senescence in cancer? Here is where things get interesting for an (old) cancer doctor. I never thought of cancers as getting old, or senescent, particularly because immortality is one of their classic hallmarks. This immortality stems from the almost universal over-expression of telomerase by human cancers.


But cancers, paradoxically, frequently include senescent cells. Oncogenes trigger senescence; indeed there is something the biologists call oncogene-induced senescence, or OIS. Work from the 1990s on emphasized OIS as an important barrier to cancer progression, preventing the transition from early pre-invasive disease to more aggressive invasive cancers. Senescence, in this view, is an evolutionary fix, a valuable negative feedback loop: turn on an oncogene, and you get senescent cells, and the cancer fails to take off.


This view is changing, or at least becoming more nuanced. OIS has its own senescence-associated secretory phenotype, a witch's brew of cytokines, growth factors, and proteases. You would think that old age was a good thing in cancer, but not always: recent work suggests that the OIS secretome in HER2-positive breast cancer (for one recent example) can promote growth, invasion, and metastasis by their non-senescent fellow-traveler cancer cells. The cytokine IL-6 plays an important role in this nastiness, and may represent a therapeutic target.


So cancer cells can take Nietzsche and Clarkson to heart: that which doesn't kill me makes me stronger. Senesce all you want, because those senescent cells can make you stronger if you are an oncogene-induced cancer. Those old souls Kelly Clarkson and Freddy Nietzsche were wise: they're singing the cancer cells' song. Stronger, stronger.